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Question 2e - 2000, Paper 1

A 58 year old man is brought in by ambulance moribund with barely palpable pulse and a sinus tachycardia. A large pulmonary embolus is confirmed. 

(e) After successful resuscitation you consider the insertion of a caval filter.  List the pros and cons of its use and explain the technique of insertion

College Answer

(e) The caval filter:

The caval filter is effective in preventing pulmonary embolism from the lower limbs, but is not without problems.  ·

PROS: Prevents PE and is particularly indicated in patients with:

•  Contraindications to anticoagulation (HITTS, haemorrhage)

•   Recurrent embolism despite anticoagulation

•  Free floating IVC thrombus

•  Immediately after embolectomy when heparin is contraindicated

CONS:        •  Requires expertise and equipment

•  IVC obstruction and long term venous stasis of the lower limbs may result

•  Technical problems:

misplacement obstructing renal veins caval perforation

fracture end embolisation

•  In one study of patients with DVT the two year mortality was not reduced and venous stasis of limbs was common

Technique: Commonly the filters are  placed by  interventional radiologists using sterile technique under II control. There are various types including removable filters. The umbrella type is outdated. Greenfield and the birdnest filter are still used in many parts of the world.

If there is extensive clot in the iliofemoral veins, upper extremity access (IJ or SV or axillary) is indicated via a Seldinger technique. The delivery system is advanced through an introducer after localisation of renal veins by contrast venography and the filter is placed below the renal veins

Thrombolytic Therapy of Pulmonary Embolism. Chest 115(6): 1999; p169-1707. Medical Progress: Pulmonary·Embolism. NEJM 339(2); 1998  p93·104

Recommended  reporting standards for vena caval filter  placement and patient follow-up. Journal ofVascular Surgery 30(3), 1999: p573-579

Discussion

LITFL have an excellent page on IVC filter placement.

For the time-rich exam candidate, this issue of CHEST published all of the most recent (9th edition) ACCP guidelines. Whereas previously they had a specific set of guidelines for IVC filters, they have now split them all up between different indications, and one needs to hunt though the articles for the recommendations. The British, however, have a set of discrete recommendations available (from 2006).

Contrary to the college answer, free-floating IVC thrombus is no longer considered an indication.

Rationale of IVC filter insertion

  • Pulmonary embolis is common, and carries with it a substantial mortality and morbidity.
  • Preventative measures such as mechanical thromboprophylaxis and prophylactic anticoagulation are not uniformly effective, and not always appropriate.
  • Certain at-risk groups will therefore be at increased risk of fatal pulmonary embolism.
  • A mechanical filter may prevent such fatal embolism at the cost of some filter-related complications
  • Therefore, there are certain groups in whom the risk of filter-related complications weighs favourably against the risk of massive PE.

Indications for insertion

  • Absolute contraindication to anticoagulation in a patient with high risk of DVT/PE
    • These might include unsecured aneurysm after SAH,  or recent major gastrointestinal haemorrhage eg. from varices.
  • Complication of anticoagulation which requires it to be reversed
    • eg. significant bleeding while anticoagulated, or HITTS
  • Inability to achieve full anticoagulation for whatever reason
  • Pulmonary emboli while fully anticoagulated
  • Previously, the indications also included pulmonary embolectomy and large free-floating iliofemoral venous thrombus.
  • "Extended indications" for placement:
    • Major trauma
    • Burns
    • cancer patients
    • Patients with clot-induced pulmonary hypertension
    • Patients with predictably poor compliance with anticoagulation

Advantages of the IVC filter

  • Can be inserted in patients with a contraindication to anticoagulation
  • May decrease the risk of fatal PE
  • Is retrievable, supposedly

Disadvantages of the IVC filter

  • These things do not prevent or treat DVT; they are not a replacement for anticoagulation
  • Venous stasis of lower limbs will occur
  • Though retrievable, in practice fewer than 60% are ever retrieved.
  • Filter related complications, eg malposition,  IVC damage, perforation, IVC thrombosis, and embolism of filter fragments. The filter may even migrate into the pulmonary artery.
  • It may offer no mortality benefit whatsoever.

Insertion of the IVC filter:

  • Interventional radiology procedure
  • Access via the femoral or IJ
  • venogram is performed to define the anatomy
  • Seldinger technique of insertion, with fluoroscopic guidance
  • Desired position is infrarenal

Evidence to support or refute the use of these devices

  • PREPIC trial (2005):  IVC filter reduced the rate of PE from 15% to 6%., but no mortality benefit was seen at 8-year follow-up. Also, all the patients were anticoagulated, and so did not meet the major indication for IVC filter insertion (i.e. contraindication to anticoagulation).
  • White et al (2000):  observational study: no difference in hospitalisation for PE recurrence in a large group of patients from California.
  • Hemmila et al, (2015): retrosepctive study of trauma patients;  also did not demonstrate any mortality benefit.

References

PulmCCM: April 12, 2013. "Inferior vena cava filters: debatable benefit; rarely removed"

ACCP: Radiologic management of IVC filters, 2012

Prasad, Vinay, Jason Rho, and Adam Cifu. "The inferior vena cava filter: how could a medical device be so well accepted without any evidence of efficacy?." JAMA internal medicine 173.7 (2013): 493-495.

You, John J., et al. "Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines." CHEST Journal 141.2_suppl (2012): e531S-e575S.

Sarosiek, Shayna, Mark Crowther, and J. Mark Sloan. "Indications, complications, and management of inferior vena cava filters: the experience in 952 patients at an academic hospital with a level I trauma center." JAMA internal medicine 173.7 (2013): 513-517.

Linsenmaier, Ulrich, et al. "Indications, management, and complications of temporary inferior vena cava filters." Cardiovascular and interventional radiology21.6 (1998): 464-469.

Baglin, T. P., J. Brush, and M. Streiff. "Guidelines on use of vena cava filters."British journal of haematology 134.6 (2006): 590-595.

Young, Tim, Hangwi Tang, and Rodney Hughes. "Vena caval filters for the prevention of pulmonary embolism." Cochrane Database Syst Rev 2.2 (2010).

Tola, Juan C., Robert Holtzman, and Lawrence Lottenberg. "Bedside placement of inferior vena cava filters in the intensive care unit." The American Surgeon65.9 (1999): 833-7.

Rohrer, Michael J., et al. "Extended indications for placement of an inferior vena cava filter." Journal of vascular surgery 10.1 (1989): 44-50.

These are the papers quoted at the end of the college answer:

Arcasoy, Selim M., and John W. Kreit. "Thrombolytic therapy of pulmonary embolism: a comprehensive review of current evidence." CHEST Journal 115.6 (1999): 1695-1707.

Goldhaber, Samuel Z. "Pulmonary Embolism" NEJM 339(2); 1998  p93·104

Greenfield, Lazar J., and Robert B. Rutherford. "Recommended reporting standards for vena caval filter placement and patient follow-up." Journal of vascular and interventional radiology 10.8 (1999): 1013-1019.

PREPIC Study Group. "Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism the PREPIC (prévention du risque d’embolie pulmonaire par interruption cave) randomized study." Circulation 112.3 (2005): 416-422.

White, Richard H., et al. "A population-based study of the effectiveness of inferior vena cava filter use among patients with venous thromboembolism." Archives of Internal Medicine 160.13 (2000): 2033-2041.

Hemmila, Mark R., et al. "Prophylactic Inferior Vena Cava Filter Placement Does Not Result in a Survival Benefit for Trauma Patients." Annals of surgery 262.4 (2015): 577-585.

Sharifi, Mohsen, et al. "Role of IVC filters in endovenous therapy for deep venous thrombosis: the FILTER-PEVI (filter implantation to lower thromboembolic risk in percutaneous endovenous intervention) trial." Cardiovascular and interventional radiology 35.6 (2012): 1408-1413.

Question 4 - 2001, Paper 1

List the pharmacodynamic properties of:

  • aprotonin
  • DDAVP
  • tranexemic acid

when used to reduce the bleeding associated with cardiac surgery.

College Answer

See Lancet 4th Dec 1999; vol 354 and J Cardiothoracic and Vasc Anesth 1999;4:6-11

The pharmacodynamic properties of:

a)   Aprotonin are:

-     non specific serine protease inhibitor

-     inhibitor of trypsin, plasmin, kalikrein, contact phase of coagulation

-     this inhibits fibrinolysis, coagulation and inflammation

-     when given before bypass it may prevent clotting activation, factor consumption and platelet dysfunction leading to reduced blood loss re-operation rate, transfusion

-     adverse effects include fever, anaphylaxis on repeat exposure

b)  DDAVP are: a vasopressin analogue that induces release of the contents of endothelial cell- associated   Weibral-Palade   bodies,   including   von   Willebrand   factor.   In   doses   used   in cardiothoracic surgery (0.3ug/kg) it potentiates primary haemostasis and may lead to water retention and vasoconstriction. It has been shown to have a small effect on transfusion rate but an associated two fold increase in perioperative myocardial infarction

c)   Tranexemic acid are:  a lysine analogue which is a potent, specific inhibitor of fibrinolysis. It has been shown to decrease transfusion rate, reoperation rate but not outcome after cardiothoracic surgery. Adverse effects reported include: myopathy, hypotension and intravascular thrombosis.

Discussion

One could overdiscuss the pharmacological properties of these substances.

A good comparison of their efficacy exists, which is helpful for this particular question. To summarise, tranexamic acid and aprotonin decrease the need for transfusion post cardiac surgery, but DDAVP does not.

That article is not available in full text, but this one is. It is a meta-analysis of drugs used to decrease bleeding during and after cardiac surgery; this is where the college got their statistic about the increased risk of MI with DDAVP.

Given the exotic nature of these substances, and given the author's delighted interest in exotic substances, this topic is afforded a slightly excessive amount of interest in the "Required Reading" section. The table of compared properties from that chapter is reproduced below, in order to simplify revision.

A Comparison of Pharmacological Haemostatic Agents
Properties DDAVP Aprotinin Tranexamic acid
Class
  • Vasopressin analogue
  • Non specific serine protease inhibitor
  • Lysine analogue
Mechanism
  • Induces release of the contents of endothelial cell- associated Weibral-Palade bodies, including  von Willebrand factor. 
  • Inhibitor of trypsin, plasmin, kalikrein, contact phase of coagulation: this inhibits fibrinolysis, coagulation and inflammation
  • Potent, specific inhibitor of fibrinolysis (a tissue plasminogen activator inhibitor)
Dose
  • 0.3μg/kg
  • 2 million KIU IV over 20-30min

  • Prime pump with 2 million KIU IV

  • Then, continuous intraoperative infusion of 0.5million KIU/hour

30 mg/kg bolus followed by 16 mg/kg/hr infusion seems to be the favoured dose.

Advantages
  • May decrease transfusion needs perioperatively
  • May antagonise persistent antiplatelet agent effects
  • May prevent clotting activation, factor consumption and platelet dysfunction, leading to reduced blood loss.
Disadvantages
  • May lead to water retention and vasoconstriction
  • A small effect on transfusion rate but a two fold increase in rate of perioperative MI.
  • Discontinued! No longer available.
  • Slight increase in the rate of MI
  • Does not improve outcome
Side effects
  • Fluid retention
  • Increased afterload
  • Hyponatremia
  • Sensitization and hypersensitivity reactions, including anaphylaxis
  •  
  • Myopathy
  • Hypotension
  • Intravascular thrombosis.

References

Laupacis, Andreas, and Dean Fergusson. "Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome." Anesthesia & Analgesia 85.6 (1997): 1258-1267.

 

Levi, Marcel, et al. "Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints." The Lancet 354.9194 (1999): 1940-1947.

Question 4 - 2001, Paper 2

A 35 year old woman, who is receiving continuous renal  replacement therapy for renal failure  associated with abdominal sepsis, is noted to have a platelet count of 40 x 109/L. How will you manage this problem?

College Answer

In this setting thrombocytopenia may be due to decreased platelet production, increased consumption or aggregation. This question should have been approached as a simple practical problem. One needs to obtain a complete history to understand whether this is an acute or a chronic problem, whether the patient is on platelet lowering drugs, did it coincide with heparin use, is there evidence of sepsis, DIC, is there a history of SLE, ITP, malaria etc. Investigations will include heparin antibody, blood film coagulation screen, and DIC screen. If no other cause is found, marrow aspiration may be indicated. Management will consist of ceasing heparin and other implicated drugs, treating underlying infection, platelet transfusion if bleeding occurs or if surgery is contemplated.

Discussion

The college insists we approach this as "a simple practical problem". However, one should not that they do not ask one to make a diagnosis, but how would you manage the problem without knowing the cause?

Well.

The following list of generic steps applies to thrombocytopenia of any cause:

Minimise platelet destruction

  • Withhold heparin and rationalise the indications for heparin, eg.:
    • Use alternative anticoagulants for the extracorporeal circuit (citrate comes to mind but there are numerous others
    • Use mechanical thromboprophylaxis or LMWH
    • Rationalise the use of dialysis
  • Manage the sepsis with appropriate antibiotics and resuscitation (as sepsis improves, DIC will resolve)
  • Address specific destructive aetiologies with appropriately targeted therapies, eg.:
    • Plasmapheresis for TTP
    • High dose methylprednisone for MAHA
    • Delivery for HELLP

Maximise platelet production

  • Ensure supply of haematinics is uninterrupted
  • Optimise nutrition, focusing on vitamins and trace elements
  • Withhold or rationalise any drugs which are bone marrow toxins
  • Correct the correctable causes of bone marrow failure and liver disease
  • Think about thrombopoietin receptor agonists (eg. eltrombopag) - some promising results have come from the RAISE trial (Cheng et al, 2010)

Protect the patient from complications of thrombocytopenia

  • Cancel or postpone all nonessential invasive procedures
  • Cover unavoidable procedures with transfusion of pooled platelets (up to a level of 50)
  • For neurosurgical procedures (or lumbar puncture, etc) aim for a level above 100
  • Otherwise, keep the level above 20
    (the above numbers derived from recommendations made by Van der Linden et al, 2012)

Diagnosis is more complicated. The differential diagnosis of thrombocytopenia is broad:

Causes of Thrombocytopenia

Decreased platelet production

  • Bone marrow suppression
    • Alcohol toxicity
    • Chemotherapy
    • Congential causes, eg. Fanconi anaemia
    • Myelofibrosis or aplastic anaemia
    • Neoplasm, eg. leukaemia or lymphoma
    • Viral infection, eg. HIV, EBV, Hep C, parvovirus, mumps, rubella, varicella...
    • Nutritional deficiency: B12 and folate deficiency
    • Liver disease - decreased production of thrombopoietin (TPO)

Increased platelet destruction

  • SLE
  • ITP
  • DIC
  • Drugs:
    • Quinine
    • Heparin
    • Valproate
  • Post-transfusion thrombocytopenia
  • Microangiopathic haemolytic anaemia
  • Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS)
  • Antiphospholipid syndrome
  • HELLP syndrome in pregnancy
  • Physical destruction in the cardiopulmonary bypass apparatus or circuit
Pseudothrombocytopenia
  • The sample was improperly anticoagulated, and there is platelet clumping on microscopy of the blood film.
  • Send a citrated tube instead- often the EDTA is to blame.
  • Abciximab can cause this, as it is an antibody to the GP IIb/IIIa receptor.

Dilution of platelets

  • Massive transfusion
  • Massive fluid resuscitation

Sequestration

  • Hypersplenism
  • Accessory spleens or splenunculi
  • Hepatic sequestration
  • Extremes of hypothermia

In order to simplify one's answer, one may be able to narrow this range to the causes which are relevant to the critically septic patient on dialysis:

  • Artifact
    • Diluted sample
    • Platelet aggregates
  • Decreased production
    • Antibiotic-associated thrombocytopenia (eg. linezolid)
    • Sepsis-associated bone marrow suppression
    • Preexisting condition (eg. malignancy)
  • Increased destruction
    • Consumption in DIC
    • Consumption by dialysis circuit
    • Consumption due to HITS
    • Autoimmune destruction
  • Sequestration
    • Hypersplenism

This is a more manageable list.

One would organise the following investigations in order to work through it:

The links point to brief explanatory notes for these tests, which one may find in the local chapter on thrombocytopenia.

References

Stasi, Roberto. "How to approach thrombocytopenia." ASH Education Program Book 2012.1 (2012): 191-197.

UpToDate: Approach to the adult patient with thrombocytopenia.

Casonato, A., et al. "EDTA dependent pseudothrombocytopenia caused by antibodies against the cytoadhesive receptor of platelet gpIIB-IIIA." Journal of clinical pathology 47.7 (1994): 625-630.

Castro, Christine, and Mark Gourley. "Diagnostic testing and interpretation of tests for autoimmunity." Journal of Allergy and Clinical Immunology 125.2 (2010): S238-S247.

Arepally, Gowthami M., and Thomas L. Ortel. "Heparin-induced thrombocytopenia." New England Journal of Medicine 355.8 (2006): 809-817.

Chong, B. H., J. Burgess, and F. Ismail. "The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia." Thrombosis and haemostasis 69.4 (1993): 344-350.

 

Question 4 - 2003, Paper 1

List the potential  causes of anaemia  in critically ill patients,  and  outline  how you would determine which factors were contributory.

College Answer

Anaemia in critically ill patients is usually multifactorial.  Potential causes can be categorised into decreased production (as a small proportion [approx 1%] of circulating RBCs are destroyed each day), increased destruction, loss of RBCs and haemodilution.  Decreased production includes problems with nutrients (eg. iron, folate, B12), disease involving bone marrow (eg. infiltration, myelodysplasia), depressant effects of drugs (eg. chemotherapy) or irradiation, and low levels of stimulatory hormones (eg. EPO in renal failure, thyroid hormones). Increased destruction can occur in haemolytic anaemias: either congenital (eg. thalassaemia major, sickle cell) or acquired (eg. Coomb’s positive auto-immune, TTP-HUS, infection with malaria or clostridiae etc).   Increased RBC loss can occur via injuries, bleeds into viscera or organs (eg. GI tract, GU tract, lungs) and iatrogenic (procedures, blood samples for testing).  Dilutional anaemia usually occurs in the context of rapid or extensive non-blood fluid resuscitation.

Evaluation of cause includes obvious but essential role of history (trauma, drugs and therapies, nutrition, chronic disease, infection, review of blood tests and procedures etc) and examination (trauma, sites of potential blood loss [including PR], jaundice, hepato-splenomegaly etc.).  Simple investigations include morphological assessment of blood (eg. MCV, blood film: red and white cell mophology), reticulocyte count, electrolytes and renal and liver function tests.  More specific tests as indicated include assays for folate/B12/ferritin, indicators of haemolysis (eg. haptoglobin, Coomb’s test), Hb electropheresis, cultures for infection (±thick/thin film) etc.

Discussion

This question is identical to Question 9 from the second paper of 2005.

References

Question 13 - 2003, Paper 2

Outline your approach to the transfusion  of red blood cells in the critically ill patient.

College Answer

A sophisticated and broad response is expected for this very common clinical issue.. Clinical Practice Guidelines were issued by NH&MRC (and Australian Society of Blood Transfusion) in 2001.

Strategies should be in place to deal with prevention: minimise blood loss (sampling, other losses, management of anticoagulation, etc.), to supply appropriate haematinics; and to individualise transfusion based on subgroups.   In general ICU patients and in elective surgery recent studies suggest benefit associated with the choice of a transfusion threshold of 70 g/L (as opposed to 100g/L), and there seems to be no harm in choosing 80 g/L as opposed to 90 g/L in patients after coronary artery bypass grafting.   These levels may be too low for uncorrected ischaemic heart disease (? >100 g/L may be better).  In the setting of acute blood loss, earlier transfusion should be considered, based on estimated blood volume lost and haemodynamics (e.g. >1000 mL or 250 mL/hr). 

 Other controversial issues include prophylactic use of erythropoeitin, routine use of filters/leukodepletion of red cells prior to transfusion, reinfusion of autologous blood (e.g. drain tubes after cardiac surgery), and the approach to those patients unwilling to be transfused.   A strategy should also be in place to deal with the potential complications associated with a massive transfusion (e.g. coagulopathy).

Discussion

The topic of transfusion in critical illness is covered elsewhere.

This answer is based not on the (gradually phased out) 2011 NHMRC guidelines, but on the more recent series of practice guidelines issued by the National Blood Authority of Australia, specificallythe Critical Care Module (4).

In brief:

  • Use judgement, rather than a numerical haemoglobin goal
  • Employ a restrictive transfusion strategy:
    • aim for a Hb of 70-90 g/L in all patients;
    • aim for a Hb 80-100 g/L in patients with an acute coronary syndrome
  • Don't use EPO
  • Use cell salvage where possible

Evidence for this:

1999 TRICC study:

  • no 30-day mortality difference but a significant in-hospital mortality difference (22% vs 28%) which favoured the restrictive transfusion strategy.

2012 Cochrane meta-analysis:

  • 19 trials involving a total of 6264 patients
  • Restrictive transfusion strategies were associated with a statistically significant reduction in hospital mortality (RR = 0.77)
  • Restrictive transfusion strategies did not appear to impact the rate of adverse events compared to liberal transfusion strategies

References

Goodnough, Lawrence T., Jerrold H. Levy, and Michael F. Murphy. "Concepts of blood transfusion in adults." The Lancet 381.9880 (2013): 1845-1854.

 

Spahn, Donat R., and Lawrence T. Goodnough. "Alternatives to blood transfusion." The Lancet 381.9880 (2013): 1855-1865.

 

There is also a rescinded document from the NHMRC (2001) which has been used to guide practice:Clinical Practice Guidelines on the Use of Blood Components.

 

To some extent this document has been superceded by the Australian and New Zealand Society of Blood Transfusion GUIDELINES FOR THE ADMINISTRATION OF BLOOD PRODUCTS.

 

The Patient Blood Management Guidelines from the National Blood Authority of Australia is another series of documents worth looking at - it contains several important modules which have been reviewed and which act as successors to the 2001 NHMRC guidelines.

 

Treleaven, Jennie, et al. "Guidelines on the use of irradiated blood components prepared by the British Committee for Standards in Haematology blood transfusion task force." British Journal of Haematology 152.1 (2011): 35-51.

 

Aoun, Elie, et al. "Transfusion‐associated GVHD: 10 years’ experience at the American University of Beirut—Medical Center." Transfusion 43.12 (2003): 1672-1676.

 

Heddle, Nancy M., and Morris A. Blajchman. "The leukodepletion of cellular blood products in the prevention of HLA-alloimmunization and refractoriness to allogeneic platelet transfusions [editorial]." Blood 85.3 (1995): 603-606.

 

Sharma, R. R., and Neelam Marwaha. "Leukoreduced blood components: Advantages and strategies for its implementation in developing countries."Asian journal of transfusion science 4.1 (2010): 3.

 

Dzik, Walter H. "Leukoreduction of blood components." Current opinion in hematology 9.6 (2002): 521-526.

 

Corwin, Howard L., and James P. AuBuchon. "Is leukoreduction of blood components for everyone?." JAMA 289.15 (2003): 1993-1995.

 

Blajchman, M. A. "The clinical benefits of the leukoreduction of blood products."Journal of Trauma-Injury, Infection, and Critical Care 60.6 (2006): S83-S90.

 

Rosenbaum, Lizabeth, et al. "The reintroduction of nonleukoreduced blood: would patients and clinicians agree?." Transfusion 51.12 (2011): 2739-2743.

 

Bilgin, Y. M., L. M. van de Watering, and A. Brand. "Clinical effects of leucoreduction of blood transfusions." Neth J Med 69.10 (2011): 441-450.

 

Australian Red Cross - Blood Service Policy on "The Age of Red Cells"

 

Hess, John R. "Red cell changes during storage.Transfusion and Apheresis Science 43.1 (2010): 51-59.

 

Bennett-Guerrero, Elliott, et al. "Evolution of adverse changes in stored RBCs."Proceedings of the National Academy of Sciences 104.43 (2007): 17063-17068.

 

Hébert, Paul C., et al. "A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care." New England Journal of Medicine340.6 (1999): 409-417.

 

Carson, Jeffrey L., Paul A. Carless, and Paul C. Hébert. "Outcomes using lower vs higher hemoglobin thresholds for red blood cell transfusion." Jama 309.1 (2013): 83-84.

 

Carson, Jeffrey L., Paul A. Carless, and Paul C. Hebert. "Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion." Cochrane Database Syst Rev 4 (2012).

 

Question 8 - 2004, Paper 1

A 45-year-old woman presents with seizures, after having had a fluctuating level of consciousness and fever. Her admission tests revealed:

Test

Value

Normal range

Haemoglobin

100

115-160 g/L

White blood cells

6.9

4.0-11.0 x10^9/L

Platelets

64

140-400x10^12/L

International Normalised Ratio

1.1

0.8 – 1.3

APTT

38

24-35 seconds

Fibrinogen

3.6

2.0-5.0 g/L

Na

142

135-145 mmol/L

K

4.8

3.5-5.5 mmol/L

Glucose

6.8

3.6-7.7 mmol/L

Urea

18.9

2.5-8.3 mmol/L

Creatinine

0.21

0.05-0.11 mmol/L

Lactate  De-Hydrogenase

540

120-250 IU/L

What is the most likely diagnosis, and what other investigations would you order to help confirm the diagnosis? What do you expect the results of these investigations to show?

College Answer

This woman has anaemia with an elevated LDH (suggestive of haemolysis), thrombocytopenia without evidence of DIC or other significant coagulation problems, renal insufficiency, fluctuating neurological abnormalities and fever. These are the “pentad” of features of the syndrome of Thrombotic Thrombocytopenic Purpura (also known as TTP-Haemolytic Uraemic Syndrome). Further tests are required to confirm the diagnosis (some by excluding significant negatives which require dramatically different treatment). Sepsis is less likely because of the normal white cell count and the presence of thrombocytopenia without evidence of DIC. Peripheral blood film should confirm a microangiopathic (i.e. red cell fragmentation) anaemia, confirm thrombocytopenia, and exclude a toxic appearance of the white cells (as they are normal in number). Haemolysis screen should demonstrate an elevated bilirubin and a reduced haptoglobin concentration, but a negative Coombs test. Urinalysis should be near normal and should exclude an active sediment. Microscopy and culture of appropriate samples (eg. urine and blood, and/or lumbar puncture to exclude meningitis) should exclude active infection. A CT scan of the head should also be performed to exclude intracranial pathology as the cause for the seizures.

Discussion

The abnormalities and characteristic historical features are:

  • anaemia
  • thrombocytopenia
  • uraemia
  • raised LDH
  • decreased level of consciousness
  • fever

The college correctly points out that these are the features of TTP. However, with the available test results, one cannot rule out other thrombotic microangiopathies.

What other investigations would you order to help confirm the diagnosis?

Well. A good article from 2013 offers a thorough discussion of the labratory features.

A systematic approach to the confirmation of the diagnosis of TTP would include the following:

  • ADAMTS-13
    • A severe functional deficiency of ADAMTS-13 is expected
  • Blood film
    • Schistocytes, fragments, and genuine thrombocytopenia (platelet aggregates which form in the blood tube tend to confuse the stupid FBC machine)
  • Conjugated/unconjugated bilirubin fraction
    • Genuine haemolysis should give rise to a disproportionately high fraction of unconjugated bilirubin
  • Direct Coombs test
    • This should be negative in TTP
  • Haptoglobin
    • This should be decreased in TTP
  • Reticulocyte count
    • This should be raised in TTP
  • Urinalysis
    • There should be proteinuria and haemoglobinuria
  • Additionally, the college wisely recommends that we exclude such things as intracranial catastrophe and sepsis. The picture they have given us is unlikely to represent DIC in sepsis, as the WCC is quite normal and there is no depletion of clotting factors. However, a CT head +/- LP cannot be left unmentioned when discussing the investigations of a febrile patient with a decreased level of consciousness.

References

George, James N. "Thrombotic thrombocytopenic purpura." New England Journal of Medicine 354.18 (2006): 1927-1935.

 

Peyvandi, Flora, et al. "von Willebrand factor cleaving protease (ADAMTS‐13) and ADAMTS‐13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura." British journal of haematology 127.4 (2004): 433-439.

 

Tsai, Han-Mou. "Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura." Journal of the American Society of Nephrology 14.4 (2003): 1072-1081.

 

Oh's Intensive Care manual:

Chapter 97 (pp. 993)  Therapeutic  plasma  exchange  and  intravenous  immunoglobulin  therapy  by Ian  Kerridge,  David  Collins  and  James  P  Isbister

 

Kakishita, Eizo. "Pathophysiology and treatment of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS)."International journal of hematology 71.4 (2000): 320-327.

 

Noris, Marina, and Giuseppe Remuzzi. "Hemolytic uremic syndrome." Journal of the American Society of Nephrology 16.4 (2005): 1035-1050.

 

Kappler, Shane, Sarah Ronan-Bentle, and Autumn Graham. "Thrombotic Microangiopathies (TTP, HUS, HELLP)." Emergency Medicine Clinics of North America (2014).

 

Veyradier, A., and D. Meyer. "Thrombotic thrombocytopenic purpura and its diagnosis." Journal of Thrombosis and Haemostasis 3.11 (2005): 2420-2427.

 

Beckford, M. D., and M. D. Shah. "Thrombotic Thrombocytopenic Purpura: A Review of the Disease Entity, its Clinical and Laboratory Features, and Management Strategies." The Medicine Forum. Vol. 12. No. 1. 2011.

Question 1 - 2005, Paper 1

List the problems associated with massive transfusion  in the critically ill.  Outline your principles of management for each.

College Answer

Massive transfusion (eg. replacement of more than 50% of blood volume in 12 to 24 hours, or  one  circulation blood volume in  24 hrs  [T Oh]) is  associated with  many potential problems which are related to a number of factors including the volume of resuscitation, factors related to the storage blood, and many other related issues. Problems include:

•    Volume  overload  (careful  monitoring  of  filling  pressure,  response  to  volume, diuresis)

•    Over-transfusion (monitor Hb regularly, titrate according to needs)

•    Hypothermia (use of fluid warmers and general measures to minimise heat loss)

•    Dilutional coagulopathy of both clotting factors and platelets (regular and early monitoring of coagulation, and involvement of haematology for replacement therapy [better than according to protocol])

•    Transfusion related lung injury (consider use of filters, leukodepletion)

•    Excessive citrate causing metabolic alkalosis and hypocalcemia (monitor pH and ionised calcium, replace calcium as necessary)

•    Hyperkalaemia (use of “younger” blood, monitor regularly, may require specific therapy)

•    Disease transmission (use of  products on  as  needed basis  only,  standard blood banking precautions)

•    Distractions resulting in not controlling source of haemorrhage, and risks of hurried cross-checking and incompatibility (allocation of sufficient resources and personnel, standard programs in place to facilitate process and anticipate needs)

•    Other problems include loss of identity (cross matching issues, loss of baseline haematological information etc.)

Discussion

Massive transfusion is discussed in greater detail elsewhere. Several definitions exist, but the replacement of 1 blood volume is a popular one.

In fact, and excellent article from Chest (2010) has a nice table (Table 1) of complications from massive transfusion. That table was a strong (dominating) influence on the following list of complications:

Acute complications

  • Acute hemolytic transfusion reactions
  • Febrile nonhemolytic transfusion reactions
  • Tranfusion-associated lung injury (TRALI)
  • Transfusion-associated circulatory overload (TACO)
  • Allergic reactions to blood products
  • Bacterial sepsis due to contaminated blood products
  • Hypocalcemia due to citrate
  • Hyperkalemia due to high PRBC K+ content
  • Acidosis due to high PRBC lactate content
  • Hypothermia due to use of recently refrigerated PRBCs
  • Dilutional coagulopathy due to inappropriate blood product replacement proportions
  • Dilutional thrombocytopenia due to lack of platelet replacement

Delayed complications

  • Delayed hemolytic transfusion reactions
  • Transfusion-related immune modulation (TRIM)  
  • Microchimerism - the persistence of an allogeneic cell population of leucocytes
  • Transfusion-transmitted diseases, eg. HIV, Hep C
  • Posttransfusion graft-vs-host disease (due to non-leukodepleted PRBCs)
  • Posttransfusion purpura

The college allso asks the candidate to "outline your management for each".

This requires a large table. The Australian Red Cross Blood Service have a nice table for management steps of transfusion reactions.

Management of Massive Transfusion-Associated Complications
Acute hemolytic transfusion reactions
  • Stop transfusion
  • Re-crossmatch
  • Maintain blood pressure with vasopressors (there may be cytokine shock)
  • Maintain adequate urine output to prevent haem-associated ATN
Febrile nonhemolytic transfusion reactions
  • Stop transfusion
  • Antipyretic agents
Allergic reaction to blood products
  • Stop transfusion
  • Antihistamine and corticosteroid
Tranfusion-associated lung injury
Transfusion-associated circulatory overload
  • Stop transfusion
  • Administer a diuretic
  • Consider a venodilator (eg. GTN) to decrease preload
  • Ventilate with a higher PEEP
Bacterial sepsis
  • Management of sepsis as per usual routine
  • Inform blood bank regarding contaminated blood products
  • Perform a blood culture and Gram stain on the bag of PRBCs
  • Keep the bag and giving set
Hypocalcemia due to citrate
  • Calcium replacement
Hyperkalemia due to high PRBC K+ content
  • Routine management of hyperkalemia (eg. calcium gluconate, bicarbonate)
Acidosis
  • Tincture of time, if your liver is normal
  • Dialysis, if the clearance mechanisms are impaired
Hypothermia
  • Aggressive rewarming
  • You should have used a blood warmer
Dilutional coagulopathy
  • Blood products will need to be replaced - FFP and cryoprecipitate to start with
Dilutional thrombocytopenia
  • Platelet transfusion
 
Delayed hemolytic transfusion reactions
  • Maintain blood pressure with vasopressors (there may be cytokine shock)
  • Maintain adequate urine output to prevent haem-associated ATN
Transfusion-related immune modulation
Microchimerism
  • Using leukodepleted PRBCs, surprisingly, is not protective.
  • Monitor for GVHD and autoimmune diseases
Transfusion-transmitted diseases
  • Councelling of the affected
  • Post-exposure prophylaxis, if relevant
  • Antiviral therapies
Posttransfusion graft-vs-host disease
  • Immunosuppression
Posttransfusion purpura
  • IV immunoglobulin
  • Plasmapheresis
  • Generally, management resembles the management for TTP

References

Sihler, Kristen C., and Lena M. Napolitano. "Complications of massive transfusion." CHEST Journal 137.1 (2010): 209-220.

 

Capon, Stephen M., and Dennis Goldfinger. "Acute hemolytic transfusion reaction, a paradigm of the systemic inflammatory response: new insights into pathophysiology and treatment." Transfusion 35.6 (1995): 513-520.

 

Perrotta, P. L., and E. L. Snyder. "Non-infectious complications of transfusion therapy." Blood reviews 15.2 (2001): 69-83.

 

Beauregard, Patrice, and Morris A. Blajchman. "Hemolytic and pseudo-hemolytic transfusion reactions: an overview of the hemolytic transfusion reactions and the clinical conditions that mimic them." Transfusion medicine reviews 8.3 (1994): 184-199.

 

Reed, William, et al. "Transfusion-associated microchimerism: a new complication of blood transfusions in severely injured patients." Seminars in hematology. Vol. 44. No. 1. WB Saunders, 2007.

 

Anderson, Kenneth C., and Howard J. Weinstein. "Transfusion-associated graft-versus-host disease." New England Journal of Medicine 323.5 (1990): 315-321.

 

Yokoyama, Ana Paula Hitomi, et al. "Diagnosis and Management Of POST-Transfusion Purpura-Case Report." Blood 122.21 (2013): 4834-4834.

Question 25 - 2005, Paper 1

A 68 yr old critically ill man with pulmonary  infiltrates  has the following haematology results.

Haemoglobin

79

(130-170 g/L)

Mean Corpuscular Volume

83.8

(80-96 fL)

White Cell Count

1.5

(4.0-11.0 x10^9/L)

Platelets

47

(140-400x10^12/L)

What is the haematological diagnosis? 

 List three potential causes of the haematological abnormalities?  

Outline what relevant information could be obtained from a bone marrow biopsy in this case.

College Answer

The  haematologic term  is  pancytopenia (sometimes called “aplastic anaemia”, but  this subset really requires demonstration of an empty bone marrow).

Potential  causes  include  aplastic  anaemia  (eg.  external  radiation,  drugs  [eg. chloramphenicol, sulphonamides etc.], toxins [eg. benzene]), replacement of marrow (eg. with malignant cells), megaloblastic hematopoiesis, myelodysplastic syndrome, and overwhelming infections.

Bone marrow biopsy would confirm diagnosis and allow therapy to be targeted. It would assess marrow cellularity, identify normality or otherwise of haematopoietic cells (eg. megaloblastic change), demonstrate infiltration or fibrosis, or macrophages engorged with haematopoietic cells (viral hemophagocytic syndrome).

Discussion

This gentleman seems to have a normocytic anaemia with the WCC and platelet lineages also in decline. The college calls it pancytopenia, which is a reasonable term. Kufe et al have an excellent book chapter (2003) on the oncological causes of pancytopenia, which are probably the most community-prevalent sort of causes (given that practically nobody gets chloramphenicol in those sorts of doses anymore, and that here in sunny Australia we don't see much radiation sickness).

However, the savvy exam candidate is expected to generate a torrential stream of differentials.

A 2013 article by Weinzierl et al arms the candidate with an exhaustingly vast list of potential aetiologies. In the interest of sanity, the list was abridged before being reproduced below:

Differential Diagnosis of Pancytopenia
  • Infectious causes
    • EBV
    • HIV
    • Hep A, B, C
    • Parvovirus
    • CMV
    • Dengue fever
  • Neoplastic causes
    • Leukaemia
    • Marrow involvement from solid tumours
  • Drugs which cause pancytopenia
    • Methyldopa
    • Carbimazole
    • Acetazolamide
    • Chloramphenicol
    • Trimethoprim/sulfamethoxazole
    • Carbamazepine
  • Idiopathic causes
    • Pregnancy (may be a coincidental association)
    • Splenomegaly (sequestration)
    • Anorexia nervosa
    • Malnutrition
    • Myelofibrosis
    • Paroxysmal nocturnal haemoglobinuria
  • Congenital causes
    • Haemophagocytic lymphohistiocytosis
    • Fanconi anaemia
    • Shwachman-Diamond syndrome
  • Autoimmune causes
    • SLE

Bone marrow biopsy is indeed the investigation of choice for pancytopenia. It will rapidly narrow the list of differentials, at least if one is able to catch some cells in one's sample. Occasionally, one finds a pocket of totally acellular marrow, which - though ominously prognostic - is frequently useless diagnostically.

References

Kufe, Donald W., et al. "Causes of Pancytopenia." (2003). Holland-Frei Cancer Medicine. 6th edition. Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Hamilton (ON): BC Decker; 2003.

 

Khodke, Kishor, et al. "Bone marrow examination in cases of pancytopenia."Indian Academy of Clinical Medicine 2 (2001): 1-2.

 

Gayathri, B. N., and Kadam Satyanarayan Rao. "Pancytopenia: A clinico hematological study." Journal of laboratory physicians 3.1 (2011): 15.

 

Weinzierl, Elizabeth P., and Daniel A. Arber. "The differential diagnosis and bone marrow evaluation of new-onset pancytopenia." American journal of clinical pathology 139.1 (2013): 9-29.

Question 9 - 2005, Paper 2

List the potential  causes of anaemia  in critically ill patients,  and outline how you would determine which factors were contributory.

College Answer

Common problems encountered related to the lack of an organised approach (eg. to history, examination and investigation). Blood loss can be occult!

Anaemia in critically ill patients is usually multifactorial. Potential causes can be categorised into decreased production (as a small proportion [approx 1%] of circulating RBCs are destroyed each day), increased destruction, loss of RBCs and haemodilution. Decreased production includes problems with nutrients (eg. iron, folate, B12), disease involving bone marrow (eg. infiltration, myelodysplasia), depressant effects of drugs (eg. chemotherapy) or irradiation, and low levels of stimulatory hormones (eg. EPO in renal failure, thyroid hormones). Increased destruction can occur in haemolytic anaemias: either congenital (eg. thalassaemia major, sickle cell) or acquired (eg. Coomb’s positive auto-immune, TTP-HUS, infection with malaria or clostridiae etc). Increased RBC loss can occur via injuries, bleeds into viscera or organs (eg. GI tract, GU tract, lungs) and iatrogenic (procedures, blood samples for testing). Dilutional anaemia usually occurs in the context of rapid or extensive non-blood fluid resuscitation.

Evaluation of cause includes obvious but essential role of history (trauma, drugs and therapies, nutrition, chronic disease, infection, review of blood tests and procedures etc) and examination (trauma, sites of potential blood loss [including PR], jaundice, hepato-splenomegaly etc.). Simple investigations include morphological assessment of blood (eg. MCV, blood film: red and white cell mophology), reticulocyte count, electrolytes and renal and liver function tests. More specific tests
as indicated include assays for folate/B12/ferritin, indicators of haemolysis (eg. haptoglobin, Coomb’s test), Hb electropheresis, cultures for infection (±thick/thin film) etc.

Important causes in ICU, which the candidate should emphasise, include:
a)  blood samples for testing
b)  EPO suppression and lack of marrow responsiveness in sepsis c)  trauma
d)  stress ulcer bleeds
e)  extracorporeal circuits blood loss

f)      hemodilution from resuscitation

g)  chemo/oncology patient groups

Discussion

This question is best approached systematically. For this purpose, anaemia can be divided into groups by function (rather than the conventional classification, by RBC morphology - into normocytic, microcytic and macrocytic).

The conventional approach is by far the better approach, because with the low haemoglobin result one usually also gets a whole panel of RBC volume and Hb content indices, which immediately allows one to classify the anaemia into groups. The Mayo Clinic Proceedings have an excellent article from 2003 which does this topic justice.

Dilution of RBC concentration

  • dilutuonal anaemia with fluid replacement
  • Artifactual anaemia due to sampling of a vessel with diluted content (i.e. the vein that has the fluids running through it).

Increased loss of RBCs

  • Extravascular loss
    • Bleeding:
      • Traumatic blood loss
      • Upper or lower GI blood loss, eg. gastric erosion/ulceration
      • Iatrogenic loss through samling and surgery
  • Intravascular loss
    • Intravascular haemolysis, eg. autoimmune hemolytic anaemia
    • DIC
    • Mechanical haemolysis, eg. due to extravascular perfusion circuits, dialysis filters, or mechanical heart valves
    • Appropriate reticuloendothelial sequestration of abnormal haemoglobin
      • Thalassaemias
      • Methaemoglobinaemia
      • Sickle cell anaemia

Decreased production of RBCs

  • Decreased hematinics
    • B12/folate deficiency
    • Drugs which interfere with B12/folate metabolism
    • Iron deficiency
  • Decreased proliferation signals
    • Decreased EPO in renal failure
    • Anaemia of chronic inflammatory states

Thus, a panel of investigations which might differentiate between the abovementioned differentials should include the following:

  • History of fluid resusictation or trauma
  • Resampling to confirm the diagnosis
  • Imaging to look for obvious blood loss
  • Faecal occult blood test and/or endoscopy to exclude GI blood loss
  • Direct Coombs test, formal blood film, conjugated/unconjugated bilirubin, LDH, haptoglobin and reticulocyte count to investigate haemolysis
  • RBC folate and B12 levels
  • Iron studies
  • Coagulation screen (looking for DIC and MAHA)
  • Renal function tests and/or EPO levels

References

Walsh, T. S. "Anaemia during critical illness." British journal of anaesthesia97.3 (2006): 278-291.

 

Vincent, Jean Louis, et al. "Anemia and blood transfusion in critically ill patients." Jama 288.12 (2002): 1499-1507.

 

Tefferi, Ayalew. "Anemia in adults: a contemporary approach to diagnosis."Mayo Clinic Proceedings. Vol. 78. No. 10. Elsevier, 2003.

Question 1 - 2006, Paper 1

A 78 year old man on warfarin  for atrial fibrillation develops a spontaneous weakness of his left hand and leg and a deteriorating conscious state.  He presents within 20 minutes of  onset   of  symptoms  and   a   CT  scan   confirms   a   right   parietal   intra-cerebral haemorrhage.   Outline your medical management of this case.

College Answer

Specific features that would alter the management plan should be sought in the history (particularly of other drugs affecting coagulation e.g. aspirin, clopidogrel) and examination. Obviously attention should be paid to resuscitation (including airway management) if required, and supportive care (including careful blood pressure control) but the predominant focus should be towards correction of coagulopathy.

Spontaneous bleeds can occur at any (or no) levels of anticoagulation but rates increase significantly where the INR is above 4. The Prothrombin time (or INR) and coagulation parameters should be measured urgently. Where there is clinical/neurological deterioration, reversal of anticoagulation should not be delayed for results.

The full effect of vitamin K in reducing the INR takes up to 24 hours to develop, even when given in larger doses with the intention of complete reversal.

For immediate reversal of clinically significant bleeding, the combination of prothrombin complex concentrate (PCC) and fresh frozen plasma (FFP) covers the period before Vitamin K has reached its full effect. Vitamin K is essential for sustaining the reversal achieved by a PCC and FFP. PCC is a three-factor concentrate, containing factors II, IX and X, but only low levels of factor VII. Therefore, the adjunctive use of FFP should be administered as a source of factor VII.

Treatment with recombinant factor VIIa within four hours of the onset of intracerebral haemorrhage has been reported to limit extension of the haematoma, reduce mortality, and improve functional outcome. However rFVIIa treatment is associated with some increase in the frequency of thromboembolic adverse events.

Discussion

At its core, this is a question about the reversal of warfarin in a patient with bleeding into a critical organ. A generic discussion of warfarin reversal guidelines takes place in another chapter, and Question 15.1 from the second paper of 2011 deals with the reversal of warfarin in a patient with a suprathereapeutic INR.

One is asked about one's medical management of this case. From this, and from the college answer, we can infer that they were not looking for a detailed discussion of EVD insertion, raised ICP management, or any of that sort of gibberish. In short, this is not a question about neurocritical care.

A structured answer would resemble the following:

Supportive measures:

A) Control the airway; assess the immediate need for endotracheal intubation.

B) Ventilate the patient ensureing normocapnea and normoxia.

Assess for features of aspiration.

C) Maintain haemodynamic stability; ensure adequate MAP to sustain cerebral perfusion.

Maintain control of aftrial fibrillation.

D) Employ standard neuroprotective measures. Solicit a neurosurgical opinion urgently, and follow on to theatre for EVD insertion or evacuation of clot, as indicated.

E) Ensure the electrolytes are well corrected.

F) Maintain adequate hydration

G) Ensure adequate nutrition

H) Investigate the extent of coagulopathy, and corrected it (see below)

Specific measures:

The main objective is to reverse any coagulopathy, so as to facilitate haemostasis.

The exact INR is unimportant, as itse reversal will take place whetehr it is therapeutic or supratherapeutic. This patient is bleeding into a critically important organ.

The most recent guidelines suggest the following multi-agent strategy:

  • 5-10mg of Vitamin K
  • prothrombinex 50.0 units/kg
  • FFP 150–300mL.

The Factor VIIa issue is still controversial, as any non-haemophilia use of this substance is still off-licence, and thus it would be medicolegally dangerous to include it in any guidelines regarding acute bleeding. However, people have reported good results. This 2006 question is probably written by somebody who has read this 2004 article, or this 2005 article, or something very much like them. Both were case series demonstrating some promising effects on survival and hemostasis. However, this early enthusiasm was diluted by the randomised-controlled trials that followed. Their data has been compiled into a 2011 meta-analysis, which has revealed the following consistent across-study effects:

  • Decreased percentage of hematoma expansion, but...
  • No improvement in mortality
  • No improvement in neurological outcome
  • Slightly increased risk of arterial thromboembolic events

The authors concluded that recombinant factor VIIa cannot be recommended for the reversal of warfarin therapy in warfarin-associated intracranial haemorrhage.

References

Ross I Baker, Paul B Coughlin, Hatem H Salem, Alex S Gallus, Paul L Harper and Erica M Wood Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis Med J Aust 2004; 181 (9): 492-497.

 

There is also this local policy document for reversal of anticoagulation.

 

Freeman, William D., et al. "Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage." Mayo Clinic Proceedings. Vol. 79. No. 12. Elsevier, 2004.

 

Brody, David L., et al. "Use of recombinant factor VIIa in patients with warfarin-associated intracranial hemorrhage." Neurocritical care 2.3 (2005): 263-267.

 

Yank, Veronica, et al. "Systematic review: benefits and harms of in-hospital use of recombinant factor VIIa for off-label indications." Annals of Internal Medicine154.8 (2011): 529-540.

 

Question 22 - 2006, Paper 2

Define the term “Transfusion Associated Lung Injury (TRALI)”. Briefly outline its pathophysiology and clinical features.

College Answer

TRALI is defined as:

a)  occurrence of acute respiratory distress during or within 6 hrs of transfusion

b)  presence of arterial desaturation on a pulse oximeter

c)  absence of other causes of acute lung injury

The clinical features include: dyspnoea, fever, hypotension or hypertension, and documented hypoxemia

The pathophysiology of TRALI is due to the presence of leukoagglutinins in the donor plasma, which promotes neutrophil aggregation and sequestration in the pulmonary vasculature. It is now recognized that there is a broader spectrum of TRALI than purely leukoagglutinin mediated.

Discussion

The Australian Red Cross has a nice summary of this issue.

A more thorough treatment is available from UpToDate.

According to the NHLBI, TRALI is diagnosed by the following criteria:

  • Onset of symptoms within 6 hours of transfusion
  • Hypoxia
  • Bilateral chest infiltrates on CXR
  • No other causes for acute lung injury (by the old ARDS definition)
  • No pre-existing acute lung injury
  • Absence of risk factors for other causes of ALI within the same time period

The clinical fatures are hypoxia, dyspnoea, fever, pulmonary oedema or pink frothy secretions from the ETT, hypotension and cyanosis.

The pathophysiology is well outlined in the below-linked article.

In short, neutrophils are sequestered in the lung parenchyma and are primed by endothelial cytokine release to repsond to trivial stimuli. The priming and sequestration seems to be due to endothelial cell activation. All of this is already happening before the trasnfusion. Then, the transfused blood is administered and it brings with it certain cytokine factors, or it results in the generation of inflammatry cytokines - either way, the increased pro-inflammatory stimulus causes all these sequestered neutrophils to activate and attack. The lung parenchyma is an innocent bystander in this.

Thus, the risk factors fro TRALI seem to be conditions with existing high levels of endothelial activation, such as:

  • Critical illness of any sort
  • Chronic alcoholism
  • Shock states
  • Smoking
  • High ventilator pressures
  • Positive fluid balance

References

Toy, Pearl, et al. "Transfusion-related acute lung injury: definition and review."Critical care medicine 33.4 (2005): 721-726.

Bux, Jürgen, and Ulrich JH Sachs. "The pathogenesis of transfusion‐related acute lung injury (TRALI)." British journal of haematology 136.6 (2007): 788-799.

Question 12 - 2007, Paper 1

Write short  notes on:

a)   Recombinant activated protein C (drotrecogin alpha)

b)  Recombinant coagulation Factor VIIa

College Answer

a)   Recombinant activated protein C (drotrecogin alpha)

a)   endogenous human protein, a component of natural anti-coagulant system b)  Recombinant version shown to improve survival in septic shock in a RCT. c)  Indications for use:septic shoe2 system failure, APACHE II> 25
d)  Possible   mechanisms:   Sepsis   decreases    APC   levels   and    therefore
administration increases levels, Improved microcirculation through alteration 
of coagulation, Anti-inflammatory and antiapoptotic e)  Side effects:Bleeding
f)  Controversies:  Not   proven   in   immunocompromised  patients, increases mortality in paediatric population
g)  Expensive

b)  Recombinant coagulation Factor VIIa

a)   Novel agent for control of intractable hemorrhage
b)  Evidence   base:   hemophilia,   trauma,   post  cardiac  bypass,   intracranial hemorhage
c)   Mechanism: Causes a thrombin burst  which in tum  converts fibrinogen  to fibrin to form a clot
d)  Complications:DVT risk

e)   Expensive

Discussion

Following the shameful worldwide withdrawal of Drotrecogin Alpha, it seems unlikely that the candidates would ever be expected to "write short notes" on it in the ultra-pragmatic CICM fellowship exam. Thus, I will leave the discussion of its merits and demerits to the historians. Moreover, given the changing nature of the fellowship exam (trending further towards easy-to-mark data interpretation questions and tabulated comparisons), it is unlikely the candidates will ever be asked to write short notes on any topic whatsoever.

Recombinant Factor VIIa remains a possibly examinable topic. One might someday be expected to tabulate its advantages and limitations, or to critically evaluate its use.

Thus:

Rationale

  • Factor VIIa is thought to act locally, binding to exposed tissue factor at the site of injury and promoting plateet binding.

Advantages

Disadvantages

Guidelines for practice

  • Currently, in Australia the recombinant Factor VIIa is licenced for use only in the treatment of bleeding in patients with haemophilia A and B, who have a circulating inhibitor of the coagulation factor.
  • Multiple guidelines for the off-licence use of this drug have emerged.
  • After reviewing the available evidence, J.L Vincent's group have suggested that Factor VIIa can be used blunt trauma, post-partum hemorrhage, uncontrolled bleeding in surgical patients, and bleeding after cardiac surgery.
  • Surgical haemostasis needs to have been achieved, say the haematologists who in Australia act as the curators of our FVIIa supplies. However, it is not clear that this is a mandatory component.  The Israeli guidelines (Martinowtz et al, 2005) specifically include as one of their indications "Failure to arrest the hemorrhage despite...  application of all accepted and available surgical measures (e.g. ligation of damaged vessels, tamponading, or packing of the bleeding site, and induction of localized thrombosis)". In short, surgical haemostasis is viewed by some to be a contraindication to the use of FVIIa. In contrast, the 2006 European guidelines (Vincent et al, 2006) recommend that "rFVIIa should be used only as an adjunctive therapy to surgical control", and there is some data that some intervention to control the haemorrhage improves mortality (Payen et al, 2016)

References

Boffard, Kenneth David, et al. "Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials." Journal of Trauma-Injury Infection and Critical Care 59.1 (2005): 8-18.

O’Connell, Kathryn A., et al. "Thromboembolic adverse events after use of recombinant human coagulation factor VIIa." Jama 295.3 (2006): 293-298.

Levi, Marcel, Marjolein Peters, and Harry R. Büller. "Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review."Critical care medicine 33.4 (2005): 883-890.

Yank, Veronica, et al. "Systematic review: benefits and harms of in-hospital use of recombinant factor VIIa for off-label indications." Annals of Internal Medicine154.8 (2011): 529-540.

Willis, Cameron David, Peter A. Cameron, and L. E. Phillips. "Clinical guidelines and off‐license recombinant activated factor VII: content, use, and association with patient outcomes." Journal of Thrombosis and Haemostasis7.12 (2009): 2016-2022.

Vincent, Jean-Louis, et al. "Recommendations on the use of recombinant activated factor VII as an adjunctive treatment for massive bleeding–a European perspective." Critical Care 10.4 (2006): R120.

Martinowitz, U., M. Michaelson, and Israeli Multidisciplinary rFVIIa Task Force. "Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force." Journal of Thrombosis and Haemostasis 3.4 (2005): 640-648.

Payen, J-F., et al. "Reduced mortality by meeting guideline criteria before using recombinant activated factor VII in severe trauma patients with massive bleeding." BJA: British Journal of Anaesthesia 117.4 (2016): 470-476.

Question 29 - 2007, Paper 1

A 23-year-old previously healthy girl involved in a motor vehicle accident is brought to ICU with multiple rib fractures and laceration of her left forearm. , no acute bleeding, She is haemodynamically stable and there is no evidence of acute bleeding. She has the following coagulation profile:

Test

Result

Normal range

INR

1.1

0.8-1.2

Prothrombin time

11

10-15

APTI

73

35-45

APTT after protamine

69

35-45

APTI with 50% normal plasma

53

35-45

Fibrinogen

3.4

2.5-5

a)  What is the likely explanation for the APTT result?  Give reasons.

b)  What further test would you order  to confirm  the aetiology of the coagulopathy?

c)  What vascular complication is this patient at risk of?

d)  What drugs might be suitable for DVT prophylaxis in this patient?

College Answer

a)  What is the likely explanation for the APTT result?  Give reasons.

Antiphospholipid antibody syndrome

Reasons: .
1)  Lack of correction with protamine excludes heparin as a cause of prolonged APTT 

2)  Lack of correction with normal plasma excludes clotting faetor deficiency. Prolongation despite normal plasma suggests circulating anticoagulant. Normal INR and PT and fibrinogen exclude DIC. In a young woman, antiphospholipid antibody syndrome

b)  What further test would you order  to confirm  the aetiology of the coagulopathy?

Lupus anticoagulant

c)  What vascular complication is this patient at risk of?

Recurrent DVTarterial thrombosis

d)  What drugs might be suitable for DVT prophylaxis in this patient?

Short term-aspirin /heparin
Long term-warfarin

Discussion

This is another one of those "why is my APTT so high" questions.

Specifically, this question closely resembles the following questions:

In this case, for some reason somebody gave the trauma patient some protamine. More commonly one would use a heparinase assay or the combination of thrombin time and reptilase time to exclude the effects of heparin, but a "protamine challange" is one way of doing it.

Antiphospholipid syndrome is discussed in greater detail elsewhere.

In brief, the major criteria for diagnosis require one clinical criterion (eg. thrombosis) and one laboratory criterion (eg. a positive anti-β2-glycoprotein-I antibody).

The laboratory tests one could order are as follows:

  • Lupus anticoagulant
  • Anticardiolipin antibody
  • anti-β2-glycoprotein-I antibody
  • Antiprothrombin antibody

The antiphospholipid syndrome patient is prone to simultaneously clotting and bleeding.

The specific list of complication is as follows:

  • DVT
  • PE
  • miscarriage
  • cerebral sinus thrombosis
  • arterial thrombosis

The most recent management guidelines suggest long term warfarin, with a target INR of 2.5.

References

Miyakis, Spyridon, et al. "International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)." Journal of Thrombosis and Haemostasis 4.2 (2006): 295-306.

 

Cervera, Ricard, and Gerard Espinosa. "Update on the catastrophic antiphospholipid syndrome and the “CAPS Registry”.Seminars in thrombosis and hemostasis. Vol. 38. No. 4. 2012.

 

Keeling, David, et al. "Guidelines on the investigation and management of antiphospholipid syndrome." British journal of haematology 157.1 (2012): 47-58.

 

 

Question 9 - 2007, Paper 2

A 34 year old woman is transferred to your hospital with a history of a prolonged generalized tonic-clonic convulsion. She is intubated and ventilated. Blood samples have been collected for a full blood count, biochemistry and a coagulation profile. Her initial non contrast CT brain shows  bilateral intracerebral hemorrhages. Her arterial blood gases and a haematology report are provided below

Parameter

Patient values

Normal range

FiO2

0.5

pH

7.15

7.35-7.45

PaCO2

35 mmHg (4.6 kPa)

35-45 mmHg (4.7-6.0 kPa)

PaO2

105 mmHg (14 kPa)

75-98 mmHg (10-13 kPa)

Bicarbonate

10.3 mmol/l

22-26 mmol/l

Parameter

Patient  values

Normal range

Hb

78 G/L

(130-150)

WCC

14.5 x 106/mm3

(4.0-11.0)

Platelets

43 x 106 /mm3

(150-300)

Blood picture: Thrombocytopaenia, fragmented cells and reticulocytosis

Coagulation profile: Normal

a) List the abnormalities on the blood gases. Give the most likely cause of each abnormality

b) Based on the history, CT scan and the hematology report, provide three possible differential diagnoses and give reasons

College Answer

a)

Metabolic acidosis: Lactic acidosis induced by status epilepticus

Respiratory acidosis (alternatively inappropriate respiratory compensation) - Central hypoventilation (alternative : inappropriate mechanical ventilation)

Increased A-a gradient : Aspiration pneumonitis (alternative : neurogenic pulmonary oedema)

b)

TTP

Eclampsia

HUS

Vasculitis

? Meningoencephalitis (lower mark)

There is evidence of MAHA with low platelets.

Discussion

This question is identical to Question 15.2 from the second paper of 2011, and Question 22.2 from the second paper of 2008.

References

Question 18 - 2007, Paper 2

. This is the haematology report of a 40 year old man who has been ventilated in intensive care 24 hours after a motor vehicle accident. He has suffered head, thoracic, abdominal  and orthopaedic injuries.

Hb

84

g/L

(130-175)*

WCC

8.3

x 109/L

(4.0-11.0)

Platelets

240

x 109/L

(150-450)

Reticulocytes

220

x 109/L

(10-80)*

Neutrophils

5.8

x 109/L

(1.8-7.5)

Lymphocytes

1.5

x 109/L

(1.5-4.0)

Monocytes

0.4

x 109/L

(0.2-0.8)

Eosinophils

0.6

x 109/L

(0.0-0.4)

Haematocrit

0.25

(0.4-0.52)*

MCV

88.4

fl

(82-98)

MCH

30.2

pg

(27.0-34.0)

MCHC

341

g/L

(310-360)

a) What is the most likely cause of the abnormalities?

b) He is due to undergo orthopaedic surgery and a laparotomy on day 2. A
coagulation profile performed prior to the procedure reveals the following.

Prothrombin
ratio

0.9

INR

(0.8-1.2)

APTT

33

sec

(24-39)

Fibrinogen

6.1

g/L

(1.5-4.0)*

What is the cause of the raised fibrinogen?

c) On day 10 in intensive care, he develops a new fever, A full blood count and a septic screen are performed. The results of the full blood count are provided below. The septic screen results are awaited.

Hb

76

g/L

(130-175)*

WCC

15.8

x 109/L

(4.0-11.0)

Platelets

1211

x 109/L

(150-450)

Reticulocytes

220

x 109/L

(10-80)*

Neutrophils

10.4

x 109/L

(1.8-7.5)

Lymphocytes

2.06

x 109/L

(1.5-4.0)

Monocytes

2.54

x 109/L

(0.2-0.8)

Eosinophils

0.48

x 109/L

(0.0-0.4)

Haematocrit

0.26

(0.4-0.52)*

MCV

92

fl

(82-98)

MCH

29.9

pg

(27.0-34.0)

MCHC

326

g/L

(310-360)

Film review: Moderate anisocytosis. Moderate polychromasia. Moderate number of target cells. Occasional Howell-Jolly bodies. Increased rouleaux formation. Marked thrombocytosis

c). What is the explanation  for the blood picture?

d)Based on this explanation  , what additional  therapy will you consider ?

e) As a consequence of the head injury, he develops a hydrocephalus which requires a ventriculo-peritoneal shunt.  He is discharged home 4 weeks later.  Six months after discharge, he presents with fever, headache and seizures.

List the 2 most likely differential diagnoses.

College Answer

a) What is the most likely cause of the abnormalities?

Acute blood loss . Hemolysis is unlikely in this setting.

b) He is due to undergo orthopaedic surgery and a laparotomy on day 2. A
coagulation profile performed prior to the procedure reveals the following.

Prothrombin
ratio

0.9

INR

(0.8-1.2)

APTT

33

sec

(24-39)

Fibrinogen

6.1

g/L

(1.5-4.0)*

What is the cause of the raised fibrinogen?
Acute phase response

c) On day 10 in intensive care, he develops a new fever, A full blood count and a septic screen are performed. The results of the full blood count are provided below. The septic screen results are awaited.

Hb

76

g/L

(130-175)*

WCC

15.8

x 109/L

(4.0-11.0)

Platelets

1211

x 109/L

(150-450)

Reticulocytes

220

x 109/L

(10-80)*

Neutrophils

10.4

x 109/L

(1.8-7.5)

Lymphocytes

2.06

x 109/L

(1.5-4.0)

Monocytes

2.54

x 109/L

(0.2-0.8)

Eosinophils

0.48

x 109/L

(0.0-0.4)

Haematocrit

0.26

(0.4-0.52)*

MCV

92

fl

(82-98)

MCH

29.9

pg

(27.0-34.0)

MCHC

326

g/L

(310-360)

Film review: Moderate anisocytosis. Moderate polychromasia. Moderate number of target cells. Occasional Howell-Jolly bodies. Increased rouleaux formation. Marked thrombocytosis

c). What is the explanation  for the blood picture?

Post splenectomy

d)Based on this explanation  , what additional  therapy will you consider ?
Immunization for HIB. Meningococcus and pneumococcus.
Penicillin or other antibiotic prophylaxis

e) As a consequence of the head injury, he develops a hydrocephalus which requires a ventriculo-peritoneal shunt.  He is discharged home 4 weeks later.  Six months after discharge, he presents with fever, headache and seizures.

List the 2 most likely differential diagnoses.

a)  Shunt infection / blocked shunt
b)  Meningitis from encapsulated bacteria.
c)  Consideration should be given to other causes such as viral and bacterial meningitis, however they will carry a lesser mark.

Discussion

a) What is the most likely cause of the abnormalities?

The college presents us with an FBC which demonstrates anaemia and a vigororus reticulocyte response. This is consistent with the bone marrow of a young man trying to regenerate a hematocrit.

b) What is the cause of the raised fibrinogen?

Fibrinogen is one of the acute phase reactant proteins; trauma and blood loss are major stimuli to increased fibrinogen synthesis by the liver. One could list all the acute phase reactants here, but there are too damn many - this NEJM article has a table (Table 1). Fibrinogen syntheis si induced by interlukin-6, and it in turn induced endothelial cell proliferation, which is good if you have open wounds to heal. Fibrinogen is also one of the reasons the ESR increases during inflammatory states.

c). What is the explanation  for the blood picture?

The blood picture demonstrates a characteristic post-splenectomy scenario.

The typical abnormalities are as follows:

  • Howel-Jolly bodies
  • Anisocytosis
  • Thrombocytosis
  • Acanthocytosis
  • Target cells
  • Pappenheimer bodies
  • Platelet aggregates

d)Based on this explanation , what additional  therapy will you consider ?

Management of the post-splenectomy patient is discussed in greather depth elsewhere. In brief summary, the management consists of the following measures:

  • The asplenic patients should carry an identifying card
  • They should receive the following vaccinations:
    • Pneumococcal vaccination
    •  Haemophilus influenzae type b conjugate vaccine
    • Meningococcal conjugate vaccine (B, C)
    • Influenza immunization
  • There may be some role for lifelong prophylactic antibiotics
  • The patient should have a supply of antibiotics for emergency use at home

e) List the 2 most likely differential diagnoses.

Fever, headache and seizures in an asplenic patient with a VP shunt simply screams "meningitis". The shunt may be infected, or simply blocked, but the smart money is on an encapsulated orgnaism of some sort, and Streptococcus pneumonia is the most likely culprit. More details can be found in the chapter on sepsis in the post-splenectomy setting.

References

Gabay, Cem, and Irving Kushner. "Acute-phase proteins and other systemic responses to inflammation." New England journal of medicine 340.6 (1999): 448-454.

 

Cadili, Ali, and Chris de Gara. "Complications of splenectomy." The American journal of medicine 121.5 (2008): 371-375.

 

Di Sabatino, Antonio, Rita Carsetti, and Gino Roberto Corazza. "Post-splenectomy and hyposplenic states." The Lancet 378.9785 (2011): 86-97.

 

Khan, Palwasha N., et al. "Postsplenectomy reactive thrombocytosis."Proceedings (Baylor University. Medical Center) 22.1 (2009): 9.

Question 21 - 2007, Paper 2

Examine the list of blood or plasma products listed in the table below. Indicate in your answer,
a)  whether crossmatch is essential with the use of each of these products
b)  one major indication for the use of each of these products.

Need for crossmatch

One major indication for use

Packed red blood cells

   

Platelets

   

Fresh frozen
plasma

   

Cryo precipitate

   

Prothrombin concentrate

   

Granulocyte concentrate

   

Intravenous immunoglobulin

   

c)  List one contraindication to the use of

i)          Platelet transfusion
ii)         IV immunoglobulin infusion

d)  Very briefly, outline the role of erythropoietin in the management of anaemia of critical illness?

College Answer

Examine the list of blood or plasma products listed in the table below. Indicate in your answer,
a)  whether crossmatch is essential with the use of each of these products
b)  one major indication for the use of each of these products.

Need for crossmatch

One major indication for use

Packed red blood
cells

Yes

a) Acute blood loss
b) Hb < 100 with concomitant IHD, c) severe anaemia, in absence of blood loss (Hb<70

Platelets

No

Platelets < 20,000 or <50,000 with bleeding, or pending interventional/surgicalprocedure, bone marrow failure - <10,000 in absence of risk factors, <20,000 in presence of risk factors

Fresh frozen
plasma

No

Warfarin overdose, coagulopathy post transfusion, post bypass bleeding

Cryo precipitate

No

DIC, coagulopathy post transfusion with low fibrinogen, hereditary hypofibrinogenemia, Hemophilia,Von willebrand’s disease

Prothrombin
concentrate

No

Warfarin overdose where FFP may be difficult to administer because of volume considerations

Granulocyte
concentrate

Yes

Neutropenic sepsis

Intravenous
immunoglobulin

No

LGB syndrome,
immune thrombocytopenia, vasculitis, myasthenia gravis, ITP

c)  List one contraindication to the use of

i)          Platelet transfusion -ITP . immune thrombocytopenia 
ii)         IV immunoglobulin infusion - Hereditary IgA deficiency

d)  Very briefly, outline the role of erythropoietin in the management of anaemia of critical illness?

Anaemia of critical illness is characterised by blunted EPO production and altered iron metabolism. EPO use has been shown to reduce transfusion requirements, but there in no proven benefit in terms of clinical outcome. A potential benefit may exist in patients who are in ICU for > 1 wk, but data are lacking. Potential side effects include red cell aplasia, EPO resistance, thromboembolic complications and hypertension.

Discussion

his question closely resembles other questions where one is expected to match a blood product with a need for transfusion.

These questions are:

  • Question 1 from the second paper of 2012
  • Question 24.2 from the second paper of 2010 (this contains a detailed dissection of crossmatching practice)

However, in contrast, this one also demands indications. These can be dug out of the old 2001 NHMRC guidelines, or read about broadly in this article. More modern guidelines are available from the Australian Red Cross Blood Service website, and these were used to construct the list below.

In brief:

The following blood products require a crossmatch:

  • Packed red blood cells
  • Granulocyte concentrate

The indications are as follows:

  • Packed red blood cells
    • Uncontrolled bleeding
    • Symptomatic anaemia
  • Platelets
    • Uncomplicated bone marrow failure (<10,000)
    • Bone marrow failure with additional risk factors for bleeding(<20,000)
    • Simple surgical procedures (<50,000)
    • Neurosurgical procedures (<100,000)
  • Fresh frozen plasma
    • Replacement of clotting factors in coagulopathy; according to the ARCBS, "You may give fresh frozen plasma to replace labile plasma coagulation factors during massive transfusion, cardiac bypass, liver disease or acute disseminated intravascular coagulation in the presence of bleeding and abnormal coagulation."
    • Replacement of ADAMTS-13 for plasma exchange in TTP
  • Cryo precipitate
    • Replacement of factor VIII, fibrinogen, factor XIII, von Willebrand factor and fibronectin.
    • Indicated specifically for the replacement of fibrinogen for the management of low fibrinogen levels or to relpace functionally abnormal fibrinogen
  • Prothrombin concentrate
    • Relacement of prothrombin to correct over-anticoagulation with Warfarin
  • Granulocyte concentrate
    • The college says "neutropenic sepsis". This is consistent with the UK guidelines. There is little Australia-specific information about this, which is reflected in this policy documentfrom The Alfred in Melbourne (an almost verbatim copy of the UK guidelines).
  • Intravenous immunoglobulin
    A good article from 2005 contains a detailed table of indications for IVIG. This table is massive and cannot (should not) be reproduced here. Highlights are as follows:
    • Guillain-Barre syndrome
    • ITP
    • Myasthenia gravis
    • Lambert-Eaton syndrome
    • Autoimmune haemolytic anaemia
    • Streptococcal toxic shock syndrome

As for the contraindications; there would probably be an excellent answer to this question somewhere in an article by Tomičić et al (2014), but it is in Croatian. Fortunately, the authors' native Russian armed him with the ability to discern that "trombocitne transfuzije kontraindicirane" probably means something about the contraindications to platelet transfusion, and from this poor quality translation the belowstated contraindications are derived.

  • Contraindication to the use of platelet transfusion include:
    • TTP/HUS -  platelet transfusion makes the organ system failure worse as the organs are clogged with debris; Goel et al (2015) found it increases mortality
    • HITS type II - though Kumar et al (2013) did not find platelets to be all that harmful in HIT patients, and all evidence to support this contraindication seem to come from case reports
    • IgA deficiency is a relative contraindication: IgA-deficient recipients may have anti-IgA antibodies, and platelets transfusion may bring enough IgA with it to cause life-threatening anaphylaxis (Davenport et al, 1992).  It is however possible to collect platelets from IgA-deficient donors or to wash them.
  • Contraindication to the use of immunoglobulin  infusion include:
    • IgA deficiency is again a relative contraindication, for the abovementioned reasons. Berger (2013) recommends you still have a try of it to see if it is tolerated. The argument is, the anti-IgA antibodies may not cause anaphylaxis - just an urticarial rash. 
    • Severe decompensated heart failure:  Immunoglobulin is usually given in a reasonably high dose (tens of grams of protein) as a hyperoncotic (10-20%) solution. Even if it were isooncotic, that would be a fairly large volume load. Pulmonary oedema may ensue.
    • Previous severe reactions (for example, stroke, renal falure, haemolytic anaemia) following IV Ig transfusion.

And as for the anaemia of critical illness: there's an excellent article on that from Azare (2008), which is unfortunately paywalled.  In short, this is a condition "hematologically similar to ...chronic anemia, except that the onset is generally sudden". A review by Rodriguez et al (2001) blames inappropriately blunted EPO secretion for this, although this is on the basis of small-scale studies. There also does not seem to be much good from EPO supplementation: Corwin et al (2002) found that though the total transfusion requirements decreased, the mortality did not. This may be another indicator that transfusion according to haemoglobin thresholds is not going to improve mortality. In answer to the college question, one would have to write that the routine use of EPO in the critically ill is not supported by robust evidence and that EPO use is not without its risks.

References

Sharma, Sanjeev, Poonam Sharma, and Lisa N. Tyler. "Transfusion of blood and blood products: indications and complications." American family physician83.6 (2011): 719.

Massey, Edwin. "CLINICAL GUIDELINES FOR THE USE OF GRANULOCYTE TRANSFUSIONS."

Jolles, S., W. A. C. Sewell, and S. A. Misbah. "Clinical uses of intravenous immunoglobulin." Clinical & Experimental Immunology 142.1 (2005): 1-11.

Tomičić, Maja, Tomislav Vuk, and Željka Hundrić-Hašpl. "Indications and contraindications for platelet transfusions in patients with thrombocytopenia." Liječnički vjesnik 136.3-4 (2014): 0-0.

Goel, Ruchika, et al. "Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality." Blood (2015): blood-2014.

Kumar, Rohit, Amy Zhou, and Roy E. Smith. "Outcomes Of Platelet Transfusion In Heparin Induced Thrombocytopenia Patients." (2013): 2311-2311.

Davenport, R. D., K. L. Burnie, and R. M. Barr. "Transfusion management of patients with IgA deficiency and anti‐IgA during liver transplantation." Vox sanguinis 63.4 (1992): 247-250.

Hamrock, David J. "Adverse events associated with intravenous immunoglobulin therapy." International immunopharmacology 6.4 (2006): 535-542.

Berger, Melvin. "Adverse effects of IgG therapy." The Journal of Allergy and Clinical Immunology: In Practice 1.6 (2013): 558-566.

Asare, Kwame. "Anemia of critical illness." Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 28.10 (2008): 1267-1282.

Rodriguez, Robert M., et al. "Nutritional deficiencies and blunted erythropoietin response as causes of the Amemia of critical illness." Journal of critical care 16.1 (2001): 36-41.

Question 3.1 - 2008, Paper 1

 54 year old male presents with a right deep vein thrombosis and haemoptysis. These blood results are from his admission.

Test

Value

Normal range

PT

12 sec

(12-14)

APTT

69 sec

(34-38)

Thrombin time

16 sec

(14-18)

APTT mixing test

60 sec

a) What is the APTT mixing test and its significance in this patient?

College Answer

It involves 1 to 1 mixing patients plasma with normal pooled platelet free plasma. If it normalises then the elevated APTT is due to factor deficiency. Partial correction suggests an inhibitor.

The results probably suggest an antiphospholipid syndrome in this patient

Discussion

The coagulation tests are discussed in greater detail elsewhere.

This question closely resembles Question 8.3 from the first paper of 2011.

The mixing studies test for the presence of coagulation inhibitors. The patient's plasma is mixed 50:50 with a random sample, and if a coagulation inhibitor is present the resulting mixture will still have a raised APTT, whereas if a factor deficiency was responsible the APTT will normalise.

In this patient, there is clearly some sort of anticoagulant factor present.

References

Hunt, Beverley J. "Bleeding and coagulopathies in critical care." New England Journal of Medicine 370.9 (2014): 847-859.

Question 3.2 - 2008, Paper 1

62 year old with a prosthetic mitral valve was noted to have the following coagulation profile

Test

Value

Normal range

PT

101 sec

(12-14)

APTT

45 sec

(34-38)

INR

8.7

(0.8-1.2)

a)  What is the likely diagnosis?

b) Outline your management of this patient

College Answer

a)  What is the likely diagnosis?

Supratherapeutic warfarinisation

b) Outline your management of this patient

If Non-bleeding
Stop warfarin
Vit K low dose iv or oral
Consider FFP if patient has a high risk of bleeding

If bleeding

Resuscitation stop warfarin
vit K low dose as possible
clotting factor FFP 10 to 15 ml per KG
consider prothrombinex (20 to 25 IU/KG especially if fluid is a problem

Discussion

This question closely resembles Question 15.1 from the second paper of 2011.

References

Hunt, Beverley J. "Bleeding and coagulopathies in critical care." New England Journal of Medicine 370.9 (2014): 847-859.

Question 3.3 - 2008, Paper 1

A 24 year old female has the following haematology and coagulation profile post admission to the intensive care unit following post partum haemorrhage.

Test

Value

Normal range

WCC

5.6

(4.0-11.0)

Hb

60*

(115-165G/L)

Platelets

30*

(150-400 X 109/L)

PT

30.6*

(10.5-13.5 sec)

APTT

>150*

(21-36 sec)

D Dimer

>10*

(<0.4 microgram/ml FEU)

Fibrinogen

0.8*

(1.1-3.2G/L)

a) What is the likely cause of these coagulation abnormalities?

b) In this context, list  3 likely causes of this coagulation profile.

c) What does an elevated D-dimer indicate ?

College Answer

a) What is the likely cause of these coagulation abnormalities?
DIC

b) In this context, list  3 likely causes of this coagulation profile.

  • Pre-eclampsia
  • AF embolism
  • Sepsis
  • Intra-uterine foetal death
  • Mismatched / massive transfusion

c) What does an elevated D-dimer indicate ?
Tests fibrinolysis. It measures the break down of the X linked fibrin

Discussion

The college asks for one likely cause of this coagulopathy. DIC is the standard answer with this sort of history. More broadly, differentials for thrombocytopenia and pan-coagulopathy could also include massive transfusion and severe liver disease.

There is quite a large number of potential peripartum causes for DIC:

  • Abruptio placentae
  • Placenta accreta
  • Amniotic fluid embolism
  • Retained dead fetus
  • Abortion induced with hypertonic fluids (saline or urea)
  • Intrauterine sepsis
  • Incompatible blood transfusion

Fibrin degradation products seem to be a valuable adjunct for the laboratory diagnosis of DIC.

In essence, a D-dimer is a small protein breakdown product, consising of two crosslinked D-fragments of fibrin.

A longer explanation, with pictures and extensive bibliography, is also available.

The presence of an elevated D-dimer confrms that somewhere fibrin is being degraded.

References

Slofstra, Sjoukje, Arnold Spek, and Hugo ten Cate. "Disseminated intravascular coagulation." The Hematology Journal 4.1 (2013): 295-302.

Levi, Marcel, and Hugo Ten Cate. "Disseminated intravascular coagulation."New England Journal of Medicine 341.8 (1999): 586-592.

Letsky, Elizabeth A. "Disseminated intravascular coagulation." Best Practice & Research Clinical Obstetrics & Gynaecology 15.4 (2001): 623-644.

Carr, J. Meehan, M. McKinney, and J. McDonagh. "Diagnosis of disseminated intravascular coagulation. Role of D-dimer." American journal of clinical pathology 91.3 (1989): 280-287.

Adam, Soheir S., Nigel S. Key, and Charles S. Greenberg. "D-dimer antigen: current concepts and future prospects." Blood 113.13 (2009): 2878-2887.

Question 9.3 - 2008, Paper 1

A 54 year old lady presented to the emergency department after having been unwell for 4 days. Her Full Blood Count (FBC) report is provided below.

Hb

* 128     g/L

(130 – 180)

WBC * 56.51  X109/L (3.50 - 11.00)
Platelet 347     X109/L (150 - 450)

RBC

5.27    X1012/L

(4.50 - 6.50)

HCT

0.414

(0.40 - 0.54)

MCV

82.6    fL

(80 – 100)

MCH

* 26.3    pg

(26.5 - 33.0)

MCHC

310     g/L

(310 – 360)

NEUTROPHIL

(96.3 %) * 54.40 X10^9/L

(1.7 - 7.0)

LYMPHOCYTE

(2.8 %) 1.60 X10^9/L

(1.5 - 4.0)

MONOCYTE

(0.7 %) 0.44 X10^9/L

(0.1 - 0.8)

EOSINOPHIL

(0.1 %) 0.05 X10^9/L

(0.04 - 0.44)

BASOPHIL

(0.1 %)0.02 X10^9/L

(0.00 - 0.20)

Moderate rouleaux. Marked neutrophilia. Dohle bodies present, toxic granulation present

a. What likely haematological  process  is revealed by the abnormal white cell and neutrophil count?

b. Cite 3 features on this FBC which support your answer in (a)

College Answer

a. What likely haematological  process  is revealed by the abnormal white cell and neutrophil count ?

1) A leukemoid reaction.

b. Cite 3 features on this FBC which support your answer in (a)
>50000 cells
Normal basophil and eosinophil count. Presence of Döhle bodies
Presence of toxic granulation

Discussion

Abnormal blood film findings and leukemoid reactions are discussed in greater detail elsewhere.

The presence of Döhle bodies is not exactly diagnostic, but their contribution to the overall picture of "toxic change" is consistent with a leukemoid reaction. In general, "Persistent neutrophilic leukocytosis above 50,000 cells/μL when the cause is other than leukemia defines a leukemoid reaction".  In this situation the college has not made the absence of leukaemia abundantly obvious, but the normal counts of all other cellular lineages suggest that bone marrow suppression by malignant infiltration is probably not taking place.

Causes of Leukemoid Reaction
  • Infection
    • Pneumonia
    • Tuberculosis
    • Pertussis
    • AIDS/HIV
  • Drugs
    • Corticosteroids
    • G-CSF
  • Increased neutrophil release
    • Stress
    • Trauma
    • Exercise
    • Sepsis
  • Inflammatory conditions
    • Empyema
  • Malignancy
    • Myeloproliferative disorders
    • Myeloid leukaemia
    • Lymphoma
    • Solid tumours, eg. lung
  • Decreased neutrophil clearance
    • Splenectomy

References

Weiner, W., and Elizabeth Topley. "Döhle bodies in the leucocytes of patients with burns." Journal of clinical pathology 8.4 (1955): 324-328.

Sakka, Vissaria, et al. "An update on the etiology and diagnostic evaluation of a leukemoid reaction." European journal of internal medicine 17.6 (2006): 394-398.

ul Haque, Anwar, and Noor ul Aan. "Leukemoid Reaction: Unusual Causes." International Journal of Pathology 8.1 (2010): 39-40.

Question 30.2 - 2008, Paper 1

A previously well 54 year old man presents with confusion. On examination  a rash is noted ( a clinical photograph provided). Temperature 37.1 The initial blood results are provided below.

Venous biochemistry

Na

135

mmol/L

(135-145)

K

3.8

mmol/L

(3.5-4.5)

Urea

18

mmol/L

(2.9-8.2)

*

Cr

177

 mol/L

(70-120)

*

Bilirubin

45

 mol/L

(<20)

*

Haematology

Hb

99

g/L

(135-180)

*

WBC

10.8

x 109/L

(4.0-11.0)

Plt

26

x 109/L

(140-400)

*

Blood film:      Schistocytes

Coagulation

PT

10

s

(9-12)

APTT

29

s

(24-39)

Fibrinogen

3.0

g/L

(1.7-4.5)

30.2

a)  What is the most likely diagnosis?

b)   What treatment needs to be instituted  urgently?

College Answer

a)  What is the most likely diagnosis?
Thrombotic thrombocytopenic purpura

b)   What treatment needs to be instituted  urgently?
•    Plasmapheresis

Discussion

This question closely resembles Question 7.2 from the second paper of 2009.

References

Question 6.1 - 2008, Paper 2

A 57 year old female has the following haematology and coagulation profile post admission  to the intensive care unit after a laparotomy for intraabdominal sepsis with significant  blood loss.

WCC *2.77 (3.5 – 11.00 x109/L)

Hb

*65

(115 –165 g/L)

Platelets

*14

(150-400 x109/L)

PT

*28.9

(12.0 – 15 Sec)

INR

*2.7

(0.8 – 1.1)

APTT

*122.5

(25.0 – 37.0 Sec)

Fibrinogen

*1.1

(2.20-4.30g/L)

 

a) What is the most likely cause of the coagulation abnormalities?


b) How would you correct the coagulopathy and briefly provide a reason for your choice of therapy or therapies?

College Answer

a) What is the most likely cause of the coagulation abnormalities?

Haemodilution with inadequate replacement of blood and clotting factors DIC

b) How would you correct the coagulopathy and briefly provide a reason for your choice of therapy or therapies?

Ensure patient is normothermic Exclude ongoing surgical haemorrhage Platelets to increase platelet count
FFP to replace factors II, V, VII, IX, X, and XI.
Cryoprecipitate to replace factor VIII, and fibrinogen if FFP does not reverse INR. Activated Factor 7

Discussion

This question is virtually identical to Question 13.1 from the second paper of 2013.

References

Question 6.2 - 2008, Paper 2

A 44 year old male presents with dyspnoea  and is diagnosed  as having multiple pulmonary emboli on Computerised tomography pulmonary angiogram (CTPA). He is commenced  on 1000 units of heparin per hour after a 5000 unit bolus.  During the night his heparin has steadily increased to 1500 units per hour.
These blood results are from the next morning.

Test

Value

Normal range

PT

12 sec

12-16

APTT

*38.3sec

25.0-37.0

Fibrinogen

3.8 g/ L

2.20-4.30

D-DIM LIA

*>20.0 mcg/ml

<0.5

a) Give 2 reasons for the relatively low APTT despite heparin therapy

b) List 4 causes for an increased predisposition to venous thromboembolic disease

College Answer

a) Give 2 reasons for the relatively low APTT despite heparin therapy

1 – Inadequate heparinisation
2.  ATIII deficiency
3.  Increased heparin clearance
4. Increased heparin binding proteins
(1.5 marks)

b) List 4 causes for an increased predisposition to venous thromboembolic disease

Protein C def Protein S def AT III def Malignancy
Factor V Leiden
Lupus anticoagulant

Discussion

This question is identical to Question 13.2 from the second paper of 2013.

References

Question 6.3 - 2008, Paper 2

A 58 year old male is admitted with haematemesis. His coagulation profile is shown below. List 2 likely causes of his coagulation abnormalities?

Test

Value

Normal range

PT

*25.9 sec

(12-14)

APTT

*39 sec

(34-38)

INR

*2.4

(0.8-1.2)

College Answer

1) Liver dysfunction due to alcoholic or viral liver disease.
2) Vit K deficiency
3) Patient on warfarin therapy.

Discussion

The question really asks, "What differen reasons could here be for an isolated PT elevation".

In a guy who is vomiting blood, alcoholism and liver disease are high up on the list.

An isolated PT elevation could be caused by:

  • Vitamin K deficiency
    • Malabsorption (leading to vitamin K deficiency)
  • Vitamin K antagonists e.g. warfarin, phenindione, rodenticides
  • Liver disease
  • Isolated Factor VII deficiency

The whole spectrum of abnormal coagulation studies is discussed in greater detail elsewhere.

References

Prothrombin Time, from the wonderful Practical-Haemostasis.com

Mariani, Guglielmo, and Francesco Bernardi. "Factor VII deficiency." Seminars in thrombosis and hemostasis. Vol. 35. No. 4. 2009.

Question 22.1 - 2008, Paper 2

A 45 year old man received an allogeneic bone marrow transplant for Acute Lymphatic Leukaemia. 26 days after the transplant the patient developed severe gastroenteritis and a maculopapular skin rash and respiratory insufficiency.
The following investigations were performed:

Hb

94 G/L

(110-150

Na (mmol/L)

132

135-145

WCC

2.3 x 109/L

(4.0-10.0)

K ( mmol/L)

3.4

3.5-.5.0

Platelets

54  x 109/L

(150-300)

Urea (mmol/L)

8.2

4.0-6.0

Creatinine (mmol/L)

0.1

0.04-0.12

Bilirubin (micromol/L)

67

<25

Alkaline phosphatase

265

<125

ALT

51

<40

AST

40

<40

Coagulation profile - normal

Stool:              Microscopy: WCC ++            Cultures: No growth
C.difficile  toxin- Not detected

a) List 3 possible diagnoses.

Over the next 3 weeks, the patient developed generalized oedema predominantly in the trunk and lower extremities. An ultrasound Doppler study of the abdomen revealed dilated  portal vein and inferior vena cava. The right atrial pressures were normal.

Portal pressure 18 mm Hg (8 – 10)

Infrahepatic IVC 20 mm Hg (9-11)

Hepatic  vein 8 mm Hg (9-10)

Suprahepatic IVC 8 mm Hg (7-8)

Right atrium    6 mm Hg

b) What  is the likely explanation for these findings?

c) Name 2 treatment measures for the diagnosis in b)

College Answer

a) List 3 possible diagnoses.

Sepsis CMV GVH

b) What  is the likely explanation for these findings?

Veno-occlusive disease of the liver

c) Name 2 treatment measures for the diagnosis in b)

TIPS procedure
Diuretics 
Fluid restriction

Discussion

This question closely resembles Question 26.2 from the first paper of 2013.

References

Question 22.2 - 2008, Paper 2

A previously healthy  34 year old woman is transferred to your hospital intubated and ventilated with a history of a prolonged generalized tonic-clonic convulsion. On arrival, she is deeply unconscious  with a GCS of 3, fixed dilated pupils, absent  tendon  reflexes and bilateral up-going plantar reflexes. An admission CT scan shows bilateral intracerebral haemorrhages. A full blood count report is as follows:

1) Hb 78 g/l                            (130-150),
2) WCC 14.5 x 106/mm3          (4.0-11.0), 
3) Platelets  43 x 106 /mm3      (150-300)

Blood picture:  Thrombocytopaenia, fragmented cells and reticulocytosis

Based on the history, CT scan and the hematology  report, provide three possible differential diagnoses

College Answer

Eclampsia
Thrombotic thrombocytopaenic purpura
HUS
Meningococcal meningitis with DIC …(although big bleed is unlikely)

Vasculitis.

Discussion

This question is identical to Question 15.2 from the second paper of 2011.

References

Question 28.2 - 2008, Paper 2

A 56 year old man was admitted to your ICU for monitoring of his deteriorating conscious state following an acute thrombotic stroke involving the carotid territory. Over the next 6 hours, the patient’s conscious state has improved significantly.  However, you are notified of an abnormal coagulation result from a sample taken at 6 hours after admission  to intensive care. There are no signs of bleeding.

PT

Baseline

13

6 hours

27

(12-16 sec)

APTT

34

120

(32-36 sec)

INR

1.1

2.1

TT

12

34

(12-14 sec)

Platelets

146

148

(150-300 X 109/L)

Fibrinogen

3.6

0.9

(2.5-4 G/L)

a)  Suggest a reason for the abnormal blood result.

College Answer

a)  Suggest a reason for the abnormal blood result.

Patient has received thrombolysis. Release of brain thromoplastin causing a DIC is unlikely as patient is clinically getting better and platelets are normal.

Discussion

There are several good reasons for this "total coagulation failure" sort of picture, which are discussed in greater detail in the chapter on abnormal coags results. In brief, they are as follows:

  • DIC
  • Massive transfusion
  • Massive warfarin overdose
  • Primary fibrinolysis
  • Post thrombolysis
  • Snake bite
  • Direct thrombin inhibitor toxicity
  • Severe liver failure

However, with the detailed history given to us by the college, we can probably can rule out snakebite. The college really wanted to hear "post-thrombolysis coagulopathy". Following thrombolysis, all screening coagulation tests are prolonged. This is a state of "hyperplasminaemia".

Basically, the final common pathway doesn't work. A part of the reason for this is that fibrinogen is massively depleted. Secondly, the fibrin degradation byproducts increase in concentration to such a level that they inhibit the cleavage of fibrinogen, rendering the remaining fibrinogen useless. APTT and TT increase as a result. PT also measures the final common pathway, and it will also be increased.

The release of thromboplastin following brain injury leads to a widespread activation of the clotting cascade, which can lead to DIC following a massive brain injury. However, as the college has rightly pointed out, this is typically a process of consumptive coagulopathy, and in this patients the platelets are clearly not being consumed.

References

Schöffel, G., et al. "Blood coagulation changes during effective thrombolysis using urokinase and heparin." Thrombosis research 25.1 (1982): 11-21.

Fassbender, Klaus, et al. "Changes in coagulation and fibrinolysis markers in acute ischemic stroke treated with recombinant tissue plasminogen activator."Stroke 30.10 (1999): 2101-2104.

MARDER, VICTOR J. "The use of thrombolytic agents: choice of patient, drug administration, laboratory monitoring." Annals of internal medicine 90.5 (1979): 802-808.

Kovacs, Iren B., and Peter Görög. "Simultaneous measurement of all thrombosis parameters from native human blood: usefulness in monitoring efficacy and complications of thrombolytic therapy." Angiology 41.10 (1990): 829-835.

Garabedian, H. D., et al. "Laboratory monitoring of hemostasis during thrombolytic therapy with recombinant human tissue-type plasminogen activator." Thrombosis research 50.1 (1988): 121-133.

Bovill, Edwin G., Richard Becker, and Russell P. Tracy. "Monitoring thrombolytic therapy." Progress in cardiovascular diseases 34.4 (1992): 279-294.

Shafer, Kenneth E., et al. "Monitoring activity of fibrinolytic agents: A therapeutic challenge." The American journal of medicine 76.5 (1984): 879-886.

Illoh, Orieji C., and Kachi Illoh. "Thrombolytic-associated coagulopathy and management dilemmas: a review of two cases." Blood Coagulation & Fibrinolysis 19.6 (2008): 605-607.

Ludlam, C. A., et al. "Guidelines for the use of thrombolytic therapy." Blood coagulation & fibrinolysis 6.3 (1995): 273-284.

Prentice, C. R. M. "Basis of antifibrinolytic therapy." Journal of Clinical Pathology 3.1 (1980): 35-40.

Harhangi, B. S., et al. "Coagulation disorders after traumatic brain injury." Acta neurochirurgica 150.2 (2008): 165-175.

Question 17.3 - 2009, paper 1

The following blood results are obtained  in a patient  post cardiac surgery.

a) What is the most likely cause of the abnormal coagulation profile ?

PT

13.9 seconds

10.5 to 13.5

INR

1.4

0.9 to 1.2

APTT

85 sec

24 to 39

ACT

240 seconds

<150 seconds

b) List 3 complications  of the agent commonly used to correct the above coagulation abnormality.

College Answer

Consistent with heparin

b) List 3 complications  of the agent commonly used to correct the above coagulation abnormality.

Anaphylaxis Pulm HT Hypotension Bleeding Bradycardia

Discussion

The question "why does this post-bypass patient still have such a high ACT" is easily answered with "duh, heparin". However, the ACT could also be raised for a large number of reasons, and Practical-Haemostasis.com give a list of alternative possibilities, many of which could be relevant with this scenario.

  • Thrombocytopenia (the circuit ate my platelets)
  • Platelet antagonists
  • Factor deficiencies (the circuit ate my clotting factors)
  • Low fibrinogen, DIC etc
  • Hemodilution
  • Hypothermia (the patient returns from theatre with a core temperature of 33.0°C)
  • Lupus anticoagulant

Yes, perhaps too little protamine was given (the dose is usually 1mg per every 100 units of heparin).

However, protamine itself can have a potent anticoagulant effect in overdose.

Its other delightful side effects are discussed in (slightly) greater detail in the chapter on unfractionated heparin. briefly, they can be listed as follows:

  • Anaphylaxis
  • Urticaria
  • Bronchospasm
  • Pulmonary hypertension
  • Hypotension
  • Bradycardia
  • Decreased cardiac output
  • Paradoxical anticoagulation.

It also has antibacterial properties, mainly hitting the Gram-positives.

References

The PI for protamine sulfate is illuminating.

Ellison, Norig, Alan J. Ominsky, and Harry Wollman. "Is Protamine a Clinically Important Anticoagulant?." Anesthesiology 35.6 (1971): 621-629.

Holland, C. L., et al. "Adverse reactions to protamine sulfate following cardiac surgery." Clinical cardiology 7.3 (1984): 157-162.

Johansen, Charlotte, T. Gill, and Lone Gram. "Antibacterial effect of protamine assayed by impedimetry." Journal of applied bacteriology 78.3 (1995): 297-303.

Jastrzebski, J., M. K. Sykes, and D. G. Woods. "Cardiorespiratory effects of protamine after cardiopulmonary bypass in man." Thorax 29.5 (1974): 534-538.

Hobbhahn, J., et al. "[Complications caused by protamine. 1: Pharmacology and pathophysiology]." Der Anaesthesist 40.7 (1991): 365-374.

Fadali, Moneim A., et al. "Mechanism responsible for the cardiovascular depressant effect of protamine sulfate." Annals of surgery 180.2 (1974): 232.

Question 24.3 - 2009, paper 1

List 3 causes of a massive splenomegaly.

College Answer

°     CML

°     Myelofibrosis

°     Chronic malaria

°     Kala Azar

Discussion

This question is strange for somebody who has never given much thought to the precise clinical definition of "massive". How big is massive? Extending beyond the umbilicus? The size of my head?

Its all a bit arbitrary. One 1989 paper takes "massive" to mean "drained weight in excess of 1kg",which most people would agree is pretty big. In spite of the obvious dififculty of assessing the dry drained weight of a spleen in vivo, this definition seems to be consistent across such sources of enlightenment as Medscape eMedicine and Wikipedia. A slightly more workable definition of "massive splenomegaly" comes from Eric Poulin, even though he used the word "severe" instead - in his view anything more than 20cm in any dimension was a real cause for concern, and therefore merited a strong superlative.

Anyway. Where did the college get this list of unusual differentials?

Well.

Turns out, truly humongous splenomegaly can only occur in a small selection of disease states:

  • Kala Azar (visceral leishmaniasis)
  • Chronic malaria (hyper-reactive malarial splenomegaly)
  • Chronic tuberculosis
  • Chronic schistosomiasis
  • Primary splenic lymphoma
  • Myelofibrosis
  • Chronic myeloid leukaemia (CML)
  • Thalassaemia major or intermedia
  • Gaucher's disease
  • Sarcoidosis
  • POEMS syndrome
  • Polycythemia vera
  • Amyloidosis
  • Waldenstrom's macroglobulinaemia

All the other causes of splenomegaly (which I though still gave rise to some pretty impressive spleens) - like EBV, portal hypertension, etc - all of these spleens are rather pedestrian by comparison.

The causes of massive splenomegaly are briefly discussed in this tropical disease oriented article.

References

Hoffbrand's Essential Haematolgy has a table with the causes of splenomegaly in chapter 10.

 

Johnson, H. A., and R. A. Deterling. "Massive splenomegaly." Surgery, gynecology & obstetrics 168.2 (1989): 131-137.

 

Poulin, E. C., J. Mamazza, and C. M. Schlachta. "Splenic artery embolization before laparoscopic splenectomy." Surgical endoscopy 12.6 (1998): 870-875.

 

Bedu-Addo, George, and Imelda Bates. "Causes of massive tropical splenomegaly in Ghana." The Lancet 360.9331 (2002): 449-454.

Question 2 - 2009, paper 1

Define tumour lysis syndrome. List the risk factors associated with its development. Outline measures to prevent it and provide a rationale for the use of each of those measures.

College Answer

Definition:
Tumor lysis syndrome (TLS) is an oncologic emergency that is caused by massive tumor cell lysis
with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation

Risk factors

Tumour-related factors

•    High tumour cell proliferation rate
•    Chemo sensitivity of the malignancy
•    Large tumour burden

Patient factors

•    Pre-treatment hyperuricemia or hyperphosphatemia
•    A pre-existing reduction in renal function
•    Volume depletion

Prevention measures

a) Fluids and hydration to achieve a urine output of at least 1 – 1.5 ml/kg (80 to 100 mL/m2) per hour.

Justification:  minimize the likelihood of uric acid precipitation in the tubules. b) Avoid fluids containing potassium and calcium
Justification: Minimize risk of hyperkalemia and calcium deposits

c) Alkalinization of urine

Justification: convert uric acid to the more soluble urate salt, thereby diminishing the likelihood of uric acid precipitation in the tubules. However, there are no data demonstrating the efficacy of this approach.

d) Allopurinol: decreasing uric acid formation by blocking xanthine oxidase.,

e) Rasburicase: Decreases uric acid levels by converting uric acid to allantoin.Justification: Thus, for patients with preexisting hyperuricemia rasburicase is the preferred hypouricemic agent

f) Role of dialysis if there is pre-existing renal dysfunction g) Posttreatment monitoring

•    uric acid, phosphate, potassium, creatinine, calcium and LDH
•    Fluid input and urine output should be assessed four to six hours after the initial administration of chemotherapy.
•    Evidence of TLS or a rising level of uric acid should prompt immediate therapeutic intervention.

Discussion

This question is identical to Question 27 from the first paper of 2013.

References

Question 13.2 - 2009, paper 1

Briefly outline the mode of action and half life of aspirin, tirofiban and clopidogrel.

College Answer

a)         Tirofiban – 2b3A inhibitor. Binds to this receptor on platelet membrane
Half life approx 2 hrs – Accumulates in renal failure

b)         ASA – Prostaglandin and Thromboxane A2 receptor – Irreversible blockade -platelets affected till replaced.

c)         Clopidogrel – Blocks ADP receptor of platelet hence reduces fibrinogen binding to platelet.
Irreversible binding – platelets affected till replaced

Discussion

The college answer is as detailed as one is expected to produce given that there is only about 90 seconds to think about it.

A slightly more detailed summary of antiplatelet agents is available. The following table is borrowed from there.

Drug

Chemical properties

Mechanism

Clearance

Half-life

Duration of effect

Aspirin

Salycilate;
Weak acid

Irreversible COX-1 inhibition, thus decreased production of the prothrombotic thromboxane A2

Renal

1-2 hrs

7-10 days

Clopidogrel

Thienopyridine

Irreversible inhibition of P2Y12 ADP receptor, thus inhibition of  cAMP-dependent platelet activation

50% renal,
50% biliary

0.5-1 hrs

7-10 days

Prasugrel

Thienopyridine

Irreversible inhibition of P2Y12 ADP receptor, thus inhibition of  cAMP-dependent platelet activation

Renal

7 hrs

7-10 days

Ticagrelor

Nucleoside (adenosine) analogue

Reversible inhibition of P2Y12 ADP receptor, thus inhibition of  cAMP-dependent platelet activation

Biliary

7-8 hrs

3-5 days

Abciximab

Fab fragment of a human monoclonal antibody

Glycoprotein IIb/IIIa inhibition, thus inhibition of platelet binding to fibrinogen and von Willebrand factor.

Reticulo-endothelial system

0.5 hr

18-24 hours

Tirofiban

Small molecule non-peptide

Glycoprotein IIb/IIIa inhibition, thus inhibition of platelet binding to fibrinogen and von Willebrand factor.

Renal

2 hrs

4-8 hours

References

Siller‐Matula, Jolanta M., Julia Krumphuber, and Bernd Jilma. "Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases." British journal of pharmacology 159.3 (2010): 502-517.

Farid, Nagy A., Atsushi Kurihara, and Steven A. Wrighton. "Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans." The Journal of Clinical Pharmacology 50.2 (2010): 126-142.

Levine, Glenn N., et al. "Newer pharmacotherapy in patients undergoing percutaneous coronary interventions: a guide for pharmacists and other health care professionals." Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 26.11 (2006): 1537-1556.

Question 17.1 - 2009, paper 1

You review a 40 year old male with chest pain and shortness of breath. He had been admitted with a deep vein thrombosis in his right leg. His coagulation profile is shown below.

INR

1

(0.9 TO 1.2)

APTT

61 seconds

(24 to 39 sec)

PT

11.5 seconds

(10.5 to 13.5 sec)

A. List 5 causes of the abnormality in the coagulation profile

B. List 5 tests that could differentiate the cause of this abnormality

College Answer

A. List 5 causes of the abnormality in the coagulation profile

Heparin
Lupus inhibitor

Haemophilia A & B

Factor xii deficiency

Factor xi deficiency
Von Willebrands disease
Artefactual (incorrect amount of blood in the tube.)

B. List 5 tests that could differentiate the cause of this abnormality

Repeat test
Heparinase assay or antibodies
Mixing test
Thrombin time and reptilase time
Factor assay
Anti-cardiolipin antibody

Discussion

This is another "What is the cause of an isolated APTT elevation" question.

The abnormal coagulation studies page deals with this in greater detail.

The approach to a patient wth abnormal coags can be summarised in the form of a table:

Assessment of Prolonged Clotting Times
  Normal PT Raised PT
Normal APTT
  • von Willebrand's disease
  • Platelet dysfunction
  • Fibrinolysis disorder

Extrinsic pathway failure

  • Warfarin therapy
  • Vitamin K deficiency
  • Liver disease
Raised APTT

Intrinsic pathway failure

Factor deficiency or anticoagulant factor? This is answered by mixing studies.

  • Anticoagulant factor:
    • Normal TT and RT:
      • antiphospholipid antibodies
    • High TT, normal RT:
      • Heparin therapy (heparinase assay)
      • heparin-like anticoaguants (malignancy)
    • High TT, high RT:
      • Low fibrinogen
      • Abnormal fibrinogen
      • Paraproteinaemia
      • Excessive fibrin degradation products
      • Amyloidosis
  • Factor deficiency
    • von Willebrand's disease (de facto Factor 8 deficiency)
    • Factor 8 deficiency (Haemophilia A)
    • Factor 9 deficiency (Haemophilia B)
    • Factor 11 deficiency (Haemophilia C, 8% of Ashkenazi Jews)
    • Factor 12 deficiency (which is freakishly rare, and usually totally asymptomatic)

Intrinsic and extrinsic pathway failure

  • DIC
  • Massive transfusion
  • Massive warfarin overdose
  • Primary fibrinolysis
  • Post thrombolysis
  • Snake bite
  • Direct thrombin inhibitor toxicity
  • Severe liver failure

In brief, the raised APPT could be caused by either an anticoagulant factor, or by a deficiency of the factors involved in the intrinsic or final common pathway.

Thus, it could be any of the following:

  • Anticoagulant factor:
    • Antiphospholipid antibodies
    • Heparin therapy
    • Heparin-like anticoaguants (malignancy)
    • Low fibrinogen
    • Functionally abnormal fibrinogen
    • Paraproteinaemia
    • Excessive fibrin degradation products
  • Factor deficiency
    • von Willebrand's disease (de facto Factor 8 deficiency)
    • Factor 8 deficiency (Haemophilia A)
    • Factor 9 deficiency (Haemophilia B)
    • Factor 11 deficiency (Haemophilia C, 8% of Ashkenazi Jews)
    • Factor 12 deficiency (which is freakishly rare, and usually totally asymptomatic)

The tests one would wish to perform?

  • Mixing studies
  • Thrombin time
  • Reptilase time
  • Heparinase assay: detects the influence of heparin
  • Fibrinogen level
  • Individual factor assays

In their answer, the college also intelligently suggest that you repeat the APTT, as it could all be an artifact of sampling.

References

 

Hunt, Beverley J. "Bleeding and coagulopathies in critical care." New England Journal of Medicine 370.9 (2014): 847-859.

 

Question 17.2 - 2009, paper 1

A 60 year old gentleman  on subcutaneous enoxaparin 80 mg bd for deep vein thrombosis has the following blood results. The blood sample was taken prior to the dose of enoxaparin


INR                          1.3                            0.9 TO 1.2
APTT                       38 SEC                    24 to 39
D dimer                    <0.2 mg/l                 <0.2 mg/l

Anti Xa                    1.8 IU/ml (therapeutic range 0.6 to 1.0 iu/ml)

List 2 likely causes of a raised Anti-Xa level in this patient?

College Answer

a) If the patient has underlying  renal failure
b)  body weight is low / incorrect dose of enoxaparin

Discussion

Anti-Xa level measurements are discussed in some detail in this article from the Australian Prescriber.

However, to answer this question, one does not need to be overfamiliar wiith the methods of anti-Xa testing. The patient has had too much enoxparin, because the level is high.

The college wants to know why he has been overdosed with clexane.

Furthermore, they have done a trough level, suggesting that they were suspecting overdose (or accumulation) to begin with. Typically, when monitoring therapeutic activity, one takes an anti-Xa level about 3-4 hours after the injection is given, to measure the peak effect.

Why might one have abnormally high Anti-Xa at trough?

Usually, this means the enoxaparin is accumulating. Either the dose was too high, or the clearance mechanisms are inadequate to remove an otherwise sensible dose.

The dose was too high:

  • The weight-base dose was incorrectly calculated.
  • The drug was accidentally administered twice (a common medication error - morning clexane doses are given around the time of the nursing handover)
  • The weight-based dose was calculated correctly, and then the patient lost weight
  • The weight-based dose was calculated correctly according to the actual body weight, but the patient is morbidly obese and clexane does not distribute into fat.
  • The volume of distribution is decreased (the patient is dehydrated) - whereas the increase of Vd in pregnancy leads to subtherapeutic Anti-Xa levels in pregnancy.

The clearance mechanisms are inadequate:

  • The patient has severe renal failure (creatinine clearance less than 30ml/hr)
  • The patient is elderly (half-life is prolonged)

References

Barras, Michael. "Anti-Xa assays." AN INDEPENDENT REVIEW (2013): 98.

The Sanofi pamphlet for its brand of enoxaparin has a surprisingly detailed breakdown of its elimination pharmacokinetics.

Fareed, Jawed, et al. "Pharmacodynamic and pharmacokinetic properties of enoxaparin." Clinical pharmacokinetics 42.12 (2003): 1043-1057.

Friedrich, E., and A. B. Hameed. "Fluctuations in anti-factor Xa levels with therapeutic enoxaparin anticoagulation in pregnancy." Journal of Perinatology30.4 (2009): 253-257.

Bazinet, Annie, et al. "Dosage of enoxaparin among obese and renal impairment patients." Thrombosis research 116.1 (2005): 41-50.

Question 7.2 - 2009, Paper 2

A previously well 54 year old man presents with confusion. On examination a rash is noted (see photograph below). Temperature is 37.10 C. The initial blood results are provided on the next page.

Venous biochemistry

Test

Value

Normal Range

Sodium

135 mmol/L

135 -145

Potassium

3.8 mmol/L

3.5 - 4.5

Urea*

18 mmol/L

2.9 - 8.2

Creatinine*

177  mol/L

70 -120

Bilirubin*

45  mol/L

<20

Haematology

Test

Value

Normal Range

Hb*

99 G/L

135 -180

WBC

10.8 x 109/L

4.0 -11.0

Platelets*

26 x 109/L

140 - 400

Blood film:      Schistocytes

Coagulation

Test

Value

Normal Range

PT

10 sec

9 -12

APTT

29 sec

24 - 39

Fibrinogen

3.0 G/L

1.7 - 4.5

 

a)          What is the most likely diagnosis? Provide 3 reasons.

b)         What definitive treatment needs to be instituted urgently?

College Answer

a)          What is the most likely diagnosis? Provide 3 reasons.

TTP

Reasons: Low platelets, renal dysfunction, presence of schistocytes suggestive of MAHA and neurological symptoms.

b)         What definitive treatment needs to be instituted urgently?

Plasma exchange

Discussion

Thrombotic thrombocytopenic purpura is discussed in greater detail elsewhere.

Characteristic features of TTP are as follows:

  • Anaemia
  • Thrombocytopenia
  • Microangiopathic haemolytic anaemia
  • Schistocytosis
  • Neurological symptoms
  • Fever
  • Renal failure

The presence or raised bilirubin suggests that intravascular hameolysis is taking place, and the presence of serious renal failure lends itself to the idea that a haemolytic-uremic syndrome may also be in play here. Those two have been together in the same category before (TTP/HUS). Nowadays, TTP and HUS and HELLP are all recognised as a spectrum of thrombotic microangiopathies.

The definitive treatment for it is plasma exchange, aiming to remove the ADAMTS-13 inhibitor while replacing the missing ADAMTS-13 protein with FFP.

Not much else can be added to this brief answer, the third in a three-part question, which is valued at ten points in total (thus one has 3.333 minutes to dedicate to it).

 

References

George, James N. "Thrombotic thrombocytopenic purpura." New England Journal of Medicine 354.18 (2006): 1927-1935.

Peyvandi, Flora, et al. "von Willebrand factor cleaving protease (ADAMTS‐13) and ADAMTS‐13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura." British journal of haematology 127.4 (2004): 433-439.

Tsai, Han-Mou. "Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura." Journal of the American Society of Nephrology 14.4 (2003): 1072-1081.

Oh's Intensive Care manual:

Chapter 97 (pp. 993)  Therapeutic  plasma  exchange  and  intravenous  immunoglobulin  therapy  by Ian  Kerridge,  David  Collins  and  James  P  Isbister

Kakishita, Eizo. "Pathophysiology and treatment of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS)."International journal of hematology 71.4 (2000): 320-327.

Noris, Marina, and Giuseppe Remuzzi. "Hemolytic uremic syndrome." Journal of the American Society of Nephrology 16.4 (2005): 1035-1050.

Question 23.1 - 2009, Paper 2

List 5 likely causes for the following coagulation profile.

Test

Value

Normal Range

PT*

35.4 Sec

12.0 - 15.0

INR*

3.5

0.8 - 1.1

APTT*

>170.0 Sec

25.0 - 37.0

FIBRINOGEN*

0.9 G/L

2.20 - 4.30

College Answer

1)  DIC
2)  Primary fibrinolysis
3)  Dilutional coagulopathy from massive transfusion
4)  Post thrombolysis
5)  Snake bite

Discussion

This question is identical to Question 30.2 from the first paper of 2010.

 

References

Question 23.2 - 2009, Paper 2

Examine the coagulation profile from a patient  in intensive care.

Test

Value

Normal Range

Prothrombin ratio (INR)

1.0

0.8 -1.2

APTT*

65 sec

24 -39

Platelets

240 x 109/L

150 - 400

Bleeding time

4 min

2 - 8

Fibrinogen

2.8 G/L

1.5 - 4.0

FDPs

<10 mg/L

0 -10

a)  List 4 possible causes of this picture.

b)  List 4 further tests which you will perform to identify the cause of the coagulopathy  in question 23.2.

College Answer

1)  Heparin
2)  Hemophilia A
3)  Hemophilia B
4)  Lupus anticoagulant

b)  List 4 further tests which you will perform to identify the cause of the coagulopathy  in question 23.2.

1)  Thrombin time
2)  Factor assay
3)  Anti-phospholipid antibody
4)  Reptilase test
5)  Mixing test

Discussion

This is a patient with an isolated abnormality of the intrinsic pathway.

The differentials for such an isolated abnormality are discussed at great length in the chapter onabnormal coagulation studies.

In brief, the possible causes of an elevated APTT are as follows:

  • Heparin therapy
  • von Willebrand's disease (de facto Factor 8 deficiency)
  • Factor 8 deficiency (Haemophilia A)
  • Factor 9 deficiency (Haemophilia B)
  • Factor 11 deficiency (Haemophilia C, 8% of Ashkenazi Jews)
  • Factor 12 deficiency (which is freakishly rare, and usually totally asymptomatic)
  • Antiphospholipid antibodies

Thus, to discriminate among all these causes, one would need to perform the following series of tests:

  • Mixing studies: excludes antophospholipid syndrome and heparin
  • Antiphospholipid antibodies
  • Factor assays

The college answer also asks for a thrombin time and a reptilase time.

In the coags pathology test chapter, these and the rest of the coagulation studies are briefly mentioned. A much better resource is PracticalHaemostasis.com, where these are discussed in greater detail.

In brief, thrombin time is a good test of the final common pathway.

It would not be affected by the absence of clotting factors (because the test itself involved dumping large amounts of thrombin into the sample). Thus, if thrombin time is completely normal and the APTT is still high, you can be confident that the fibrinogen is of normal quality, and that there is no exaggerated antithrombin-III effect (i.e. heparin is not to blame).

A reptilase time is a similar test, where instead of thrombin one uses some Botrox viper venom. This venom is not sensitive to the effects of heparin, and so the reptilase time would only ever be elevated in situations where the fibrinogen is low, or somehow abnormal, or there are abundant proteins to interfere with the process (eg. amyloidosis or paraproteinaemia).

In this case, if heparin was responsible for the raised APT, the thrombin time would be elevated, but the reptilase time would not.

 

References

Question 29.1 - 2010, Paper 1

A patient recovering from long term critical illness was found to have a Hb of 65G/L.
You request 3 units of packed RBCs. The blood bank informs you that the patient has  an  uncommon  blood  group  and  the  only  blood  available  although  safe,  is nearing the end of its storage life.

Outline the factors that may contribute to the reduced efficacy of such blood and what clinical consequences might be expected?

College Answer

Storage lesions begin after 2 to 3 weeks of storage and progress with duration of storage – with storage RBCs undergo structural and functional changes that may reduce function and viability after transfusion.

Effects include: 

  • Decreased deformability which impedes microvascular flow
  • depletion of 2,3 DPG shifts oxyhaemoglobin curve to the left and reduces O2 delivery
  • increased adhesiveness and aggregability
  • reduced concentrations of nitric oxide (bound as nitrosothiol,SNO)
  • reduced  ATP
  • reduced ability to maintain biconcave shape
  • accumulation of proinflammatory bioactive substances

Transfusion  of  red  cells  stored  for  more  than  14  days  has  been  associated  with increased  peri  operative  complications  ,  organ  failure  ,  sepsis  and

 mortality  after cardiac surgery ( Koch, NEJM: 2008 ).
In particular survival in the first 6 months after surgery was reduced.
Other studies have demonstrated an association between an increased duration of storage and multiorgan failure, sepsis and death in other populations including post surgical and general ICU patients.

Discussion

Storage lesions of packed red blood cells are discussed in greater detail in another chapter

One can also find an (out of date)  Blood Service Policy on "The Age of Red Cells" from the Australian Red Cross.

Theoretical objections to the use of old PRBCs are raised by Aubron et al in their 2013 article.

In brief summary, the storage lesions are as follows:

  • Decreased 2,3-DPG levels (thus, left shift of the oxyhaemoglobin dissociation curve)
  • Decreased ATP levels
  • Decreased deformability of erythrocytes
  • Red cell membrane vesciculations
  • Haemolysis and the release of free haemoglobin
  • Accumulation of toxic byproducts, esp. potassium and lactate
  • Accumulation of proinflammatory molecules

Thus, the almost-expired blood has a number of disadvantages:

  • Poor oxygen transport
  • Poor microvascular perfusion
  • Inflammatory potential

The clinical consequences of transfusing someone with such blood?

  • The Koch paper from NEJM (2008) which is quoted by the college is not a small trial (in total 5002 patient were enrolled) and it indeed found a strong association between the infusion of older PRBCs with some serious adverse outcomes, such as:
    •  In-hospital mortality
    • 1-year mortality
    • Length of intubation >72 hrs
    • Renal failure
    • Sepsis

However, on meta-analysis, some of the other adverse effect risks were not supported:

  • No evidence for increased ICU stay
  • No evidence for increased duration of ventilation
  • No evidence for increased risk of hospital-acquired infection
  • No evidence for increased risk of renal failure
  • Apart from the abovementioned positive studies, 14 other studies failed to demonstrate any increase in mortality.

More recent evidence from the ABLE trial  (Lacroix et al, 2015) confirms essentially all of the above. The authors could not find any difference in any of the outcomes between the patients who got 6-day-old cells and those who got 22-day-old cells. Results of the AustralianTRANSFUSE study are still awaited, but generally speaking it is becoming apparent that the theoretical disadvantages of using older PRBCs do not materialise in practice.

 

References

Wang, Dong, et al. "Transfusion of older stored blood and risk of death: a meta‐analysis." Transfusion 52.6 (2012): 1184-1195.

 

Aubron, Cécile, et al. "Age of red blood cells and transfusion in critically ill patients." Ann Intensive Care 3.1 (2013): 2.

 

 

Koch, Colleen Gorman, et al. "Duration of red-cell storage and complications after cardiac surgery." New England Journal of Medicine 358.12 (2008): 1229-1239.

 

Lacroix, Jacques, et al. "The Age of Blood Evaluation (ABLE) randomized controlled trial: study design." Transfusion medicine reviews 25.3 (2011): 197-205.

Question 29.2 - 2010, Paper 1

Leukodepleted blood is being introduced into clinical practice in Australia. What are the perceived benefits of using such blood?

College Answer

Benefits include : 
1.   Reduction in non haemolytic transfusion reactions
2.   Reduction in CMV transmission risk
3.   Improved chance of finding an organ transplant match if required
4.   Reduction in storage lesion effect
5.   Reduction in graft v host disease risk
6.   Hebert   has   shown   (JAMA   2003)   reduction   in   mortality   after   universial leukodepetion n populations which include cardiac surgical, orthopaedic and trauma.

Discussion

Benefits of leukodepleted blood are discussed in greater detail elsewhere.

In lieu of a detailed summary, I reproduce this table:

Advantages of Leukodepleted Red Cell Transfusion
  • Reduced risk of TRALI
  • Reduced febrile non-hemolytic reactions
  • Reduced storage lesions
  • Reduced incidence of transfusion-associated GVHD
  • Reduced CMV infection risk
  • Reduced risk of transmission of CJD
  • Reduced risk of alloimmunisation to Class I HLA antigens (a major contributor to platelet refractoryness)

As a brief aside, Australian PRBCs are now routinely leukodepleted, whereas back in the day one would run the undepleted PRBCs through a filter at the bedside. Some believe that there is a good reason we spend money on this practice, even though there is no evidence to support the "extended indications" for leukoreduction.

The hard indications for leukoreduced blood products are as follows:

  • People who are likely to receive a massive transfusion
  • People in whom being platelet refractory would be problematic
  • People at risk of febrile reaction (eg. those alloimmunised during pregnancy)
  • People at risk of severe CMV infection (eg. BMT recipients)

There is no evidence that the use of leukodepleted red cells is having any influence on mortality of transufusion recipients, outside of the above indication.

References

Goodnough, Lawrence T., Jerrold H. Levy, and Michael F. Murphy. "Concepts of blood transfusion in adults." The Lancet 381.9880 (2013): 1845-1854.

 

Spahn, Donat R., and Lawrence T. Goodnough. "Alternatives to blood transfusion." The Lancet 381.9880 (2013): 1855-1865.

 

There is also a rescinded document from the NHMRC (2001) which has been used to guide practice:Clinical Practice Guidelines on the Use of Blood Components.

 

To some extent this document has been superceded by the Australian and New Zealand Society of Blood Transfusion GUIDELINES FOR THE ADMINISTRATION OF BLOOD PRODUCTS.

 

The Patient Blood Management Guidelines from the National Blood Authority of Australia is another series of documents worth looking at - it contains several important modules which have been reviewed and which act as successors to the 2001 NHMRC guidelines.

 

Treleaven, Jennie, et al. "Guidelines on the use of irradiated blood components prepared by the British Committee for Standards in Haematology blood transfusion task force." British Journal of Haematology 152.1 (2011): 35-51.

 

Aoun, Elie, et al. "Transfusion‐associated GVHD: 10 years’ experience at the American University of Beirut—Medical Center." Transfusion 43.12 (2003): 1672-1676.

 

Heddle, Nancy M., and Morris A. Blajchman. "The leukodepletion of cellular blood products in the prevention of HLA-alloimmunization and refractoriness to allogeneic platelet transfusions [editorial]." Blood 85.3 (1995): 603-606.

 

Sharma, R. R., and Neelam Marwaha. "Leukoreduced blood components: Advantages and strategies for its implementation in developing countries."Asian journal of transfusion science 4.1 (2010): 3.

 

Dzik, Walter H. "Leukoreduction of blood components." Current opinion in hematology 9.6 (2002): 521-526.

 

Corwin, Howard L., and James P. AuBuchon. "Is leukoreduction of blood components for everyone?." JAMA 289.15 (2003): 1993-1995.

 

Blajchman, M. A. "The clinical benefits of the leukoreduction of blood products."Journal of Trauma-Injury, Infection, and Critical Care 60.6 (2006): S83-S90.

 

Rosenbaum, Lizabeth, et al. "The reintroduction of nonleukoreduced blood: would patients and clinicians agree?." Transfusion 51.12 (2011): 2739-2743.

 

Bilgin, Y. M., L. M. van de Watering, and A. Brand. "Clinical effects of leucoreduction of blood transfusions." Neth J Med 69.10 (2011): 441-450.

Question 30.1 - 2010, Paper 1

A 62 year old lady has very significant bleeding following an uncomplicated total hip replacement. Her coagulation profile post blood transfusion is as follows:

Test

Value

Normal Range

PT

13.5 sec

(12.0 – 15.0)

INR

1.0

(0.8 – 1.1)

APTT*

45 sec

(25.0 – 37.0)

APTT (After mixing with normal plasma)

29 sec

(25.0-37.0)

Platelet count

225 X109/L

(150 – 450)

(a)        List two (2) likely causes of her deranged coagulation profile.

(b)        List two (2) additional  pieces  of information  from her history  which  might  be of importance.

(c)        Name  two  (2)  further  tests  you  will  undertake  to  elucidate  the  cause  of  her coagulopathy and bleeding tendency.

College Answer

(a)        List two (2) likely causes of her deranged coagulation profile.

•    Factor 8 deficiency
•    Factor 9 deficiency
•    Dilutional coagulopathy
•    vWD

(b)        List two (2) additional  pieces  of information  from her history  which  might  be of importance.

•    Patient – past history of bleeding
•    Family history of bleeding
•    History of anti-platelet drugs

(c)        Name  two  (2)  further  tests  you  will  undertake  to  elucidate  the  cause  of  her coagulopathy and bleeding tendency.

•     Factor assay.
•     A Von Willebrands Disease screen.

Discussion

Abnormal coagulation studies and the physiological relatioships of coags tests to the clotting cascade are discussed in greater detail elsewhere. The breakdown of various abnormalities is presented as a table below.

Assessment of Prolonged Clotting Times
  Normal PT Raised PT
Normal APTT
  • von Willebrand's disease
  • Platelet dysfunction
  • Fibrinolysis disorder

Extrinsic pathway failure

  • Warfarin therapy
  • Vitamin K deficiency
  • Liver disease
Raised APTT

Intrinsic pathway failure

  • Heparin therapy
  • von Willebrand's disease (de facto Factor 8 deficiency)
  • Factor 8 deficiency (Haemophilia A)
  • Factor 9 deficiency (Haemophilia B)
  • Factor 11 deficiency (Haemophilia C, 8% of Ashkenazi Jews)
  • Factor 12 deficiency (which is freakishly rare, and usually totally asymptomatic)
  • Antiphospholipid antibodies

Intrinsic and extrinsic pathway failure

  • DIC
  • Massive transfusion
  • Massive warfarin overdose
  • Primary fibrinolysis
  • Post thrombolysis
  • Snake bite

In the patient presented by the question, the APTT is deranged, whereas the PT is normal.

Because at least one of them is normal, the final common pathway must be intact, otherwise there would be a derangement of both PT and APTT.

Thus, this is some sort of intrinsic pathway failure. Quoting from the table above:

  • Heparin therapy
  • von Willebrand's disease (de facto Factor 8 deficiency)
  • Factor 8 deficiency (Haemophilia A)
  • Factor 9 deficiency (Haemophilia B)
  • Factor 11 deficiency (Haemophilia C, 8% of Ashkenazi Jews)
  • Factor 12 deficiency (which is freakishly rare, and usually totally asymptomatic)
  • Antiphospholipid antibodies

One assumes that heparin has been ruled out as a cause. Decreased levels of Factors 8, 9, 11 and 12 can be responsible; antiphospholipid syndrome is ruled out by the negative mixing study (which demonstrates that there is no anticoagulant factor, and the coagulopathy is completely reversed by the addition of replacment factors).

Additionally, Factor 8 production may be normal, but there may be a deficiency of von Willebrand factor which normaly complexes with Factor 8 and keeps it from being rapidly degraded by the plasma. In this way vWF deficiency manifests as a raised APTT.

The college offer a model answer with Factor 8 and Factor 9 deficiency in it. They also mention von Willebrands disease and dilutional coagulopathy (which should ideally result in the deterioration of both intrinsic and extrinsic pathway activity).

As for the pieces of history which might be "of importance" - yes, a family history and a personal hisory of bleeding diathesis might be useful, as it would cause you to launch a series of tests for rare and unusual hereditary conditions.

For some reason, the college would also like to know about the recent use of antiplatelet drugs. Sure, this has real-world relevance, because with antiplatelet drugs on board the patient will bleed more vigorously. Buut I have no idea how to relate this to the coagulation parameters. Thus far I have not been able to find any evidence of antiplatelet agents causing a factor deficiency.

The specific tests one would launch in such a situation would be the assay of all intrinsic pathway clotting factors, which would be 12, 11, 9, and 8. Additionally, one would send off a vWF assay.

References

Kamal, Arif H., Ayalew Tefferi, and Rajiv K. Pruthi. "How to interpret and pursue an abnormal prothrombin time, activated partial thromboplastin time, and bleeding time in adults." Mayo Clinic Proceedings. Vol. 82. No. 7. Elsevier, 2007.

 

Wagenman, Benjamin L., et al. "The laboratory approach to inherited and acquired coagulation factor deficiencies." Clinics in laboratory medicine 29.2 (2009): 229-252.

Question 30.2 - 2010, Paper 1

List five (5) likely causes for the following coagulation profile:

Test

Value

Normal Range

PT*

35.4 sec

(12.0 – 15.0)

INR*

3.5

(0.8 – 1.1)

APTT*

>170.0 sec

(25.0 – 37.0)

FIBRINOGEN*

0.9 G/L

(2.20 – 4.30)

College Answer

•     DIC
•    Primary fibrinolysis
•    Dilutional coagulopathy from massive transfusion
•    Post thrombolysis
•    Snake bite

Discussion

Everything is wrong in this coags panel. Both the intrinsic and extrinsic pathways have become deranged, and the fibrinogen is depleted. The latter is a clue that some sort of consumption coagulopathy is taking place.

Again, I reproduce this table, from this chapter:

Assessment of Prolonged Clotting Times
  Normal PT Raised PT
Normal APTT
  • von Willebrand's disease
  • Platelet dysfunction
  • Fibrinolysis disorder

Extrinsic pathway failure

  • Warfarin therapy
  • Vitamin K deficiency
  • Liver disease
Raised APTT

Intrinsic pathway failure

  • Heparin therapy
  • von Willebrand's disease (de facto Factor 8 deficiency)
  • Factor 8 deficiency (Haemophilia A)
  • Factor 9 deficiency (Haemophilia B)
  • Factor 11 deficiency (Haemophilia C, 8% of Ashkenazi Jews)
  • Factor 12 deficiency (which is freakishly rare, and usually totally asymptomatic)
  • Antiphospholipid antibodies

Intrinsic and extrinsic pathway failure

  • DIC
  • Massive transfusion
  • Massive warfarin overdose
  • Primary fibrinolysis
  • Post thrombolysis
  • Snake bite
  • Direct thrombin inhibitor toxicity
  • Severe liver failure

So, the differentials for this sort of pan-coagulopathy are

 

  • DIC
  • Massive transfusion (dilutional coagulopathy)
  • Massive warfarin overdose
  • Primary fibrinolysis
  • Post thrombolysis
  • Snake bite
  • Severe liver failure

References

Hunt, Beverley J. "Bleeding and coagulopathies in critical care." New England Journal of Medicine 370.9 (2014): 847-859.

 

Question 30.3 - 2010, Paper 1

A 78 year old man presented after a fall resulting in a bruised hip.

His Full blood count is the following:

Test

Value

Normal Range

Hb

120 G/L

115 – 165

WBC*

1.91 x 10^9/L

3.50 – 11.00

PLT*

28        X10^9/L

150 – 450

RBC*

3.01      X10^12/L

3.80 – 5.80

HCT*

0.358

0.37 – 0.47

MCV*

118.9 fL

80 – 100

MCH*

39.9 pg

26.5 – 33.0

MCHC

335 G/L

310 – 360

NEUTROPHIL 79.6% *

1.5 x 10^9/L

1.7 – 7.0

LYMPHOCYTE 17.3% *

0.3 x 10^9/L

1.5 – 4.0

MONOCYTE 3.1% *

0.06 x 10^9/L

0.1 – 0.8

EOSINOPHIL 0.0% *

0.00 x 10^9/L

0.04 –0.44

BASOPHIL 0.0%

0.00 x 10^9/L

0.00 – 0.20

Moderate anisocytosis. Marked macrocytosis.

(a)        List four (4) causes for the raised MCV

College Answer

•    B12 deficiency
•    Folate deficiency
•    Myelodysplastic syndrome
•    Therapy with cytotoxics or immunosuppresants
•     Alcohol
•     Hypothyroidism
•    Alcohol  and  hypothyroidism  do not  produce  such  high  levels  of  MCV
usually, but if mentioned answers accepted.

Discussion

This is another one of those "how many causes of macrocytosis can you list" questions.

To arm the candidate for such questions, a master list of differentials has been created, and it can be found in the chapter dedicated to blood film abnormalities.

To simplify revision, I reproduce the table below:

There are several common causes:

  • Alcoholism
  • Vitamin B12 deficiency
  • Folate deficiency
  • Myelodysplastic syndromes

There are also a few uncommon causes:

  • Reticulocytosis
  • Nonalcoholic and alcoholic liver disease
  • Hypothyroidism
  • Multiple myeloma
  • Aplastic anemia
  • Acute leukemia
  • Drugs:
    • trimethoprim, triamterine, nitrous oxide, phenytoin, valproate, chemotherapy agents, HIV antiretrovirals and metformin.

One can find a discussion of the many causes of macrocytosis in this article.

References

Aslinia, Florence, Joseph J. Mazza, and Steven H. Yale. "Megaloblastic anemia and other causes of macrocytosis." Clinical medicine & research 4.3 (2006): 236-241.

 

Walker, H. Kenneth, et al. "Peripheral blood smear." (1990). in Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition.

Question 24.1 - 2010, Paper 2

A 45 year old man was admitted with life threatening shock after being involved in a motor vehicle accident. He suffered extensive limb and thoracic injuries requiring emergency surgery. Intra operative course was complicated by major blood loss and haemodynamic  instability.  Post operatively following return to ICU, he was noted to become hypotensive  and febrile and oozy from various drip and operative sites. Red urine was noted.

The following were the laboratory tests:

Test

Value

Normal Range

Hb*

87 G/L

(130 – 150)

WCC*

18.9 x 109/L

(4 – 11)

Platelets*

127 x 109/L

(150 – 300)

Urea*

14.1 mmol/L

(4 – 6)

Creat*

0.18 mmol/L

(0.04 – 0.12)

CK*

2000 U/L

(<50)

Myoglobin

Trace

Urine Hemoglobin

++

a)  Based on his clinical history and the lab report, what is the likely cause of his post operative deterioration?

b)  How will you confirm your diagnosis?

College Answer

a)  Based on his clinical history and the lab report, what is the likely cause of his post operative deterioration?

Mismatched transfusion

b)  How will you confirm your diagnosis?

Check patient’s and donor groups and re check cross match

Discussion

Hypotensive, febrile AND red urine? A haemolytic process is taking place, and a mismatched transfusion is a handy way to explain this. Transfusion reactions are discussed in greater detail elsewhere; in this answer one can summarise the process as follows:

  • The recipient having antibodies to antigens on the donated RBCs.
  • Transfused RBCs are thus coated with immunoglobulin, and become opsonised
  • This leads to a widespread systemic inflammatory reaction, as complement is activated; fever and hypotension ensue.
  • The RBCs are lysed by this process, releasing haemoglobin
  • Haemoglobinuria develops as a result.
  • Acute renal failure can follow, owing to the nephrotoxic effects of haemoglobin.

How does one confirm their diagnosis of an acute hemolytic reaction?

Well, apart from history and a strong suspicion, one rarely needs to perform any further tests. Apart from the examiners' sensible suggestion to repeat the crossmatch (which is more of a step towards management, ensuring that the future transfusions don't cause a reaction) one can perform the standard haemolytic screen:

  • DAT
  • Haptoglobin
  • Blood film
  • LDH

One may also wish to test the coags, given that this sort of reaction is often complicated by DIC.

References

NZBLOOD Transfusion Medicine Handbook (2008)

Bux, Jürgen, and Ulrich JH Sachs. "The pathogenesis of transfusion‐related acute lung injury (TRALI)." British journal of haematology 136.6 (2007): 788-799.

 

Fontaine, Magali J., et al. "Diagnosis of transfusion-related acute lung injury: TRALI or not TRALI?." Annals of Clinical & Laboratory Science 36.1 (2006): 53-58.

 

Kleinman, Steven, et al. "Toward an understanding of transfusion‐related acute lung injury: statement of a consensus panel." Transfusion 44.12 (2004): 1774-1789.

 

Gajic, Ognjen, Michael A. Gropper, and Rolf D. Hubmayr. "Pulmonary edema after transfusion: how to differentiate transfusion-associated circulatory overload from transfusion-related acute lung injury." Critical care medicine 34.5 (2006): S109-S113.

 

Vincent, E. Chris, and Tracy Willett. "Post-Transfusion Purpura." The Journal of the American Board of Family Practice 4.3 (1991): 175-177.

 

Capon, Stephen M., and Dennis Goldfinger. "Acute hemolytic transfusion reaction, a paradigm of the systemic inflammatory response: new insights into pathophysiology and treatment." Transfusion 35.6 (1995): 513-520.

Question 24.2 - 2010, Paper 2

Examine the list of blood or plasma products listed in the table below. Indicate in your answer, whether cross match is essential with the use of each of these products.

Product

Need for cross match

Cryo precipitate

 

Fresh frozen plasma

 

Granulocyte concentrate

 

Intravenous immunoglobulin

 

Packed red blood cells

 

Platelets

 

Prothrombin concentrate

 

College Answer

Product

Need for cross match

Cryo precipitate

No

Fresh frozen plasma

No

Granulocyte concentrate

Yes

Intravenous immunoglobulin

No

Packed red blood cells

Yes

Platelets

No

Prothrombin concentrate

No

Discussion

According to the college answer, only the red cells and granulocytes need crossmatching - the other blood products can apparently be given willy-nilly. This makes some sense in the context of the physiology of transfusion reactions; only RBCs and granulocytes are likely to have the relevant antigens on their surface. This refers to crossmatching specifically, where the compatibility between the patient and the donor product is tested by mixing samples to detect ABO incompatibility. The contrast between this and the "group and screen" is that the group and screen merely tests for blood group and screens for antibodies, whereas the crossmatch mixes samples to confirm compatibility and then the compatible PRBC bags are put aside for that specific patient.

As far as grouping and screening goes, the Australian Red Cross Blood Service also recommend that "where possible, patients should receive ABO-identical blood products". The main reason for this is not a lifethreatening transfusion reaction, but rather the immediate and frustrating destruction of the transfused platelets (for example). Additionally, though uncrossmatched plasma and plasma components are generally held to be safe, the ARCBS also recommends they be ABO group-compatible, because the transfused plasma may occasionally contain some antibodies to the recipient's native RBCs. The amount of antibodies transfused in this way will be very small, and the reaction will be on a smaller scale, but it is still an avoidable source of morbidity.

The ANZBT Guidelines for Pretransfusion Laboratory Practice reflect these issues, suggesting that for plasma transfusion a pretransfusion crossmatch is not required, but that products should ideally be compatible with the ABO group of the recipient's red cells. Additionally, they support the recommendation for the use of ABO-compatible platelets.

Thus, when amended with these recommendations, the college answer would look like this:

Product

Need for cross match

Need for group and antibody screen

Cryo precipitate

No

Yes, ABO ideally

Fresh frozen plasma

No

Yes, ABO ideally

Granulocyte concentrate

Yes

Yes, always - ABO and RhD

Intravenous immunoglobulin

No

No

Packed red blood cells

Yes

Yes, always - ABO and RhD

Platelets

No

Yes, ABO ideally

Prothrombin concentrate

No

No

References

Australian Red Cross Blood Service: Blood Group Compatibility

Australian & New Zealand Society of Blood Transfusion Ltd Guidelines for Pretransfusion Laboratory Practice (5th ed, March 2007)

Question 24.3 - 2010, Paper 2

Examine the following haematology data set.

Test

Value

Normal Range

WBC

9.5 x 109/L

(4.0 – 10.5)

RBC*

3 x 1012/L

(4.3 – 5.7)

Hb*

88 G/L

(130 – 170)

PCV*

0.36

(0.38 – 0.49)

MCV*

103fL

(83 – 98)

MCH

30 pg/L

(28 – 33)

MCHC*

370

(330 – 360)

Platelets

190 x 109/L

(150 – 400)

Reticulocytes 5%, Occasional erythroblast, spherocytes, Heinz bodies +++

a)  Provide an explanation for the above set of results.

College Answer

a)  Provide an explanation for the above set of results.

•    A high reticulocyte count, a high MCV are indicative of hemolysis
•    Heinz bodies indicate oxidative stress
•    Heinz bodies are seen in the setting of G6PD deficiency and drugs such as primaquine, in alpha thallasemia, chronic liver disease and splenectomy

Discussion

Heinz bodies, also known as Heinz-Ehrlich bodies are collections of denatured haemoglobin within the red cells, associated with the following conditions:

Increased oxidative stress due to toxins

  • Primaquine
  • Toxic solvents, eg. aniline, benzene, naphthalene
  • Quinidine
  • Dapsone toxicity

Unstable haemoglobins

  • Chronic liver disease
  • Alpha-thalassaemia
  • Certain congenital "Heinz body anaemias"
  • Methylene blue methaemoglobinaemia
  • Dapsone-induced methaemoglobinaemia

Deranged RBC metabolism

  • Glucose-6-phosphate dehydrogenase deficiency
  • Trimethoprim-sulfamethoxazole (Bactrim)

Decreased clearance of defective RBCs

  • Post splenectomy

Thus, these bodies form in oxidative stress of toxic exposure, with unstable haemoglobin subtypes, and in context of deranged RBC metabolism. In this case the cells are also macrocytic, and there seems is a reactive increase in reticulocyte count. Does this scream "haemolysis"? Probably not. So, what could have caused such a picture? G6PD deficiency is usually associated with macrocytosis, and haemolytic anaemia, but rarely with spherocytosis.

References

HARLEY, JOHN D., and ALVIN M. MAUER. "Studies on the formation of Heinz bodies. II. The nature and significance of Heinz bodies." Blood 17.4 (1961): 418-433.

JANDL, JAMES H. "The Heinz body hemolytic anemias." Annals of internal medicine 58.4 (1963): 702-709.

FERTMAN, MANUEL H., and Mildred B. Fertman. "Toxic anemias and Heinz bodies." Medicine 34.2 (1955): 131-192.

Selwyn, J. G. "Heinz bodies in red cells after splenectomy and after phenacetin administration." British journal of haematology 1.2 (1955): 173-183.

GOLDSTEIN, BERNARD D. "Exacerbation of dapsone-induced Heinz body hemolytic anemia following treatment with methylene blue." The American journal of the medical sciences 267.5 (1974): 291-297.

Coleman, M. D. "Dapsone: modes of action, toxicity and possible strategies for increasing patient tolerance." British Journal of Dermatology 129.5 (1993): 507-513.

Question 8.3 - 2011, Paper 1

A  50  year  old  female  presents  with  a  right  deep  vein  thrombosis   and haemoptysis.

These blood results are from her admission:

Test

Value

Normal Range

PT

12 seconds

12 – 14

APTT*

69 seconds

34 – 38

Thrombin time

16 seconds

14 – 18

APTT mixing test

60 seconds

a)   What is the APTT mixing test and what is its significance in this patient?

College Answer

a)   What is the APTT mixing test and what is its significance in this patient?

It involves mixing patient’s plasma with normal pooled platelet free plasma. If it normalized then the elevated APTT is due to factor deficiency. Partial correction suggests an inhibitor.

These results suggest antiphospholipid syndrome in this patient

Discussion

Mixing studies and their intepretation are discussed elsewhere. Essentially, the failure of normal plasma to correct the coagulopathy suggests that all the factors which it had contributed to the patient's plasma were inhibited by some sort of mysterious inhibitory factor. In the absence of anticoagulant therapy, one would be forced to blame some sort of antiphospholipid antibody.

References

Hunt, Beverley J. "Bleeding and coagulopathies in critical care." New England Journal of Medicine 370.9 (2014): 847-859.

 

Question 8.1 - 2011, Paper 1

A 40 year old previously well male presents with a ruptured appendix and associated   peritonitis   (Day  0).  He  returns   to  theatre   3  days  later  with ischaemic  colitis  and requires  a right  hemicolectomy.  At laparotomy,  he is noted to have extensive thrombosis in his superior mesenteric vein and portal vein. Attempts to anticoagulate him postoperatively (day 5 onwards) with intravenous heparin have been unsuccessful.

His post op haematology results are as follows:

Day 0

Day 1

Day 3

Day 5

Day 7

Day 9

Range

INR

1.2

1.7

1.8

1.6

0.8 – 1.3 seconds

APTT

36

38

36

28*

31*

37*

24 – 35 seconds

Fibrinogen

5.8

1.8

1.4

1.7

2.0 – 5.0 g/L

INR mix

1.9

0.8 – 1.3 seconds

APTT mix

32.5

30 – 40 seconds

D dimer

>4.0

< 0.5 mg/L

* On I.V. heparin

APTT therapeutic range for I.V. heparin therapy: 60 – 90 seconds

Additional tests performed on Day 7

A. Tests of hypercoagulability (plasma)
Antithrombin (functional) 20% (Reference: 80 – 120%)

B. Factor assays (plasma)
Factor VIII 4.10 IU/ml (Reference: 0.5 – 1.5)

C. Anti-Factor Xa assay (plasma)
Anti-Factor Xa 0 IU/ml            (Reference for IV heparin therapy: 0.3 – 0.7)

a)  What  are  the  possible  factors  preventing  therapeutic  anticoagulation  in this patient?

b)  List 2 strategies to effect anticoagulation with intravenous heparin.

College Answer

a)  What  are  the  possible  factors  preventing  therapeutic  anticoagulation  in this patient?

•    Disseminated intravascular coagulation
•    High clot burden
•    Antithrombin III deficiency
•    High Factor VIII levels

b)  List 2 strategies to effect anticoagulation with intravenous heparin.

•    Change to low molecular heparin, instead of unfractionated heparin
•    Give  cryoprecipitate  and/or  fresh  frozen  plasma  (if  there  is  confirmed ATIII deficiency )
•    Give antithrombin III concentrate

Discussion

Some discussion of the management of heparin resistance goes on in the end of my brief pharmacological entry on unfractionated heparin. In short, there are several strategies one can employ. The specific choice relies on what exactly is causing the heparin resistance.

•    Change to low molecular heparin, instead of unfractionated heparin
•    Give  cryoprecipitate  and/or  fresh  frozen  plasma  (if  there  is  confirmed ATIII deficiency )
•    Give antithrombin III concentrate

This CICM question asks specifically about increasing the effect of heparin, and candidates who suggested using something else (such as a direct thrombin inhibitor) would probably have earned no marks.

References

Anderson, J. A. M., and E. L. Saenko. "Editorial I Heparin resistance." British journal of anaesthesia 88.4 (2002): 467-469.

Young, E., et al. "Heparin binding to plasma proteins, an important mechanism for heparin resistance." Thrombosis and haemostasis 67.6 (1992): 639-643.

Hirsh, J., et al. "Heparin kinetics in venous thrombosis and pulmonary embolism." Circulation 53.4 (1976): 691-695.

Beresford, C. H. "Antithrombin III deficiency." Blood reviews 2.4 (1988): 239-250.

The PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group Dalteparin versus Unfractionated Heparin in Critically Ill Patients N Engl J Med 2011; 364:1305-1314April 7, 2011

Koster, Andreas, et al. "Management of heparin resistance during cardiopulmonary bypass: the effect of five different anticoagulation strategies on hemostatic activation." Journal of cardiothoracic and vascular anesthesia 17.2 (2003): 171-175.

Isil, Canan Tulay, et al. "Management of heparin resistance in an emergency cardiac surgical patient." Indian journal of anaesthesia 56.4 (2012): 430.

 

Question 8.2 - 2011, Paper 1

A 28 year old man  presented  with  a persistent  epistaxis  to the emergency department.

The coagulation profile was as follows:

Test

Value

Normal Range

INR

1.2

0.8 – 1.2

APTT

50 seconds

25 – 39

Platelets

250 X 109 / L

150 – 350

Bleeding time*

16 minutes

2 – 8

Fibrinogen

3 g/L

1.5 – 4

FDPs

< 10 mg/L

0 – 10

Thrombin clotting time

15 seconds

12 – 17

a)  What is the most likely diagnosis?

b)  What would you confirm your diagnosis

College Answer

a)  What is the most likely diagnosis?
Von Willebrand’s disease

b)  What would you confirm your diagnosis
•    History – easy bruising, mucosal bleeding
•    Family history
•    Plasma vWF levels
•    Factor VIII levels /activity

Discussion

There is only one situation in which one might have essentially normal APTT, but an elevated bleeding time. The APTT test would be slightly elevated because Factor 8 relies on vWF activity, and in the absence of vWF one is effectively Factor 8-deficient. The PT would be normal.

Pathophysiology

  • Most common inherited bleeding disorder (autosomal dominant)
  • Prevalence is about 1–2%
  • Only one in every ten cases have clinically relevant disease
  • Caused by the deficiency or abnormality of VWF.
  • VWF is required for platelet adhesion to the subendothelium
  • VWF also serves as carrier of Factor VIII, protecting it from Protein C mediated inactivation (hence in VWD Factor VIII levels are low, or effectively low).

There are three main types of VWD:

  • Type 1: incomplete absence of VWF; mild symptoms (most common)
  • Type 2: presence of dysfunctional VWF; mild symptoms
  • Type 3: virtually complete absence of VWF; severe symptoms. 

Investigations of suspected Von Willebrand disease

History and examination

  • Beyond looking for ecchymoses and acute bleeding, the examination has nothing specific to offer.
  • Similarly, "history of bleeding" is very nonspecific. Many people may complain of excessive bleeding, and most would not have VWF. History is unreliable, and the use of standardised bleeding history questionnaires is recommended to compute some sort of objective "bleeding risk". People with a high bleeding risk should go on to be tested biochemically.
  • Severity of bleeding usually correlates with Factor VIII level.
  • Type 1 usually has epistaxis and mucosal haemorrhages, bleeding after dental work, etc
  • Type 3 may have haemarthrosis and deep haematomas similar to haemophilia.

Blood biochemistry and coags

  • Von Willebrand Factor level
  • Factor VIII level
  • Ristocetin co-factor activity (VWF:RCo)
  • von Willebrand factor collagen binding (VWF:CB)

Management

  • DDAVP
  • Replacement therapy (concentrated VWF and Factor VIII)
  • In an acutely bleeding patient, platelet transfusion and tranexamic acid are indicated.

References

Budde, Ulrich, et al. "Laboratory diagnosis of congenital von Willebrand disease."Seminars in thrombosis and hemostasis. Vol. 28. No. 02. Copyright© 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.:+ 1 (212) 584-4662, 2002.

Kamal, Arif H., Ayalew Tefferi, and Rajiv K. Pruthi. "How to interpret and pursue an abnormal prothrombin time, activated partial thromboplastin time, and bleeding time in adults." Mayo Clinic Proceedings. Vol. 82. No. 7. Elsevier, 2007.

 

 

Question 15.1 - 2011, Paper 2

A 68-year-old male with chronic atrial fibrillation is noted to have the following coagulation profile

Parameter Patient Value Normal Range
PT 101 12-14
APTT 45 34-38
INR 8.7 0.8-1.2

a) What is the likely diagnosis?

b) Outline your management of this patient?

College Answer

a) What is the likely diagnosis?
Supratherapeutic warfarinisation


b) Outline your management of this patient?
If not bleeding:
Stop warfarin
Vitamin K
Consider FFP or prothrombinex if high risk of bleeding

If bleeding:
Resuscitation
Stop warfarin
Vitamin K in as low a dose as possible
FFP 10-15ml/kg or prothrombinex 20-25IU/kg

Discussion

This question stems from guidelines for the reversal of anticoagulation.

 It does not take a great deal of cognitive effort to deduce that this AF patient must be on warfarin, and the high INR suggests he has had a little too much.

The model answer for management is derived from anticoagulation reversal guidelines, which vary from place to place but ultimately derive from the 2004 MJA article I have referenced below. Certainly, my local reversal guidelines seem to be based on this. A brief entry on the reversal of anticoagulant therapy deals with this mundane irritation in slightly more detail. In brief, the general trend is to follow various published consensus statements.

Thus:

  • INR 4.5 – 10.0 and no bleeding: stop warfarin
  • INR 4.5 – 10.0 and high risk of bleeding: Vitamin K (1 – 2 mg orally or 0.5 – 1.0 mg iv).
  • Immediate reversal: Prothrombinex 25 – 50 iu/kg.
  • Acutely bleeding: high dose of Vitamin K - 5-10mg IV. It does not matter what the INR is.
  • Haemorrhage into a critical organ: 5-10mg of Vit K and prothrombinex 50.0 units/kg, and FFP 150–300mL.
  • FFP is generally reserved for situations when the prothrominex is not readily available. The maximum dose is 15ml/kg.

Thus, one would merely withhold warfarin for a patient with low risk of bleeding. If the risk of bleeding is high, one would give vitamin K or FFP/prothrombinex. If bleeding has already occurred, one would resuscitate the patient and also give FFP/prothrombinex.

References

Ross I Baker, Paul B Coughlin, Hatem H Salem, Alex S Gallus, Paul L Harper and Erica M Wood Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis Med J Aust 2004; 181 (9): 492-497.

There is also this local policy document.

 

Question 15.2 - 2011, Paper 2

A 34-year-old woman is intubated and ventilated following a prolonged generalized tonic-clonic seizure. Initial non-contrast CT brain shows bilateral intracerebral haemorrhages. Arterial blood gases and haematology results post intubation are as follows:

Parameter Patient value Normal range
Arterial Blood Gas    
FiO2 0.5  
pH 7.15 7.35 – 7.45
PaCO2 35 mmHg (4.6 kPa) 35 – 45 (4.6 – 6.0)
PaO2 105 mmHg (14 kPa)
HCO3 12* mmol/l 22 – 26
Haematology    
Haemoglobin 78 g/l 130 – 150
WCC 14.5 l 4.0 – 11.0
Platelets 43 l 150 – 300

Blood picture: Thrombocytopaenia, fragmented cells and reticulocytosis
Coagulation profile: Normal

a) List the abnormalities on the arterial blood gas and give the most likely cause in each case

b) Give three possible diagnoses for her presentation based on the history and investigations

College Answer

a) List the abnormalities on the arterial blood gas and give the most likely cause in each case
Metabolic acidosis – lactic acidosis induced by prolonged seizure
Respiratory acidosis / inadequate compensation – inappropriate mechanical ventilation
Increased A-a gradient – aspiration pneumonitis (neurogenic pulmonary oedema)

b) Give three possible diagnoses for her presentation based on the history and investigations
TTP
Eclampsia
HUS
Vasculitis
(Meningo-encephalitis – lower mark)
Evidence of MAHA with low platelets

Discussion

This question assesses ones ability to generate a list of differentials for the causes of seizures, thrombocytopenia and anaemia in a young woman.

The ABG does not give a lactate, but presents us with a severe metabolic acidosis (bicarb 12, pH 7.15). The history of seizures lends itself to the suggestion that lactate is responsible. With this sort of acidosis, respiratory compensation would be maximal - PCO2 in a conscious person would approach the limit of respiratory compensation; but because the woman is ventilated the CO2 is higher, hence the respiratory acidosis.

As for the hypoxia, aspiration and neurogenic pulmonary oedema are good differentials (in the context of seizure) and one may also wish to add pulmonary embolism.

Now, as for reasons why a young lady might become simultaneously anaemic and thrombocytopenic, with normal coags- there are numerous.

Thrombotic thrombocytopenic purpura is a possibility no matter what the presentation.

Eclampsia is a good differential because it incorporates seizures and the intracranial hameoprrhage (implying that it was due to hypertension).

One may also wish to mention HELLP.

Hemolytic-uraemic syndrome certainly results in thrombocytopenia.

Vasculitis is mentioned, but specific vasculitic pathologies are not.

Microangiopathic hemolytic anaemia (MAHA) is called upon, and this certainly results in both anaemia and thrombocytopenia.

DIC is not mentioned because the coags are normal.

References

For thrombocytopenia, I turned to UpToDate: Approach to the adult patient with thrombocytopenia.

 

Or if you dont like paying for things, turn to Stasi, Roberto. "How to approach thrombocytopenia." ASH Education Program Book 2012.1 (2012): 191-197.

 

For eclampsia,

American College of Obstetricians and Gynecologists. Diagnosis and management of preeclampsia and eclampsia ACOG practice bulletin, number 33, jan. 2002

 

For HUS,

Noris, Marina, and Giuseppe Remuzzi. "Hemolytic Uremic Syndrome." Journal of the American Society of Nephrology 16.4 (2005): 1035.

 

For MAHA,

chapter 51 in Williams' Hematology, reproduced here.

 

Question 21 - 2011, Paper 2

A 35-year-old woman (gravida 2, para 1), 34 weeks pregnant, has been admitted to your ICU with pre-eclampsia. Her blood pressure is 160/100, she has moderate proteinuria, normal liver function and a platelet count of 120 x 109 /L. There is no evidence of foetal distress. Her significant past history includes a Factor V Leiden mutation and a history of proximal vein thrombosis during her first pregnancy.

a) What pharmacological regimen would you recommend for DVT prophylaxis? Briefly outline your rationale.

b) List three other inherited thrombophilias that may predispose to DVT in pregnancy?

c) Despite appropriate DVT prophylaxis this patient develops clinical features suggestive of a proximal vein DVT. What investigations would you do to help establish the diagnosis and why?

College Answer


a) What pharmacological regimen would you recommend for DVT prophylaxis? Briefly outline your rationale.

Subcutaneous heparin – unfractionated previously standard of care but recommendation now for low molecular weight heparins eg enoxaparin or dalteparin:

  • Weight based dosing without the need for monitoring
  • ?Reduced risk of bleeding compared to UF heparin
  • Reduced risk of HITS
  • Reduced risk of heparin induced osteoporotic fractures

PROTECT study concluded that in critically ill patients dalteparin was not superior to UF heparin in decreasing incidence of proximal vein thrombosis but proportion of patients with PE and incidence of HITS was lower in dalteparin group.

Heparin does not cross placenta unlike warfarin so no risk of foetal haemorrhage.


b) List three other inherited thrombophilias that may predispose to DVT in pregnancy?

  • Prothrombin gene mutation
  • Antithrombin deficiency
  • Protein S deficiency
  • Protein C deficiency

c) Despite appropriate DVT prophylaxis this patient develops clinical features suggestive of a proximal vein DVT. What investigations would you do to help establish the diagnosis and why?

  • Compression ultrasonography (sensitivity 97% and specificity 94%).
    • Non-invasive, safe and test of choice in pregnancy.
  • D-dimer – levels increase with progression of normal pregnancy so need to interpret in combination
    with other tests. Negative test has predictive value of 100%. Positive test has sensitivity of 100% and specificity of 60%.


If iliac vein thrombosis suspected, consider:

  • MRI – good specificity and sensitivity and no harm to foetus
  • Pulsed Doppler study
  • CT scan of iliac veins – NB radiation exposure to foetus

Discussion

This question interrogates the candidate's ability to recall anticoagulation guidelines in pregnancy, and tests their knowledge of the sensitivity and specificity of routine investigations for deep vein thrombosis.

The pharmacological management of DVT in pregnancy has previously rested on unfractionated heparin. The college answer lists the known benefits of LMW heparin dosing, and then refers to the PROTECT study.

This study did not find much difference in the rate of DVT (still around 5.6%), but the LMWH group had fewer PEs and there was a trend towards less HITS.

Then, the candidate is invited to produce a list of inherited thrombophilias. There is a good UpToDate article on this, available to the paying public. There is a point-form list in it, which essentially mirrors the college answer:

  • Factor V Leiden deficiency
  • Prothrombin gene mutation
  • Protein C deficiency
  • Protein S deficiency
  • Antithrombin III deficiency

I will move on to the question about the investigations of DVT, because this is where the candidate is expected to produce numbers to prove their knowledge of the literature.

The D-dimer is certainly useful in ruling out a DVT; a systematic review by Stein et al has show that a negative quantitative D-dimer is "as diagnostically useful as a normal lung scan or negative duplex ultrasonography finding for excluding VTE". But a positive D-dimer does nothing to improve your decisionmaking, given that in pregnancy it will almost certainly be elevated.

Compression ultrasonography, then, is the ideal investigation. It has been shown to have excellent sensitivity and specificity. The exact numbers from the college answer (sensitivity 97% and specificity 94%) don't come from this study; they probably found them in the Zierler paper, which quotes the same statistics but does not mention their origin.

Iliac vein MRI is also mentioned, as well as pulsed doppler.

There is not much MRI information in pregnancy; one study from 1995 is waved around, but it dates back to 1995, and was performed on only 10 patients. Those results were encouraging. A much later systematic review also applauds the sensitivity and specificity of MRI venography in the pelvis, but laments that the studies are few, and that the MRI techniques are wildly heterogeneous in a comparison-defeating sort of way.

References

The PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group Dalteparin versus Unfractionated Heparin in Critically Ill Patients N Engl J Med 2011; 364:1305-1314April 7, 2011

Kline JA, Williams GW, Hernandez-Nino J. D-dimer concentrations in normal pregnancy: new diagnostic thresholds are needed.Clin Chem. 2005 May;51(5):825-9. Epub 2005 Mar 11.

Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, Biel RK, Bharadia V, Kalra NK D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. .Ann Intern Med. 2004 Apr 20;140(8):589-602.

Polak JF, Wilkinson DL. Ultrasonographic diagnosis of symptomatic deep venous thrombosis in pregnancy. Am J Obstet Gynecol. 1991 Sep;165(3):625-9.

Zierler, Brenda K. "Ultrasonography and diagnosis of venous thromboembolism." Circulation 109.12 suppl 1 (2004): I-9.

Spritzer CE, Evans AC, Kay HH. Magnetic resonance imaging of deep venous thrombosis in pregnant women with lower extremity edema. Obstet Gynecol. 1995 Apr;85(4):603-7.

Fiona C. Sampson, Steve W. Goodacre, Steven M. Thomas, Edwin J. R. van Beek The accuracy of MRI in diagnosis of suspected deep vein thrombosis: systematic review and meta-analysis European Radiology January 2007, Volume 17, Issue 1, pp 175-181

 

Question 29.1 - 2011, Paper 2

A 24-year-old woman has the following haematology and coagulation profile post 
admission to the intensive care unit following post partum haemorrhage.

Parameter Patient Value Normal Range
White cell count 5.6 x 109/l 4.0 – 11.0
Haemoglobin 60 g/l 115 – 165
Platelets 30 x 109/l 150 – 400
PT 30.6 sec 10.5 – 13.5
APTT >150 sec 21 – 36
D-dimer >10 µgm/ml FEU <0.4
Fibrinogen 0.8 g/l 1.1 – 3.2



a) What does this pattern of coagulation abnormalities suggest?

b) List three likely causes of this coagulation profile in this patient

c) What does an elevated D-dimer indicate?

College Answer

a) What does this pattern of coagulation abnormalities suggest 

DIC 

b) List three likely causes of this coagulation profile in this patient 

Pre-eclampsia 
Amniotic fluid embolism 
Sepsis 
Intra-uterine fetal death 
Mismatched / massive transfusion

c) What does an elevated D-dimer indicate?

Tests fibrinolysis. Measures the break down of the cross-linked fibrin

 

Discussion

This question is one of pattern recognition, and it interrogates the candidate's ability to generate a list of differential causes for DIC at the end of pregnancy.

There isn't much else this list of abnormalities could represent.

There is evidence of accelerated fibrinolysis (D-dimer elevation), a low fibrinogen suggestive of its consumption, evidence for the depletion of clotting factors (high PT and APTT) and thrombocytopenia with anaemia, suggestive of microangiopathy.

The causes of DIC are numerous, but in the context of pregnancy and PPH one can narrow down one's list of possibilities.

There are actually quite a large number of potential peripartum causes for DIC:

  • Abruptio placentae
  • Placenta accreta
  • Amniotic fluid embolism
  • Retained dead fetus
  • Abortion induced with hypertonic fluids (saline or urea)
  • Intrauterine sepsis
  • Incompatible blood transfusion
     

An excellent review article lists these, and others, and delves deep into their pathophysiology and management.

So, what indeed does an elevated D-dimer indicate? The college seems to have expected a one-line answer.

It seems to be a valuable adjunct for the laboratory diagnosis of DIC.

In essence, a D-dimer is a small protein degradation product, consising of two crosslinked D-fragments of fibrin.

A longer explanation, with pictures and extensive bibliography, is also available. The presence of an elevated D-dimer confrms that somewhere fibrin is being degraded.

References

Slofstra, Sjoukje, Arnold Spek, and Hugo ten Cate. "Disseminated intravascular coagulation." The Hematology Journal 4.1 (2013): 295-302.

 

Levi, Marcel, and Hugo Ten Cate. "Disseminated intravascular coagulation."New England Journal of Medicine 341.8 (1999): 586-592.

 

Letsky, Elizabeth A. "Disseminated intravascular coagulation." Best Practice & Research Clinical Obstetrics & Gynaecology 15.4 (2001): 623-644.

 

Carr, J. Meehan, M. McKinney, and J. McDonagh. "Diagnosis of disseminated intravascular coagulation. Role of D-dimer." American journal of clinical pathology 91.3 (1989): 280-287.

 

Adam, Soheir S., Nigel S. Key, and Charles S. Greenberg. "D-dimer antigen: current concepts and future prospects." Blood 113.13 (2009): 2878-2887.

 

Question 11.2 - 2012, Paper 1

A 64-year-old woman presents with lethargy, shortness of breath on exertion and jaundice.

Hb

64 g/L

(115-155)

MCV

102.4 fl

(80.0-98.0)

Platelets

114 X 109/L

(150-400)

White Cell Count

101 X 109/L

(4.0-11.0)

Neutrophils

0.22%

2.3 X 109/L

(1.8-7.5)

Lymphocytes

97%

98.7 X109/L

(1.0-3.5)

Monocytes

0.0%

0.0X109/L

(0.20-0.80)

Eosinophils

0.0%

0.0X109/L

(0.02-0.50)

Basophils

0.0%

0.0X109/L

(0.0-0.10)

Nucleated RBCs

3.6 per 100 WBC

Reticulocyte count

280 X 109/L

(20-150)

Polychromasia. Poikilocytosis. Spherocytes. Smudge cells.

i. What is your interpretation of the leucocytosis?

ii. What is your interpretation of the anaemia?

iii. What additional test would you perform to help determine the underlying cause of the anaemia?

College Answer

i. CLL given lymphocytosis and smudge cells.

ii. Jaundice, presence of spherocytes, and reticulocytosis suggest haemolysis.

    Autoimmune haemolytic anaemia associated with warm antibody.

iii. Additional test: Direct Coomb’s test

Discussion

The real question should read "try to recall the meaning of smudge cells as a blood film abnormality".

That is fairly straightforward. Smudge cells are deformed lymphocytes which are associated with chronic lymphocytic leukaemia. Look, here's a whole bunch of them at the ASH Image Bank.

However, the warm antibody thing is very different. If one were to forget that jaundice formed part of the initial flavour text, one might be tempted to instead jump on the macrocytosis, and ask for B12 and folate studies, or maybe even a bone marrow biopsy.

What do they mean by "warm"? Well, in this instance its a case of an autoimmune haemolytic anaemia with antibodies maximally active at human body temperature. How this spectrum of activity was derived from the clinical history? Probably because cold exposure was never mentioned.According to this article on the topic, the hemolytic anaemia usually associated with leukaemia is indeed a "warm" variety, whereas Waldenstroms and lymphoma tend to cause a "cold" autoimmune haemolytic anaemia.

A good overview of this topic can be found in the American Journal of Haematology.

Their breakdown of the classifications of haemolytic anaemia looks a little like this:

 

Differential Causes of Autoimmune Haemolytic Anaemia
Warm haemolytic anaemia  Cold haemolytic anaemia
  • Idiopathic primary haemolytic anaemia
  • Viral infections, including HIV
  • Drugs, eg. penicillin, methyldopa, 5-FU, diclofenac, etc...
  • Lymhoproliferative disorders:
    • CLL
    • Lymphoma
    • Multiple myeloma
    • Hodgkins lymphoma
    • Waldenstrom's macroglobulinaemia
  • Autoimmune disorders, particularly SLE and rheumatoid arthritis
  • Post-infectious colad agglutinin disease
    • Syphilis
    • Post-viral
    • Mycoplasma pneumoniae
    • EBV, VZV, CMV, HIV
    • Adenovirus
    • Influenza viruses
  • Paroxysmal cold haemoglobinuria
    • Idiopathic
    • Virus-associated (EBV, CMV, etc)

Additional tests:

Laboratory features common to all haemolytic anaemias

  • Morphologic RBC abnormalities: such as spherocytosis or fragmented RBCs, as well as pathognomonic erythrocytes such as sickle cells.
  • High reticulocyte count: because a normal bone marrow responds to anaemia by ramping up the production of RBCs.
  • High LDH:  lactate dehydrogenase is an enzyme which leaks out of pretty much any damaged cells, and so is not specific for haemolysis. However, nor is bilirubin. Regardless, the college will expect you to mention both in an exam answer.
  • Haptoglobin: the protein responsible for iron transport will usually be low when there is too much iron to transport. It is also an acute phase reactant, which means it does not necessarily have to be low in the presence of haemolysis.
  • Free haemoglobin will be elevated as it spills out of RBCs. There may even be haemoglobinuria.

Laboratory features specific to autoimmune causes of haemolytic anaemia

  • DAT, direct antiglobulin test or direct Coombs Test, demonstrates that the RBCs are coated with antibody and/or complement. .
  • DAT helps discriminate between a  "warm" and a "cold" haemolytic anaemia.
  • When haemolysis is "warm", the autoimmune haemolytic anaemia is caused by antibodies maximally active at human body temperature, and this is usually caused by IgG. The DAT comes back positive for both IgG and C3d, the latter being a complement product
  • Hamolysis caused by IgM usually occurs in cold conditions, and the DAT comes back positive for C3d but not IgG.

References

Zeerleder, S. "Autoimmune haemolytic anaemia-a practical guide to cope with a diagnostic and therapeutic challenge." Neth J Med 69.4 (2011): 177-84.

Gehrs, Bradley C., and Richard C. Friedberg. "Autoimmune hemolytic anemia."American journal of hematology 69.4 (2002): 258-271.

Question 11.3 - 2012, Paper 1

A 70-year-old man presents with a seven-day history of recurrent epistaxis, bruising and increasing haemoptysis. He has no significant past medical history other than a TIA for which he takes Aspirin. He does not have any epistaxis at present. His INR and APTT are normal.

Hb

96 g/L *

(135-175)

RBC

3.32 x 1012 /L*

(4.50-6.00)

PCV

0.29 *

(0.40-0.50)

MCV

86.7 fl

(80.0-98.0)

MCH

28.9 pg

(27.0-33.0)

MCHC

333g/L

(315-355)

Platelets

2 x 109/L*

(150-400)

Immature Platelet Forms

17%*

(1.1-6.1)

Reticulocytes

0.6%

(0.5-2.0)

White Cell Count

8.82 x 109/L

(4.0-11.0)

i. List 6 potential aetiologies for the above blood picture in this patient.

College Answer

  • Decreased platelet production
    • Marrow failure (eg aplastic anaemia, myelodysplasia)
    • Exposure to drugs (eg quinine)
    • Marrow infiltration (eg neoplastic)
    • Nutritional
  • Increased platelet destruction
    • Immune thrombocytopenic purpura (incl idiopathic, CT disease, lymphoproliferative disease, medications, infection (eg HIV, Hep C)).
    • Thrombotic microangiopathy
    • Drug-induced
  • Increased sequestration of platelets
    • Hypersplenism

Discussion

This question favours the candidate who can generate a large number of differentials.   Specifically, the differentials are for the question "what causes peripheral platelet breakdown". Because there is a large proportion of immature forms, one can presume that the bone marrow is functioning normally. However, the college offers a few differentials which involve bone marrow failure.

Furthermore, thrombotic microangiopathy is brought up, which would also cause a haemolysis of red cells. (well, the man is a little anaemia, but he has been having epistaxis for 7 days so its far from surprising)

So: I give up.

Here is a link to an article with a diagnostic approach to thrombocytopenia. The well-resourced candidate will also draw on UpToDate: Approach to the adult patient with thrombocytopenia.

Causes of Thrombocytopenia

Decreased platelet production

  • Bone marrow suppression
    • Alcohol toxicity
    • Chemotherapy
    • Congential causes, eg. Fanconi anaemia
    • Myelofibrosis or aplastic anaemia
    • Neoplasm, eg. leukaemia or lymphoma
    • Viral infection, eg. HIV, EBV, Hep C, parvovirus, mumps, rubella, varicella...
    • Nutritional deficiency: B12 and folate deficiency
    • Liver disease - decreased production of thrombopoietin (TPO)

Increased platelet destruction

  • SLE
  • ITP
  • DIC
  • Drugs:
    • Quinine
    • Heparin
    • Valproate
  • Post-transfusion thrombocytopenia
  • Microangiopathic haemolytic anaemia
  • Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS)
  • Antiphospholipid syndrome
  • HELLP syndrome in pregnancy
  • Physical destruction in the cardiopulmonary bypass apparatus or circuit
Pseudothrombocytopenia
  • The sample was improperly anticoagulated, and there is platelet clumping on microscopy of the blood film.
  • Send a citrated tube instead- often the EDTA is to blame.
  • Abciximab can cause this, as it is an antibody to the GP IIb/IIIa receptor.

Dilution of platelets

  • Massive transfusion
  • Massive fluid resuscitation

Sequestration

  • Hypersplenism
  • Accessory spleens or splenunculi
  • Hepatic sequestration
  • Extremes of hypothermia

References

Stasi, Roberto. "How to approach thrombocytopenia." ASH Education Program Book 2012.1 (2012): 191-197.

UpToDate: Approach to the adult patient with thrombocytopenia.

Question 1 - 2012, Paper 2

A 43-year-old woman is transferred to your Intensive Care Unit from a regional hospital following a motor vehicle crash. She is in haemorrhagic shock secondary to abdominal and pelvic trauma and received 3L crystalloid and 8 units O Rh(D) negative blood prior to arrival in your hospital.

  • What are the risks of giving O negative uncrossmatched blood to this patient?
  • Indicate whether crossmatch is needed or not for each of the following blood products:
    • Packed red blood cells
    • Platelets 
    • Fresh frozen plasma
    • Cryoprecipitate 
    • Prothrombin concentrate
    • Granulocyte concentration 
    • Intravenous immunoglobulin
 

College Answer

a) 
Risks common to all blood transfusions

(infection, allergy, haemolysis, TRALI, fluid overload, dilutional coagulopathy, etc)

Risks specific to O-ve uncrossmatched 
Mixed field group and screen (unclear blood group)

Prolong group and cross match if specimen not taken before.

Non-ABO, non Rh (D) antigens/antibodies leading to allo-immunisation (sensitization) and delayed haemolytic reactions

b)

Blood Product

Need for Crossmatch

Packed red blood cells

Yes

Platelets

No

Fresh Frozen Plasma

No

Cryoprecipitate

No

Prothrombin concentrate

No

Granulocyte concentrate

Yes

Intravenous immunoglobulin

No

Discussion

Type O uncrossmatched blood generally seems safe enough to use when needed.

In general, the adverse events associated with of blood transfusion are diminishing in incidence, but one should know what they are:

  • ABO-incompatible blood transfusion (due to administrative error)
  • Bacterial contamination of platelet components (1:2,000)
  • Sepsis from bacterial contamination of red cell components(1:500,000)
  • HIV infection ( 1:2,135,000)
  • Hep C infection (1:1,935,000)
  • Hep B infection (1:205,000)
  • Human T-lymphocytic viruses (1:2,993,000)
  • Transfusion-related acute lung injury (TRALI)
  • Fluid overload and heart failure
  • Dilutional coagulopathy

Mixed-field RBC agglutination is a case of "false chimerism" where there are two very different blood cell populations, confusing the automated testing apparatus. It may take longer for the technicians to identify some safely transfuseable crossmatched blood after receiving a specimen like that.

On top of this, sensitization can occur, leading to hemolytic reactions. The chances of this happening are around 0.4%.

And, lastly, only the red cells and granulocytes need crossmatching - the other blood products can be given willy-nilly.

References

SCHWAB, C. WILLIAM, JOHN P. SHAYNE, and JOHN TURNER. "Immediate trauma resuscitation with type O uncrossmatched blood: a two-year prospective experience." Journal of Trauma and Acute Care Surgery 26.10 (1986): 897-902.

Busch, Michael P., Steven H. Kleinman, and George J. Nemo. "Current and emerging infectious risks of blood transfusions." Jama 289.8 (2003): 959-962.

Sandler, S. G., H. Yu, and N. Rassai. "Risks of blood transfusion and their prevention." Clinical advances in hematology & oncology: H&O 1.5 (2003): 307-313.

Bluth, Martin H., Marion E. Reid, and Noga Manny. "Chimerism in the immunohematology laboratory in the molecular biology era." Transfusion medicine reviews 21.2 (2007): 134-146.

Goodell, Pamela P., et al. "Risk of hemolytic transfusion reactions following emergency-release RBC transfusion." American journal of clinical pathology134.2 (2010): 202-206.

Question 12.1 - 2012, Paper 2

The following is the haematological profile of a 22-year-old previously healthy female admitted to ICU with community acquired pneumonia:

Parameter

Result

Normal Range

INR

1.1

0.8 – 1.2

Prothrombin time

11 seconds

10 – 15

APTT

73 seconds*

35 – 45

APTT after protamine

69 seconds*

35 – 45

APTT with 50% normal plasma

53 seconds*

35 – 45

Fibrinogen

3.4 G/L

2.5 – 5

  • What is the likely explanation for the APTT result? Give the reasons for your response.
  • What further test would you order to confirm the underlying disorder?
  • Give two potential complications of which this patient is at risk
 

College Answer

a)

  • Antiphospholipid antibody syndrome

b)

  • Lupus anticoagulant / Antiphopholipid antibody

c)

  • Recurrent DVT / PE
  • Arterial thrombosis
  • Recurrent miscarriage

Discussion

So, the patient is coagulopathic - and the extrinsic pathway is intact, so there must be some problem with the intrinsic pathway or the final common pathway. Protamine admnistration - which would normally reverse heparinisation - fails to improve the situation. So, the doctor seems to have thought about checking for an anticoagulant in the serum (hence the mixing study). When mixed with normal plasma, the APTT of the sample remains high, confirming that something is in there, blocking the normal coagulation cascade.

In a young woman, one's thoughts would turn to lupus. Specifically, antiphospholipid syndrome.One would confirm this diagnosis by ordering a lupus anticoagulant and an antiphospolipid antibodyassays. Certainly, one could spend hours talking about esoterica like the Russel Viper Venom Time, but this question really is not worth enough marks.

This young woman is thus prone to simultaneously clotting and bleeding. She is at risk of DVT, PE, miscarriage, cerebral sinus thrombosis, arterial thrombosis, and so on.

References

Levine, Jerrold S., D. Ware Branch, and Joyce Rauch. "The antiphospholipid syndrome." New England Journal of Medicine 346.10 (2002): 752-763.

Pengo, V., et al. "ISTH SSC 2009 Updated Guidelines for Lupus Anticoagulant."Bulletin No: ST (2011): 01.

Thiagarajan, Perumal, Vittorio Pengo, and Sandor S. Shapiro. "The use of the dilute Russell viper venom time for the diagnosis of lupus anticoagulants." Blood68.4 (1986): 869-874.

Question 12.2 - 2012, Paper 2

A 72-year-old man is admitted to ICU post-operatively for multi-trauma following a motor vehicle crash. 10 days post admission he develops a new fever. Septic screen results are pending and the full blood count is as follows:

Parameter

Result

Normal Range

Haemoglobin

76 G/L*

130 – 175

White Cell Count

15.8 x 109/L*

4.0 – 11.0

Platelets

1211 x 109/L*

150 – 450

Reticulocytes

220 x 109/L*

10 – 80

Neutrophils

10.4 x 109/L*

1.8 – 7.5

Lymphocytes

2.06 x 109/L

1.5 – 4.0

Monocytes

2.54 x 109/L*

0.2 – 0.8

Eosinophils

0.48 x 109/L*

0.0 – 0.4

Haematocrit

0.26*

0.4 – 0.52

MCV

92 fl

82 – 98

MCH

29.9 pg

27.0 – 34.0

MCHC

326 g/L

310 – 360

Comment on blood film: Moderate anisocytosis. Moderate polychromasia. Moderate number of target cells. Occasional Howell-Jolly bodies. Increased rouleaux formation. Marked thrombocytosis.

  • What is the explanation for this blood picture?
  • What treatment will you consider to prevent complications of this condition when this man is discharged from hospital?
 

College Answer

  • Post splenectomy​
  • Antibiotic prophylaxis with Penicillin or equivalent
  • Immunisation prior to hospital discharge for Haemophilus, Meningococcus and Pneumococcus

Discussion

With this blood picture, one might safely wager that this patient has had a splenectomy. Howel-Jolly bodies are bits of lefteover DNA in the erythrocytes. The rest of the RBC morphologies commented on are essentially just cellular garbage. Normally, the spleen would view these as pollutants of the bloodstream, not to be tolerated; and they would be rapidly destroyed. The asplenic man, therefore, must put up with factory seconds of haematopoiesis.

As for protecting him from complications - one must immunise him, and protect him from the thromboembolic complications of thrombocytosis. Thrombosis after splenectomy has an incidence of about 5%, and can be managed wth either aspirin or (in extreme circumstances) with hydroxyurea.

The vaccinations prevent severe infection by encapsulated organisms - because the encapsulated organisms are poorly opsonised by complement, and the spleen was the only organ which could remove them. Thus, one must protect this patient from these bugs. There has been a 2011 revision of the guidelines for such prophylaxis. The most recent iteration of the immunisation schedule can be found here, at Spleen Australia.

  • The asplenic patients should carry an identifying card
  • They should receive the following vaccinations:
    • Pneumococcal vaccination
    • Haemophilus influenzae type b conjugate vaccine
    • Meningococcal conjugate vaccine (polyvalent)
    • Influenza immunization
  • There may be some role for lifelong prophylactic antibiotics
  • The patient should have a supply of antibiotics for emergency use at home

References

Vaccines recommended for adults (>18 years) with asplenia/hyposplenism  -from Spleen Australia

Corazza, G. R., et al. "Howell‐Jolly body counting as a measure of splenic function. A reassessment." Clinical & Laboratory Haematology 12.3 (1990): 269-275.

Bain, Barbara J. "Diagnosis from the blood smear." New England Journal of Medicine 353.5 (2005): 498-507.

Cadili, Ali, and Chris de Gara. "Complications of splenectomy." The American journal of medicine 121.5 (2008): 371-375.

Di Sabatino, Antonio, Rita Carsetti, and Gino Roberto Corazza. "Post-splenectomy and hyposplenic states." The Lancet 378.9785 (2011): 86-97.

Hirsh, J., J. A. McBride, and J. V. Dacie. "Thrombo-embolism and increased platelet adhesiveness in post-splenectomy thrombocytosis." Australasian annals of medicine 15.2 (1966): 122-128.

Davies, John M., et al. "Review of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen: Prepared on behalf of the British Committee for Standards in Haematology by a Working Party of the Haemato‐Oncology Task Force." British journal of haematology 155.3 (2011): 308-317.

Khan, Palwasha N., et al. "Postsplenectomy reactive thrombocytosis."Proceedings (Baylor University. Medical Center) 22.1 (2009): 9.

Question 12.3 - 2012, Paper 2

The following is the full blood count of a 66-year-old man admitted to the High Dependency Unit following a gastro-intestinal haemorrhage:

Parameter

Result

Normal Range

Haemoglobin

84 G/L*

130 – 175

White Cell Count

8.3 x 109/L

4.0 – 11.0

Platelets

240 x 109/L

150 – 450

Reticulocytes

220 x 109/L*

10 – 80

Neutrophils

5.8 x 109/L

1.8 – 7.5

Lymphocytes

1.5 x 109/L

1.5 – 4.0

Monocytes

0.4 x 109/L

0.2 – 0.8

Eosinophils

0.6 x 109/L*

0.0 – 0.4

Haematocrit

0.25*

0.4 – 0.52

MCV

88.4 fl

82 – 98

MCH

30.2 pg

27.0 – 34.0

MCHC

341 g/L

310 – 360

What is the most likely cause of this haematological profile?

 

College Answer

Acute blood loss

Discussion

If one were obsessive, one could also point out that the slight elevation of the eosinophil count could point to eosinophilic oesophagitis- but it could just as easily be a reaction to the transfusion of blood products.

Overall, the blood results have nothing weird in them except anaemia.

References

Sgouros, Spiros N., Christina Bergele, and Apostolos Mantides. "Eosinophilic esophagitis in adults: a systematic review." European journal of gastroenterology & hepatology 18.2 (2006): 211-217.

Question 12.4 - 2012, Paper 2

List five likely causes for the following coagulation profile:

Parameter

Result

Normal Range

PT

35.4 secs*

12.0 – 15.0

INR

3.5*

0.8 – 1.1

APTT

>170.0 secs*

25.0 – 37.0

Fibrinogen

0.9 G/L*

2.20 – 4.30

 

College Answer

  • DIC
  • Primary fibrinolysis 
  • Dilutional coagulopathy from massive transfusion
  • Post thrombolysis 
  • Snake bite

Discussion

All the coagulation parameters are deranged.

Of the differentials presented by the college, the unfamiliar ones are primary fibrinolysis and snake bite.

Snake bite can be pro or anti-coagulant. One might be unlucky enough to be bitten by Russell's Viper.

"Primary fibrinolysis" refers to some sort of a normal process of clot breakdown. It occurs when massive amounts of some sort of plasminogen activator enter the circulation - for instance, after trauma. The distinction between this and DIC is the absence of fibrin deposition. Platelet count should be normal in primary fibrinolysis, as they are not being consumed.

One might ask, "how is this not warfarin toxicity", but the low fibrinogen does not favour this differential. It's hard to say that it completely excludes it, but one does not normally expect such a low fibrinogen level in warfarin overdose. This case report by Card et al (2014) had a normal fibrinogen in a patient who ingested an amount of difenacoum described as "massive". Lip et al (1995) did not find any low fibrinogen levels among long-term warfarinised patients.

 

References

White, Julian. "Snake venoms and coagulopathy." Toxicon 45.8 (2005): 951-967.

Kashuk, Jeffry L., et al. "Primary fibrinolysis is integral in the pathogenesis of the acute coagulopathy of trauma." Annals of surgery 252.3 (2010): 434-444.

Card, David John, et al. "Case Report: Superwarfarin poisoning and its management.BMJ case reports 2014 (2014).  

Lip, Gregory YH, et al. "Effects of warfarin therapy on plasma fibrinogen, von Willebrand factor, and fibrin D-dimer in left ventricular dysfunction secondary to coronary artery disease with and without aneurysms.American Journal of Cardiology76.7 (1995): 453-458.  

Question 23 - 2012, Paper 2

1) List the differential diagnoses of a low platelet count in the critically ill.

2) A 68-year-old man commenced on continuous renal replacement therapy for Acute Kidney Injury (AKI) following repair of a ruptured abdominal aortic aneurysm is noted to have a platelet count of 40 x 109/L. What is your management of this problem?

College Answer

a)

  • Cause of thrombocytopenia in most ICU patients is multi-factorial, due to some combination of following four mechanisms:
    • Increased destruction or consumption
    • Decreased production 
    • Dilution
    • Sequestration
  • Increased destruction 
    • Non-immune mediated – DIC, TTP, HELLP
    • Immune-mediated (drug) – eg Type 2 HITS, Glycoprotein IIb/IIIa inhibitors, NSAIDS, anti-epileptic drugs
    • Immune-mediated (non-drug) – ITP Mechanical – extracorporeal circuits
  • Decreased production
    • Bone marrow suppression – drugs (eg linezolid), toxins, infections, nutritional deficiencies, metastases
  • Dilutional
    • After massive transfusion and fluid resuscitation
  • Sequestration 
    • Splenomegaly
    • Portal hypertension
    • May also be spurious due to clumping of platelets in collection tubes

Management consists of establishing the diagnosis and specific and supportive treatment.

The most likely causes in this patient are:

  • DIC
  • HITS 
  • Other anti-platelet agents
  • Dilutional from massive transfusion

Other causes to be considered if indicated from history or examination

  • Investigations 
    • FBC and Blood film
    • Coagulation screen including DIC screen 
    • HITS screen
    • LFTs 
    • Sepsis screen
    • Consider ADAMTS-13 (for TTP)

Treatment

  • Stop heparin and any other possible causative agents
  • Stop ongoing bleeding
  • Alternative agent for heparin in CRRT and alternative strategy for thromboprophylaxis
  • Platelet transfusion if bleeding, high risk or interventions scheduled
  • Look for and treat sepsis

Discussion

The differential diagnosis of thrombocytopenia in general is presented in a table in the discussion section of Question 11.3 from the first paper of 2012.

At risk of damaging SEO, I will reproduce it here:

Causes of Thrombocytopenia

Decreased platelet production

  • Bone marrow suppression
    • Alcohol toxicity
    • Chemotherapy
    • Congential causes, eg. Fanconi anaemia
    • Myelofibrosis or aplastic anaemia
    • Neoplasm, eg. leukaemia or lymphoma
    • Viral infection, eg. HIV, EBV, Hep C, parvovirus, mumps, rubella, varicella...
    • Nutritional deficiency: B12 and folate deficiency
    • Liver disease - decreased production of thrombopoietin (TPO)

Increased platelet destruction

  • SLE
  • ITP
  • DIC
  • Drugs:
    • Quinine
    • Heparin
    • Valproate
  • Post-transfusion thrombocytopenia
  • Microangiopathic haemolytic anaemia
  • Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS)
  • Antiphospholipid syndrome
  • HELLP syndrome in pregnancy
  • Physical destruction in the cardiopulmonary bypass apparatus or circuit
Pseudothrombocytopenia
  • The sample was improperly anticoagulated, and there is platelet clumping on microscopy of the blood film.
  • Send a citrated tube instead- often the EDTA is to blame.
  • Abciximab can cause this, as it is an antibody to the GP IIb/IIIa receptor.

Dilution of platelets

  • Massive transfusion
  • Massive fluid resuscitation

Sequestration

  • Hypersplenism
  • Accessory spleens or splenunculi
  • Hepatic sequestration
  • Extremes of hypothermia

No sensible or specific additions can be made to the non-specific manageemnt suggested by the college in the second part of this question. This patient is probably having his platelets eaten by the dialysis filter, or is developing DIC from sepsis, or he has developed HITS. The bottom line is, you would stop anticoagulating him.

The following list of generic steps applies to thrombocytopenia of any cause:

Minimise platelet destruction

  • Withhold heparin and rationalise the indications for heparin, eg.:
    • Use alternative anticoagulants for the extracorporeal circuit (citrate comes to mind but there are numerous others
    • Use mechanical thromboprophylaxis or LMWH
    • Rationalise the use of dialysis
  • Manage the sepsis with appropriate antibiotics and resuscitation (as sepsis improves, DIC will resolve)
  • Address specific destructive aetiologies with appropriately targeted therapies, eg.:
    • Plasmapheresis for TTP
    • High dose methylprednisone for MAHA
    • Delivery for HELLP

Maximise platelet production

  • Ensure supply of haematinics is uninterrupted
  • Optimise nutrition, focusing on vitamins and trace elements
  • Withhold or rationalise any drugs which are bone marrow toxins
  • Correct the correctable causes of bone marrow failure and liver disease
  • Think about thrombopoietin receptor agonists (eg. eltrombopag) - some promising results have come from the RAISE trial (Cheng et al, 2010)

Protect the patient from complications of thrombocytopenia

  • Cancel or postpone all nonessential invasive procedures
  • Cover unavoidable procedures with transfusion of pooled platelets (up to a level of 50)
  • For neurosurgical procedures (or lumbar puncture, etc) aim for a level above 100
  • Otherwise, keep the level above 20
    (the above numbers derived from recommendations made by Van der Linden et al, 2012)

References

Stasi, Roberto. "How to approach thrombocytopenia." ASH Education Program Book 2012.1 (2012): 191-197.

UpToDate: Approach to the adult patient with thrombocytopenia.

Casonato, A., et al. "EDTA dependent pseudothrombocytopenia caused by antibodies against the cytoadhesive receptor of platelet gpIIB-IIIA." Journal of clinical pathology 47.7 (1994): 625-630.

Castro, Christine, and Mark Gourley. "Diagnostic testing and interpretation of tests for autoimmunity." Journal of Allergy and Clinical Immunology 125.2 (2010): S238-S247.

Arepally, Gowthami M., and Thomas L. Ortel. "Heparin-induced thrombocytopenia." New England Journal of Medicine 355.8 (2006): 809-817.

Chong, B. H., J. Burgess, and F. Ismail. "The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia." Thrombosis and haemostasis 69.4 (1993): 344-350.

Question 26.3 - 2013, Paper 1

A previously healthy 34-year-old female is transferred to your hospital intubated and ventilated with a history of a prolonged generalized tonic-clonic convulsion. On arrival, she is deeply unconscious with a GCS of 3, fixed dilated pupils, absent tendon reflexes and bilateral up-going plantar reflexes. An admission CT scan shows bilateral intracerebral haemorrhages.

A full blood count report is as follows:

Test

Value

Normal Adult Range

Haemoglobin*

78 G/L

115 – 155

White Cell Count*

14.5 x 109 / L

4.0 – 11.0

Platelets*

43 x 109 /L

150 – 300

Blood picture:

Thrombocytopaenia, fragmented red cells and reticulocytosis.

  • Based on the history, CT findings and full blood count report, give three possible diagnoses.
 

College Answer

  1. Eclampsia
  2. TTP
  3. HUS
  4. Meningococcal meningitis with DIC (big bleed less likely)
  5. Vasculitis

Discussion

The combination of thrombocytopenia, haemorrhage and a MAHA-like blood film all suggest the following differentials:

  • Eclampsia and HELP syndrome
  • MAHA with vasculitis - the fragmented red cells and thrombocytopenia generally suggest some sort of consumptive coagulopathy
  • TTP - this can present with neurological symptoms, which are due to microvascular occlusion - it is concievable that these patients might have seziures and intracranial haemorrhage
  • HUS - however no renal function findings are available
  • DIC due to sepsis (which, I suppose, could be meningits-associated - and meningococcal meningitis is the more likely one to cause DIC)
  • Infective endocarditis - septic emboli with haemorrhagic transformation

  •  

References

Question 27 - 2013, Paper 1

Define tumour lysis syndrome (TLS).

List the risk factors associated with the development of tumour lysis syndrome.

List the strategies used for the prevention and/or treatment of tumour lysis syndrome and provide a rationale for the use of each strategy.

 

College Answer

a)

Definition 
Tumor lysis syndrome (TLS) is an oncological emergency that is caused by massive tumor cell lysis with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation

b)

Risk factors

  • Tumour-related factors: 
    • High tumour cell proliferation rate or large tumour burden
    • Chemo sensitivity of the malignancy 
    • Transformation to acute leukemia
  • Patient factors: 
    • Pre-treatment hyperuricemia or hyperphosphatemia
    • A pre-existing reduction in renal function
    • Volume depletion
    • Surgery/Stress
    • Steroid treatment

c)

  • Ongoing Intensive monitoring of electrolyte (K, calcium, phosphate, uric acid, urea creatinine) and fluid status important as part of both prevention and treatment
    • Justification - significant changes in electrolytes expected - hyperkalemia, hypocalcamia and hyperphosphataemia and early identification of onset of TLS.

Prevention

  • Hydration to achieve urine output of at least 1 – 1.5 ml/kg (or 80 to 100 mL/m2) per hour.
    • Justification: To minimize the chance of uric acid precipitation in the renal tubules.
  • Avoid potassium and calcium containing fluids and medications
    • Justification: To minimize risk of hyperkalemia and calcium phosphate deposits
  • Allopurinol in doses ranging from 300 to 600 mg/day
    • Justification: To decrease uric acid formation by blocking xanthine oxidase enzyme
  • Rasburicase: this is recombinant urate oxidase enzyme that converts uric acid to allantoin (5-10 times more soluble than uric acid).
    • Justification: Conversion of uric acid to allantoin makes it more soluble. Rasburicase is particularly useful in patients with pre-existing hyperuricemia.
  • Alkalinization of urine eg with ural – not a common strategy
    • Justification: To convert uric acid to a more soluble urate salt, thereby diminishing the likelihood of uric acid precipitation in the tubules. However, there are no data demonstrating the efficacy of this approach.

Treatment

    • Repeated dose of rasburicase Justification as before
    • Consideration of fluids + diuretic therapy Justification as before
    • Specific management of hyperkalemia, hypocalcamia and hyperphosphataemia Justification – avoid adverse effects and maintain normal physiology
    • Haemodialysis, for standard indications; severe electrolyte abnormalities, oliguria, fluid overload, acidosis.
      • Justification: Removes metabolites accumulated as a result of renal failure and also lowers uric acid levels very effectively

Discussion

Tumour lysis syndrome is a metabolic disorder characterized by hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia brought about by rapid tumor cell turnover. A good NEJM review article is available for the time-rich exam candidate. The current classification system demands at least two of the abovementioned electolyte abnormalities 2-7 days after the commencement of cancer therapy.

The same NEJM article contains within it Table 2, which lists the following risk factors:

  • Large amount of tumour mass
  • Organ infiltration by tumour
  • Bone marrow involvement
  • Pre-existing renal disease
  • High mittic tumour activity
  • The tumour's high sensivity to the cancer therapy
  • High intensity of cancer therapy
  • Dehydration
  • Acidic urine
  • Nephrotoxin exposure
  • Wanton and unchecked potassium and phosphate replacement
  • Barriers to the clearance of uric acid
  • Pre-existing gout

Prevention and treatment are well covered by the college answer.

In brief summary:

Preventative measures:

  • Adequate hydration
  • Electrolyte monitoring
  • Intelligent electrolyte replacement
  • Allopurinol
  • Rasburicase
  • Alkalinisation of urine

Management strategies:

  • Rasburicase
  • Forced diuresis
  • Electrolyte correction
  • Hemodialysis

References

Tiu, Ramon V., et al. "Tumor lysis syndrome." Seminars in thrombosis and hemostasis. Vol. 33. No. 4. New York: Stratton Intercontinental Medical Book Corporation, c1974-, 2007.

Howard, Scott C., Deborah P. Jones, and Ching-Hon Pui. "The tumor lysis syndrome." New England Journal of Medicine 364.19 (2011): 1844-1854.

Cairo, Mitchell S., and Michael Bishop. "Tumour lysis syndrome: new therapeutic strategies and classification." British journal of haematology 127.1 (2004): 3-11.

Question 12.1 - 2013, Paper 1

A 21-year-old African American female has been admitted with mild dyspnoea and severe back and abdominal pain. Pulse oximetry on room air is 94%.

Full Blood Count report is as follows:

Test

Value

Normal Adult Range

White Cell Count*

16.52 x 109/L

4.0 – 11.0

Haemoglobin*

82 g/L

115 – 155

Platelets*

529 x 109/L

150 – 400

Haematocrit*

0.23

0.40 – 0.54

Mean Corpuscular Volume

93.5 fL

79 – 99

Red Cell Count*

2.47 x 1012/L

4.5 – 6.5

Mean Corpuscular

Haemoglobin

33.2 pg

27 – 34

Mean Corpuscular

Haemoglobin Concetration

355 g/L

320 – 360

Neutrophils %

58%

40 – 80

Blood film comment:

Target cells – occasional 
Spherocytes – occasional 
Sickle cells – occasional 
Neutrophilia with toxic granulation

  • Give the most likely explanation of her signs and symptoms.
  • Briefly describe your management of this problem.
  • List three other conditions associated with the presence of target cells on the blood film.

College Answer

a)

Sickle cell crisis

b)

Ensure adequate ABC – in particular supplemental oxygenation to keep saturations above 96% 
IV fluids 
Adequate analgesia

Investigate possible precipitants.

c)

Haemoglobinopathies

Iron deficiency

Spleen removal

Liver disease

Thalassaemia

Deficiency of enzyme lecithin cholesterol acyl transferase

Discussion

This is a sickle cell crisis.

What makes it so? well, the sickle cells are a dead giveaway.

The precipitants?

  • Infection
  • Hypoxia,
  • Exposure to cold
  • Dehydration
  • Physical exertion,
  • Acidosis
  • Extensive trauma or injury
  • Psychological stress

Management of a sickle cell crisis depends somewhat on what sort of crisis it is. They come in vasoocclusive, aplastic and sequestration flavours.

All will require oxygen, analgesia and rehydration.

Most will require blood transfusion.

As for target cells:

You will see lots of target cells in

  • Thalassemia
  • Hepatic disease with jaundice
  • Hemoglobin C disorders
  • Postsplenectomy

Fewer target cells are seen in

  • sickle cell anemia
  • iron deficiency
  • lead intoxication
  • Deficiency of enzyme lecithin cholesterol acyl transferase

References

Okpala, Iheanyi E. "Sickle cell crisis." Practical Management of Haemoglobinopathies (2004): 63-71.

Walker, H. Kenneth, et al. "Peripheral blood smear." (1990). in Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition.

Bessis, Marcel. "Codocytes and Target Cells." Corpuscles. Springer Berlin Heidelberg, 1974. 59-64.

Jones, Kathy W. "Evaluation of Cell Morphology and Introduction to Platelet and White Blood Cell Morphology." I do not know which textbook this is form, but it is a chapter which is available for free online ... for now.

Bull, BRIAN S., J. Breton-Gorius, and E. Beutler. "Morphology of the erythron."New York, McGraw Hill (2001): 271-288. - this is an online re-posting of a chapter of Williams' Haematology, but without the figures.

Question 12.2 - 2013, Paper 1

A 72-year-old male has presented acutely unwell to the Emergency Department and found to be in acute renal failure. You have been asked to review him.

His Full Blood Count report is as follows:

Test

Value

Normal Adult Range

White Cell Count

6.45 x 109/L

4.0 – 11.0

Haemoglobin*

97 g/L

130 – 180

Platelets

181 x 109/L

150 – 400

Haematocrit*

0.282

0.40 – 0.54

Mean Corpuscular

Volume*

101.1 fL

79 – 99

Red Cell Count*

2.79 x 1012/L

4.5 – 6.5

Mean Corpuscular

Haemoglobin*

34.8 pg

27 – 34

Mean Corpuscular 
Haemoglobin Concentration

344 g/L

320 – 360

Red Cell Distribution 

Width – Standard

Deviation

53.2 fL

Red Cell Distribution

Width – Coefficient

Variation

14.4%

10.0 – 17.0

Neutrophils %

64.1%

  • List four possible causes of this blood picture.
  • List four possible blood tests specific to aiding diagnosis in this case.

College Answer

a)

  • Alcohol abuse
  • Liver disease
  • Haemolysis
  • Haemorrhage
  • Folate deficiency
  • Vitamin B12 deficiency
  • Exposure to chemotherapy or other drugs
  • Myelodysplasia
  • Hypothyroidism

b)

  • Reticulocyte count
  • Serum B12
  • Serum + red cell folate
  • Serum EPG Immunoglobulins
  • LFT
  • Thyroid function tests
  • Haptoglobins
  • LDH

Discussion

This is macrocytic hypochromic anaemia.

One can find the many causes of macrocytosis in this article.

  • Drugs:
    • trimethoprim, triamterine, nitrous oxide, phenytoin, valproate, chemotherapy agents, HIV antiretrovirals and metformin.
  • Alcoholism
  • Reticulocytosis
  • Nonalcoholic and alcoholic liver disease
  • Hypothyroidism
  • Vitamin B12 deficiency
  • Folate deficiency
  • Multiple myeloma
  • Myelodysplastic syndromes
  • Aplastic anemia
  • Acute leukemia

Four tests to rule them all?

  • TFTs
  • LFTs
  • B12 levels
  • Folate levels

The college also throws in several other tests, eg. a reticulocyte count and haptoglobin. If one is considering myelodysplasia or B12/folate deficiency, then one might also consider a blood film. Classic morphological features (anisocytosis and poikilocytosis) would be seen in the former. The latter is more characterised by dysplasia of red and white cells with spared platelets. If we are going on this tangent, then one might view a bone marrow biopsy as the ultimate gold standard, but the college did ask for blood tests specifically.

References

Aslinia, Florence, Joseph J. Mazza, and Steven H. Yale. "Megaloblastic anemia and other causes of macrocytosis." Clinical medicine & research 4.3 (2006): 236-241.

Question 12.3 - 2013, Paper 1

With respect to the peripheral blood film of an adult:

  • List four conditions in which plasma cells may appear.
  • List four conditions in which nucleated red blood cells may appear.
  • Explain the significance of rouleaux formation.

College Answer

a)

Multiple myeloma

B cell lymphoma

Plasmocytoma

Spherocytosis

Varicella zoster infection

TB
Leprosy

Hepatitis Active/chronic HBV

Serum sickness
Plasma cell leukaemia

MGUS
Waldenstroms macroglobulinaemia

b)

Hyposplenism
Compensatory erythropoeisis with anaemia

Hypoxia
Marrow replacement/ invasion

Extramedullary haematopoeisis

Other – uraemia, sepsis, liver disease, renal transplant, thermal injury, chemotherapy.

c)

Rouleaux are stacked/clumped groups of red cells caused by the presence of high levels of circulating acute-phase proteins which increase red cell 'stickiness'. They are often an indicator that a patient has a high ESR and are seen in infections, autoimmune conditions, chronic inflammation, paraproteinaemia and myeloma.

Discussion

Plasma cells swarming in the blodstream can be a marker of numerous illnesses, and it is difficult to find just one article which might summarise the whole spectrum. In this Nature article, Table 2 lists several plasma cell disorders:

  • MGUS
  • Multiple myeloma
  • Waldenström's macroglobulinemia
  • Solitary plasmacytoma
  • Systemic AL amyloidosis
  • POEMS syndrome

A 1958 article reports on a few more causes:

  • Adenocarcinoma of the colon
  • Pulmonary tuberculosis
  • Cirrhosis of the liver
  • Aplastic anaemia
  • Syphilis

The college answer also includes the following causes, for which there is not much literature:

There are numerous others.

For instance, one article (recording the finding of peripheral plasmacytosis in a patient with Dengue fever) also mentions (and backs with references) the following causes:

  • Primary infection and reactivation of Epstein–Barr virus
  • Acute respiratory infections
  • Parvovirus B19 infection
  • Rubella
  • Hepatitis virus A infection

Nucleated red cells are an immature subtype, and their abundance in a blood sample reflects that either the bone marrow s struggling to keep up with the losses of red cells, or that there are insufficient resources to complete the normal maturation process.

Thus, any nutritional hematinic deficiency and any stimulus for erythropoisesis can cause their appearance.

A review article from Laboratory Medicine lists several causes of nucleated red cells in the peripheral blood:

  • Asplenia
  • Anaemia
  • Hypoxia
  • Bone marrow invasion by malignancy
  • Extramedulary haemopoiesis
  • Uremia
  • Sepsis
  • Liver disease
  • Diabetic ketoacidosis
  • Inflammatory bowel disease
  • Renal transplant
  • Thermal injury
  • Chemotherapy

If you notice those last few causes seem to be in a very familiar order, you are not crazy - the college has used this exact same article to write their answer. In fact, their list is a word-for-word facsimile of the table on page 225, "Mechanisms and Conditions Associated With Normoblastemia".

As for rouleaux formation, one can find numerous articles describing the phenomenon, but one really only needs a basic understanding of it. The answer to this CICM question does not require one to wax lyrical about macromolecule bridging. One merely needs to be familiar with this as a form of reversible RBC aggregation, and to be dimly aware of it as a cause of altered blood rheology. In 1926 Eric Ponder published on the subject, and his paper contains beautifully drawn diagrams of his experimental design. In short, anything which might increase your ESR will cause rouleaux formation, and thus the differentials include a broad range of conditions:

  • Infection of any sort
  • Inflammatory disease of any sort
  • Hyperviscosity syndromes
  • Multiple myeloma (or any sort of hyergammaglobulinaemia)
  • Malignancy of any sort
  • Dehydration
  • Diabetes
  • Chronic liver disease (albumin has a counter-aggregatory effect on RBCs)

References

Kyle, R. A., and S. V. Rajkumar. "Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma." Leukemia 23.1 (2009): 3-9.

Fadem, Robert S., and JOHN E. McBIRNIE. "PLASMACYTOSIS IN DISEASES OTHER THAN THE PRIMARY PLASMACYTIC DISEASES A REPORT OF SIX CASES." Blood 5.2 (1950): 191-200.

Aherne, W. A. "The differentiation of myelomatosis from other causes of bone marrow plasmacytosis." Journal of clinical pathology 11.4 (1958): 326-329.

Constantino, Benie T., and Bessie Cogionis. "Nucleated RBCs—significance in the peripheral blood film." Lab Medicine 31.4 (2000): 223-229.

SCHMIDT, JOHN J., HAROLD J. ROBINSON, and CHARLES S. PENNYPACKER. "Peripheral plasmacytosis in serum sickness." Annals of internal medicine 59.4 (1963): 542-546.

Bäumler, H., et al. "Basic phenomena of red blood cell rouleaux formation."Biorheology 36.5 (1999): 439-442.

Wagner, Christian, Patrick Steffen, and Saša Svetina. "Aggregation of red blood cells: From rouleaux to clot formation." Comptes Rendus Physique 14.6 (2013): 459-469.

REPLOGLE, ROBERT L., HERBERT J. MEISELMAN, and EDWARD W. MERRILL. "SPECIAL ARTICLE Clinical Implications of Blood Rheology Studies." Circulation 36.1 (1967): 148-160.

Ponder, Eric. "On sedimentation and rouleaux formation-I." Experimental Physiology 15.3 (1925): 235-252.

Question 21 - 2013, Paper 1

With respect to thrombotic thrombocytopaenic purpura (TTP):

  • List the classical clinical features of TTP.
  • Describe the underlying pathophysiological process
  • Plasma exchange has been used to treat TTP and Guillain Barre syndrome. Outline the important differences between the plasma exchange treatment regimens used for each condition
  • Explain the difference between plasmafiltration and plasmapheresis
  • Steroids and rituximab are two drug therapies commonly recommended as adjunctive therapy in TTP. Outline the mechanism of action for each in treating TTP

College Answer

a)

Thrombocytopaenia, Microangiopathic haemolytic anaemia, fever, neurological symptoms, renal failure.

b)

A trigger such as infection, surgery, pancreatitis, pregnancy, produces endothelial activation. ADAMTS 13 is a von Willebrand factor cleaving protein. When endothelial activation occurs and ADAMTS 13 activity is low (often due to an autoantibody inhibitor), large vWF multimers accumulate causing microvascular thrombosis and haemolysis

c)

In TTP daily exchanges of 1.5 plasma volumes are used until remission has occurs (platelet count > 150). Replacement with cryodepleted plasma has been recommended as it has less vWF than standard FFP and adequate amounts of ADAMTS 13, but there is no clearly demonstrated clinical advantage over replacement with standard FFP. Replacement with 4% albumin would be inappropriate.

In Guillain Barre Syndrome a course of treatment is given, typically 1.5 plasma volumes every second day for a total of 5 exchanges. The treatment is NOT continued until remission. Replacement with albumin has a lower complication rate than with FFP, and so is preferred.

d)

With plasmafiltration, the patient’s blood is pumped through a circuit similar to a renal replacement therapy circuit. The membrane used filters plasma off. The filtered plasma is replaced with a colloid such as 4% albumin or FFP.

With plasmapheresis, the patient’s blood drains into a reservoir where it is centrifuged into its compents. The non-plasma components are returned to the patient. The discarded plasma is replaced with a colloid such as 4% albumin or FFP

e)

Steroids such as methylprednisolone or prednisolone bind to steroid receptors in the cytoplasm, and are then translocated into the nucleus where they interaction with specific DNA sequences to either enhance or suppress gene transcription. This causes widespread effects on both innate and acquired immunity, suppressing the immune response.

Rituximab is an antibody against CD20 receptors on B cells, resulting killing of these cells, and hence suppressing the immune response.

Discussion

With such succinct college answers it is difficult to find room for improvement. References for further reading will have to suffice.

A good NEJM review article is available from 2004, and within it one may be able to find the majority of the answers to the first parts of the question.

Characteristic features of TTP:

  • Anaemia
  • Thrombocytopenia
  • Microangiopathic haemolytic anaemia
  • Schistocytosis
  • Neuorological symptoms
  • Fever and renal failure are actually uncommon

Underlying pathophysiological process of TTP:

Low ADAMTS-13 levels are clearly implicated. One could really get carried away with the details of pathogenesis here. A brief explanation would have to be limited to the statement that a loss of ADAMTS-13-mediated vWF destruction leads to an exccess of vWF and thus to a systemic prothrombotic state, with microvascular thrombosis responsile for all the organ system damage.

Plasma exchange regimens for TTP and for Guillain-Barre syndrome

Plasma exchange in TTP aims to remove the ADAMTS-13 inhbitor while replacing the missing ADAMTS-13 protein, and thus the replacement fluid needs to be FFP (as a pure albumin solution would have no ADAMTS-13 in it). One is obliged to continue the treatments until the microvascular thrombosis and thrombocytopenia are no longer posing a problem.

Plasma exchange for Guillain-Barre syndrome aims to clear the aetiological autoantibody from the bloodstream. In essence, we say "we have no idea which antibody is causing the demyelination, so we will get rid of all of them". The evidence seems to support a 5-treatment regimen; it seems that six treatments are no better than four. Because there is no missing proteins to replace, the exchanged plasma can be FFP or albumin - it does not seem to matter to the resolution of disease. However, because FFP has a slightly higher risk of transfusion reactions, so in general albumin is the recommended replacement solution, unless there are specific reasons to replace blood proteins.

The technique of plasmapheresis is discussed in a frustrating article of which only view the first two pages are available to the subscriptionless reader. It is at a basic level the centrifugal separation of blood components.

In contrast, a decent quality plasma filtration article is available to the pennyless public. It describes the process as being virtually identical to the hemofiltration of renal replacement therapy, with the main difference being the size of the membrane pores (they need to be large enough to allow the extrusion of all non-cellular blood components).

A good review of the immunosuppressant mechanism of corticosteroid therapy was published in 2011 in Molecular and Cellular Endocrinology. Its 35 pages are a wild excess of detail for the time-poor exam candidate. For a workmanlike understanding of the mechanism, the CICM answer will suffice.

As for Rituximab, the monoclonal CD20 antibody- one can avail oneself of the Roche propaganda pamphlet, or read about the mechanism of its effect in the 2010 article from the Seminars in Hematology. The pragmatic exam candidate will probably limit themselves to the understanding that an attack on the CD20 receptor results in a complement-mediated B cell holocaust.

References

Batlle, Daniel C., et al. "The use of the urinary anion gap in the diagnosis of hyperchloremic metabolic acidosis." New England Journal of Medicine 318.10 (1988): 594-599.

George, James N. "Thrombotic thrombocytopenic purpura." New England Journal of Medicine 354.18 (2006): 1927-1935.

Peyvandi, Flora, et al. "von Willebrand factor cleaving protease (ADAMTS‐13) and ADAMTS‐13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura." British journal of haematology 127.4 (2004): 433-439.

Tsai, Han-Mou. "Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura." Journal of the American Society of Nephrology 14.4 (2003): 1072-1081.

Zheng, X. Long, et al. "Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura." Blood103.11 (2004): 4043-4049.

McLeod, Bruce C. "Therapeutic apheresis: use of human serum albumin, fresh frozen plasma and cryosupernatant plasma in therapeutic plasma exchange."Best Practice & Research Clinical Haematology 19.1 (2006): 157-167.

Raphael, J. C., et al. "Plasma exchange for Guillain-Barré syndrome." Cochrane Database Syst Rev 2.2 (2002).

Reimann, P. M., and P. D. Mason. "Plasmapheresis: technique and complications." Intensive care medicine 16.1 (1990): 3-10.

Coutinho, Agnes E., and Karen E. Chapman. "The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights." Molecular and cellular endocrinology 335.1 (2011): 2-13.

Question 26.2 - 2013, Paper 1

A 45-year-old male received an allogeneic bone marrow transplant for acute lymphatic leukaemia (ALL). Twenty-six days after the transplant he developed severe gastroenteritis and a maculopapular skin rash and respiratory insufficiency.
 

The following investigations were performed:

Test

Value

Normal Adult Range

Haemoglobin*

94G/L

110 – 150

WCC*

2.3 x 109/L

4.0–10.0

Platelets*

54 x 109/L

150 – 300

Sodium*

132 mmol/L

135 – 145

Potassium*

3.4 mmol/L

3.5–5.0

Urea*

8.2 mmol/L

4.0–6.0

Creatinine

100 µmol/L

40 – 120

Bilirubin*

67 µmol/L

<25

ALP*

265 IU/L

<125

AST

40IU/L

<40

ALT*

51IU/L

<40

Coagulation profile: Normal

Stool:

  • Microscopy: WCC ++ 
  • Cultures: No growth 
  • C.difficile toxin: Not detected

a)  List three possible diagnoses.

Over the next 3 weeks, he developed generalized oedema predominantly in the trunk and lower extremities.

An ultrasound Doppler study of the abdomen revealed dilated portal vein and inferior vena cava and the following pressure measurements were obtained:

Test

Value

Normal Adult Range

Portal pressure*

18 mmHg

8– 10

Infrahepatic IVC*

20 mmHg

9– 11

Hepatic vein*

8 mmHg

9– 10

Suprahepatic IVC

8 mmHg

7– 8

Right atrium

6 mmHg

5- 10

  1. Give the likely explanation for these findings.
  2. List two treatment measures.
 

College Answer

a)

Sepsis
CMV infection
Graft v Host disease

b)

Veno-occlusive disease of the liver

c)

TIPS procedure
Diuretics
Fluid restriction

Discussion

Somewhat unfairly, the college has presented us with a patient suffering from some nonspecific symptoms. This young man is anaemic, thrombocytopenic, and has raised LFTs which may explain the high bilirubin. On the plus side, he seems to have engrafted.

Differentials would have to include GVHD (given the rash), CMV infection (given the gastroenteritis) and maybe sepsis - but DIC is ruled out by the absence of coagulopathy.

Generally speaking, the manifestatations of GVHD are as follows:

  • Rash, ranging from maculopapular to bullous erythroderma
  • Raised bilirubin
  • Diarrhoea and abdominal pain, progressing to ileus

The college reminds us to think broad by throwing a sepsis and a CMV in there. Manifestations of CMV infection following bone marrow transplant are protean, and may include all of the features mentioned in the college question.

For example:

  • CMV retinitis
  • CMV mucositis
  • CMV encephalitis
  • CMV pneumonitis
  • CMV myocarditis
  • CMV hepatitis
  • CMV colitis
  • CMV nephritis
  • CMV pancreatitis

Is there an organ system it does not affect?

The suddenly increased portal pressure (normal is 5-10mmHg) is suggestive of veno-occlusive disease of the bone marrow transplant recipient. These pressure measurements are not diagnostic values, however. There are the Seattle criteria and there are the Baltimore criteria, neither of which actually mention any pressures at all - they demand hepatomegaly, ascites and raised bilirubin.

However, the pressure values are given for a reason.

  • The RA pressure is normal, which should give the candidate the impression that there is no cardiac congestive hepatopathy present.
  • The portal pressure is raised, up from the normal 5-10mmHg.
  • The data given to us does not allow us to calculate the hepatic venous pressure gradient, which would require a WHVP (wedged hepatic venous pressure). However, the pressure in the IVC and the pressure in the portal vein are so different that one might infer the HVPG is elevated.

The current BCSH/BSBMT guidelines suggest the following management options:

  • Defibrotide
  • Methylprednisolone
  • Careful fluid management (which means basically diuretics and fluid restriction)
  • TIPS
  • Liver transplant

References

Baron, Frédéric, Manuel Deprez, and Yves Beguin. "The veno-occlusive disease of the liver." Haematologica 82.6 (1997): 718-725.

Dignan, Fiona L., et al. "BCSH/BSBMT guideline: diagnosis and management of veno‐occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation." British journal of haematology 163.4 (2013): 444-457.

Richardson, Paul G., et al. "Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial." Biology of Blood and Marrow Transplantation 16.7 (2010): 1005-1017.

Couriel, Daniel, et al. "Acute graft‐versus‐host disease: Pathophysiology, clinical manifestations, and management." Cancer 101.9 (2004): 1936-1946.

Ljungman, Per, Paul Griffiths, and Carlos Paya. "Definitions of cytomegalovirus infection and disease in transplant recipients." Clinical Infectious Diseases 34.8 (2002): 1094-1097.

Bearman, Scott I. "The syndrome of hepatic veno-occlusive disease after marrow transplantation." Blood 85.11 (1995): 3005-3020.

Coppell, Jason A., et al. "Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome." Biology of Blood and Marrow Transplantation 16.2 (2010): 157-168.

Mcdonald, George B., et al. "Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors."Hepatology 4.1 (1984): 116-122.

Jones, Richard J., et al. "Venoocclusive disease of the liver following bone marrow transplantation." Transplantation 44.6 (1987): 778-783.

Kumar, Ashish, Praveen Sharma, and Shiv Kumar Sarin. "Hepatic venous pressure gradient measurement: time to learn." Indian J Gastroenterol 27.2 (2008): 74-80.

Question 13.1 - 2013, paper 2

A 57-year-old female has the following haematological and coagulation profile post admission to the ICU after a laparotomy for intra-abdominal sepsis with significant blood loss.

Parameter

Patient Value

Normal Adult Range

Haemoglobin

65 G/L*

115 – 165

White cell count

2.77 x 109/L*

3.5 – 11.0

Platelets

14 x 109/L

150 – 400

Prothrombin Time

28.9 seconds*

12.0 – 15.0

International Normalised Ratio

2.7*

0.8 – 1.1

Activated Partial Thromboplastin Time

122.5 seconds*

25.0 – 37.0

Fibrinogen

1.1 G/L*

2.2 – 4.3

a) List two likely causes of the coagulation abnormalities.

b) State how you would correct the coagulopathy and give your reasoning.

College Answer

a) 

Haemodilution with inadequate replacement of blood and clotting factors

DIC.

b)

  • Ensure patient is normothermic amd correct acidosis
  • Platelets to increase platelet count
  • FFP to replace factors II, V, VII, IX, X, and XI.
  • Cryoprecipitate to replace factor VIII, and fibrinogen if FFP does not reverse INR.
  • Consider tranexamic acid and/or Activated Factor 7
  • Exclude on-going surgical haemorrhage

Discussion

a) One does not need to degrade oneself with discussions of direct thrombin inhibitor toxicity and post-thrombolysis complications. The answer is obviously a massive transfusion associated with dilutional coagulopathy, with inadequate blood product replacement, and possibly also DIC.

b)

A structured approach would resemble the following:

  • Establish that haemostasis has been achieved, and return to theatre if necessary
  • Control acidosis
  • Restore normothermia
  • Replace clotting factors and platelets:
    • FFP (APTT is high)
    • Cryoprecipitate (fibrinogen is low)
    • Platelets (they are low)
    • Factor VII can be considered
  • Replace RBCs (2 more uints of PRCBc)
  • Consider trahexamic acid

brief discussion of the clotting cascade and of the various factor replacement blood products is available elsewhere.

References

DeMuro, J. P., and A. F. Hanna. "Trauma Induced Coagulopathy: Prevention and Intervention."Scand J Trauma Resusc Emerg Med 20.47 (2014): 4.

Question 13.2 - 2013, paper 2

A 44-year-old male presents with dyspnoea and is diagnosed as having multiple pulmonary emboli on a computerised tomography pulmonary angiogram (CTPA). He is commenced on 1000 units of heparin per hour IVI after a 5000 unit intravenous bolus. During the night his heparin infusion has steadily increased to 1500 units per hour.
 
These blood results are from the following morning:

Parameter

Patient Value

Normal Adult Range

Prothrombin Time

12 seconds

12 – 16

Acivated Partial Thromboplastin Time

38.3 seconds*

25.0 – 37.0

Fibrinogen

3.8 G/L

2.2 – 4.3

D-Dimer

> 20.0 mg/ml*

< 0.5

a) Give two reasons for the relatively low APTT despite heparin therapy.
 
b) List four causes for an increased predisposition to venous thromboembolic disease.

College Answer

a)

  • ATIII deficiency
  • Increased heparin clearance
  • Increased heparin binding proteins
  • Technical problems such as drug preparation error, disconnected IV line, pump problem, extravasated IV cannula

b)

  • Protein C def Protein S def
  • AT III def
  • Malignancy
  • Factor V Leiden Lupus anticoagulant
  • Immobility
  • Smoking
  • Cardiac failure
  • Local venous obstruction
  • Surgery
  • Trauma
  • Obesity

 

Discussion

Some discussion of the management of heparin resistance goes on in the end of my brief pharmacological entry on unfractionated heparin.

Reasons one might be resistant to heparin:

  • Increased heparin-binding protein levels (all of them are acute phase reactants)
  • Low antithrombin-III levels (i.e. nothing for heparin to bind)
  • Increased heparin clearance (eg. due to splenomegaly in liver disease)
  • Factitious heparin resistance (eg. the heparin is not even connected to the line)

Predisposing factors for PE:

  • Major general surgery
  • Major orthopedic surgery
  • Spinal cord injury
  • Hip, pelvis and long bone fractures
  • Multiple trauma
  • Malignancy
  • Myocardial infarction
  • CCF
  • Prior PE
  • Obesity
  • Age (>40)
  • Immobility
  • Varicose veins
  • Pregnancy
  • Oral contraceptives
  • Smoking
  • Antiphospholipid syndrome
  • Protein C and S deficiency
  • Antithrombin deficiency
  • Factor V Leiden mutation

References

Anderson, J. A. M., and E. L. Saenko. "Editorial I Heparin resistance." British journal of anaesthesia 88.4 (2002): 467-469.

Young, E., et al. "Heparin binding to plasma proteins, an important mechanism for heparin resistance." Thrombosis and haemostasis 67.6 (1992): 639-643.

Hirsh, J., et al. "Heparin kinetics in venous thrombosis and pulmonary embolism." Circulation 53.4 (1976): 691-695.

Anderson, Frederick A., and Frederick A. Spencer. "Risk factors for venous thromboembolism." Circulation 107.23 suppl 1 (2003): I-9.

Question 8 - 2014, paper 2

a) Define tumour lysis syndrome (TLS).

b) List the risk factors associated with the development of TLS.

c) List the strategies used for the prevention and/or treatment of TLS and provide a rationale for the use of each strategy.

College Answer

a)

Definition 
Tumor lysis syndrome (TLS) is an oncological emergency that is caused by massive tumor cell lysis with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation

b)

Risk factors

  • Tumour-related factors: 
    • High tumour cell proliferation rate or large tumour burden
    • Chemo sensitivity of the malignancy 
    • Transformation to acute leukemia
  • Patient factors: 
    • Pre-treatment hyperuricemia or hyperphosphatemia
    • A pre-existing reduction in renal function
    • Volume depletion
    • Surgery/Stress
    • Steroid treatment

c)

  • Ongoing Intensive monitoring of electrolyte (K, calcium, phosphate, uric acid, urea creatinine) and fluid status important as part of both prevention and treatment
    • Justification - significant changes in electrolytes expected - hyperkalemia, hypocalcamia and hyperphosphataemia and early identification of onset of TLS.

Prevention

  • Hydration to achieve urine output of at least 1 – 1.5 ml/kg (or 80 to 100 mL/m2) per hour.
    • Justification: To minimize the chance of uric acid precipitation in the renal tubules.
  • Avoid potassium and calcium containing fluids and medications
    • Justification: To minimize risk of hyperkalemia and calcium phosphate deposits
  • Allopurinol in doses ranging from 300 to 600 mg/day
    • Justification: To decrease uric acid formation by blocking xanthine oxidase enzyme
  • Rasburicase: this is recombinant urate oxidase enzyme that converts uric acid to allantoin (5-10 times more soluble than uric acid).
    • Justification: Conversion of uric acid to allantoin makes it more soluble. Rasburicase is particularly useful in patients with pre-existing hyperuricemia.
  • Alkalinization of urine eg with ural – not a common strategy
    • Justification: To convert uric acid to a more soluble urate salt, thereby diminishing the likelihood of uric acid precipitation in the tubules. However, there are no data demonstrating the efficacy of this approach.

Treatment

    • Repeated dose of rasburicase Justification as before
    • Consideration of fluids + diuretic therapy Justification as before
    • Specific management of hyperkalemia, hypocalcamia and hyperphosphataemia Justification – avoid adverse effects and maintain normal physiology
    • Haemodialysis, for standard indications; severe electrolyte abnormalities, oliguria, fluid overload, acidosis.
      • Justification: Removes metabolites accumulated as a result of renal failure and also lowers uric acid levels very effectively

Discussion

Tumour lysis syndrome is a metabolic disorder characterized by hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia brought about by rapid tumor cell turnover. A good NEJM review article is available for the time-rich exam candidate. The current classification system demands at least two of the abovementioned electolyte abnormalities 2-7 days after the commencement of cancer therapy.

The same NEJM article contains within it Table 2, which lists the following risk factors:

  • Large amount of tumour mass
  • Organ infiltration by tumour
  • Bone marrow involvement
  • Pre-existing renal disease
  • High mittic tumour activity
  • The tumour's high sensivity to the cancer therapy
  • High intensity of cancer therapy
  • Dehydration
  • Acidic urine
  • Nephrotoxin exposure
  • Wanton and unchecked potassium and phosphate replacement
  • Barriers to the clearance of uric acid
  • Pre-existing gout

Though it is described by the college as an oncological emergency, it could be pointed out that haematological malignancies are much more likely to cause tumour lysis syndrome, and it is less well known among solid tumours. This could be because of the increased vascular exposure of the haematological malignancy as compared to the relatively walled-off solid tumours. Mirrakhimov et al (2014) also suggest that the haematological malignancies are at the same time more aggressive and therefore more sensitive to chemotherapy, i.e. a larger proportion of the maligant cells will die with the first act of oncological chemoterrorism

Prevention and treatment are well covered by the college answer.

In brief summary:

Preventative measures:

  • Adequate hydration
  • Electrolyte monitoring
  • Intelligent electrolyte replacement
  • Allopurinol
  • Rasburicase
  • Alkalinisation of urine

Management strategies:

  • Rasburicase
  • Forced diuresis
  • Electrolyte correction
  • Hemodialysis

References

Tiu, Ramon V., et al. "Tumor lysis syndrome." Seminars in thrombosis and hemostasis. Vol. 33. No. 4. New York: Stratton Intercontinental Medical Book Corporation, c1974-, 2007.

Howard, Scott C., Deborah P. Jones, and Ching-Hon Pui. "The tumor lysis syndrome." New England Journal of Medicine 364.19 (2011): 1844-1854.

Cairo, Mitchell S., and Michael Bishop. "Tumour lysis syndrome: new therapeutic strategies and classification." British journal of haematology 127.1 (2004): 3-11.

Mirrakhimov, Aibek E., et al. "Tumor lysis syndrome in solid tumors: an up to date review of the literature." Rare tumors 6.2 (2014): 68-76.

Question 26 - 2014, paper 2

A 50-year-old male patient is admitted to ICU following a laparotomy, splenectomy and partial hepatectomy for intra-abdominal bleeding following a high-speed motor vehicle crash with isolated abdominal trauma. He has had a massive transfusion in theatre. He continues to be fluid responsive with a falling haemoglobin concentration consistent with on-going intraabdominal bleeding.

a) Outline your management of this problem.

The International Normalised Ratio (INR) result is >10 and subsequent history reveals the patient was taking warfarin for recurrent deep vein thromboses.

b) List the steps you would take to correct the INR.

The INR corrects to 2.0 and a thromboelastometry is performed with the resultant graphs (Image A) as shown on page 11. (Graphs from a normal individual, Image B, are included for comparison.)

Image A: the patient

Image B: normal

c) What coagulopathy do the patient’s graphs represent and what therapy is indicated?

College Answer

a)
Clinical examination:
Haemodynamics, abdominal examination, drain losses, exclude other sources of bleeding,
temperature, urine output.
Investigations:
 Ensure blood cross-matched and available
 FBC and Coagulation tests: aPTT, PR, Platelet count, D-Dimers, TEG, Fibrinogen
 ABG
 CXR
Resuscitation:
 Volume replacement
 Transfusion of blood products
 Correction of electrolyte associated with massive transfusion; e.g. hypcalcaemia
 Prevention and treatment of hypothermia
May consider haematology input and activation of a massive transfusion protocol or similar.
Discuss with the surgical team re returning to theatre.
The INR result is >10 and subsequent history reveals the patient was taking warfarin for recurrent
DVTs

b)
Prothrombin Complex concentrate dose 25-50units/kg
Vitamin K 10-20mg
Fresh frozen plasma if ongoing bleeding.(contains Factor VII which is not in PCC)

c)
Thrombocytopaenia / Platelet dysfunction
Platelet therapy +/- cryoprecipitate
Consider DDAVP

Discussion

c) The ROTEM interpretation aspect of this question killed the mood for a lot of people in this exam. The college did not include their ROTEM images in the paper made public on their site, presumably because they plan to recycle them. However, in various ways people are able to get hold of the old papers. If one looks closely enough, one might discover that the college used this Haemoview powerpoint presentation slide for their "normal" image (go to slide 7) and this Haemoview training document for their example of a ROTEM with poor clot stability. Of course, I could have used the same images, but that would have been lazy (and possibly illegal). Instead, de novo synthesis of ROTEM graphs was performed.

Viscoelastic tests of clotting function (TEG and ROTEM) are discussed in greated detail elsewhere. Also, on the ROTEM data interpretation page there are examples of normal and abnormal ROTEM graphs for a series of coagulopathy scenarios. In order to simplify revision, I reproduce the table of normal variables below:

Test CT CFT alpha-angle MCF A10 LI30 ML
INTEM 100-240 30-110 70-83 50-72 44-66 94-100 <15
EXTEM 38-79 34-159 63-83 50-72 43-65 94-100 <15
HEPTEM 100-240 30-110 70-83 50-72 44-66 94-100 n/a
APTEM 38-79 34-159 63-83 50-72 43-65 n/a n/a
FIBTEM n/a n/a 30-70 9-25 7-23 n/a n/a

To arrive at a sensible interpretation, let us go through the thromboelastometry data in systematic detail:

  • The CT intervals for all four tests are within the normal range, suggesting that the coagulation factors are functioning normally.
  • The CFT for EXTEM INTEM and APTEM is abnormally prolonged, suggesting that there is a problem with clot propagation. This finding is not especially specific, and could be attributed to either low platets, poor platelet function or low fibrinogen.
  • The alpha-angle for EXTEM and APTEM is slightly increased, suggesting that there is normal (or slightly increased) reactivity to Tissue Factor, meaning that the warfarin-induced coagulopathy has been well reversed. The INTEM alpha-angle is normal. In short, the initiation of clotting is satisfactory.
  • The A10 and the MCF  for EXTEM INTEM and APTEM are abnormally low, suggesting that clot stability is poor. A low MCF or A10 could be attributed to either low platelets, poor platelet function, low fibrinogen or hyperfibrinolysis. However, given that none of the amplitudes narrow with time, hyperfibrinolysis is clearly not the problem.
  • Looking at the FIBTEM, one can conclude that there is no problem with the fibrinogen. The FIBTEM A10 is quite normal (you would only get worried if it got under 9mm), which suggests that there is plenty of fibrinogen, and that it is functioning normally.  The problem is therefore either low platelet number or poor platelet function.
  • On the basis of this, the college suggests platelet transfusion +/- DDAVP. Cryoprecipitate is also mentioned, presumably because it contains a lot of von Willebrand factor.

References

Practical Haemostasis - best explanation ever.

Question 18.1 - 2015, Paper 1

The following data refer to a 65-year-old male admitted to ICU with septic shock on a background of active rheumatoid arthritis.

Parameter Patient Value Normal Adult Range
Haemoglobin 86 g/L* 125 – 180
Serum ferritin 298 μg/L 15 – 300
Serum iron 7 μmol/L* 9 – 27
Total Iron Binding Capacity (TIBC) 52 μmol/L 47 – 70
Transferrin Saturation (Iron / TIBC x 100) 28% 16 – 40
Erythropoietin level 15 U/L 4 – 28
C-reactive protein (CRP) 321 mg/L* <8

a) What abnormality is demonstrated in this patient? Give your reasoning. (20% marks)

b)  What is the pathogenesis of these changes? (20% marks)

c)  What specific treatment strategy would correct the demonstrated abnormality? (10% marks)

College Answer

a)

Anaemia of Inflammation demonstrated by:

  • decreased haemoglobin
  • decreased iron
  • normal to high ferritin
  • suppressed erythropoietin
  • elevated CRP
 
 

b)

Inflammation -> cytokines (IL6) -> increased hepcidin -> decreased iron release from bone marrow, decreased iron release from macrophages, decreased absorption of iron -> suppressed erythopoeisis

c)

Control inflammation, no value to iron replacement, no value to the use of erythropoietin.

Discussion

Local resources to help with such questions include the following chapters:

In the above, there is a table of typical findings which is reproduced below:

Interpretation of Abnormal Iron Studies
Condition MCV MCHC Serum iron Ferritin Transferrin Transferrin
saturation
TIBC
Iron deficiency anaemia low low low low high <20% high
Anaemia of inflammation (chronic disease) low low low normal low normal low or normal
Acute phase response normal normal low high low low low
Iron overload normal normal high high normal high high

The college answer refers to "Anaemia of Inflammation", a nomenclature which has superseded "anaemia of chronic disease" as  the description of the anaemia which has low serum iron in spite of normal body iron stores (i.e. normal ferritin). This "inflammation" could actually be anything proinflammatory, and so it would be difficult to comment whether the rheumatoid arthritis is more responsible then the sepsis, or vice versa. In either case, the biochemical picture would be more or less the same.

Alternative explanations for these laboratory results could also include the anaemia of decreased erythropoietin release associated with renal failure; but the college specifically gave us RA, sepsis and a raised CRP, clearly aiming the candidates at something inflammatory. Iron studies in anaemia of chronic renal failure tend to demonstrate iron deficiency, i.e. the ferritin is also low, but there is a group in whom there is a "functional" iron deficiency with normal ferritin levels and a failure of iron release from body stores (Babitt & Lyn, 2012). If the inflammatory elements were omitted from the story, this would be a legitimate alternative explanation

The mechanism of anaemia of inflammation can be summarised as follows:

  • Decreased iron availability
    • Cytokine release in inflammation (mainly IL-6) stimulates the synthesis of hepcidin, a regulatory molecule which controls the release of iron into the circulation.
    • A high hepcidin level decreases the availability of iron by promoting "iron trapping" within the bone marrow and macrophages. Thus, the iron stores in this form of anaemia are normal, which renders iron infusion pointless.
    • In the absence of circulating iron, erythropoiesis is restricted.
  • Increased erythrocyte phagocytosis
    • Cytokine-activated macrophages destroy red cells at an increased rate
    • This reduces the lifespan of erythrocytes.
  • Decreased erythropoiesis signals
    • Cytokines act directly on the bone marrow to reduce the rate of erythropoiesis, independent of the levels of circulating erythropoietin
    • Occasionally the level of erythropoietin is also suppressed, which is thought to be a cytokine-related effect acting on its renal secretion.

Routine management of such an anaemia is therefore somewhat unexciting:

  • Iron infusion is futile, as the iron stores are essentially intact
  • Erythropoietin supplementation is futile, as the bone marrow won't respond anyway
  • Blood transfusion is what you'd resort to while treating the cause of the inflammation

But let's say that for some reason you've lost interest in treating causes of things. Can we cosmetically make the iron study numbers look better? Turns out that yes, we can. There are several possible treatments for this sort of anaemia which specifically target the mechanism of its pathogenesis:

  • Tocilizumab, a monoclonal antibody against the IL-6 receptor
  • A thus-far unnamed hepcidin-binding monoclonal antibody may soon become available (apparently, in 2014 it was in Phase 2 trials)
  • Heparin reduces hepcidin production, but in prescribing overmuch heparin to the anaemic patient one might be merely exchanging one problem for another.

References

Hawkins, Stephen F., and Quentin A. Hill. "Diagnostic Approach to Anaemia in Critical Care." Haematology in Critical Care: A Practical Handbook (2014): 1-8.

Gross, I. "Laboratory Studies in the Diagnosis of Iron Deficiency, Latent Iron Deficiency and Iron Deficient Erythropoiesis". from http://iron.sabm.org

Pieracci, Fredric M., et al. "A Multicenter, Randomized Clinical Trial of IV Iron Supplementation for Anemia of Traumatic Critical Illness*." Critical care medicine 42.9 (2014): 2048-2057.

Litton, Edward, et al. "The IRONMAN trial: a protocol for a multicentre randomised placebo-controlled trial of intravenous iron in intensive care unit patients with anaemia." Crit Care Resusc 16 (2014): 285-290.

Corwin, Howard L., et al. "Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial." Jama 288.22 (2002): 2827-2835.

Mesgarpour, Bita, et al. "Safety of off-label erythropoiesis stimulating agents in critically ill patients: a meta-analysis." Intensive care medicine 39.11 (2013): 1896-1908.

Nemeth, Elizabeta, and Tomas Ganz. "Anemia of inflammation." Hematology/Oncology Clinics 28.4 (2014): 671-681.

Babitt, Jodie L., and Herbert Y. Lin. "Mechanisms of anemia in CKD." Journal of the American Society of Nephrology (2012): ASN-2011111078.

Nemeth, Elizabeta, and Tomas Ganz. "Anemia of inflammation." Hematology/Oncology Clinics 28.4 (2014): 671-681.

Question 18.2 - 2015, Paper 1

The following data refer to a 48-year-old female admitted electively to ICU following extensive pelvic surgery for invasive endometrial carcinoma. The patient has remained in ICU for 22 days because of complications including acute kidney injury.

Parameter Patient Value Normal Adult Range
Haemoglobin 66 g/L* 125 – 180
Serum ferritin 14 μg/L* 15 – 300
Serum iron 3 μmol/L* 9 – 27
Total Iron Binding Capacity (TIBC) 86 μmol/L* 47 – 70
Transferrin Saturation 9%* 16 – 40
Erythropoietin level 41 U/L* 4 – 28
C-reactive protein (CRP) 60 mg/L* <8

a) What abnormality is demonstrated in this patient? Give your reasoning. (20% marks)

b) Give two potential causative factors in this patient. (10% marks)

c) Briefly outline the available treatment options to correct the demonstrated abnormality including any disadvantages / risks. (20% marks)

College Answer

a)

Iron deficiency anaemia as evidenced by:

  • decreased haemoglobin
  • decreased iron
  • decreased ferritin
  • increased erythropoietin
  • increased TIBC.

b)

Blood loss
Pre-existing dietary deficiency

c)

IV iron replacement – no demonstrated benefit and risks of adverse effects (awaiting Ironman study)
Oral iron replacement
Erythropoeitin – expensive and no demonstrated benefit
Blood transfusion – risks of transfusion including immunosuppression
Nil – may have reduced oxygen carrying capacity for some time until correction of Hb

Discussion

Local resources to help with such questions include the following chapters:

In the above, there is a table of typical findings which is reproduced below:

Interpretation of Abnormal Iron Studies
Condition MCV MCHC Serum iron Ferritin Transferrin Transferrin
saturation
TIBC
Iron deficiency anaemia low low low low high <20% high
Anaemia of chronic disease low low low normal low normal low or normal
Acute phase response normal normal low high low low low
Iron overload normal normal high high normal high high

Following from this, the results in this SAQ are pretty clearly iron deficiency anaemia (low haemoglobin, low iron, high TIBC, etc). The erythropoietin level is appropriately elevated, but not essential to making the diagnosis. Apart from blood loss and dietary deficiency, there's not much that can be added to the "potential causative factors".

The available treatment options are:

  • Iron supplementation
  • Blood transfusion

The college also included "do nothing" as a management option, though one might object that conceptually this would be the very opposite of a management plan. They also included recombinant human EPO as one of the treatment options, but then they also gave us a serum EPO which is significantly elevated. This defies logic-  adding more exogenous EPO to the already high EPO level is unlikely to achieve a glorious haemopoietic victory, as the haemoglobin was still low even with the EPO levels almost double the upper range of normal.  Moreover, giving EPO is not going to do anything to replenish your iron stores.

The most logical solution would be to give iron, or actual blood. Blood transfusion is of course the last option. The pros and cons of  blood transfusion in the ICU are discussed in greater detail elsewhere. Iron replacement is probably somewhat less toxic, and seems like a sensible solution to a condition where the deficiency of iron is the main problem. One should not be deterred from doing this, even though the IRONMAN trial did not find any improvement in the rate of blood transfusion in their iron-infused group. Those patients did end up with a significantly higher haemoglobin at discharge, even though they were not specifically selected for having iron deficiency.

The objection to the use of IV iron is based in the finding that the iron-infused group has an increased nosocomial infection rate (28.6% vs. 22.9%). Apart from this, there was no major difference in the adverse event rate between the two groups. In any case, you don't have to give the iron intravenously. Oral iron replacement is not without its charm, and only slightly less effective (Bonovas et al, 2016).

References

Question 4 - 2015, Paper 1

The following list refers to classes of oral anticoagulation regimens for use in chronic atrial fibrillation:

  1.     Antiplatelet agents
  2.     Vitamin K antagonists
  3.     Antithrombin agents
  4.     Anti Xa agents

a)  Give an example of a drug for each class of drug listed. (10% marks)

b)  Compare and contrast these regimens specifically with respect to:

  •     The relative advantages and disadvantages
  •     The appropriate laboratory tests to assess coagulation status
  •     Management of life-threatening bleeding

(You may tabulate your answer.) (90% marks)

College Answer

Regimen / Agent Advantages / Disadvantages Assessment of coagulation status Life-threatening bleeding
Anti-platelet agentsAspirin, clopidogrel, ticagrelor

A – Simple, no testing

.D – Poor efficacy; prolonged action; limited reversibility,

Minor increased risk of (non- traumatic) ICH

APTT, INR, platelets Bleeding time, TEG/ROTEM, Platelet function tests Platelet transfusion
Vit K anatagonistsWarfarin

A – Remains gold standard; easy reversibility.

D – Requires frequent monitoring; multiple drug (and alcohol) interactions.

3-4% risk of (any) bleeding; 2-5x risk of ICH (absolute risk .3-0.8%)

APTT, INR, platelets Vit K / Prothrombin complex concentrate (Prothrombinex) / FFP
Direct antithrombin agentsDabigatran

A – No testing.

D – Twice daily dosing; not suitable in severe renal impairment (80% renally cleared); no direct antidote; interacts with amiodarone.

ICH risk lower than warfarin in some patient groups, but ischaemic stroke risk raised in prosthetic heart valves

No specific tests Activated charcoal if recent ingestionAntifibrinolytic (tranexamic acid)

Dialysis if co- existing renal impairment

Anti Xa agentsRivaroxaban, apixaban

A – No testing.

D – Twice daily dosing for apixaban; no direct antidote (yet); dose modification in renal impairment (33% & 27% renally cleared)

Anti-Xa levels

Activated charcoal if recent ingestion

Antifibrinolytic (tranexamic acid)

Additional comments:
Some  candidates  included  agents  given  by  intravenous  or  subcutaneous  routes  instead  of
focusing on oral agents as asked.

Discussion

The college table is probably as succinct an answer as one can manage in under ten minutes. FOAM and non-FOAM resources to help answer this question include the following:

This bibliography is perhaps more extensive than is reasonable for a single SAQ. In order to answer the question, the table offered below has been reassembled from the following chapters:

A Comparison of Oral Antiplatelet Agents and Anticoagulants
for the Management of Atrial Fibrillation
Advantages Disadvantages Tests Reversal
Antiplatelet agents- aspirin, clopidogrel
  • Simple to use
  • No monitoring
  • Daily dosing
  • Long half-life
  • Difficult to reverse
  • Limited effect in AF
  • PFA-100
  • TEG/ROTEM
  • Aggregometry
  • Platelet transfusion
Vitamin K antagonists - warfarin
  • Easily reversed
  • Cheap
  • Familiar
  • Easy to monitor
  • Unaffected by even severe renal failure
  • Narrow therapeutic window
  • Patients vary considerably in dose response
  • Many interactions with drugs and diet
  • PT (INR)
  • Vitamin K: from 1mg to 10mg
  • Fresh frozen plasma (FFP) up to 15ml/kg
  • Prothrombinex 25-50 IU/kg
Direct Thrombin Inhibitors - dabigatran
  • Rapid onset
  • Rapid offset
  • No food interactions
  • Wide therapeutic window
  • Convenient (no need to monitor)
  • Contraindicated in renal failure
  • Difficult to monitor
  • Rapid decline of efficacy with missed doses
  • Expensive
  • Without immediate antidote
  • Thrombin time (TT)
  • Ecarin clotting time (ECT)
  • APTT increases 2-3fold in high doses (eg. in overdose)
  • FFP
  • prothrombinex
  • Factor VIIa
  • Idarucizumab 
  • Dialysis:  60% of the drug removed over 2-3 hours.
Factor Xa  inhibitors- apixaban, rivaroxaban
  • Rapid onset
  • Rapid offset
  • No food interactions
  • Wide therapeutic window
  • Convenient (no need to monitor)
  • Difficult to monitor
  • Rapid decline of efficacy with missed doses
  • Expensive
  • Without immediate antidote
  • Anti-Factor Xa
  • PT and APTT increase in overdose
  • Thrombin time  will be normal
  • Prothrombinex 25-50 IU/kg
  • Tranexamic acid
  • Factor VIIa\
  • Andexanet alfa

But, let us say that instead of wanting to answer a fellowship exam question you actually wanted to anticoagulate somebody for AF. Which drugs are best? What do the guidelines say? AHA/ACC/HRS (2014) make some specific recommendations:

  • AF and mechanical valves: warfarin; but not dabigatran (evidence of harm)
  • AF with normal valves, with prior stroke or CHADS-VASC >2: warfarin (level A), novel oral agents (level B). If INR control is poor, go with novel oral agents (level C)
  • AF with  CHADS-VASC =1: aspirin or novel oral agents (level C)
  • AF post revascularisation: clopidogrel and novel oral agents, without aspirin (level B)

In this grand list of reversal agents, it is also worth mentioning idarucizumab (which already well known but not yet trialed in Phase II trails until August of 2015 by Pollack et al, well after this paper was sat and graded). Also in late 2015 the ANNEXA-A and ANNEXA-R trials (Siegal et al, 2015) demonstrated the efficacy of andexanet alfa in reversing rivaroxaban and apixaban. Future iterations of this question will expect these details. In coming years the availability of the "universal" reversal agent ciraparantag will likely render all this primitive witchcraft obsolete (Galliazzo et al, 2018) - this substance binds all the heparins and DOACS by hydrogen bonds, disabling them and neutralising their effects.

References

Tran, Huyen, et al. "New oral anticoagulants: a practical guide on prescription, laboratory testing and peri‐procedural/bleeding management." Internal medicine journal 44.6 (2014): 525-536.

Ansell, Jack, et al. "The pharmacology and management of the vitamin K antagonists." Chest 126.suppl 3 (2004): 204S-233S.

January, Craig T., et al. "2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary." J Am College Cardiol (2014).

Stangier, Joachim, and Andreas Clemens. "Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor." Clinical and Applied Thrombosis/Hemostasis (2009).

Kreutz, Reinhold. "Pharmacodynamic and pharmacokinetic basics of rivaroxaban." Fundamental & clinical pharmacology 26.1 (2012): 27-32.

Perzborn, Elisabeth, et al. "Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro." Thrombosis research 133.4 (2014): 671-681.

Scaglione, Francesco. "New oral anticoagulants: comparative pharmacology with vitamin K antagonists." Clinical pharmacokinetics 52.2 (2013): 69-82.

Frost, Charles, et al. "Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects." British journal of clinical pharmacology 75.2 (2013): 476-487.

Ward, Christopher, et al. "Practical management of patients on apixaban: a consensus guide." Thromb J 11.1 (2013): 27.

Pollack Jr, Charles V., et al. "Idarucizumab for dabigatran reversal." New England Journal of Medicine 373.6 (2015): 511-520.

Siegal, Deborah M., et al. "Andexanet alfa for the reversal of factor Xa inhibitor activity." New England Journal of Medicine373.25 (2015): 2413-2424.

Galliazzo, S., M. P. Donadini, and W. Ageno. "Antidotes for the direct oral anticoagulants: What news?." Thrombosis research164 (2018): S119-S123.

Question 13.2 - 2015, Paper 1

The following data refer to a 34-year-old male admitted to ICU twenty days after an allogeneic stem cell transplant for acute myeloid leukaemia. Over the last few days he had been complaining of right upper quadrant abdominal pain, and observed to have gained several kilos in weight.

Venous Biochemistry
Parameter Patient Value Normal Adult Range
Sodium 142 mmol/L 135 – 145
Potassium 4.8 mmol/L* 3.5 – 4.5
Chloride 97 mmol/L 95 – 105
Bicarbonate 22 mmol/L 22 – 26
Urea 11.2 mmol/L* 2.9 – 8.2
Creatinine 134 μmol/L* 70 – 120
Calcium 2.13 mmol/L 2.10 – 2.55
Phosphate 1.21 mmol/L 0.65 – 1.45
Total bilirubin 342 μmol/L* 0 – 25
Aspartate aminotransferase (AST) 175 U/L* < 40
Gamma glutamyl transferase (GGT) 123 U/L* < 40
Alanine aminotransferase (ALT) 87 U/L* < 40

a)  Give the most likely diagnosis. (15% marks)

b)  How would you confirm this? (15% marks)

College Answer

a)
Veno-occlusive disease of the liver (sinusoidal obstruction syndrome)

b)
Liver USS showing ascites and reversal of portal vein flow

Discussion

Let us dissect the results systematically.

The electrolytes look deceptively normal. However, an exam candidate accustomed to playing these games will recognise the presented panel as an invitation to calculate the anion gap. If one does this, one will discover that it is raised.

 (142 + 4.8) - (97 + 22) = 27.8

There does not seem to be much of a metabolic acidosis associated with this, which is a little weird (delta ratio is very high, which could suggest that there is some sort of pre-existing metabolic alkalosis present). 

The ure and creatinine are raised, but not to a significant degree. Certainly not by a degree that might explain this weight gain with renal-related fluid overload.

The calcium and phosphate are trivially deranged; the normal phosphate suggests that the accumulation of retained non-volatile acids of renal failure is probably not responsible for the high anion gap.

Liver enzymes are deranged. ALT AST and GGT are all elevated, and even though alkaline phosphatase is not reported one can generally comment that there is non-specific liver injury occurring (i.e. the right upper quadrant pain is probably not acute cholecystitis, but rather the feeling of a swollen liver distending its capsule). The liver injury also suggests that lactate could explain the raised anion gap. 

In summary:

  • High anion gap, probably due to lactate
  • Renal impairment
  • Liver injury
  • Oedema

None of these are parfticularly specific and you'd be struggling to narrow your list of differentials, but the college helpfully threw in the story about a recent bone marrow transplant. That's a giveaway. In the pattern recognition algorithm of the exam candidate,  liver injury + BMT = VOD. Veno-occlusive disease tends to occur in the first three weeks after the transplant, and typically manifests with weight gain and a painful liver. The major clinical criteria for diagnosis (Seattle criteria and Baltimore criteria) usually also demand ascites, hepatomegaly and a bilirubin level (which we were not supplied with; it would have to be over 34 mmol/L).

Diagnosis does not require ultrasound, but it is usually ordered in this context. The BCSH/BSBMT guidelines (2013) concluded that "the main role of ultrasound is to exclude the presence of other diagnoses" because the ultrasound findings which are usually associated with VOD are insufficiently sensitive and specific. In any case, here they are:

  • Ultrasound-confirmed ascites
  • Ultrasound-confirmed hepatomegaly
  • Splenomegaly
  • Attenuated or reversed hepatic venous flow
  • Thickened gallbladder wall
  • Ultrasound evidence of increasing hepatic artery  vascular resistance (there is a "hepatic artery vascular resistance index",  which is helpful in the diagnosis if it is greater than 0.75.)

References

Mohty, M., et al. "Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation." Bone marrow transplantation 51.7 (2016): 906-912.

Baron, Frédéric, Manuel Deprez, and Yves Beguin. "The veno-occlusive disease of the liver." Haematologica 82.6 (1997): 718-725.

Dignan, Fiona L., et al. "BCSH/BSBMT guideline: diagnosis and management of veno‐occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation." British journal of haematology 163.4 (2013): 444-457.

Richardson, Paul G., et al. "Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial." Biology of Blood and Marrow Transplantation 16.7 (2010): 1005-1017.

Couriel, Daniel, et al. "Acute graft‐versus‐host disease: Pathophysiology, clinical manifestations, and management." Cancer 101.9 (2004): 1936-1946.

Ljungman, Per, Paul Griffiths, and Carlos Paya. "Definitions of cytomegalovirus infection and disease in transplant recipients." Clinical Infectious Diseases 34.8 (2002): 1094-1097.

Bearman, Scott I. "The syndrome of hepatic veno-occlusive disease after marrow transplantation." Blood 85.11 (1995): 3005-3020.

Coppell, Jason A., et al. "Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome." Biology of Blood and Marrow Transplantation 16.2 (2010): 157-168.

Mcdonald, George B., et al. "Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors."Hepatology 4.1 (1984): 116-122.

Jones, Richard J., et al. "Venoocclusive disease of the liver following bone marrow transplantation." Transplantation 44.6 (1987): 778-783.

Kumar, Ashish, Praveen Sharma, and Shiv Kumar Sarin. "Hepatic venous pressure gradient measurement: time to learn." Indian J Gastroenterol 27.2 (2008): 74-80.

Cheuk, D. K., et al. "Interventions for prophylaxis of hepatic veno-occlusive disease in people undergoing haematopoietic stem cell transplantation." The Cochrane database of systematic reviews 5 (2015): CD009311-CD009311.

Mohty, M., et al. "Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation." Bone marrow transplantation 51.7 (2016): 906-912.

Question 13.3 - 2015, Paper 1

The following data refer to a 67-year-old male 8 days following initiation of treatment for acute leukaemia:

Parameter Patient Value Normal Adult Range
Haemoglobin 102 g/L* 130 – 180
White Cell Count 111 x 109/L* 4 – 11
Platelets 21 x 109/L* 150 – 350
Blasts 100 x 109/L* 0
Sodium 136 mmol/L 136 – 145
Potassium 6.1 mmol/L* 3.5 – 5.0
Chloride 95 mmol/L* 98 – 106
Bicarbonate 17 mmol/L* 23 – 28
Urea 21.8 mmol/L* 2.9 – 7.1
Creatinine 209 μmol/L* 60 – 120
Calcium (corrected) 2.48 mmol/L 2.20 – 2.60
Phosphate 2.76 mmol/L* 0.80 – 1.45
Magnesium 0.81 mmol/L 0.60 – 1.10
Urate 0.84 mmol/L* 0.20 – 0.42
Total protein 59 g/L* 60 – 78
Albumin 27 g/L* 35 – 55
Bilirubin 9 μmol/L < 20
Alkaline phosphatase (ALP) 587 U/L* 36 – 92
Alanine transferase (ALT) 42 U/L* < 35
Gamma glutamyl transferase (GGT) 110 U/L* < 30
Lactate dehydrogenase (LDH) 7157 U/L* 60 – 100

a)  Give the underlying cause of the above abnormalities and give your reasoning to explain these findings. (20% marks)

b)  List the treatment options for this condition. (30% marks)

College Answer

a)

Tumour lysis syndrome
Renal impairment with hyperkalaemia, hyperphosphataemia, hyperuraecamia and increased LDH

b)
Resuscitation – Adequate IV hydration
Treatment of hyperkalaemia – Calcium chloride, bicarbonate if ECG changes, dextrose- insulin, dialysis, resonium
Renal replacement therapy – metabolic acidosis, hyperkalaemia and hyperphosphataemia Allopurinol
Rasburicase

Discussion

Let us dissect the results systematically. 

The abnormalities and their potential explanations are: 

  • Anaemia: from bone marrow suppression (leukaemia or chemotherapy)
  • Leukocytosis (leukaemia)
  • Thrombocytopenia: from bone marrow suppression (leukaemia or chemotherapy)
  • High blast count (leukaemia)
  • Hyperkalemia (tumour lysis syndrome)
  • Acidosis (low bicarbonate); probably due to some combination of urate lactate and other retained non-volatile acids in renal failure
  • High anion gap;  (136 + 6.1) - (95 + 17) = 30.1
  • Hyperuciaemia (tumour lysis syndrome)
  • Hyperphosphataemia (tumour lysis syndrome; though surprisingly the calcium is normal)
  • Hypoalbuminaemia (critical illness; it is a "negative acute phase reactant")
  • Raised alkaline phosphatase is probably due to leukaemia itself (immature leukocytes have increased ALP levels, as per Masakazu et al, 2005). It is an isolated finding, with the other LFTs remaining relatively normal.
  • Raised LDH (tumour lysis syndrome)

The patient also has a white cell count of 111. This gives rise the the supicion that the hyperkalemia may be "pseudohyperkalemia of malignancy". The presence of haematological malignancy generally means a high white cell count; these extra cells are immature blasts which are structurally unsound, being exempt from normal cellular quality control mechanisms. The very act of aspirating these fragile cells into a syringe or vacutainer may give rise to wholesale cellular destruction by shear stress. The result is a falsely elevated potassium level. Kintzel and Scott presented a case report of this (2012) where the potassium level was 9.8mmol/L in the badly lysed sample and 4.1 mmol/L in the heparinised tube.

The treatment options are:

  • Adequate hydration: aim for a urine output of 150-300ml/hr (i.e. 2-4ml/kg/hr). 
  • Alkalinisation of urine using oral or IV bicarbonate
  • Cessation of nephrotoxins.
  • Electrolyte monitoring and intelligent electrolyte replacement
  • Xanthine oxidase inhibitors (allopurinol or febuxostat)
  • Recombinant urate oxidase to enhance clearance of urate: rasburicase,  0.15-0.20mg/kg for 5-7 days
  • Haemodialysis  is ultimately the most immediately effective solution for the whole host of metabolic abnormalities.

References

Tiu, Ramon V., et al. "Tumor lysis syndrome." Seminars in thrombosis and hemostasis. Vol. 33. No. 4. New York: Stratton Intercontinental Medical Book Corporation, c1974-, 2007.

Howard, Scott C., Deborah P. Jones, and Ching-Hon Pui. "The tumor lysis syndrome." New England Journal of Medicine 364.19 (2011): 1844-1854.

Cairo, Mitchell S., and Michael Bishop. "Tumour lysis syndrome: new therapeutic strategies and classification." British journal of haematology 127.1 (2004): 3-11.

Locatelli, Franco, and Francesca Rossi. "Incidence and pathogenesis of tumor lysis syndrome." Hyperuricemic Syndromes: Pathophysiology and Therapy. Vol. 147. Karger Publishers, 2005. 61-68.

Hsu, Hsiang-Hao, Yi-Ling Chan, and Chiu-Ching Huang. "Acute spontaneous tumor lysis presenting with hyperuricemic acute renal failure: clinical features and therapeutic approach." Journal of nephrology 17.1 (2004): 50-56.

Tiu, Ramon V., et al. "Tumor lysis syndrome." Seminars in thrombosis and hemostasis. Vol. 33. No. 04. Copyright© 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA., 2007.

Oda, Masako, et al. "Loss of urate oxidase activity in hominoids and its evolutionary implications." Molecular biology and evolution 19.5 (2002): 640-653.

Kintzel, Polly E., and William L. Scott. "Pseudohyperkalemia in a patient with chronic lymphoblastic leukemia and tumor lysis syndrome." Journal of Oncology Pharmacy Practice 18.4 (2012): 432-435.

Izumi, Masakazu, et al. "Increased serum alkaline phosphatase activity originating from neutrophilic leukocytes." Clinical chemistry 51.9 (2005): 1751-1752.

Question 8 - 2015, Paper 2

With respect to thromboelastography and haemostasis:

The image depicted in Figure 1 represents a normal thromboelastogram.

With reference to the parameters labelled in Figure 1:

i.    CT (or R)

ii.    CFT (or K)

iii.    Alpha angle
iv.    MCF (or MA)

v.    LI30 (or LY30 or CL)

a)    Explain what each parameter represents and what it measures.    (60% marks)

Review the following thromboelastograms labelled A – E.

Diagram A represents a normal coagulation profile.

b)    Describe the coagulation status indicated by diagrams B – E.    (40% marks)

College Answer

a)

R (reaction time or clotting time) is the time elapsed until first measurable clot forms (amplitude of 2mm) and indicates the initiation of haemostasis and is dependent on presence of clotting factors.

K (kinetics or clot formation time) is the time taken to achieve a certain level of clot firmness (amplitude of 20mm) and indicates amplification of the clotting process. Dependent on fibrinogen.

Alpha angle reflects the speed of fibrin accumulation. Dependent on fibrinogen.

MA/MCF is the maximum amplitude or maximum clot firmness and is the highest vertical amplitude of the TEG tracing. Dependent on platelets and fibrin.

LY30 /CL (clot lysis) is the percentage of amplitude reduction 30 min after maximum amplitude and is a measure of fibrinolysis.

b)

B – Anticoagulant therapy or factor deficiency

C – Platelet dysfunction or thrombocytopaenia or fibrinogen deficiency

D – Fibrinolysis e.g. use of t-PA

E – Hypercoagulable state

Discussion

In short form:

  • R (CT) =  clotting factors
  • K =  fibrinogen
  • α-angle =  fibrinogen.
  • MA/MCF = platelets and fibrinogen.
  • LY30 /CL = fibrinolysis.

With detail:

CT and R values:

  • The TEG uses "R" and ROTEM uses "CT" to describe the time it takes for the amplitude to start climbing.  Arbitrarily, the 2mm point is used as a marker that the clotting cascade has started. Causes of a raised CT include any deficiency of clotting factors, or defect in clotting factor function:
    • Anything that causes a raised PT and APTT:
      • Deficiency of clotting factors
      • Heparin (very sensitive - prolonged by 0.15 units per ml of blood, or a systemic heparin dose of less than 750 units for a 70kg adult)
      • Warfarin
    • Direct thrombin inhibitors

CFT and K values:

  • These values describe the time from clot initiation (2mm) to 20mm. They also relate to the activity of the clotting factors, but also incorporates a measure of the effectiveness of fibrin polymerisation, platelet activity and Factor XIII activity.
    • Causes of prolonged CFT
      • Thrombocytopenia
      • Platelet dysfunction
      • Low fibrinogen
      • Severe deficiency of other factors
    • Causes of Shortened CFT
      • Hypercoaguable states

The α-angle:

  • This is different between the machines. TEG uses the slope of a line connecting the point at which the R interval ends and the point at which the K interval ends. ROTEM, in contrast, uses the slope of the line at the 2mm amplitude mark. is the slope of the line connecting the end of the R interval with the end of the K interval. In either case, the slope is determined by the rate of reaction between platelets, fibrin and the clotting cascade factors. It is therefore probably a nonspecific variable. However, the manufacturer of the device insists that fibrinogen activity plays the greatest role in determining the α-angle.
    • Causes of a decreased α-angle
      • Low fibrinogen
      • Poor fibrinogen polymerisation
      • Thrombocytopenia, or platelet dysfunction 

Maximum clot firmness (MCF) and maximum amplitude (MA):

  • This variable is primarily a measure of platelet count, platelet function and fibrinogen concentration. There is a strong linear correlation between the log platelet count and MA.

LY30 and CL (or CLT)

  • The TEG  defines the term CLT as 2mm from MA, i.e. the time it takes for the clot to soften enough for the amplitude to decrease by 2mm from its maximum. The ROTEM term LOT (Lysis Onset Time) refers to the time it takes for the amplitude to drop by a 15% difference from the MCF, which is a slightly different parameter. The ROTEM term LY30 refers to the amplitude after 30 minutes has passed, and is another measure of fibrinolysis.
    • Causes of a raised LY30 or CLT include
      • Hyperfibrinolysis
      • Administration of thrombolytic drugs

As for the examples:

A is a normal-looking TEG

B has an extremely prolonged CT, but a normal α-angle and a reasonably normal MCF. One might surmise that either something is missing among the clotting factors, or there is some inhibitor present. The platelet count and fibrinogen levels are probably near normal. One might find such a picture in a patient on warfarin, heparin, or receiving a direct thrombin inhibitor.

C is a TEG of a patient who has plenty of clotting factors; the reaction starts quickly.  The MCF is inadequate, suggesting that platelet dysfunction (or thrombocytopenia) are to blame. The college mention that there may also be a problem with the fibrinogen level, but the good α-angle would suggest otherwise.

D is a TEG of a patient with hyperfirbrinolysis from whatever cause.

E is a patient with a hypercoagulable state; the blood clots quickly, with a very firm clot generated in no time.

References

The LITFL page for TEG is ideal to answer this question: they have lovely TEG silhouettes available for the "important patterns".

Practical haemostasis - page on TEG and ROTEM

Sankarankutty, Ajith, et al. "TEG® and ROTEM® in trauma: similar test but different results." World J Emerg Surg 7.Suppl 1 (2012): S3.

Coakley, Margaret, et al. "Transfusion triggers in orthotopic liver transplantation: a comparison of the thromboelastometry analyzer, the thromboelastogram, and conventional coagulation tests." Journal of cardiothoracic and vascular anesthesia 20.4 (2006): 548-553.

Venema, Lieneke F., et al. "An assessment of clinical interchangeability of TEG® and ROTEM® thromboelastographic variables in cardiac surgical patients." Anesthesia & Analgesia 111.2 (2010): 339-344.

Nielsen, Vance G. "A comparison of the Thrombelastograph and the ROTEM." Blood Coagulation & Fibrinolysis 18.3 (2007): 247-252.

Wikkelsoe, A. J., et al. "Monitoring patients at risk of massive transfusion with Thrombelastography or Thromboelastometry: a systematic review." Acta Anaesthesiologica Scandinavica 55.10 (2011): 1174-1189.

Question 27 - 2015, Paper 2

A 60-year old male with no significant past medical history has been treated in your ICU for 21 days for severe staphylococcal sepsis and multi-organ failure, for which he is receiving linezolid.

He requires continuous renal replacement therapy (CRRT) and, despite therapeutic heparin to facilitate this, his filter keeps clotting. His platelet count has reduced from 154 x 106/L to 56 x 106/L from day 18 to day 21.

a)  List the four most likely differential diagnoses for the thrombocytopenia.    (20%    marks)
b)  Discuss your investigation for the thrombocytopenia.    (40%    marks)
c)  Outline your immediate management of this problem.    (40%    marks)

College Answer

a)
i.    Linezolid

ii.    Consumption coagulopathy (from clotting on renal replacement therapy)
iii.    Pseudothrombocytopenia (i.e., platelet clumping)

iv.    Sepsis induced including DIC
v.    Heparin induced (HIT or HITTS)
vi.    TTP/HUS (less likely)

b)

Exclude pseudothrombocytopaenia

Increased consumption

  1. Repeat blood count and request for film to determine platelet clumping, evidence of haemolysis (schistocytes)
  2. Coagulation testing to include D-dimers, fibrinogen
  3. Blood cultures
  4. HITTS screen
  5. ELISA test for anti-platelet factor 4 antibody
  6. More specific but more technically difficult - platelet aggregation test
  7. Autoimmune screen (dsDNA)
  8. ADAMTS13 screening for TTP

Decreased production

  1. Bone marrow aspiration (+/-bone marrow biopsy)
  1. Urea / creatinine for HUS
  1. ‘HIT screen’
  1. Miscellaneous

a.  Drugs, sepsis, alcohol, bone marrow suppression

c)

  1. Reassess need for linezolid but it will need to be ceased and commenced on less bone marrow toxic anti-microbial to cover Staph aureus (vancomycin/teicoplanin)
  2. No need to provide platelet support unless bleeding actively
  3. Minimise need for renal support while trying to understand thrombocytopenia, if urgently needed will need to consider safety of anti-coagulating circuit in view of low platelet count.
  4. Consider alternative strategies for circuit maintenance
    1. No anticoagulation
    2. Citrate
    3. Prostacyclin
    4. Thrombin antagonists
    5. LMWH
    6. Increased systemic heparinisation (if HITTS unlikely)

Additional Examiners’ Comments:

Most candidates passed but there was overall a knowledge gap on the management of this clinical problem

Discussion

Possible differentials for thrombocytopenia? There is a vast array. Observe:

Causes of Thrombocytopenia

Decreased platelet production

  • Bone marrow suppression
    • Alcohol toxicity
    • Chemotherapy
    • Congential causes, eg. Fanconi anaemia
    • Myelofibrosis or aplastic anaemia
    • Neoplasm, eg. leukaemia or lymphoma
    • Viral infection, eg. HIV, EBV, Hep C, parvovirus, mumps, rubella, varicella...
    • Nutritional deficiency: B12 and folate deficiency
    • Liver disease - decreased production of thrombopoietin (TPO)

Increased platelet destruction

  • SLE
  • ITP
  • DIC
  • Drugs:
    • Quinine
    • Heparin
    • Valproate
  • Post-transfusion thrombocytopenia
  • Microangiopathic haemolytic anaemia
  • Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS)
  • Antiphospholipid syndrome
  • HELLP syndrome in pregnancy
  • Physical destruction in the cardiopulmonary bypass apparatus or circuit
Pseudothrombocytopenia
  • The sample was improperly anticoagulated, and there is platelet clumping on microscopy of the blood film.
  • Send a citrated tube instead- often the EDTA is to blame.
  • Abciximab can cause this, as it is an antibody to the GP IIb/IIIa receptor.

Dilution of platelets

  • Massive transfusion
  • Massive fluid resuscitation

Sequestration

  • Hypersplenism
  • Accessory spleens or splenunculi
  • Hepatic sequestration
  • Extremes of hypothermia

In order to simplify one's answer, one may be able to narrow this range to the causes which are relevant to the critically septic patient on dialysis. This exact list is also offered in the discussion section of Question 4 from the second paper of 2001, which offers an essentialy identical scenario.

In brief:

  • Artifact
    • Diluted sample
    • Platelet aggregates
  • Decreased production
    • Antibiotic-associated thrombocytopenia (eg. linezolid)
    • Sepsis-associated bone marrow suppression
    • Preexisting condition (eg. malignancy)
  • Increased destruction
    • Consumption in DIC
    • Consumption by dialysis circuit
    • Consumption due to HITS
    • Autoimmune destruction
  • Sequestration
    • Hypersplenism

This is a more manageable list.

One would organise the following investigations in order to work through it:

The links point to brief explanatory notes for these tests, which one may find in the local chapter on thrombocytopenia.

The following list of generic steps applies to thrombocytopenia of any cause:

Minimise platelet destruction

  • Withhold heparin and rationalise the indications for heparin, eg.:
    • Use alternative anticoagulants for the extracorporeal circuit (citrate comes to mind but there are numerous others
    • Use mechanical thromboprophylaxis or LMWH
    • Rationalise the use of dialysis
  • Manage the sepsis with appropriate antibiotics and resuscitation (as sepsis improves, DIC will resolve)
  • Address specific destructive aetiologies with appropriately targeted therapies, eg.:
    • Plasmapheresis for TTP
    • High dose methylprednisone for MAHA
    • Delivery for HELLP

Maximise platelet production

  • Ensure supply of haematinics is uninterrupted
  • Optimise nutrition, focusing on vitamins and trace elements
  • Withhold or rationalise any drugs which are bone marrow toxins
  • Correct the correctable causes of bone marrow failure and liver disease
  • Think about thrombopoietin receptor agonists (eg. eltrombopag) - some promising results have come from the RAISE trial (Cheng et al, 2010)

Protect the patient from complications of thrombocytopenia

  • Cancel or postpone all nonessential invasive procedures
  • Cover unavoidable procedures with transfusion of pooled platelets (up to a level of 50)
  • For neurosurgical procedures (or lumbar puncture, etc) aim for a level above 100
  • Otherwise, keep the level above 20
    (the above numbers derived from recommendations made by Van der Linden et al, 2012)

References

Stasi, Roberto. "How to approach thrombocytopenia." ASH Education Program Book 2012.1 (2012): 191-197.

UpToDate: Approach to the adult patient with thrombocytopenia.

Casonato, A., et al. "EDTA dependent pseudothrombocytopenia caused by antibodies against the cytoadhesive receptor of platelet gpIIB-IIIA." Journal of clinical pathology 47.7 (1994): 625-630.

Castro, Christine, and Mark Gourley. "Diagnostic testing and interpretation of tests for autoimmunity." Journal of Allergy and Clinical Immunology 125.2 (2010): S238-S247.

Arepally, Gowthami M., and Thomas L. Ortel. "Heparin-induced thrombocytopenia." New England Journal of Medicine 355.8 (2006): 809-817.

Chong, B. H., J. Burgess, and F. Ismail. "The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia." Thrombosis and haemostasis 69.4 (1993): 344-350.

Question 29 - 2015, Paper 2

You are the Intensivist looking after a 30-year-old male, with no significant past medical history, who has been in the Intensive Care Unit for eight days with severe community acquired pneumonia and septic shock.

Although there are no overt signs of bleeding, his haemoglobin has slowly dropped and is now 65 g/L. He has been recommenced on low dose noradrenaline and you have decided to transfuse one unit of packed cells.

His wife has concerns about the “safety” of this and refuses to consent until she speaks to you.

Outline the key points of your discussion with the patient’s wife, including the pros and cons of, and alternatives to blood transfusion in this context.

College Answer

Discussion should cover:

  • Involving patient If competent
  • Ensure wife appropriate patient advocate
  • Listening to and clarifying wife’s concerns including religious / cultural objections
  • Patient’s wishes if known
  • Pros and cons of transfusion in this situation
  • Non-transfusion strategies

Pros:

  • Transfusion at this low threshold is evidence based i.e. consistent with a restrictive approach as advocated by the National Guidelines. Transfusion is probably appropriate given the information available, but is not mandated.
  • Administration of a single unit followed by reassessment is consistent with the National Guidelines. May improve oxygen delivery, enable cessation of noradrenaline, and potentially positively affect
  • organ function and outcomes.
  • Red cell transfusion is safe, with risks of viral transmission (HIV & HCV), CJD and fatal haemolytic reactions being less than 1 in 1 million.

Cons:

  • There is insufficient evidence to suggest that transfusion in this situation will have a positive effect on mortality.
  • This young man is relatively well compensated (although on noradrenaline), not actively bleeding and is unlikely to have significant ischaemic heart disease. Discussions with the family should weigh up the pros and cons of transfusion, and time devoted to hearing and clarifying their worries and concerns.
  • There is some evidence that transfusion is associated with increased rates of VAP and other infections.
  • Real risk of circulatory overload (up to 1 in 100 or Calman rating high), but probably less likely in this patient.
  • Risk of TRALI (said to be 1 in 5000 to 1 in 190000, or low to minimal
  • Anaphylaxis or non-fatal haemolytic reactions (very low)
  • In the event of a blood transfusion being administered, consent will be needed
  • It is also reasonable to wait
  • Set a trigger for transfusion (absolute Hb, clinical parameters) with the family)
  • A second opinion or even a substitute decision maker/legal opinion may need to be sought if clear harm or death is likely to result in the future without transfusion and consent is not likely to be forthcoming.

Non-transfusion strategies should be employed

  • Maximising nutrition
  • Minimising haemodilution
  • Consideration of haematinics / EPO
  • Minimising blood volume for tests by using paediatric tubes etc.
  • Haematology input if necessary.

Calman scale of risk useful in this context:

Negligible (less than 1 in a million or dying of lightning strike)

Minimal, Very low, Low (1 in a thousand to 1 in 10000 or dying in a road accident)

High (>1 in 1000)

Additional Examiners’ Comments:

Candidates were not expected to give this much detail and were given credit for valid points not included in the answer template

Discussion

I love it when they invite you to give less detail.

A "routine transfusion" in this setting is the transfusion which has a "numeric trigger" as opposed to a clinical indication (i.e. the patient is asymptomatic).

Rationale for some sort of strategy

  • Blood products are a scarce resource (and very expensive outside of an Australia-like socialised health care system)
  • Blood products are not without risk; specifically, there is a real nonzero risk of contracting a disabling infectious disease, or developing a life-threatening reaction.
  • Benefits of transfusion of stored red cells are unclear in this "borderline" population
  • Risk of transfusion needs to be weighed against benefit

Arguments in support of routine transfusion to a Hb of >70

  • Transfusion in the developed world is impressively safe.
  • Clinical features of anaemia may be insidious in onset, and it is possible to survive at a dramatically decreased haemoglobin - the argument is that this may not be the best quality of care for critically ill patients.
  • In the critically ill patients, the adverse effects of anaemia may be obscured by the ongoing critical illness.
  • Anaemia increases myocardial oxygen demand and reduced myocardial oxygen supply.
  • There are certain groups of critically ill patients for whom "routine" transfusion to a certain Hb level appears to be well supported by evidemce. These groups include patients with ongoing myocardial ischaemia and those undergoing ECMO.

Arguments against the routine transfusion to a Hb of >70

  • Anaemia with a poor systemic or myocardial oxygen supply/demand relationship is unlikely to be clinically silent (and nobody is arguing against transfusion for clinically significant anaemia)
  • There has never been any mortality benefit show for this practice in the critically ill population (outside of the acute coronary syndrome population)
  • Transfusion of stored cells contributes cells with a diminished oxygen carrying capacity
  • There are situations where exposure to foreign cells is to be avoided at all costs on medical grounds (eg. in patients being worked up for a transplant)

Practical approach to a questionably indicated transfusion

  • Need for consent is unquestioned (if the patient is exsanguinating, different story)
  • Involving the patient, ideally
  • Involving the family, as surrogates- in which case, validity of their involvement should be considered (eg. are these next of kin, or work friends?)
  • Cultural background needs to be considered (eg. Jehovah's Witness)
  • Age needs to be considered (underage? Covered by duty of care? The family may have little recourse, but the patient who is transfused against their will may be excommunicated from the cult).
  • If no cultural or ethical barriers, consider the blood bank may not supply the blood without an indication. Consider that "the haemoglobin's low" is not an indication. Will you manufacture an indication and lie, or will you engage with them on a theoretical level, talking about oxygen carrying capacity of blood and whatnot?

Alternatives to transfusion

Spahn et al (2013) have done an excellent review of this for  Lancet. In summary:

  • Transfuse something not quite blood, or less risky blood
    • Autologous transfusion (eg. pre-banked blood) - though usually the JWs do not go for this option
    • Blood surrogates (largely experimental)
  • Avoidance of blood loss
    • Advanced haemostasis measures intraoperatively, eg. topical haemostatic agents
    • Use of low volume blood tubes
    • Rationalisation of blood tests
  • Support of effected (or supra-normal) erythropoiesis
    • Good nutrition
    • Adequate micronutrients
    • Adequate haematinic vitamins
    • Avoidance of bone marrow toxins
    • Iron infusion
    • Erythropoietin

References

Goodnough, Lawrence T., Jerrold H. Levy, and Michael F. Murphy. "Concepts of blood transfusion in adults." The Lancet 381.9880 (2013): 1845-1854.

Spahn, Donat R., and Lawrence T. Goodnough. "Alternatives to blood transfusion." The Lancet 381.9880 (2013): 1855-1865.

There is also a rescinded document from the NHMRC (2001) which has been used to guide practice: Clinical Practice Guidelines on the Use of Blood Components.

To some extent this document has been superceded by the Australian and New Zealand Society of Blood Transfusion GUIDELINES FOR THE ADMINISTRATION OF BLOOD PRODUCTS.

The Patient Blood Management Guidelines from the National Blood Authority of Australia is another series of documents worth looking at - it contains several important modules which have been reviewed and which act as successors to the 2001 NHMRC guidelines.

Treleaven, Jennie, et al. "Guidelines on the use of irradiated blood components prepared by the British Committee for Standards in Haematology blood transfusion task force." British Journal of Haematology 152.1 (2011): 35-51.

Aoun, Elie, et al. "Transfusion‐associated GVHD: 10 years’ experience at the American University of Beirut—Medical Center." Transfusion 43.12 (2003): 1672-1676.

Heddle, Nancy M., and Morris A. Blajchman. "The leukodepletion of cellular blood products in the prevention of HLA-alloimmunization and refractoriness to allogeneic platelet transfusions [editorial]." Blood 85.3 (1995): 603-606.

Sharma, R. R., and Neelam Marwaha. "Leukoreduced blood components: Advantages and strategies for its implementation in developing countries."Asian journal of transfusion science 4.1 (2010): 3.

Dzik, Walter H. "Leukoreduction of blood components." Current opinion in hematology 9.6 (2002): 521-526.

Corwin, Howard L., and James P. AuBuchon. "Is leukoreduction of blood components for everyone?." JAMA 289.15 (2003): 1993-1995.

Blajchman, M. A. "The clinical benefits of the leukoreduction of blood products."Journal of Trauma-Injury, Infection, and Critical Care 60.6 (2006): S83-S90.

Rosenbaum, Lizabeth, et al. "The reintroduction of nonleukoreduced blood: would patients and clinicians agree?." Transfusion 51.12 (2011): 2739-2743.

Bilgin, Y. M., L. M. van de Watering, and A. Brand. "Clinical effects of leucoreduction of blood transfusions." Neth J Med 69.10 (2011): 441-450.

Australian Red Cross - Blood Service Policy on "The Age of Red Cells"

Hess, John R. "Red cell changes during storage.Transfusion and Apheresis Science 43.1 (2010): 51-59.

Bennett-Guerrero, Elliott, et al. "Evolution of adverse changes in stored RBCs."Proceedings of the National Academy of Sciences 104.43 (2007): 17063-17068.

Hébert, Paul C., et al. "A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care." New England Journal of Medicine340.6 (1999): 409-417.

Carson, Jeffrey L., Paul A. Carless, and Paul C. Hébert. "Outcomes using lower vs higher hemoglobin thresholds for red blood cell transfusion." Jama 309.1 (2013): 83-84.

Lelubre, C., J. L. Vincent, and F. S. Taccone. "Red blood cell transfusion strategies in critically ill patients: lessons from recent randomized clinical studies." Minerva anestesiologica (2016).

Spahn, Donat R., and Lawrence T. Goodnough. "Alternatives to blood transfusion." The Lancet 381.9880 (2013): 1855-1865.

Question 23.3 - 2015, Paper 2

A 70-year-old male presents to the ED with a 2-week history of increasing dyspnoea, cough with altered sputum and fever. Past history includes chronic obstructive airways disease (COPD), lung cancer seven years ago treated with chemotherapy and radiation therapy with no sign of recurrence since.

Examination findings included RR 30 breaths/min, BP 110/70mmHg, HR 145 bpm, Temp 37.4ºC, anxious and distress but tired and peripherally cold and cyanosed.

CXR shows findings consistent with COPD and right lower lobe infiltrate.

The following arterial blood gas is taken one hour after receiving 2 litres of fluid resuscitation, antibiotics and bi-level non-invasive ventilation (NIV), at FiO2 = 1.0.

Parameter

Patient Value

   

Normal Adult Range

FiO2

1.0

       

pH

7.16*

7.35

– 7.45

 

PCO2

33 mmHg* (4.3 kPa)*

35

45 (4.6 – 6.0)

 

PO2

272 mmHg (38.5 kPa)

       

Bicarbonate

11 mmol/L*

22

30

 

Base Excess

-17 mmol/L*

-3 – +3

 

Sodium

138 mmol/L

135 – 145

 

Potassium

4.3 mmol/L

3.5 – 5.0

 

Chloride

121 mmol/L*

95

110

 

Glucose

13.1 mmol/L*

3.5 – 7.8

 

Lactate

6.4 mmol/L*

0.6 – 2.4

 

Haemoglobin

131 g/L*

135 – 175

 

Creatinine

150 micromol/L*

70

120

 

Six hours later the patient remains on NIV, is conscious, reports feeling slightly better, feet remain cyanosed, BP 105/72 mmHg, HR 108 bpm, RR 30 breaths/min, urine output 10 – 20 mL/hr and the following biochemistry profile is obtained:

Parameter

Patient Value

Normal Adult Range

Sodium

139 mmol/L

135 – 145

Potassium

5.5 mmol/L*

3.5 – 5.2

Chloride

110 mmol/L

95

– 110

Bicarbonate

12 mmol/L*

22

– 32

Urea

20.0 mmol/L*

2.7 – 7.8

Creatinine

220 μmol/L*

70

– 120

Estimated glomerular filtration rate (eGFR)

25 mL/min/1.73 m2*

> 90

Anion gap

22 mmol/L*

8 – 18

Total protein

57 g/L*

60

– 80

Albumin

27 g/L*

35

– 50

Total bilirubin

24.9 μmol/L

< 25

Alkaline phosphatase (ALP)

81 IU/L

30

– 110

Alanine transaminase (ALT)

6138 IU/L*

< 65

Aspartate transaminase (AST)

10122 IU/L*

< 50

g-Glutamyl transferase (GGT)

88 IU/L

< 90

C-reactive protein (CRP)

22.5 mg/L*

< 8

The patient’s haematology results are as follows:

Parameter

Patient Value

Normal Adult Range

Haemoglobin

87 g/L*

130 – 180

White cell count

2.1 x 109/L

4 – 11

Platelets

54 x 109/L

140 – 440

International normalised ratio (INR)

2.4

0.8 – 1.2

Activated partial thromboplastin time (APTT)

38 sec*

25 – 35

c)  What is your interpretation of these findings?            (20% marks)

College Answer

c)

Acute anaemia, acute or chronic leucopaenia, acute or chronic thrombocytopaenia, coagulopathy with raised INR

No unifying diagnosis

Acute drop in haemoglobin over 2 hours is most likely due to haemorrhage or massive fluid infusion. Massive haemolysis is less likely given the bilirubin is not raised

Sepsis most likely cause of leucopaenia, thrombocytopaenia and raised INR

Acute liver failure may explain raised INR

Bone marrow failure would explain leucopaenia and thrombocytopaenia if they are chronic.

Any cause of bone marrow failure also accepted.

Discussion

This is the third part of this SAQ. Question 23.1 is an ABG interpretation question, and Question 23.2 is more about the differential diagnosis of deranged LFTs.

The following list of differentials can be reproduced from the pancytopenia chapter:

Differential Diagnosis of Pancytopenia
  • Infectious causes
    • EBV
    • HIV
    • Hep A, B, C
    • Parvovirus
    • CMV
    • Dengue fever
  • Neoplastic causes
    • Leukaemia
    • Marrow involvement from solid tumours
  • Drugs which cause pancytopenia
    • Methyldopa
    • Carbimazole
    • Acetazolamide
    • Chloramphenicol
    • Trimethoprim/sulfamethoxazole
    • Carbamazepine
    • Cytotoxic agents
  • Idiopathic causes
    • Pregnancy (may be a coincidental association)
    • Splenomegaly (sequestration)
    • Anorexia nervosa
    • Malnutrition
    • Myelofibrosis
    • Paroxysmal nocturnal haemoglobinuria
  • Congenital causes
    • Haemophagocytic lymphohistiocytosis
    • Fanconi anaemia
    • Shwachman-Diamond syndrome
  • Autoimmune causes
    • SLE
  • Traumatic causes
    • Radiation toxicity

These are all forms of a "unifying diagnosis" which is perhaps not appropriate here. The college answer seems to tolerate an individual list of differentials for each individual blood test abnormality, rather than expecting the candidates to connect the dots and make a diagnosis of haemophagocytic lymphohistiocytosis or some such. However, the trainees might not be aware of this. Some readers of Deranged Physiology have been in correspondence regarding this matter, and their profanity-laced comments suggest that to have a unifying diagnosis for these sorts of SAQs is one of their expectations. When asked "what is your interpretation of the findings", the correct answer should not be "these findings defy interpretation" or "just about anything, or several things, could be the cause".

References

Question 7.1 - 2016, Paper 1

The following blood results are from a 51 -year-old female who presented with arthralgia, jaundice and dark urine.

Parameter

Patient Value

Normal Adult Ran e

Haemoglobin

68 g/L

115 - 160

White Cell Count

33.1 x 109/L

4.0 — 11.0

Platelets

307 x 109/L

150 - 400

Red Cell Count

2.22 x 1012/L *

3.80 - 4.80

Haematocrit

0.19*

0.37 - 0.47

Mean Cell Volume

88 fL

80 - 100

Mean Cell Haemoglobin

30.7

27.0 - 32.0

Mean Cell Haemoglobin Concentration

350 g/L

320 - 360

Reticulocyes

2.5%*

0.2 - 2.0

Reticulocytes Absolute

56 x 109/L

20 - 130

Comment: The red cells show moderate numbers of spherocytes

Serum Haptoglobins

< 0.10 g/L

0.30 - 2.00

Serum Lactate Dehydrogenase

948 U/L*

140 - 280

Total Protein

69 g/L

60 - 80

Albumin

33 g/L

35 - 50

Globulins

36 g/L

25 - 42

Total Bilirubin

119 mol/L*

< 20

Alanine Aminotransferase

276 U/L*

< 35

Alkaline Phosphatase

120 U/L*

30 - 1 10

Gamma-GlutamyI Transferase

114 U/L*

< 40

Direct Antiglobulin Test:

IgG

Positive

C3d

Positive

a) What is the diagnosis? (20% marks)

b) List three treatment options. (15% marks)

College Answer

a)

  • Warm autoimmune haemolytic anaemia.

b)

  • Corticosteroids
  • IV immunoglobulin
  • Rituximab
  • Splenectomy
  • Danazol
  • Other cytotoxics / immunosuppressants (e.g. cyclophosphamide, azathioprine, cyclosporine)
  • Red cell transfusion

Discussion

a) The only possible answer is autoimmune haemolytic anaemia. Overall, the differential diagnosis of autoimmune haemolytic anaemias looks like this:

Differential Causes of Autoimmune Haemolytic Anaemia
Warm haemolytic anaemia  Cold haemolytic anaemia
  • Idiopathic primary haemolytic anaemia
  • Viral infections, including HIV
  • Drugs, eg. penicillin, methyldopa, 5-FU, diclofenac, etc...
  • Lymhoproliferative disorders:
    • CLL
    • Lymphoma
    • Multiple myeloma
    • Hodgkins lymphoma
    • Waldenstrom's macroglobulinaemia
  • Autoimmune disorders, particularly SLE and rheumatoid arthritis
  • Post-infectious colad agglutinin disease
    • Syphilis
    • Post-viral
    • Mycoplasma pneumoniae
    • EBV, VZV, CMV, HIV
    • Adenovirus
    • Influenza viruses
  • Paroxysmal cold haemoglobinuria
    • Idiopathic
    • Virus-associated (EBV, CMV, etc)

In this scenario, the patient probably has one of the warm haemolytic anaemias, because both the IgG and C3d were found coating the red cells (IgM and C3d are found in cold haemolysis). The WCC is raised suggestive of a lymphoproliferative disorder as the cause. Arthralia may be due to some sort of autoimmune disease (SLE or RA), or it may be a subtle hint that the patient has been taking diclofenac to soothe her aching joints (which is a drug known to cause warm autoimmune haemolysis).

b)

Generic management of warm autoimmune haemolytic anaemia could have included any three of the following options:

  • Corticosteroids appear to be effective as the first-line treatment. Among other thngs, the steroids reduce the synthesis of autoantibodies by B-cells.
  • Splenectomy is the second-line treatment. The spleen's macrophages are responsible for removing IgG-coated RBCs; also the spleen is a site of antibody production.
  • Cyclophosphamide / azathioprine  are reserved for those who fail steroids and splenctomy (or cannot have a splenectomy).
  • IV immunoglobulin is not strongly indicated: some reports show benefit, others don't.
  • Plasmapheresis is only indicated in fulminant acute haemolysis. Only a temporary improvement is to be expected, as this treatment does nothing to treat the underlying autoantibody production.
  • Rituximab, a CD20 monoclonal antibody, has been effective in cases of cold haemolytic anaemia where a B-cell dominant lymphoproliferative disorder is at fault. It seems to be more effective in warm haemolysis.
  • Eculizumab, a terminal complement inhibitor (monoclonal C5 antibody) has been found effective in various case reports (eg. Kim et al, 2016), even though it is indicated only for atypical HUS and paroxysmal nocturnal haemolobinuria.
  • Danazol, a synthetic steroid derivative of ethisterone, is very old school (Pignon et al, 1993) - it is usually used for endometriosis.

References

Zeerleder, S. "Autoimmune haemolytic anaemia-a practical guide to cope with a diagnostic and therapeutic challenge." Neth J Med 69.4 (2011): 177-84.

Gehrs, Bradley C., and Richard C. Friedberg. "Autoimmune hemolytic anemia."American journal of hematology 69.4 (2002): 258-271.

Birgens, Henrik, et al. "A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia." British journal of haematology 163.3 (2013): 393-399.

Lechner, Klaus, and Ulrich Jäger. "How I treat autoimmune hemolytic anemias in adults." Blood 116.11 (2010): 1831-1838.

Salama, A., and B. Mayer. "Diagnostic pitfalls of drug-induced immune hemolytic anemia." Immunohematology 30.2 (2014): 80-4.

Zantek, Nicole D., et al. "The direct antiglobulin test: a critical step in the evaluation of hemolysis." American journal of hematology 87.7 (2012): 707-709.

Ma, Kim, and Stephen Caplan. "Refractory IgG Warm Autoimmune Hemolytic Anemia Treated with Eculizumab: A Novel Application of Anticomplement Therapy." Case reports in hematology 2016 (2016).

Pignon, Jean‐Michel, Emmanuelle Poirson, and Henri Rochant. "Danazol in autoimmune haemolytic anaemia." British journal of haematology 83.2 (1993): 343-345.

Question 7.2 - 2016, Paper 1

A 33-year-old male who is 4 weeks after gunshot wounds to his chest and abdomen has the following report on his blood film:

  • Moderate anisocytosis.
  • Moderate polychromasia.
  • Occasional Howell-Jolly bodies.
  • Increased rouleaux formation.

a) What is meant by the term 'polychromasia' and what is its significance? (10% marks)

b) What are Howell-Jolly bodies, and what is their significance?  (15% marks)

c) List two other features you might expect to see on the blood picture of a patient with Howell-Jolly bodies. (10% marks)

College Answer

a)

  • Variation in RBC colour due to immature forms. Consistent with bone marrow stimulation.

b)

  • Residual nuclear remnants in red cells that have not been removed the spleen.
  • Usually indicates hypofunctional or absent spleen – presumably secondary to the trauma. (Occasionally seen in haemolysis or megaloblastic anaemia)

c)

  • Any two of:
    • Heinz bodies
    • target cells
    • siderocytes
    • poikilocytosis
    • acanthocytes
    • spherocytes
    • Pappenheimer bodies

Discussion

a)

Polychromasia is another one of those morphological RBC abnormalities which the college love so much. It is an abnormally large raneg of colour variation among the (usually, red) erythrotcytes. It indicates  the presence of an increased number of morphologically immature RBCs which have RNA inside them (and which therefore stain grey-blue with the giemsa stain). The stolen image below has helpful arrows pointing at them.

These cells are significant, because they represent either increased bone marrow stress or a failure of normal regulatory mechanisms responsible for "quality control" of erythrocytes.  

Possible causes of polychromasia include:

  • Response to red cell loss by normal marrow:
    • Haemorrhage
    • Haemolysis
  • Recovery of normal marrow function
    • Iron infusion
    • Vitamin B12 replacement
    • Erythropoietin injection
    • Recovery following chemotherapy
  • Failure of bone marrow to sustain normal function
    • Myelofibrosis
    • Malignant marrow infiltration
  • Failure of RBC quality control
    • Splenectomy

b)

Howell-Jolly bodies are bits of lefteover DNA in the erythrocytes. Normally, the spleen would view these as defective, and they would be removed. They are typically seen in patients who have had a splenectomy.

Other associations include the following conditions:

  • Pernicious anaemia
  • Macrocytosis of any cause
  • Corticosteroid use

c)

In this patient, splenectomy is the most likely common unifying diagnosis. There is a history of trauma to a vaguely spleeny area, and he has rouleaux (which suggest he may have post-splenectomy thrombocytosis). This question therefore resembles Question 18 from the second paper of 2007, which asked for the features of a post-splenectomy blood film.

The typical post-splenectomy blood film abnormalities are as follows:

  • Howel-Jolly bodies
  • Anisocytosis
  • Thrombocytosis
  • Acanthocytosis
  • Target cells
  • Pappenheimer bodies
  • Platelet aggregates

References

Davidson, E. "The significance of blue polychromasia." Journal of clinical pathology 12.4 (1959): 322.

Ponder, Eric. "On sedimentation and rouleaux formation-I." Experimental Physiology 15.3 (1925): 235-252.

Walker, H. Kenneth, et al. "Peripheral blood smear." (1990). in Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition.

Question 7.3 - 2016, Paper 1

 73-year-old female with a background of rheumatoid arthritis has been admitted to your ICU with a history of acute shortness of breath and a fluctuating conscious state. She has been having severe headaches for the last three weeks.

The following investigations were obtained:

Parameter

Patient Value

Normal Adult Ran e

Haemoglobin

76

1 15 - 160

White Cell Count

23.8 x 10

4.0 - 1 1.0

Platelets

198 x 10 IL

150 - 450

Blood Film

2% Plasma cells and rolueaux formation

Parameter

Patient Value

Normal Adult Range

Sodium

137 mmol/L

135 - 145

Potassium

4.3 mmol/L

3.2 -4.5

Chloride

106 mmol/L

100 - 1 10

Bicarbonate

25 mmol/L

22 - 27

Urea

15.0 mmol/L*

3.0 - 8.0

Creatinine

280 umol/L*

70 - 120

Total Calcium

2.75 mmol/L*

2.15 - 2.60

Phosphate

1.3 mmol/L

0.7 — 1.4

Albumin

26 g/L*

33 — 47

Globulins

92.3 g/L*

25 — 45

a) Give the diagnosis. (20% marks)

b) What urgent treatment is indicated? (10% marks)

College Answer

a)

  • Hyperviscosity syndrome secondary to multiple myeloma.

b)

  • Plasmapheresis.

Discussion

a)

This looks like a hyperviscosity syndrome due to hypergammaglobulinaemia, a complication of Waldenström's macroglobulinemia or (less likely) multiple myeloma or plasmacytoma.

Features of this presentation which suggest hyperviscosity:

  • Acute shortness of breath, which suggests heart failure
  • A fluctuating conscious state, which suggests cerebrovascular disease
  • Severe headaches,  which suggests cerebrovascular disease
  • Leukocytosis, which suggests haematological malignancy
  • An elevated globulin level
  • An elevated plasma cell count, which suggests plasmacytoma or Waldenström's macroglobulinemia

Other clinical features of symptomatic hyperviscosity include:

  • Constitutional symptoms: fatigue, malaise, and shortness of breath.
  • Haemorrhagic symptoms:  gingival or mucosal bleeding, or epistaxis.
  • Blurred vision due to central retinal vein occlusion
  • Headaches due to increased intracranial pressure (due to venous occlusion)
  • Fundoscopy reveals dilated, tortuous retinal veins, as well as flame-shaped haemorrhages.
  • Stroke, seizures, coma (usually, venous cerebral infarction)
  • Renal failure
  • Aggravated heart failure (more difficult to pump the viscous blood)
  • Priapism

Even though multiple myeloma is quoted by the college, Waldenström's macroglobulinemia is the disorder where clinically significant hyperviscosity occurs most frequently, according to this article by Mehta et al (2003). This is because Waldenström's macroglobulinemia is characterised by the excess production of IgM, which is a massive molecule. However, numerous other causes of plasmacytosis exist:

  • MGUS
  • Multiple myeloma
  • Waldenström's macroglobulinemia
  • Solitary plasmacytoma
  • Systemic AL amyloidosis
  • POEMS syndrome
  • Adenocarcinoma of the colon
  • Pulmonary tuberculosis
  • Cirrhosis of the liver
  • Aplastic anaemia
  • Syphilis
  • Leprosy
  • Varicella zoster infection
  • Serum sickness
  • Primary infection and reactivation of Epstein–Barr virus
  • Acute respiratory infections
  • Parvovirus B19 infection
  • Rubella
  • Hepatitis virus A infection

b) Plasmapheresis is the usual urgent treatment for this. You centrifuge away the monoclonal badness and replace with nice clean albumin.

References

Mehta, Jayesh, and Seema Singhal. "Hyperviscosity syndrome in plasma cell dyscrasias." Seminars in thrombosis and hemostasis. Vol. 29. No. 05. Copyright© 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.:+ 1 (212) 584-4662, 2003.

Question 3.1 - 2016, Paper 2

A 62-year-old male has been admitted to your ICU for routine post-operative monitoring after a vascular
surgical procedure.
His pre-operative full blood count is displayed below:

Parameter

Patient Value

Normal Adult Range

Haemoglobin

125 q/L*

130 - 180

White Cell Count

7.4 x 10 /L

4.5 - 11.0

Platelets

255 x 10 /L

150 - 400

Mean Cell Volume

110 fl*

80 - 98

Mean Cell Haemoqlobin

30 oa/cell

27 - 33

Mean Cell Haemoglobin Concentration

320 g/L

310 - 360

Give six possible causes for the findings on his full blood count. (20% marks)

College answer

Liver disease (including alcoholism)

Folate deficiency B12 deficiency

Hypothyroidism

Myelodysplasia

Drug related (one example required for mark – methotrexate, AZT, trimethoprim, phenytoin, some chemotherapeutic agents, cyclophosphamide. Multiple examples do not gain more marks)

Reticulocytosis

Familial

Discussion

This is macrocytosis, defined as a mean corpuscular volume (MCV) of over 100fl.

There are several common causes:

  • Alcoholism
  • Vitamin B12 deficiency
  • Folate deficiency
  • Myelodysplastic syndromes

There are also a few uncommon causes:

  • Reticulocytosis
  • Nonalcoholic and alcoholic liver disease
  • Hypothyroidism
  • Multiple myeloma
  • Aplastic anemia
  • Acute leukemia
  • Drugs:
    • trimethoprim, triamterine, nitrous oxide, phenytoin, valproate, chemotherapy agents, HIV antiretrovirals and metformin.

One can find a discussion of the many causes of macrocytosis in the 2006 article by Aslinia et al.

References

Aslinia, Florence, Joseph J. Mazza, and Steven H. Yale. "Megaloblastic anemia and other causes of macrocytosis." Clinical medicine & research 4.3 (2006): 236-241.

Question 3.2 - 2016, Paper 2

Inspect the following full blood count:

Parameter

Patient Value

Normal Adult Range

Haemoqlobin

96 q/L*

130 - 175

White Cell Count

17.4 x 10 /L*

4.0 - 11.0

Platelets

168 x 109/L

150 - 450

Neutrophils

12.4 x 10 /L*

1.8 - 7.5

Lymphocytes

2.06 x 10 /L

1.50 - 4.00

Monocytes

0.5 x 10 /L

0.2 - 0.8

Eosinophils

0.3 x 10/L

0.0 - 0.4

Film: Circulating nucleated red blood cells, immature granulocytes and band forms observed.

a)    What is the term used to describe these findings on a blood film?    (20% marks)

b)    Give four possible reasons these findings may be observed in a critically ill patient.
(20% marks)

College answer

  1. Leucoerythroblastic anaemia/reaction                                                                  
  1.  
  • Sepsis
  • Trauma
  • Any marrow infiltrative process, carcinomas, myeloproliferative disorders
  • Rebound following bone marrow failure or suppression      

Discussion

The key findings are anaemia, nucleated red cells, immature granulocytes and band forms.

These abnormalities can be described as a  "leukoerythroblastic" blood film picture

In summary, the possible causes of leukoerythroblastosis are:

  • Bone marrow inflitration ("myelophthisis")
    • Leukaemia
    • Myelofibrosis
    • Solid tumour infiltration, eg. breast cancer
    • Miliary tuberculosis
  • Extramedullary haematopoiesis
  • States of widespread bone marrow activation
    • Sepsis
    • Inflammatory states, eg. autoimmune disease
    • Severe haemorrhage or haemolysis
    • Use of GM-CSF
    • Marrow recovery following marrow suppression
  • Exotic stuff
    • Still disease
    • Gaucher's disease
    • Myocardial infarction
    • Chronic lung diseases

References

Shamdas, Glenn J., et al. "Leukoerythroblastic anemia in metastatic prostate cancer. Clinical and prognostic significance in patients with hormone‐refractory disease." Cancer 71.11 (1993): 3594-3600.

Weick, J. K., A. B. Hagedorn, and J. W. Linman. "Leukoerythroblastosis. Diagnostic and prognostic significance." Mayo Clinic Proceedings. Vol. 49. No. 2. 1974.

Question 22.1 - 2016, Paper 2

A 56-year-old male presents with one-month history of weight loss and shortness of breath.

The results of his blood tests are as follows:

Parameter

Patient Value

Normal Adult Range

Haemoglobin

128g/L*

135 - 180

White Cell Count

6.1 x 109/L

4.0 - 11.0

Platelets

35 x 10l;l/L*

150 - 400

Prothrombin time

23.3 sec*

12.0 - 16.5

International normalised ratio

2.0*

0.9 - 1.3

Activated partial thrombop lastin time

45.7 sec*

27.0 - 38.5

Fibrinoqen

0.7 q/L*

2.0 - 4.0

Total Protein

39 a/L*

60 - 80

Albumin

24 q/L*

35 - 50

Total Bilirubin

215 umol/L*

< 20

Alanine  aminotransferase

202 U/L*

< 40

Alkaline phosphatase

243 U/L*

30 - 110

y-Glutamvl transferase

394 U/L*

< 60

Ferritin

120000 ua/L*

30 - 620

Iron

15 µmol/L

9 - 30

Transferrin

13 µmol/L*

23 - 43

Transferrin saturation

58%*

14 - 45

a) Give the diagnosis indicated by these results. (20% marks)

b) Give three possible underlying causes. (15% marks)

College answer

a)    Haemophagocytic lymphohistiocytosis (HLH)                     
 
b)    Viral infection e.g. EBV, HSV, HINI influenza                          
Lymphoma 
Malignancy 
Immune deficiency states 
Rheumatological disorders 
Other infection – bacterial and fungal less likely 
 

Discussion

a)

The only thing ever to produce a serum ferritin level of 120, 000? Surely, the college wanted to hear "haemophagocytic syndrome", but there are a variety of possibilites:

  • Malignancy
  • Iron overload syndromes
    • Hereditary haemochromatosis
  • Adult-onset Still's disease
  • Systemic juvenile idiopathic arthritis
  • Haemophagocytic lymphohistiocytosis
  • Chronic inflammatory rheumatological diseases
  • Chronically transfused disease states
    • Sickle cell
    • Thalassaemia
  • Acute inflammatory states:
    • Sepsis
  • Chronic inflammatory states:
    • Chronic advanced liver disease (mainly alcohol-related)
    • Chronic renal failure
    • HIV

b)

Causes of haemophagocytic syndrome:

Congenital:

  • familial HLH (FHLH)
  • Chediak-Higashi syndrome (CHS 1)
  • Griscelli syndrome (GS 2)
  • X-linked proliferative syndrome (XLP)
  • The UpToDate article has whole pages listing obscure-sounding loci of mutation.

Acquired causes

  • Infectious
    • EBV
    • CMV
    • HIV
    • Leishmania
  • Neoplastic
    • Lymphoma, especially T and NK-cell
  • Autoimmune
    • SLE
    • Kawasaki disease

References

Moore Jr, Charles, Michelle Ormseth, and Howard Fuchs. "Causes and significance of markedly elevated serum ferritin levels in an academic medical center." JCR: Journal of Clinical Rheumatology 19.6 (2013): 324-328.

Lee, Mark H., and Robert T. Means. "Extremely elevated serum ferritin levels in a university hospital: associated diseases and clinical significance." The American journal of medicine 98.6 (1995): 566-571.

Hearnshaw, Sarah, Nick Paul Thompson, and Andrew McGill. "The epidemiology of hyperferritinaemia." World journal of gastroenterology 12.36 (2006): 5866. - ! WARNING ! this link will download the whole September issue, with the potential to fatally clog your internet hole.

Janka, Gritta E. "Hemophagocytic syndromes." Blood reviews 21.5 (2007): 245-253.

Question 22.2 - 2016, Paper 2

A 52-year-old female presents with bruising and a retroperitoneal haematoma five weeks after starting warfarin for a proximal deep vein thrombosis (DVT) with a target international normalised ratio (INR) of 2.5.

Her investigations are as follows:

Parameter

Patient Value

Normal Adult Range

Haemoglobin White Cell Count

122 q/L*

135 - 180

10.1 x 109/L

4.0 - 11.0

Platelets

298 x 109/L

150 - 400

Prothrombin time

29.3 sec*

12.0 - 16.5

International normalised ratio

2.3*

0.9 - 1.3

Activated partial thromboplastin time

117.0 sec*

27.0 - 38.5

Fibrinogen

3.9 a/L

2.0 - 4.0

a) Give the likely underlying cause for this coagulation profile. (20% marks)

b) Give a test you could do to confirm this. (15% marks)

College answer

a)    Factor deficiency  - either VIII, IX, XI or XII                          
 
b)    
Mixing study (patient plasma mixed with normal plasma 1:1 should show correction of APTT if case of factor deficiency). 
Factor levels. 
 

Discussion

a)

This patient has an appropriate therapeutic INR, and an unexplains raised APTT.  The college asks for the "likely underlying cause", as if there was only one possibility.

Causes of raised APTT are in fact numerous, and can be divided into factor deficiencies and factor inhibitors:

  • Anticoagulant factor:
    • Normal TT and RT:
      • antiphospholipid antibodies
    • High TT, normal RT:
      • Heparin therapy (heparinase assay)
      • heparin-like anticoaguants (malignancy)
    • High TT, high RT:
      • Low fibrinogen
      • Abnormal fibrinogen
      • Paraproteinaemia
      • Excessive fibrin degradation products
      • Amyloidosis
  • Factor deficiency
    • von Willebrand's disease (de facto Factor 8 deficiency)
    • Factor 8 deficiency (Haemophilia A)
    • Factor 9 deficiency (Haemophilia B)
    • Factor 11 deficiency (Haemophilia C, 8% of Ashkenazi Jews)
    • Factor 12 deficiency (which is freakishly rare, and usually totally asymptomatic)

This patient has no reported history of lupus, but this whole history of a proximal DVT raises the possibility of antiphospholipid syndrome, which could result in a raised APTT with a relatively normal warfarinised PT.

Alternatively, one could make the conceptual leap and discuss direct thrombin inhibitor toxicity (as these might have been used to manage the DVT instead of warfarin).

b)

The ideal test would be a mixing study (to discriminate between the abovelisted differentials). However, the college did not want that- they asked for a test to "confirm the diagnosis" .

So:

  • If you thought about antiphospholipid syndrome, a lupus anticagulant should be sent.
  • If you bet on direct thrombin inhibitors, a thrombin time (TT) would be appropriate
  • In most sane scenarios, a mixing study would be done.
  • In a resource-rich environment, one could test the actual factor levels.

References

Hunt, Beverley J. "Bleeding and coagulopathies in critical care." New England Journal of Medicine 370.9 (2014): 847-859.

Kamal, Arif H., Ayalew Tefferi, and Rajiv K. Pruthi. "How to interpret and pursue an abnormal prothrombin time, activated partial thromboplastin time, and bleeding time in adults." Mayo Clinic Proceedings. Vol. 82. No. 7. Elsevier, 2007.

Question 22.3 - 2016, Paper 2

A 49-year-old female presents with confusion. The results of her blood tests are as follows:

Parameter

Patient Value

Normal Adult Range

Haemoglobin

86 q/L*

135 - 180

White Cell Count

11.2 x 109/L*

4.0 - 11.0

Platelets

23 x 109/L*

150 - 400

Prothrombin time

14.0 sec

12.0 - 16.5

Activated partial thromboplastin time

35.0 sec

27.0 - 38.5

Fibrinogen

2.1 q/L

2.0 - 4.0

Thrombin time

14.0 sec*

11.5 - 13.5

Urea

12.1 mmol/L*

3.0 - 8.0

Creatinine

356 µmol/L*

45 - 90

Lactate  dehydrogenase

2342 U/L*

140 - 280

a) Give the likely diagnosis. (20% marks)

b) Give an additional test to support your diagnosis. (10% marks)

College answer

a)    Thrombotic thrombocytopaenic purpura                      
Haemolytic-uraemic syndrome 
Systemic lupus erythromatosis 
MAHA (1 mark only) 
 
b)    ADAMTS13 (TTP)                                     
Positive Shiga toxin / Entero-haemorrhagic E coli test (HUS)  
ANA / anti-dsDNA (SLE)  
Blood film 
Reticulocyte count 
Haptoglobins 
 

Discussion

a)

The diagnosis of TTP/HUS suggests itself, even though the "pentad" of symptoms is incomplete:

  • Thrombocytopenia is present
  • Microangiopathic hemolytic anemia is suggested by the LDH ad low haemoglobin
  • Neurologic abnormalities are present
  • Renal failure is present
  • Fever is absent

The low-ish fibrinogen suggests that a TTP-related excess of vWF has produced a systemic prothrombotic state, with microvascular thrombosis consuming all the fibrinogen.

b)

ADAMTS-13 level is of course the most important supportive test. The relevanc of this protein is discussed in the chapter on TTP/HUS.

References

George, James N. "Thrombotic thrombocytopenic purpura." New England Journal of Medicine 354.18 (2006): 1927-1935.

Question 9.2 - 2017, Paper 1

The following blood results were obtained from a previously fit and well patient undergoing a prolonged respiratory wean following an episode of severe community acquired pneumonia one month earlier.

Parameter

Patient Value

Adult Normal Range

Haemoglobin

78 g/l

115- 155

Haematocrit

0.20

0.35 - 0.45

Mean Cell Volume

85 fL

80-99

Mean Cell Haemoglobin

28 pg

27 - 33

White Cell Count

15.3 X 10

4.0 - 11.0

Neutrophils

120 x 109/L

1.9 -7.5

Platelets

758 x

150 - 400

Reticulocyte count

40 x IO9/L

30- 130

Iron

8 mmol/L•

10-30

Ferritin

798

20 - 450

Transferrin saturation

0.10

0.15 - 0.50

Vitamin BIZ

700 pmol/L

200 - 900

Folate

1 5 nmol/L

C-reactive rotein

210

Albumin

25

35 - 50

Interpret the abnormal results and justify your reasoning.   (40% marks)

College answer

Normochromic normocytic anaemia of chronic disease with on-going inflammation NOT Fe deficiency anaemia because:

  • Normochromic normocytic anaemia
  • Low Fe
  • Transferrin saturation mildly reduced
  • Raised ferritin
  • Raised CRP (inflammatory state)

Discussion

The abnormalities are as follows:

  • Anaemia, which is normocytic and normochromic
  • Raised CRP, WCC, neutrophil count and platelet count, suggesting an inflammatory response
  • Low serum iron
  • High serum ferritin (it is an acute phase reactant)
  • Normal levels of haematinic vitamins.
  • Low reticulocyte count, suggesting depressed bone marrow function. In this case the college give you an absolute reticulocyte count, which actually needs to be corrected for the severity of anaemia. The corrected reticulocyte count is adjusted by the haematocrit (it is assumed that the maturation time of circulating reticulocytes is related to the haematocrit), i.e. with a haematocrit of 0.20 the maturation time is 2 days. Thus the corrected reticulocyte count is actually low (40,000/2 = 20,000). 

This is consistent with an anaemia of chronic disease, which is usually a microcytic hypochromic affair (i.e MCV and MCH is usually lower in those cases). The reticulocyte count is typically low, which indicates underproduction of red cells. This comes from the review article by Weiss and Goodnough (NEJM, 2005)

For each of these "interpret iron studies" questions, this table ends up in the discussion section:

Interpretation of Abnormal Iron Studies
Condition MCV MCHC Serum iron Ferritin Transferrin Transferrin
saturation
TIBC
Iron deficiency anaemia low low low low high <20% high
Anaemia of chronic disease low low low normal low normal low or normal
Acute phase response normal normal low high low low low
Iron overload normal normal high high normal high high

References

Hawkins, Stephen F., and Quentin A. Hill. "Diagnostic Approach to Anaemia in Critical Care." Haematology in Critical Care: A Practical Handbook (2014): 1-8.

IRON STUDIES STANDARDISED REPORTING PROTOCOL - RCPA, 2013

Hearnshaw, Sarah, Nick Paul Thompson, and Andrew McGill. "The epidemiology of hyperferritinaemia." World journal of gastroenterology 12.36 (2006): 5866. - ! WARNING ! this link will download the whole September issue, with the potential to fatally clog your internet hole.

Janka, Gritta E. "Hemophagocytic syndromes." Blood reviews 21.5 (2007): 245-253.

Weiss, Guenter, and Lawrence T. Goodnough. "Anemia of chronic disease." New England Journal of Medicine 352.10 (2005): 1011-1023.

Koepke, J. F., & Koepke, J. A. (1986). Reticulocytes. Clinical & Laboratory Haematology, 8(3), 169–179.

Question 30.3 - 2017, Paper 1

List six causes of hepato-splenomegaly.                (30% marks)

College answer

• Chronic liver disease with portal hypertension
• Viral infections e.g. viral hepatitis, EBV
• Myeloproliferative disease e.g. myelofibrosis
• Lymphoma
• Leukaemia
• Pernicious anaemia
• Amyloidosis
• Malaria
• Sarcoidosis
• Acromegaly
• Thyrotoxicosis
• SLE
• Metabolic storage disease
• Obesity
• Kala-Azar (visceral leischmaniasis)

Discussion

Massive splenomegaly is also discussed in Question 24.3 from the first paper of 2009, but that time there was nothing hepato about it. 

The lists of causes for hepatosplenomegaly and massive splenomegaly are actually quite similar. Here they are side by side:

Causes of Massive splenomegaly and Hepato-Splenomegaly
Causes common to  both
Massive splenomegaly Hepato-splenomegaly
  • Kala-Azar (visceral leischmaniasis)
  • Malaria
  • Myelofibrosis
  • Sarcoidosis
  • Amyloidosis
  • Chronic myeloid leukaemia (CML)
  • Lymphoma
  • Chronic liver disease
  • Kala-Azar (visceral leischmaniasis)
  • Malaria
  • Myelofibrosis
  • Sarcoidosis
  • Amyloidosis
  • Chronic myeloid leukaemia (CML)
  • Lymphoma
  • Chronic liver disease 
Causes unique to one or the other:
  • Pernicious anaemia
  • Acromegaly
  • Thyrotoxicosis
  • SLE
  • Metabolic storage disease
  • Obesity
  • Viral infections, eg. EBV

References

Luo, Esther J., and Lee Levitt. "Massive splenomegaly." Hospital Physician 31 (2008).

Hoffbrand's Essential Haematolgy has a table with the causes of splenomegaly in chapter 10.

Johnson, H. A., and R. A. Deterling. "Massive splenomegaly." Surgery, gynecology & obstetrics 168.2 (1989): 131-137.

Poulin, E. C., J. Mamazza, and C. M. Schlachta. "Splenic artery embolization before laparoscopic splenectomy." Surgical endoscopy 12.6 (1998): 870-875.

Bedu-Addo, George, and Imelda Bates. "Causes of massive tropical splenomegaly in Ghana." The Lancet 360.9331 (2002): 449-454.

Raje, Noopur, and Judith A. Ferry. "Case 27-2001: A 50-Year-Old Man with Marked Splenomegaly and Anemia." New England Journal of Medicine 345.9 (2001): 682-687.

Wyler, David J., and Anthony R. Mattia. "Case 11-1994: A 35-Year-Old Ethiopian Man with Splenomegaly and Recurrent Fever." New England Journal of Medicine 330.11 (1994): 775-781.

Vick, Eric J., et al. "Proliferation through activation: hemophagocytic lymphohistiocytosis in hematologic malignancy." Blood advances 1.12 (2017): 779-791.

Question 9.1 - 2017, Paper 2

A 74 year old female has been admitted to your ICU with urosepsis. She is previously well with no previous hospital admissions. She was commenced on prophylactic subcutaneous heparin on day one of her admission and the following blood results were obtained:

Parameter         Patient Value                     Adult  Normal Range
Haemoglobin       10.1 g/L*   9.8 g/L*     9.6 g/L*       120.0 - 160.0
White Cell Count       18.4 x 109/L* 14.2 x 109/L* 10.5 x 109/L   4.0 - 11.0  
Platelet count       120 x 109/L* 101 x 109/L*   88 x 109/L*     150 - 350  

On day three, one of your trainees performs a "HITTS screen" which is reported as positive. The patient has remained clinically stable.
 
Describe your approach to this situation and give a rationale.                                              
(70% marks)

College answer

Probability of HITTS is low due to:

Timing of onset is too fast with no history of previous exposure

The platelet fall is not greater than 50%

There is no associated thrombosis or skin necrosis

There is a likely alternative cause – sepsis

The HITTS ELISA test has is not very specific and may give false positives

Therefore:

Reasonable to stop heparin in short term (although not mandatory)

No requirement for commencing alternatives

Could repeat test in short term

More accurate test (SRA- serotonin release test) not likely to be immediately available but will guide future management

Discussion

Let's reason through this:

  • The patient has not had any heparin exposure in the last 90 days, so it's probably not the "rapid onset" HIT syndrome
  • The patient has not been on heparin for the 5-10 days that it would usually take to develop the syndrome, so the timing is off
  • The platelets have not fallen by the official 30% threshold (as 88 is 73% of 120)
  • There's no mention of any thrombosis
  • There's urosepsis, severe enough to come to ICU - which is a good explanation for the drop in platekets

So, the "4T" score is in fact 0. That's associated with the lowest possible pre-test probability for HIT.
(Here is the scoring system in case the reasoning above does not make sense)

4T score from Greinacher, 2015

The positive ELISA test for anti-PF4 antibodies is meaningless, because is screening studies only 2-15% of all positive patients went on to develop any sort of clinically significant HIT.

 So, the approach to this situation would be:

  • Continue the prophylactic heparin 
  • Ignore the test result
  • Continue to monitor the platelet count
  • Re-educate the trainee by referring them to the excellent NEJM article by Andreas Greinacher (2015). Somebody needs to have a word with them. Those tests aren't cheap. The serotonin functional assay and HIT ELISA together cost $194 in 2011-era Canadian money.

References

Arepally, Gowthami M., and Thomas L. Ortel. "Heparin-induced thrombocytopenia." New England Journal of Medicine 355.8 (2006): 809-817.

Patel, Vipul P., Matthew Bong, and Paul E. Di Cesare. "Heparin-induced thrombocytopenia and thrombosis." AMERICAN JOURNAL OF ORTHOPEDICS-BELLE MEAD- 36.5 (2007): 255.

Greinacher, Andreas. "Heparin-induced thrombocytopenia." New England Journal of Medicine 373.3 (2015): 252-261.

Greinacher, A., I. Michels, and C. Mueller-"Heparin-associated thrombocytopenia: the antibody is not heparin specific."Eckhardt. "Heparin-associated thrombocytopenia: the antibody is not heparin specific." Thrombosis and haemostasis 67.5 (1992): 545-549.

Pravinkumar, Egbert, and Nigel Robert Webster. "HIT/HITT and alternative anticoagulation: current concepts." British journal of anaesthesia 90.5 (2003): 676-685.

Nanwa, Natasha, et al. "The direct medical costs associated with suspected heparin-induced thrombocytopenia.Pharmacoeconomics 29.6 (2011): 511-520

Kelton, John G., and Theodore E. Warkentin. "Heparin-induced thrombocytopenia: a historical perspective." Blood 112.7 (2008): 2607-2616.

Wartekin, T. E., B. H. Chong, and A. Greinacher. "Heparin-induced thrombocytopenia: towards consensus." Thromb Haemostas 79 (1998): 1-7.

Warkentin, Theodore E. "Heparin‐induced thrombocytopenia: pathogenesis and management." British journal of haematology121.4 (2003): 535-555.

Visentin, Gian Paolo, Chao Yan Liu, and Richard H. Aster. "Molecular immunopathogenesis of Heparin-induced thrombocytopenia.Heparin-induced Thrombocytopenia. New York: Marcel Dekker (2004): 179-196.

Lo, G. K., et al. "Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin‐induced thrombocytopenia in two clinical settings." Journal of Thrombosis and Haemostasis 4.4 (2006): 759-765.

Warkentin, Theodore E., et al. "Impact of the patient population on the risk for heparin-induced thrombocytopenia." Blood 96.5 (2000): 1703-1708.

Question 9.2 - 2017, Paper 2

A 45-year-old male was admitted with life threatening shock after being involved in a motor vehicle accident, requiring emergency surgery with large volume blood loss. Post-operatively following return to ICU, he was noted to become hypotensive, febrile and oozy from various drip and operative sites. Red urine was noted. 

The following blood results were obtained: 

Parameter               Patient Value         Adult Normal Range
Haemoglobin             87 g/L*             120 - 160
White Cell Count             18.9 x 109/L*           4.0 - 11.0  
Platelet count             132 x 109/L*          150 - 350  
                                           
Sodium               138 mmol/L           135 - 145  
Potassium               4.3 mmol/L           3.5 - 5.0    
Chloride               102 mmol/L           95 - 105    
Bicarbonate             20.0 mmol/L*           22.0 - 26.0  
Glucose               5.3 mmol/L       .       3.5 - 6.0    
Urea               15.2 mmol/L*           3.0 - 8.0    
Creatinine               80 µmol/L           45 - 90    
Creatinine Kinase             2000 U/L*           55 - 170    

Urine Myoglobin: trace

Urine Haemoglobin: ++

Based on his clinical history and the lab report (shown on page 7), what is the likely cause of his post-operative deterioration? How will you confirm your diagnosis?          

(30% marks)


 

College answer

Mismatched transfusion.

Check patient’s and donor groups and re check cross match.

Discussion

A systematic discussion of the results:

  • There is anaemia
  • The WCC is raised, consistent with ..something going on.
  • There is thrombocytopenia, which is not particularly severe
  • The electrolyte biochemistry is relatively normal, albeit with a mild acidosis
  • The urea is slightly deranged, which may be accounted for by the hypercatabolic response to trauma or dehydration intraoperatively
  • The CK is raised appropriately, given that there has been extensive muscle damage; however this level would not support the diagnosis of rhabdoimyolysis
  • The urinary myoglobin is low, which also suggests that there is no rhabdomyolysis
  • The urinary haemoglobin is high, which may demonstrate that there is intravascular haemolysis. Depending on the type of testing, this sort of result could also be produced by haematuria (i.e. the test may not discriminate between intact red cells and liberated haemoglobin)

Overall everything points to an acute haemolytic transfusion reaction. It would have been nice for the college to offer a picture; the urine of haemoglobinuria is classically bright red but translucent, in contrast to the muddy clot-filled haematuria which might result from some sort of renal trauma. 

To confirm the diagnosis, the Australian Red Cross recommends the following steps:

  • Confirm haemolysis:
    • Serum haptoglobin
    • Blood film looking for fragmented cells
  • Confirm that it is autoimmune  
    • Perform Direct Antiglobulin Test (DAT) and Indirect Antiglobulin Test (IAT),
  • Check transfusion records and document the blood products the patient had received
  • Repeat patient ABO grouping and antibody screen in both pre- and post-transfusion samples.

References

Question 12 - 2017, Paper 2

You have been asked to assess a 76-year-old male, scheduled to have a verv large incisional hernia repaired electively. He has a history of obstructive sleep apnoea (OSA) requiring nocturnal continuous positive airway pressure (CPAP). A recent echocardiogram, done to evaluate pedal oedema and newly diagnosed elevated creatinine, has revealed an ejection fraction of 55%, a right ventricular systolic pressure RVSP of 90 mmH , and moderate tricuspid regurgitation (TR). He has a history of recurrent deep venous thrombosis (DVT) and pulmonary embolism (PE) due to deficiency of Factor V Leiden and is currently on Rivaroxaban.

a) List the specific risks associated with his co-morbidities in the perioperative period.
(40% marks)

b) Outline strategies that could be used to minimize these risks in the perioperative period.
(60% marks) 

College answer

a) 
OSA:  
•    Acute respiratory failure,  
•    Cardiac arrhythmias,  
•    Cardiac ischaemia including cardiac arrest 
•    Risk of exacerbation by opiates may make analgesic management difficult 
 
Pulm hypertension:  
•    Acute right heart failure during perioperative period related to hypoxia and pain, Severe hypoxaemia,  
•    Cardiac dysrhythmias,  
•    Renal failure 
 
Renal dysfunction:  
•    Fluid overload,  
•    Electrolyte and acid base imbalance,  
•    Altered drug metabolism 
 
DVTs, PE, Factor V Leiden deficiency:  
•    High risk of thrombotic events esp PE with exacerbation of RHF.  
 
Anticoagulation:  
•    Bleeding risk,  
•    Thrombotic risk if ceased and not adequately covered. 
 
b) 
Preop: 
•    Consider need for surgery,  
•    Consider timing of surgery o Surgery should be done when co-morbidities are optimised 
o    Organisational factors: Surgery should be conducted when ICU support available, experienced surgical and anaesthetic team available, early on list (so not cancelled), in hospital with appropriate support (ICU and usual physicians) 
 

•    May be relevant to discuss goals of therapy with patient, surgical team and pre-existing physicians 
•    Optimise cardiac status especially with respect to pulmonary hypertension,? need for pulmonary vasodilators. Cardiology input would be valuable 
•    Optimise respiratory status especially with respect to nocturnal NIV; settings, interface 
•    Plan anticoagulation over perioperative period. 
•    OK to mention IVC filter if recent PE. But not necessary 
•    Optimise renal function; may need renal consult and exclusion of reversible causes 
•    Liase with surgeon, anaesthetist, treating physicians regarding management plan 
 
Intra-operative 
•    Use of regional techniques / local blocks to reduce requirement for systemic analgesia 
•    Appropriate monitoring and lines 
 
Post-operative If intubated: 
o    Early extubation and early mobilisation to avoid atelectasis if possible o Consider role of extubation to NIV o Continue usual nocturnal NIV 
•    Consider opiate sparing analgesic regimen, consider regional techniques (will need to consider anticoagulation issues) 
o    Avoid NSAIDS due to renal dysfunction 
•    Avoid fluid overload

o Maintain vascular tone with low dose noradrenaline 
o    Consider vasopressin if high dose pressor required due to less effect on pulmonary vasculature 
•    Restart anticoagulation as soon as safe, in keeping with pre-operative plan o Consider surveillance duplex monitoring if > 24-48hours off anticoagulation 
•    Avoid nephrotoxic medications 
 
Organise follow-up with usual physicians on discharge to the ward. 
 

Discussion

a)

Lets list the problems and consider the risks associated with them, in order of their appearance.

Problem Risks
Expected extensive abdominal procedure
  • Increased risk of post-op atelectasis, which will increase the pulmonary resistance even further
  • Significant analgesia requirements
  • Long procedure
OSA on CPAP
  • Prolonged recovery time
  • Propensity to somnolence and hypoxia with sedatives
Pulmonary hypertension
  • Haemodynamic compromise and right heart decompensation with positive pressure ventilation
Factors V Leiden deficiency
  • Increased propensity to develop DVTs and PEs in this context (the procedure by itself already confers a high risk of this)
Anticoagulation with DOAC
  • Potential for bleeding intra- and post-operatively
  • Makes neuraxial anaesthesia more risky

b)

To mitigate some of these risks, the following strategies may be considered:

Risk Strategy

Increased risk of post-op atelectasis

  • Intraoperatively, carefully titrate PEEP 
  • Extubate on to NIV

Significant analgesia requirements

  • Thoracic epidural
  • Multimodal analgesia

Long complex procedure

  • Early multidisciplinary engagement with the surgical team and anaesthetics, so a plan of management can be decided upon.

Prolonged  recovery from anaesthetic

  • Use short-acting anaesthetic agents, eg. desflurane
  • Rely on non-opiate analgesia, eg epidural or regional techniques
  • Admit the patient to the ICU intubated
  • Wake in the ICU and extubate when completely awake

OSA: Propensity to somnolence and hypoxia with sedatives

  • Intermittent CPAP following extubation
  • Rely on non-opiate analgesia
  • Instruct the patient to bring their CPAP machine with them
  • Consult their respiratory physician for advice on titrating the pressure in the post-operative period, and organise an early follow-up
  • Consider perioperative weight loss, if the procedure can be delayed (and if the patient is obese)
  • Consider corrective airway surgery prior to this abdominal surgery

Worsening of pulmonary hypertension

  • Consider perioperative pulmonary vasodilators
  • Post-operative nitric oxide or nebulised prostacycline
  • Avoid excessive preload for the RV (restrictive fluid resuscitation strategy)
  • Inotrope/vasodilator/avasopressor/fluid therapy should be guided by advanced haemodynamic monitoring, be it PA catheter or TOE
  • Ensure normoxia (hypoxia may worsen the RV afterload)
  • Avoid excessive use of noradrenaline (think about using vasopressin instead)

Thrombophilia and anticoagulation

  • Stop Rivaroxaban two days before the procedure
  • Bridge with another shorter acting or reversible anticoagulant: either admit the patient to start a heparin infusion, or use subcutaneous therapeutic dose enoxaparin at home.
  • Ensure the use of mechanical thromboprophylaxis
  • If there is an epidural, debate with the anaesthetist as to when and how the epidural should be removed in terms of timing it with a pause in anticoagulation

Interestingly, the college recommends to avoid fluid overload. That's probably accurate as the term "overload" implies "excessive load", which is by definition bad. You should avoid excessive bad fluid loading. But, the term "adequate fluid resuscitation" is good. Or at least adequate. Gille et al (2014) recommended the use of a "restrictive" strategy, guided by TOE or PA catheter.

References

Question 25 - 2017, Paper 2

A 34-year-old male, who was previously well, has been admitted to your ICU with vomiting, malaise and oliguria. He has a new diagnosis of diffuse large B cell lymphoma and received his first round of chemotherapy four days ago. The following blood results were obtained:

Parameter   Patient Value Adult Normal Range
Sodium 138 mmol/L    - 135 - 145
Potassium 6.2 mmol/L* 3.5 - 5.0
Bicarbonate 17.0 mmol/L* 22.0 - 26 .0
Urea 21.0 mmol/L* 3.0 - 8.0
Creatinine 398 µmol/L* 45 - 90
Glucose 5.3 mmol/L 3.5 - 6.0
Magnesium 1.10 mmol/L*  it- 0.75 - 0.95
Calcium corrected 1.78 mmol/L* 2.12 - 2.62
Phosphate 3.9 mmol/L*   "t- 0.8 - 1.5
Urate   10 mmol/L 0.20 - 0.42

a) List a differential diagnosis for the kidney injury. (20% marks)

b) Outline your assessment and management of this patient. (80% marks)

College answer

    a)                                                         
It is likely the patient has tumour lysis syndrome (10/20). 
 
Other differentials of acute kidney injury should be considered turn into list 
•    pre-renal (e.g. hypovolaemia, reduced perfusion) 
•    renal (e.g. glomerulonephritis, interstitial nephritis, vasculitis, ATN, acute cortical necrosis, drugs, pyelonephritis) 
•    post-renal (e.g. obstruction for calculi, tumour, clot) 
•    Chronic kidney injury which would put the patient at greater risk of tumour lysis is possible, but not likely if he is previously well.  
•    Sepsis is possible although it would usually occur at a later stage  
 
(Marking Guide: 1 Mark for TLS; 0.25 marks for each reasonable differential) 
 
    b)                                                     
Resuscitation as needed to ensure adequate oxygenation and tissue perfusion. 
 
Exclude differential diagnoses (history, examination and investigation including renal ultrasound). 
•    ECG, and if ECG changes consistent with hyperkalaemia, consider early intervention with (1) CaCl2 or Ca gluconate for temporary ECG stabilisation (new broad QRS or arrhythmia) 
•    (2) shift K intracellularly with either B2 agonist therapy (e.g. ventolin neb), insulin dextrose, or NaHCO3 if indicated 
 
Specific management of tumour lysis syndrome 
•    IV fluids to encourage a diuresis  
•    Once well hydrated diuretics could be considered to encourage a diuresis (frusemide is most widely used, acetazolamide may alkalinise the urine which will increase the solubility of uric acid but reduce the solubility of CaPO4 and hence is less widely used) 
•    Rasburicase (to break down uric acid) o Urine alkalinisation not recommended if rasburicase has been given 
o If rasburicase not available allopurinol maybe given (however, this is not as effective and will not breakdown uric acid, it merely reduces further uric acid formation) 
 
Haemodialysis and/or filtration is generally instituted for standard indications, although it maybe instituted earlier in tumour lysis syndrome or if the patient remains oliguric. 
      
Treat hypocalaemia only if symptomatic (cramps, paraesthesia) as excessive Ca replacement may precipitate CaPO4. 
      
Hyperphosphataemia is most efficiently treated with haemodialysis and/or filtration, insulin dextrose and oral phosphate binders have a limited role. 
      
Seek and treat sepsis. 
      
Consider excluding renal obstruction with US. 
 
Routine supportive care 
Optimise oxygenation (if fluid overloaded maybe need supplemental oxygen) 
Optimise perfusion and blood pressure 
Withhold nephrotoxic medications drugs (NSAIDS, ACE-I, ARBs) 
Consider dose modification of renally excreted drugs 
DVT prophylaxis 
Single room/ neutropenic precautions 
 

Discussion

The college certainly seems to love tumour lysis syndrome. This is the fourth time it has come up in the exam. It is certainly the top differential in this context. Nothing else could ever give rise to a urate level of 10mmol/L. 

The list of other differentials might include:

  • Nephrotoxicity from chemotherapy agents
  • Sepsis
  • Dehydration
  • Hyperproteinaemia (i.e hyperviscosity syndrome)
  • Renal vein thrombosis 
  • Renal vascular supply compression by para-aortic lymphadenopathy
  • Infiltration by tumour

And there is no reason why all of these might not co-exist simultaneously.

Assessment will consist of:

  • History
    • Time course of the symptoms
    • History of oral intake
    • Changes in urine colour and volume
    • Fevers
    • Pain
    • Other background history
    • History of recent medication use, eg. NSAIDs, ACE-inhibitors etc
  • Examination:
    • Hydration status
    • Haemodynamic parameters, i.e. looking for septic shock
    • Organomegaly
    • Lymph nodes
    • Renal angle tenderness
    • Temperature
    • Gouty joints
  • Investigations
    • Urinalysis looking for myoglobinuria
    • Blood count looking for WCC 
    • Biochemistry looking for protein levels
    • Coags and platelet count looking for coagulopathy (as the patient may require a vas cath)

Specific management will consist of:

  • Rehydration and forced diuresis
    • Balanced crystalloid infusion, to help correct acidosis
    • Frusemide infusion to encourage diuresis
  • Management of hyperuricaemia and other electrolyte abnormalities
    • Rasburicase 
    • Calcium gluconate as cardioprotective agent
    • Insulin and dextrose in order to correct hyperkalemia
  • Management of acute kidney injury
    • Observe for improvement with rehydration and forced diuresis (AKI may resolve over the subsequent days)
    • If oliguria does not resolve or other criteria for urgent dialysis are met, obtain vascular access for CRRT and commence CVVHDF.

References

Tiu, Ramon V., et al. "Tumor lysis syndrome." Seminars in thrombosis and hemostasis. Vol. 33. No. 4. New York: Stratton Intercontinental Medical Book Corporation, c1974-, 2007.

Howard, Scott C., Deborah P. Jones, and Ching-Hon Pui. "The tumor lysis syndrome." New England Journal of Medicine 364.19 (2011): 1844-1854.

Cairo, Mitchell S., and Michael Bishop. "Tumour lysis syndrome: new therapeutic strategies and classification." British journal of haematology 127.1 (2004): 3-11.

Question 29 - 2017, Paper 2

Compare and contrast heparin induced thrombotic thrombocytopaenia syndrome (HITTS) and thrombotic thrombocytopaenlc purpura (TTP) with respect to their pathogenesis, clinical features, relevant laboratory findings, and treatment.

College answer

Condition

TTP

HITTS

Aetiology

1 mark each

  1. Reduction in ADAMTS 13 level
    1. Hereditary causes
    2. Acquired causes e.g. Sepsis, surgery, pancreatitis, pregnancy
  2. Anitbodies to ADAMTS 13:

Autoantibodies to platelet factor 4 (PF4) complexed with heparin

Clinical

Features

1 mark each

Small vessel thrombosis-

Microangiopathic haemolytic anaemia with multisystem involvement but renal and CNS dominate- 

Occurs within 4-10 days of heparin administration- arterial and venous thrombosis, thrombocytopenia

Laboratory

2 marks each

Low platelets, intravascular haemolysis with evidence of micrangiopathic changes to RBC morphology. LDH, Haptoglobin, COOMBS test, ADAMTS 13 deficiency

Ant PF4 antibody, Functional

Assays- (serotonin release,

Heparin induced platelet activation)

Treatment  1 mark each

Plasmapharesis is the mainstay of treatment for Acquired TTP, FFP for hereditary TTP

Cessation heparin

Non heparin based anticoagulation

( Lepuridin etc)

Discussion

A "compare and contrast" question is typically something that benefits from a tabulated answer.

Observe:

Domain HITS TTP-HUS
Pathogenesis
  • IgG directed against PF4 complexed with heparin (PF4 is "Platelet Factor 4", a little cytokine which is normally released from platalet α-granules)
  • When anti-PF4 antibodies bind to PF4 it  activating more platelets and triggers the release of more PF4, providing more substrate for antibody binding in a positive feedback loop
  • The IgG-coated platelets are then removed by reticuloendothelial system macrophages. Thrombocytopenia ensues.
  • The patient is ADAMTS 13 deficient (ADAMTS 13 is a von Willebrand factor cleaving protein).
  • A trigger such as infection, surgery, pancreatitis, pregnancy, produces endothelial activation.
  • When endothelial activation occurs and ADAMTS 13 activity is low (often due to an autoantibody inhibitor), large vWF multimers accumulate causing microvascular thrombosis and haemolysis.
  • An excess of vWF leads to a systemic prothrombotic state, with microvascular thrombosis responsible for all the organ system damage.
Clinical features
  • Onset 5-10 days after heparin exposure
  • Thrombosis
  • Thrombocytopenia
  • No other cause for thrombocytopenia

Classic "pentad"

  • Anaemia
  • Thrombocytopenia
  • Microangiopathic haemolytic anaemia
  • Schistocytosis
  • Neurological symptoms
  • Fever and renal failure are actually uncommon
Laboratory findings
  • Thrombocytopenia
  • Anti-PF4 antibodies
  • Positive serotonin release assay (SRA)
  • Thrombocytopenia
  • Raised urea and creatinine
  • Blood film abnormalities, eg. schistocytes and fragmented RBCs

  •  
Treatment
  • Anticoagulation
  • Withdrawal of heparin
  • Plasmapheresis
  • Repacement with FFP

References

George, James N. "Thrombotic thrombocytopenic purpura." New England Journal of Medicine 354.18 (2006): 1927-1935.

Peyvandi, Flora, et al. "von Willebrand factor cleaving protease (ADAMTS‐13) and ADAMTS‐13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura." British journal of haematology 127.4 (2004): 433-439.

Tsai, Han-Mou. "Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura." Journal of the American Society of Nephrology 14.4 (2003): 1072-1081.

Oh's Intensive Care manual: Chapter 97 (pp. 993)  Therapeutic  plasma  exchange  and  intravenous  immunoglobulin  therapy  by Ian  Kerridge,  David  Collins  and  James  P  Isbister

Kakishita, Eizo. "Pathophysiology and treatment of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS)."International journal of hematology 71.4 (2000): 320-327.

Noris, Marina, and Giuseppe Remuzzi. "Hemolytic uremic syndrome." Journal of the American Society of Nephrology 16.4 (2005): 1035-1050.

Kappler, Shane, Sarah Ronan-Bentle, and Autumn Graham. "Thrombotic Microangiopathies (TTP, HUS, HELLP)." Emergency Medicine Clinics of North America (2014).

Moake, Joel L. http://www.danielyoung.net/articles/NEJM%20TTP-HUS%202002.pdf "Thrombotic microangiopathies." New England Journal of Medicine 347.8 (2002): 589-600.

Arepally, Gowthami M., and Thomas L. Ortel. "Heparin-induced thrombocytopenia." New England Journal of Medicine 355.8 (2006): 809-817.

Patel, Vipul P., Matthew Bong, and Paul E. Di Cesare. "Heparin-induced thrombocytopenia and thrombosis." AMERICAN JOURNAL OF ORTHOPEDICS-BELLE MEAD- 36.5 (2007): 255.

Greinacher, Andreas. "Heparin-induced thrombocytopenia." New England Journal of Medicine 373.3 (2015): 252-261.

Question 19.3 - 2018, Paper 1

The following results were obtained from a patient in the ICU

Parameter

Patient Value

Adult Norma' Range

Prothrombin time

15.0 s

10.0 - 15.0

International normalised ratio (INR)

1.20

0.80 - 1.20

Activated Partial Thromboplastin Time (APTT)

40.8 s*

25.0 -35 0

Fibrinogen

2.0 g/L

2.0 —4.0

      a) List four possible causes.                                                                                         (20% marks)

College answer

  • Anticoagulants – e.g. heparin
  • Lupus anticoagulant-type inhibitors 
  • Factor deficiencies – FXI, XII 
  • Artefactual

Discussion

This  is somewhat unsatisfying, as no history is given other than the patient is in ICU.

In summary, the results are:

  • Normal PT; slightly elevated INR (1.2)
  • Slightly elevated APTT
  • Borderline low fibrinogen

Of these results the only actually abnormal one is the APTT.

Four possible causes of a slightly  raised APTT are:

  • Dilutional coagulopathy (as PT is also borderline)
  • Heparin therapy
  • Factors 8, 9 11 or 12 deficiency
  • von Willebrand's disease

References

Kamal, Arif H., Ayalew Tefferi, and Rajiv K. Pruthi. "How to interpret and pursue an abnormal prothrombin time, activated partial thromboplastin time, and bleeding time in adults." Mayo Clinic Proceedings. Vol. 82. No. 7. Elsevier, 2007.

DeMuro, J. P., and A. F. Hanna. "Trauma Induced Coagulopathy: Prevention and Intervention."Scand J Trauma Resusc Emerg Med 20.47 (2014): 4.

White, Julian. "Snake venoms and coagulopathy." Toxicon 45.8 (2005): 951-967.

Kashuk, Jeffry L., et al. "Primary fibrinolysis is integral in the pathogenesis of the acute coagulopathy of trauma." Annals of surgery 252.3 (2010): 434-444.

De Stefano, Valerio, Guido Finazzi, and Pier Mannuccio Mannucci. "Inherited thrombophilia: pathogenesis, clinical syndromes, and management [see comments]." Blood 87.9 (1996): 3531-3544.

Hunt, Beverley J. "Bleeding and coagulopathies in critical care." New England Journal of Medicine 370.9 (2014): 847-859.

Question 9.2 - 2018, Paper 2

A 32-year-old female has been admitted to the ICU following an emergency response call for generalised tonic clonic seizures and obtundation. No past history is available. Non-contrast CT brain scan is normal. The following results are obtained:

Parameter

Patient Value

Adult Normal Range

Sodium 

143 mmol/L

135 – 145

Potassium  

3.0 mmol/L*

3.5 – 5.0

Chloride 

116 mmol/L*

95 – 105

Bicarbonate 

15.0 mmol/L*

22.0 – 26.0 

Glucose 

5.2 mmol/L

3.5 – 6.0

Urea 

12.4 mmol/L*

3.0 – 8.0

Creatinine  

202 μmol/L*

45 – 90 

Magnesium

0.75 mmol/L

0.75 – 0.95

Albumin 

14 g/L*

35 – 50 

Protein 

49 g/L*

60 – 80

Total bilirubin 

35 μmol/L*

< 26

Aspartate aminotransferase (AST) 

58 U/L*

< 35

Alanine aminotransferase (ALT)

50 U/L*

< 35

Alkaline phosphatase (ALP)

145 U/L*

30 – 110

-Glutamyl transferase (GGT)

45 U/L*

< 40

Ionised calcium 

1.90 mmol/L*

1.10 – 1.35

Calcium corrected 

2.90 mmol/L*

2.12 – 2.62

Phosphate 

1.8 mmol/L*

0.8 – 1.5

Creatinine Kinase 

356 U/L*

55 – 170 

Lactate dehydrogenase

450 U/L*

120 – 150

Haemoglobin 

75 g/L*

120 – 160

White Cell Count  

20.0 x 109/L*

4.0 – 11.0

Platelet count 

60 x 109/L*

150 – 350 

  1. List three differentials for the above-mentioned clinical presentation and pathology results.  (30% marks)
  1. List three further pathology tests that would aid your diagnosis.              (30% marks)

College answer

a)                                                                                                                                         
•    Thrombotic thrombocytopenic purpura 
•    HELLP syndrome 
•    Septic -meningo-encephalitis 
•    Drug - induced 
•    Vasculitis  
•    Malignancy 
 
b) 
•    Blood film for schistocytosis 
•    Blood cultures/lumbar puncture  
•    Vasculitic screen 
•    Serology for pneumococcus/meningococcus 
•    Pregnancy test 
 

Examiners Comments: 
 
Generally, these questions were answered well. Those candidates that failed, missed all or part of the question or misinterpreted what was being asked, reiterating how important it is to read the question and understand what is required before starting to answer. 

 

Discussion

The abnormalities in this set of results are:

  • Acidosis, likely metabolic, with an anion gap of 15 which (even when using a normal value corrected for the shockingly low albumin) give a delta ratio of 0.67, i.e. predominantly a normal anion gap metabolic acidosis.
  • Renal failure, of indeterminate acuity
  • Low albumin and serum protein, which are nonspecific findings in critical illness
  • Raised bilirubin, which in the presence of essentially normal LFTs raises the suspicion of haemolysis
  • Hypercalcemia and hyperphosphataemia, as well as a slightly elevated alkaline phosphatase, suggestive of increased rate of bone resorption
  • Raised CK, which is not sufficiently elevated to suggest rhabdomyolysis
  • Raised LDH, which is a non-specific finding suggestive of cellular injury, but which in the presence of a raised bilirubin could be consistent with haemolysis, and in the presence of hypercalcemia suggests malignancy
  • Anaemia
  • Thrombocytopenia
  • Leukocytosis

So; this mixture of abnormalities has to play along with a history of being young, female and seizury. The differentials therefore need to explain a decreased level of consciousness, renal failure, haematological disturbance with anaemia and theromobocytopenia, and seizures. 

  • TTP
  • Sepsis with DIC
  • Vasculitis with MAHA
  • Intoxication
  • Haematological malignancy

It is hard to say how HELP syndrome could have attracted any marks here, as you're missing the EL. Also, none of the differentials (apart from malignancy) explain the hypercalcemia. Also, malar

Thus, one would order a broadside of tests:

  • Conjugated ad =unconjugated bilirubin levels
  • "Vasculitic screen" including ADAMTS-13 levels
  • Fibrinogen level and coags
  • Blood cultures
  • Lumbar puncture (given that sepsis with DIC could be due to  Neisseria meningitides)

References

Question 12.1 - 2019, Paper 1

The following data refer to a 65-year-old male admitted to ICU with septic shock on a background of active rheumatoid arthritis.

Parameter

Patient Value

Adult Normal Range

Haemoglobin

86 g/L*

125 – 180

Serum ferritin

298 µg/L

15 – 300

Serum iron

7 µmol/L*

9 – 27

Total Iron Binding Capacity (TIBC)

52 µmol/L

47 – 70

Transferrin Saturation (Iron / TIBC x 100)

28%

16 – 40

Erythropoietin level

15 U/L

4 – 28

C-reactive protein (CRP)

321 mg/L*

< 8

a) What abnormality is demonstrated in this patient? Give your reasoning. (20% marks)

b) What is the pathogenesis of these changes?                                               (20% marks)

c) What are the principles of management?                                                      (10% marks)

College answer

  1. Anaemia of Inflammation demonstrated by:
    • decreased haemoglobin
    • decreased iron
    • normal to high ferritin
    • suppressed erythropoietin
    • elevated CRP.
  1. Inflammation -> cytokines (IL6) -> increased hepcidin -> decreased iron release from bone marrow, decreased iron release from macrophages, decreased absorption of iron -> suppressed erythopoeisis
  1. Control inflammation, no value to iron replacement, no value to the use of erythropoietin.

Discussion

This question is essentially identical to Question 18.1 from the first paper of 2015, except in the older SAQ question (c) reads "what specific treatment strategy would correct the demonstrated abnormality" instead of "what are the principles of management".  These two alternative wordings must surely mean the exact same thing, because  the college answer was identical for both versions of the question.

Anyway: a generic iron studies interpretation rubrik looks like this:

Interpretation of Abnormal Iron Studies
Condition MCV MCHC Serum iron Ferritin Transferrin Transferrin
saturation
TIBC
Iron deficiency anaemia low low low low high <20% high
Anaemia of inflammation (chronic disease) low low low normal low normal low or normal
Acute phase response normal normal low high low low low
Iron overload normal normal high high normal high high

The college answer refers to "Anaemia of Inflammation", a nomenclature which has superseded "anaemia of chronic disease" as  the description of the anaemia which has low serum iron in spite of normal body iron stores (i.e. normal ferritin). This "inflammation" could actually be anything proinflammatory, and so it would be difficult to comment whether the rheumatoid arthritis is more responsible then the sepsis, or vice versa. In either case, the biochemical picture would be more or less the same.

Alternative explanations for these laboratory results could also include the anaemia of decreased erythropoietin release associated with renal failure; but the college specifically gave us RA, sepsis and a raised CRP, clearly aiming the candidates at something inflammatory. Iron studies in anaemia of chronic renal failure tend to demonstrate iron deficiency, i.e. the ferritin is also low, but there is a group in whom there is a "functional" iron deficiency with normal ferritin levels and a failure of iron release from body stores (Babitt & Lyn, 2012). If the inflammatory elements were omitted from the story, this would be a legitimate alternative explanation.

The erythropoietin level is a weird thing to add because it is expensive and not usually a part of the normal panel. The  RPCA Manual lists it as one of the tests "occasionally indicated" to discriminate primary from secondary erythrocytosis. It is not essential to the diagnosis of anaemia.

The mechanism of anaemia of inflammation can be summarised as follows:

  • Decreased iron availability
    • Cytokine release in inflammation (mainly IL-6) stimulates the synthesis of hepcidin, a regulatory molecule which controls the release of iron into the circulation.
    • A high hepcidin level decreases the availability of iron by promoting "iron trapping" within the bone marrow and macrophages. Thus, the iron stores in this form of anaemia are normal, which renders iron infusion pointless.
    • In the absence of circulating iron, erythropoiesis is restricted.
  • Increased erythrocyte phagocytosis
    • Cytokine-activated macrophages destroy red cells at an increased rate
    • This reduces the lifespan of erythrocytes.
  • Decreased erythropoiesis signals
    • Cytokines act directly on the bone marrow to reduce the rate of erythropoiesis, independent of the levels of circulating erythropoietin
    • Occasionally the level of erythropoietin is also suppressed, which is thought to be a cytokine-related effect acting on its renal secretion.

Routine management of such an anaemia is therefore somewhat unexciting:

  • Iron infusion is futile, as the iron stores are essentially intact
  • Erythropoietin supplementation is futile, as the bone marrow won't respond anyway
  • Blood transfusion is what you'd resort to while treating the cause of the inflammation

But let's say that for some reason you've lost interest in treating causes of things. Can we cosmetically make the iron study numbers look better? Turns out that yes, we can. There are several possible treatments for this sort of anaemia which specifically target the mechanism of its pathogenesis:

  • Tocilizumab, a monoclonal antibody against the IL-6 receptor
  • A thus-far unnamed hepcidin-binding monoclonal antibody may soon become available (apparently, in 2014 it was in Phase 2 trials)
  • Heparin reduces hepcidin production, but in prescribing overmuch heparin to the anaemic patient one might be merely exchanging one problem for another.

References

Hawkins, Stephen F., and Quentin A. Hill. "Diagnostic Approach to Anaemia in Critical Care." Haematology in Critical Care: A Practical Handbook (2014): 1-8.

Gross, I. "Laboratory Studies in the Diagnosis of Iron Deficiency, Latent Iron Deficiency and Iron Deficient Erythropoiesis". from http://iron.sabm.org

Pieracci, Fredric M., et al. "A Multicenter, Randomized Clinical Trial of IV Iron Supplementation for Anemia of Traumatic Critical Illness*." Critical care medicine 42.9 (2014): 2048-2057.

Litton, Edward, et al. "The IRONMAN trial: a protocol for a multicentre randomised placebo-controlled trial of intravenous iron in intensive care unit patients with anaemia." Crit Care Resusc 16 (2014): 285-290.

Corwin, Howard L., et al. "Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial." Jama 288.22 (2002): 2827-2835.

Mesgarpour, Bita, et al. "Safety of off-label erythropoiesis stimulating agents in critically ill patients: a meta-analysis." Intensive care medicine 39.11 (2013): 1896-1908.

Nemeth, Elizabeta, and Tomas Ganz. "Anemia of inflammation." Hematology/Oncology Clinics 28.4 (2014): 671-681.

Babitt, Jodie L., and Herbert Y. Lin. "Mechanisms of anemia in CKD." Journal of the American Society of Nephrology (2012): ASN-2011111078.

Nemeth, Elizabeta, and Tomas Ganz. "Anemia of inflammation." Hematology/Oncology Clinics 28.4 (2014): 671-681.

Question 12.2 - 2019, Paper 1

The following data refer to a 48-year-old female admitted electively to ICU following extensive pelvic surgery for invasive endometrial carcinoma. The patient has remained in ICU for 22 days because of complications including acute kidney injury.

Parameter

Patient Value

Adult Normal Range

Haemoglobin

66 g/L*

125 – 180

Serum ferritin

14 µg/L*

15 – 300

Serum iron

3 µmol/L*

9 – 27

Total Iron Binding Capacity (TIBC)

86 µmol/L*

47 – 70

Transferrin Saturation (Iron / TIBC x 100)

9%*

16 – 40

Erythropoietin level

41 U/L*

4 – 28

C-reactive protein (CRP)

60 mg/L*

< 8

a) What abnormality is demonstrated in this patient? Give your reasoning.      (20% marks)

b) Give two potential causative factors in this patient.                                            (10% marks)

c) Briefly outline the available treatment options to correct the demonstrated abnormality including any disadvantages / risks.                                                (20% marks)

College answer

  1. a)

    Iron deficiency anaemia as evidenced by:

    • decreased haemoglobin
    • decreased iron
    • decreased ferritin
    • increased erythropoietin
    • increased TIBC.

    b)

    Blood loss

    Pre-existing dietary deficiency

    c)

    IV iron replacement – no demonstrated benefit and risks of adverse effects (infection risk- IRONMAN)

    Oral iron replacement?

    Erythropoeitin – expensive and no demonstrated benefit

    Blood transfusion – risks of transfusion including immunosuppression?

    No treatment – may have reduced oxygen carrying capacity for some time until correction of Hb

Discussion

This question is essentially identical to Question 18.2 from the first paper of 2015, except in 2015 the results of the IRONMAN study were not yet available. Apart from including a mention of this 2016 trial by Litton et al, the college examiners made the curious choice of taking management recommendations from the 2015 version of the question and rewording them in the form of questions ("Oral iron replacement?").

Anyway. Local resources to help with such questions include the following chapters:

In the above, there is a table of typical findings which is reproduced below:

Interpretation of Abnormal Iron Studies
Condition MCV MCHC Serum iron Ferritin Transferrin Transferrin
saturation
TIBC
Iron deficiency anaemia low low low low high <20% high
Anaemia of chronic disease low low low normal low normal low or normal
Acute phase response normal normal low high low low low
Iron overload normal normal high high normal high high

Following from this, the results in this SAQ are pretty clearly iron deficiency anaemia (low haemoglobin, low iron, high TIBC, etc). The erythropoietin level is appropriately elevated, but not essential to making the diagnosis. Apart from blood loss and dietary deficiency, there's not much that can be added to the "potential causative factors".

The available treatment options are:

  • Iron supplementation
  • Blood transfusion

The college also included "do nothing" as a management option, though one might object that conceptually this would be the very opposite of a management plan. They also included recombinant human EPO as one of the treatment options, but then they also gave us a serum EPO which is significantly elevated. This defies logic-  adding more exogenous EPO to the already high EPO level is unlikely to achieve a glorious haemopoietic victory, as the haemoglobin was still low even with the EPO levels almost double the upper range of normal.  Moreover, giving EPO is not going to do anything to replenish your iron stores.

The most logical solution would be to give iron, or actual blood. Blood transfusion is of course the last option. The pros and cons of  blood transfusion in the ICU are discussed in greater detail elsewhere. Iron replacement is probably somewhat less toxic, and seems like a sensible solution to a condition where the deficiency of iron is the main problem. One should not be deterred from doing this, even though the IRONMAN trial did not find any improvement in the rate of blood transfusion in their iron-infused group. Those patients did end up with a significantly higher haemoglobin at discharge, even though they were not specifically selected for having iron deficiency.

The objection to the use of IV iron is based in the finding that the iron-infused group has an increased nosocomial infection rate (28.6% vs. 22.9%). Apart from this, there was no major difference in the adverse event rate between the two groups. In any case, you don't have to give the iron intravenously. Oral iron replacement is not without its charm, and only slightly less effective (Bonovas et al, 2016).

References

Question 20 - 2019, Paper 1

a)    List the risk factors, clinical features and relevant investigations for occlusive upper limb deep venous thrombosis (ULDVT) in critically ill patients.    (50% marks)

b)    Discuss the available management options.    (50% marks)

College answer

a)

Risk factors: (20% Marks)

  1. Catheter Insertion
    1. Size /number of lumens increases risk
    2. Position – PICC > Central
    3. Malposition of catheter
    4. Difficulty in placement
    5. Irritant infusion – e.g. TPN, Chemotherapy
    6. Catheter infection
  2. Systemic Conditions
    1. Malignancy
    2. Upper limb trauma
    3. Hypercoagulable state
    4. Previous thrombosis Marking Guide: 8-10 correct  2 marks

5-7 correct          1 mark

<5 correct           0.5 mark

Clinical Features: (20% Marks)

  1. May be asymptomatic
  2. Symptoms: discomfort, pain, paraesthesia and weakness
  3. Signs:
    1. limb swelling, oedema, venous collaterals
    2. Superior vena cava syndrome; oedema of face, neck and upper torso; dyspnoea; syncope; positive Pemberton’s sign.

Investigations: (10% Marks)

Compression ultrasound is the diagnostic standard, with >95% sensitivity and specificity. (this detail not required)

Doppler and CT may be required to diagnosis intrathoracic/super vena cava (SVC) obstruction.

 

b)

Treatment: (50% Marks)

Treatments aim to alleviate the symptoms, prevent thrombin propagation and pulmonary embolism, and prevent post-thrombotic syndromes.

  1. Anti-coagulation:
    • Initiate with unfractionated heparin infusion or low molecular weight heparin (preferred)
    • Followed by either low molecular weight heparin or oral anticoagulants for 3 to 6 months
  2. Thrombolysis:
    • Limited evidence
    • Catheter-directed thrombolysis is upper limb has extensive swelling and functioned impairment
  3. Mechanical catheter intervention:
    • Aspiration of the thrombus, fragmentation and thrombectomy should be considered in patients with persistent severe symptoms, despite anticoagulation or thrombolysis.
  4. SVC filters:
    • Evidence is lacking
    • Prevention of pulmonary embolism in patients with ULDVT in whom anticoagulation is contraindicated or thrombus progression despite anticoagulants.
    • Significant complications including cardiac tamponade and aortic perforations reported.
  5. Catheter/device removal:
    • No need for routine removal
    • Remove if infected
    • Factors to be considered include the ongoing need for the catheter and difficulty in venous access.

(Highlighted points in treatment section are required for a pass mark.)

Examiners Comments:

Topic was poorly understood, with little knowledge beyond superficial. It was suspected that that relates to poor exposure and experience of more advanced interventions (thrombolysis, possible radiology directed treatments). Little was mentioned around importance of lines in thrombosis and almost everyone who remembered wanted to pull the lines out without thought or consideration of the implications.

Discussion

Risk factors for upper limb DVT from Kommareddy et al (2002):

Gene mutations

  • Factor V (G1691 A)
  • Prothrombin (G20210A) Methylene-tetrahydrofolate
    reductase MTHFR (C677T)
  • Protein C
  • Protein S
  • Fibrinogen
  • Antithrombin

Acquired thrombophilias

  • Cancer
  • Congestive heart failure
  • Pregnancy
  • Antiphospholipid syndrome Nephrotic syndrome
  • Liver disease
  • Disseminated intravascular coagulation
  • Sepsis
  • Heparin-induced thrombocytopenia
  • Vasculitic disorders
  • Inflammatory bowel disease

Other factors

  • Thoracic outlet syndrome
  • Strenuous effort
  • Central venous catheters
  • Implanted pacemakers
  • Trauma
  • Previous thrombosis
  • Antineoplastic agents
  • Oral contraceptives

Specific difference between upper limb and lower limb DVT risk factor profiles, according to Cote et al (2017)

  • Recent surgery was less common in the upper limb DVT patients (12% vs 18%)
  • Malignancy was more common (50% had a malignancy, vs 30%)
  • Age was less of a risk factor (younger patients developed upper limb DVTs), except where the upper limb clot was provoked by a catheter
  • Immobility was much less of a risk factor (19% vs 43% for lower limb DVT)
  • Oral contraception or hormone replacement therapy was twice as common among the upper limb DVT group (20% vs 9.2%)
  • Upper limb central lines were a major risk factor.

Clinical features:

  • Generic clinical features of DVT:
    • Pain
    • Limb swelling
    • Oedema
    • Paraesthesia
    • Cord-like structure on palpation
    • Redness due to phlebitis
    • Coolness due to poorer perfusion
    • Decreased mobility or dexterity of the limb
  • Features unique to upper limb DVT:
    • Neck stiffness
    • Facial swelling
    • Pemberton's sign (with SVC obstruction)
    • Failure to insert upper limb CVCs ("the catheter just won't thread")
  • There are also a few clinical features unique to catheter-associated DVTs:
    • Inability to withdraw blood from the catheter
    • Inability to inject into the catheter
    • Loss of transducer waveform

Investigations:

  • DSA or plain radiocontrast venography is the gold standard
  • Ultrasound is substituted in virtually every situation as a nontoxic noninvasive alternative
  • Imaging with CT venography is the main approach to diagnosis if ultrasound is not available or for some reason uninformative (eg. the patient is covered in burns dressings). Additionally, CT of the veins is often the only way to map the venous circulation of the mediastinum and the pelvis.
  • Impedance plethysmography (Hull et al, 1986) where the electrical impedance of the limb is measured with electrodes before and after cuff deflation
  • Molecular tracer imaging (Houshmand et al, 2014), where the patient is injected with a radioactive tracer which binds to the clot and reveals it on a scintigraphy scan (PET/CT).

Management:

Guidelines from the American College of Chest Physicians (Kearon et al, 2012) recommend the following anticoagulation regimen:

  • Isolated brachial vein thrombosis: 
    no anticoagulation unless symptomatic or associated with a CVC
  • Proximal, provoked by some significant factor, which is now gone:
    anticoagulant therapy for 3 months. 
  • Proximal and associated with malignancy:
    anticoagulant therapy for 3-6 months.
  • Proximal and associated with a central line:
    anticoagulant therapy for 3 months if you removed it;
    or, anticoagulant therapy until you decide to take it out.

In addition to this (not instead of it), one may need acute intervention:

  • Systemic thrombolysis (not recommended but is one of the options)
  • Regional thrombolysis (i.e. you pick a vein distal to the clot and inject a small amount of thrombolytic agent into it)- generally not recommended but is one of the options
  • Catheter-directed thrombolysis (where a central venous catheter is introduced into the clot from a distant site, and then used to infuse the clot with a thrombolytic agent) - not very popular since the ATTRACT trial (Vedantham et al, 2017) which demonstrated an increased risk of bleeding without much of an improvement in patient-centred outcomes
  • Surgical thrombectomy for patients in whom no other method is available
  • Vena cava filter placement is mentioned by the college in the management strategies for DVT, but this makes no logical sense as the filter itself does nothing to treat the DVT, unless one accidentally fragments the clot with their filter in the process of insertion. It is a risk mitigation strategy in patients who have failed anticoagulation or for whom anticoagulation is absolutely contraindicated.

References

Cook, Deborah, et al. "Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors." Critical care medicine 33.7 (2005): 1565-1571.

Miri, MirMohammad, Reza Goharani, and Mohammad Sistanizad. "Deep vein thrombosis among intensive care unit patients; an epidemiologic study." Emergency 5.1 (2017).

Wheeler, H. B. "Diagnosis of deep vein thrombosis. Review of clinical evaluation and impedance plethysmography." American journal of surgery 150.4A (1985): 7-13.

Williams, Michael T., et al. "Venous thromboembolism in the intensive care unit.Critical care clinics 19.2 (2003): 185-207.

Hirsch, Denise R., Edward P. Ingenito, and Samuel Z. Goldhaber. "Prevalence of deep venous thrombosis among patients in medical intensive care." Jama 274.4 (1995): 335-337.

Hong, Kee Chun, et al. "Risk factors and incidence of deep vein thrombosis in lower extremities among critically ill patients." Journal of clinical nursing 21.13-14 (2012): 1840-1846.

MAl-Dorzi, Hasan, and Yaseen M. Arabi. "Venous Thromboembolism in Critically Ill Patients: Risk Stratification and Prevention." Critical Care Update 2019 (2019): 29.

García-Olivares, Pablo, et al. "PROF-ETEV study: prophylaxis of venous thromboembolic disease in critical care units in Spain." Intensive care medicine 40.11 (2014): 1698-1708.

Obi, Andrea T., et al. "Validation of the Caprini venous thromboembolism risk assessment model in critically ill surgical patients." JAMA surgery 150.10 (2015): 941-948.

Ellis, Martin H., Yosef Manor, and Moshe Witz. "Risk factors and management of patients with upper limb deep vein thrombosis." Chest 117.1 (2000): 43-46.

Cote, Lauren P., et al. "Comparisons between upper and lower extremity deep vein thrombosis: a review of the RIETE registry." Clinical and Applied Thrombosis/Hemostasis 23.7 (2017): 748-754.

Kommareddy, Aruna, Michael H. Zaroukian, and Houria I. Hassouna. "Upper extremity deep venous thrombosis." Seminars in thrombosis and hemostasis. Vol. 28. No. 01. Copyright© 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.:+ 1 (212) 584-4662, 2002.

Hill, Stephen L., and Robert E. Berry. "Subclavian vein thrombosis: a continuing challenge." Surgery 108.1 (1990): 1-9.

Saber, W., et al. "Risk factors for catheter‐related thrombosis (CRT) in cancer patients: a patient‐level data (IPD) meta‐analysis of clinical trials and prospective studies." Journal of Thrombosis and Haemostasis 9.2 (2011): 312-319.

Kinnison, Malonnie L., et al. "Upper-extremity venography using digital subtraction angiography." Cardiovascular and interventional radiology 9.2 (1986): 106-108.

HULL, RUSSELL D., et al. "Diagnostic efficacy of impedance plethysmography for clinically suspected deep-vein thrombosis: a randomized trial." Annals of Internal Medicine102.1 (1985): 21-28.

Houshmand, Sina, et al. "The role of molecular imaging in diagnosis of deep vein thrombosis." American journal of nuclear medicine and molecular imaging 4.5 (2014): 406.

Malato, Alessandra, et al. "The impact of deep vein thrombosis in critically ill patients: a meta-analysis of major clinical outcomes." Blood Transfusion 13.4 (2015): 559.

McKelvie, Penelope A. "Autopsy evidence of pulmonary thromboembolism." Medical journal of Australia 160.3 (1994): 127-128.

Tran, Huyen A., et al. "New guidelines from the Thrombosis and Haemostasis Society of Australia and New Zealand for the diagnosis and management of venous thromboembolism." Medical Journal of Australia 210.5 (2019): 227-235.

Noyes, ADAM M., and John Dickey. "The arm is not the leg: pathophysiology, diagnosis, and management of upper extremity deep vein thrombosis." RI Med J 100 (2017): 33-36.

Kearon, Clive, et al. "Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines.Chest 141.2 (2012): e419S-e496S.

Watson, Lorna, Cathryn Broderick, and Matthew P. Armon. "Thrombolysis for acute deep vein thrombosis." Cochrane Database of Systematic Reviews 11 (2016).

Vedantham, Suresh, et al. "Guidance for the use of thrombolytic therapy for the treatment of venous thromboembolism." Journal of thrombosis and thrombolysis41.1 (2016): 68-80.

Vedantham, Suresh, et al. "Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis." New England Journal of Medicine 377.23 (2017): 2240-2252.

Comerota, Anthony J. "The current role of operative venous thrombectomy in deep vein thrombosis." Seminars in vascular surgery. Vol. 25. No. 1. WB Saunders, 2012.

Question 21 - 2019, Paper 1

With respect to transfusion protocols for massive haemorrhage; discuss the advantages and disadvantages of using a protocol guided by thromboelastography (TEG guided) compared to one that uses a fixed ratio of product replacement (e.g. FFP : platelets : packed cells = 1 : 1 : 1).

College answer

Background

Heterogeneous nature of the critically bleeding trauma patient and the spectrum of trauma induced coagulopathy may mean fixed ratio protocol (FRP) is too simplistic to apply to all patients. Although a FRP may improve survival, the optimal ratio of packed cells to other blood components is unknown. TEG-guided algorithms allow rapid identification and correction of patient-specific coagulation abnormalities. Trauma induced coagulopathy in the critically bleeding patient is complex and changes throughout time of resuscitation, therefore TEG allows repeated assessment and correction throughout resuscitation period.

TEG-guided MHP algorithms, as compared to FRP may limit unnecessary blood product transfusion and the associated complications (e.g. TRALI, volume overload) of giving high volumes of plasma and other products, while ensuring appropriate clotting factors are replaced as required (i.e. allows targeted intervention to replace coagulopathy with fewer side effects)

Advantages of TEG compared with FRP

Patient specific – therefore may limit unnecessary blood product transfusion and the associated complications (e.g. TRALI, transfusion reaction, volume overload, TACO, immunomodulation, allergy)

Patient specific – therefore ensures appropriate clotting factors are replaced when required (i.e. allows rapid targeted intervention to replace coagulopathy with fewer side effects)

Aids rapid identification of when there is an ongoing medical cause of bleeding (i.e. ongoing coagulopathy) versus purely surgical bleeding with the need to progress surgical intervention.

Detects fibrinolysis and hyperfibrinolysis which may be particularly relevant in the critically bleeding trauma patient.

TEGs have a higher sensitivity than standard laboratory tests to detect trauma induced coagulopathy and are faster than lab-based tests.

Even a 1:1:1 (plasma:platelets:packed cells) delivers dilute coagulation factors compared with whole blood; ideal ratio of blood products to packed cells in FRP remains debated.

Disadvantages of TEG compared with FRP

Machine (ROTEM or TEG) not available in all centres;

More expensive than standard laboratory coagulation testing

Ability to manage MHPs in multiple trauma patients simultaneously limited by number of machines available

Requires adequate volume of blood sample to run test and can’t be performed on intraosseous sample; therefore, may not be able to be performed on critically unwell patient with difficult iv access.

May delay lab preparation (thawing) of blood products while awaiting result; compared with fixed ratio protocol where products immediately thawed and delivered. (i.e. FRP allows rapid delivery of blood products independent of test results)

Requires interpretation of values to guide blood product use.

Not valid to assess effects of platelet function, direct thrombin inhibitors, LMWH, warfarin

Evidence

Controversial; evidence exists to support TEG in identifying trauma induced coagulopathy, but limited RCT trials on role of TEG-guided MHP algorithms

STATA trial currently ongoing (FRP vs thromboelastometry guided MHP in trauma patients)

Single centre RCT reports reduced blood transfusion rates and improved-survival with TEG-guided MHP (Gonzalez 2016) (compared with MTP guided by conventional coagulation assays)

Systematic review (2014) – 55 observational studies on use of TEG to guide blood product use in trauma:

  • Findings overall inconclusive
  • Only one cohort in one study with penetrating trauma and packed cells>10 showed improved mortality with TEG-guided MHP

FRP:

 
  • PROMMTT (2013): observational – higher ratios of plasma and platelets early → decreased mortality
  • PROPPR (2015): RCT severe trauma – 1:1:1 vs 1:1:2 (plasma:plts:packed cells)
    • More haemostasis and less death due to exsanguination @ 24hr
    • No overall difference in mortality at 24 hrs or 30 days
    • better haemastasis & less death from exsanguination
 

Note: The level of detail in the evidence section was not expected.

Examiner Comments:

A very topical question that was generally answered in a very superficial way. Detailed reference to the weak evidence base was not required, but some recognition of this fact was expected. Better structure often ensured better marks.

Discussion

The examiners referred to TEG specifically in the question and throughout the answer, but it is clear that they were using the term interchangeably with ROTEM, and so in the discussion to follow TEG is also used as a surrogate for all forms of global testing for clotting function. Though the question asked specifically for a discussion of advantages and disadvantages, the college answer was formulated in a "critically evaluate" fashion which typically calls for a description of the rationale and supporting evidence  As such, some mutant combination of the two answer formats is offered here, as a compromise which satisfies the authors' unhealthy preoccupation with tabulated answers.

Rationale for TEG-guided massive transfusion

  • Scenarios which call for massive transfusion are diverse in aetiology (variceal bleed, postpartum haemorrhage, ruptured AAA, anticoagulant toxicity)
  • Diversity of aetiology produces a diversity of transfusion requirements
  • Ergo, transfusion should be individually tailored wherever possible 
  • Empirical replacement of whole-blood-like products may over-replace some products and under-replace others depending on the scenario
  • Individually tailored transfusion should therefore prevent wasteful use of blood products and increase the chances of correcting the coagulopathy
  • To tailor the transfusion process to an individual case requires the ability to monitor all aspects of clotting function including platelet function and fibrinolysis
  • TEG offers these capabilities in a single point of care test 
A comparison of TEG and empirical massive transfusion

Advantages of TEG

  • Rapid (10-20min)
  • Cheaper than wasting blood products
  • Conserves blood bank resources
  • Rapidly becoming more common
  • Tests fibrinolysis, which otherwise you cannot conveniently do
  • Individualised care: compensates for intercase variability of clotting factor consumption
  • Can be used to demonstrate that coagulopathy is fully corrected, as a means of promoting surgical management (i.e. excludes "medical bleeding")

Disadvantages of TEG

  • Not as rapid as empirical transfusion (wastes valuable minutes)
  • More expensive than coags if you incorporate the added recalibration and maintenance cost
  • Rare in smaller and regional centres
  • Assessment of fibrinolysis is often omitted in place of routinely giving (cheap, safe) tranexamic acid
  • Requires training to use and interpret
  • Precision is poor (UK NEQAS data)
  • Does not account for coagulopathy of hypothermia
  • Does not identify warfarin or most NOACs (Nielsen et al, 2013) - the findings are nonspecific (just long R time) 
  • TEG-guided algorithms do not enjoy widespread familiarity and are not universally accepted as valid

Advantages of fixed ratio massive transfusion

  • Rapidly available (time-limited by the thawing of FFP only)
  • Available almost everywhere
  • Easily protocolised, i.e. easy to order and thus it does not divert focus from managing the trauma 
  • Cost of products themselves is the only expense; i.e. maintenance cost for the blood bank staff and equipment is not purely for support of MTPs.
  • Widespread familiarity with the standard transfusion ratio
  • Does not interfere with the use of TEG (i.e. one may simply order the MTP pack while waiting for the TEG  sample to cook)

Disadvantages of fixed ratio massive transfusion

  • The exact ration (eg. 1:1:1) is still a matter of debate
  • The fixed ratio of products does not account for the possibility of fibrinolysis (sure, everybody gets tranexamic acid, but strictly speaking it is not part of the transfusion pack)
  • The practice of fixed ratio massive transfusion is non-diagnostic, i.e. unlike TEG it is not an investigation of clotting function but rather a management protocol which is implemented before results are available. It does not give you any information by itself.

Evidence which compares TEG-guided protocols with fixed ratio transfusion

  • "Systematic review (2014)" mentioned by the college examiners is probably Da Luz et al (2014), a descriptive systematic review which used relaxed criteria to drag-net 55 studies (12,489 patients). TEG appeared to uncover all sorts of coagulopathies which would not have been discovered by conventional testing (eg. hypercoagulability, hyperfibrinolysis, platelet dysfunction) which was an interesting finding. Of the total 55 studies, only three were rated as having a low risk of bias.
  • Hunt et al (2015), on TEG in trauma-induced coagulopathy performed a meta-analysis using different criteria (Cochrane) and also only found the same three 3 studies worth analysing. which turned this into a narrative review. Even with the risk of bias being low, there was not enough data to make a call on this. "This evidence strongly suggests that at present these tests should only be used for research", the authors concluded.
  • Wikkelsø et al (2017) reviewed all the data on TEG use and found 17 trials with a total of 1493 participants; this was more favourable:
    • Blood product use was demonstrably reduced
    • Transition to surgery was not affected
    • Mortality appeared to be lower in the TEG cohort as compared to historical controls (3.9% vs 7.4%) but it would be hard to attribute this to TEG use or to take it seriously in any other sense
    • Evidence was largely of a low quality, and most of it came from trials involving cardiac surgical patients
  • STATA trial mentioned by the college examiners is currently in progress at the University of Sao Paulo General Hospital;  interim analysis in 2015 demonstrated that the intervention group (TEG-guided) does not have any increase in their mortality or morbidity.
  • Gonzalez et al (2016) mentioned by the college examiners found an implausibly higher survival rate in their TEG group (19.6% vs. 36.4%) among a small cohort of trauma patients (n =111). Less plasma and platelet use was also noted, which is probably more objective and genuine.

References

Practical haemostasis - page on TEG and ROTEM

LITFL - Thromboelastogram

Sankarankutty, Ajith, et al. "TEG® and ROTEM® in trauma: similar test but different results." World J Emerg Surg 7.Suppl 1 (2012): S3.

Coakley, Margaret, et al. "Transfusion triggers in orthotopic liver transplantation: a comparison of the thromboelastometry analyzer, the thromboelastogram, and conventional coagulation tests." Journal of cardiothoracic and vascular anesthesia 20.4 (2006): 548-553.

Venema, Lieneke F., et al. "An assessment of clinical interchangeability of TEG® and ROTEM® thromboelastographic variables in cardiac surgical patients." Anesthesia & Analgesia 111.2 (2010): 339-344.

Nielsen, Vance G. "A comparison of the Thrombelastograph and the ROTEM." Blood Coagulation & Fibrinolysis 18.3 (2007): 247-252.

Wikkelsoe, A. J., et al. "Monitoring patients at risk of massive transfusion with Thrombelastography or Thromboelastometry: a systematic review." Acta Anaesthesiologica Scandinavica 55.10 (2011): 1174-1189.

Hunt, Harriet, et al. "Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma‑induced coagulopathy in adult trauma patients with bleeding." Cochrane Database of Systematic Reviews 2 (2015).

Nielsen, Jorn Dalsgaard, and Galloway Gregg. "Monitoring novel anticoagulants dabigatran, rivaroxaban and apixaban by thrombelastography. Proof of concept." (2013): 4813-4813.

Wikkelsø, A., et al. "Thromboelastography (TEG) or rotational thromboelastometry (ROTEM) to monitor haemostatic treatment in bleeding patients: a systematic review with meta‐analysis and trial sequential analysis." Anaesthesia 72.4 (2017): 519-531.

Gonzalez, Eduardo, et al. "Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays." Annals of surgery 263.6 (2016): 1051.

Da Luz, Luis Teodoro, et al. "Effect of thromboelastography (TEG®) and rotational thromboelastometry (ROTEM®) on diagnosis of coagulopathy, transfusion guidance and mortality in trauma: descriptive systematic review." Critical Care 18.5 (2014): 518.