Printable list of all haematology and oncology SAQs

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 The umbrella type is outdated.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.

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.

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.

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:

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:

• Peripheral blood smear, and a repeat platelet count in a citrated tube
• DIC screen: coagulation tests, D-dimers and fibrinogen
• Vitamin B12 level and full blood count
• HITTS screen: anti-platelet factor 4 antibody and platelet aggregation tests
• Autoimmune screen, including tests for SLE and other vasculitic diseases
• ADAMTS13 screening for TTP
• Bone marrow biopsy

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.

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

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).

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.

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.

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.

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:

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.

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.

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.

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.

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

• According to RCTs, it decreases transfusion requirements in trauma
• "Relatively safe" according to a 2005 meta-analysis

Disadvantages

• Insanely expensive
• May promote thrombosis, eg. DVTs
• Not actually approved for use in lifethreatening haemorrhage; most use is thus off-licence.
• No improvement in mortality has ever been found.

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.

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 DVT/ arterial 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:

• Question 12.1 from the second paper of 2012
• Question 8.3 from the first paper of 2011
• Question 3.1 from the first paper of 2008

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.

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

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.

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.

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.

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.

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.

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

​

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.

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.

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.

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.

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.

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

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

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.

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

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

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.

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

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.

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.

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:

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.

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.

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.

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.

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.

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

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

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 elsewhere.

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

• Increased mortality was confirmed according to a 2012 meta-analysis of multiple RCTs
• Higher risk of developing multi-organ system failure was also a consistent finding of the various trials

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.

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:

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.

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.

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.

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:

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.

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.

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.

College Answer

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:

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)

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.

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.

College Answer

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.

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.

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

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.

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.

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.

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:

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.

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.

References

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

UpToDate: Approach to the adult patient with thrombocytopenia.

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)

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.

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.

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.

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.

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.  

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:

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

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.

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:

• Leprosy
• Varicella zoster infection
• Serum sickness

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)