A 58 year old man is brought in by ambulance moribund with barely palpable pulse and a sinus tachycardia. A large pulmonary embolus is confirmed.
(e) After successful resuscitation you consider the insertion of a caval filter. List the pros and cons of its use and explain the technique of insertion
(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 The umbrella type is outdated.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
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
Indications for insertion
Advantages of the IVC filter
Disadvantages of the IVC filter
Insertion of the IVC filter:
Evidence to support or refute the use of these devices
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.
List the pharmacodynamic properties of:
when used to reduce the bleeding associated with cardiac surgery.
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.
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.
Properties | DDAVP | Aprotinin | Tranexamic acid |
Class |
|
|
|
Mechanism |
|
|
|
Dose |
|
|
30 mg/kg bolus followed by 16 mg/kg/hr infusion seems to be the favoured dose. |
Advantages |
|
|
|
Disadvantages |
|
|
|
Side effects |
|
|
|
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.
A 35 year old woman, who is receiving continuous renal replacement therapy for renal failure associated with abdominal sepsis, is noted to have a platelet count of 40 x 109/L. How will you manage this problem?
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.
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
Maximise platelet production
Protect the patient from complications of thrombocytopenia
Diagnosis is more complicated. The differential diagnosis of thrombocytopenia is broad:
Decreased platelet production
|
Increased platelet destruction
|
Pseudothrombocytopenia
|
Dilution of platelets
Sequestration
|
In order to simplify one's answer, one may be able to narrow this range to the causes which are relevant to the critically septic patient on dialysis:
This is a more manageable list.
One would organise the following investigations in order to work through it:
The links point to brief explanatory notes for these tests, which one may find in the local chapter on thrombocytopenia.
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.
List the potential causes of anaemia in critically ill patients, and outline how you would determine which factors were contributory.
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.
This question is identical to Question 9 from the second paper of 2005.
Outline your approach to the transfusion of red blood cells in the critically ill patient.
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).
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:
Evidence for this:
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).
A 45-year-old woman presents with seizures, after having had a fluctuating level of consciousness and fever. Her admission tests revealed:
Test |
Value |
Normal range |
Haemoglobin |
100 |
115-160 g/L |
White blood cells |
6.9 |
4.0-11.0 x10^9/L |
Platelets |
64 |
140-400x10^12/L |
International Normalised Ratio |
1.1 |
0.8 – 1.3 |
APTT |
38 |
24-35 seconds |
Fibrinogen |
3.6 |
2.0-5.0 g/L |
Na |
142 |
135-145 mmol/L |
K |
4.8 |
3.5-5.5 mmol/L |
Glucose |
6.8 |
3.6-7.7 mmol/L |
Urea |
18.9 |
2.5-8.3 mmol/L |
Creatinine |
0.21 |
0.05-0.11 mmol/L |
Lactate De-Hydrogenase |
540 |
120-250 IU/L |
What is the most likely diagnosis, and what other investigations would you order to help confirm the diagnosis? What do you expect the results of these investigations to show?
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.
The abnormalities and characteristic historical features are:
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:
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.
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.
A 68 yr old critically ill man with pulmonary infiltrates has the following haematology results.
Haemoglobin |
79 |
(130-170 g/L) |
Mean Corpuscular Volume |
83.8 |
(80-96 fL) |
White Cell Count |
1.5 |
(4.0-11.0 x10^9/L) |
Platelets |
47 |
(140-400x10^12/L) |
What is the haematological diagnosis?
List three potential causes of the haematological abnormalities?
Outline what relevant information could be obtained from a bone marrow biopsy in this case.
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).
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.
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.
List the problems associated with massive transfusion in the critically ill. Outline your principles of management for each.
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.)
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
Delayed complications
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.
Acute hemolytic transfusion reactions |
|
Febrile nonhemolytic transfusion reactions |
|
Allergic reaction to blood products |
|
Tranfusion-associated lung injury |
|
Transfusion-associated circulatory overload |
|
Bacterial sepsis |
|
Hypocalcemia due to citrate |
|
Hyperkalemia due to high PRBC K+ content |
|
Acidosis |
|
Hypothermia |
|
Dilutional coagulopathy |
|
Dilutional thrombocytopenia |
|
Delayed hemolytic transfusion reactions |
|
Transfusion-related immune modulation |
|
Microchimerism |
|
Transfusion-transmitted diseases |
|
Posttransfusion graft-vs-host disease |
|
Posttransfusion purpura |
|
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.
List the potential causes of anaemia in critically ill patients, and outline how you would determine which factors were contributory.
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
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
Increased loss of RBCs
Decreased production of RBCs
Thus, a panel of investigations which might differentiate between the abovementioned differentials should include the following:
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.
A 78 year old man on warfarin for atrial fibrillation develops a spontaneous weakness of his left hand and leg and a deteriorating conscious state. He presents within 20 minutes of onset of symptoms and a CT scan confirms a right parietal intra-cerebral haemorrhage. Outline your medical management of this case.
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.
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:
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:
The authors concluded that recombinant factor VIIa cannot be recommended for the reversal of warfarin therapy in warfarin-associated intracranial haemorrhage.
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.
Define the term “Transfusion Associated Lung Injury (TRALI)”. Briefly outline its pathophysiology and clinical features.
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.
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:
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:
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.
Write short notes on:
a) Recombinant activated protein C (drotrecogin alpha)
b) Recombinant coagulation Factor VIIa
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
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
Advantages
Disadvantages
Guidelines for practice
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.
A 23-year-old previously healthy girl involved in a motor vehicle accident is brought to ICU with multiple rib fractures and laceration of her left forearm. , no acute bleeding, She is haemodynamically stable and there is no evidence of acute bleeding. She has the following coagulation profile:
Test |
Result |
Normal range |
INR |
1.1 |
0.8-1.2 |
Prothrombin time |
11 |
10-15 |
APTI |
73 |
35-45 |
APTT after protamine |
69 |
35-45 |
APTI with 50% normal plasma |
53 |
35-45 |
Fibrinogen |
3.4 |
2.5-5 |
a) What is the likely explanation for the APTT result? Give reasons.
b) What further test would you order to confirm the aetiology of the coagulopathy?
c) What vascular complication is this patient at risk of?
d) What drugs might be suitable for DVT prophylaxis in this patient?
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
This is another one of those "why is my APTT so high" questions.
Specifically, this question closely resembles the following questions:
In this case, for some reason somebody gave the trauma patient some protamine. More commonly one would use a heparinase assay or the combination of thrombin time and reptilase time to exclude the effects of heparin, but a "protamine challange" is one way of doing it.
Antiphospholipid syndrome is discussed in greater detail elsewhere.
In brief, the major criteria for diagnosis require one clinical criterion (eg. thrombosis) and one laboratory criterion (eg. a positive anti-β2-glycoprotein-I antibody).
The laboratory tests one could order are as follows:
The antiphospholipid syndrome patient is prone to simultaneously clotting and bleeding.
The specific list of complication is as follows:
The most recent management guidelines suggest long term warfarin, with a target INR of 2.5.
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.
A 34 year old woman is transferred to your hospital with a history of a prolonged generalized tonic-clonic convulsion. She is intubated and ventilated. Blood samples have been collected for a full blood count, biochemistry and a coagulation profile. Her initial non contrast CT brain shows bilateral intracerebral hemorrhages. Her arterial blood gases and a haematology report are provided below
Parameter |
Patient values |
Normal range |
FiO2 |
0.5 |
|
pH |
7.15 |
7.35-7.45 |
PaCO2 |
35 mmHg (4.6 kPa) |
35-45 mmHg (4.7-6.0 kPa) |
PaO2 |
105 mmHg (14 kPa) |
75-98 mmHg (10-13 kPa) |
Bicarbonate |
10.3 mmol/l |
22-26 mmol/l |
Parameter |
Patient values |
Normal range |
Hb |
78 G/L |
(130-150) |
WCC |
14.5 x 106/mm3 |
(4.0-11.0) |
Platelets |
43 x 106 /mm3 |
(150-300) |
Blood picture: Thrombocytopaenia, fragmented cells and reticulocytosis
Coagulation profile: Normal
a) List the abnormalities on the blood gases. Give the most likely cause of each abnormality
b) Based on the history, CT scan and the hematology report, provide three possible differential diagnoses and give reasons
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.
This question is identical to Question 15.2 from the second paper of 2011, and Question 22.2 from the second paper of 2008.
. This is the haematology report of a 40 year old man who has been ventilated in intensive care 24 hours after a motor vehicle accident. He has suffered head, thoracic, abdominal and orthopaedic injuries.
Hb |
84 |
g/L |
(130-175)* |
WCC |
8.3 |
x 109/L |
(4.0-11.0) |
Platelets |
240 |
x 109/L |
(150-450) |
Reticulocytes |
220 |
x 109/L |
(10-80)* |
Neutrophils |
5.8 |
x 109/L |
(1.8-7.5) |
Lymphocytes |
1.5 |
x 109/L |
(1.5-4.0) |
Monocytes |
0.4 |
x 109/L |
(0.2-0.8) |
Eosinophils |
0.6 |
x 109/L |
(0.0-0.4) |
Haematocrit |
0.25 |
(0.4-0.52)* |
|
MCV |
88.4 |
fl |
(82-98) |
MCH |
30.2 |
pg |
(27.0-34.0) |
MCHC |
341 |
g/L |
(310-360) |
a) What is the most likely cause of the abnormalities?
b) He is due to undergo orthopaedic surgery and a laparotomy on day 2. A
coagulation profile performed prior to the procedure reveals the following.
Prothrombin |
0.9 |
INR |
(0.8-1.2) |
|
APTT |
33 |
sec |
(24-39) |
|
Fibrinogen |
6.1 |
g/L |
(1.5-4.0)* |
What is the cause of the raised fibrinogen?
c) On day 10 in intensive care, he develops a new fever, A full blood count and a septic screen are performed. The results of the full blood count are provided below. The septic screen results are awaited.
Hb |
76 |
g/L |
(130-175)* |
WCC |
15.8 |
x 109/L |
(4.0-11.0) |
Platelets |
1211 |
x 109/L |
(150-450) |
Reticulocytes |
220 |
x 109/L |
(10-80)* |
Neutrophils |
10.4 |
x 109/L |
(1.8-7.5) |
Lymphocytes |
2.06 |
x 109/L |
(1.5-4.0) |
Monocytes |
2.54 |
x 109/L |
(0.2-0.8) |
Eosinophils |
0.48 |
x 109/L |
(0.0-0.4) |
Haematocrit |
0.26 |
(0.4-0.52)* |
|
MCV |
92 |
fl |
(82-98) |
MCH |
29.9 |
pg |
(27.0-34.0) |
MCHC |
326 |
g/L |
(310-360) |
Film review: Moderate anisocytosis. Moderate polychromasia. Moderate number of target cells. Occasional Howell-Jolly bodies. Increased rouleaux formation. Marked thrombocytosis
c). What is the explanation for the blood picture?
d)Based on this explanation , what additional therapy will you consider ?
e) As a consequence of the head injury, he develops a hydrocephalus which requires a ventriculo-peritoneal shunt. He is discharged home 4 weeks later. Six months after discharge, he presents with fever, headache and seizures.
List the 2 most likely differential diagnoses.
a) What is the most likely cause of the abnormalities?
Acute blood loss . Hemolysis is unlikely in this setting.
b) He is due to undergo orthopaedic surgery and a laparotomy on day 2. A
coagulation profile performed prior to the procedure reveals the following.
Prothrombin |
0.9 |
INR |
(0.8-1.2) |
|
APTT |
33 |
sec |
(24-39) |
|
Fibrinogen |
6.1 |
g/L |
(1.5-4.0)* |
What is the cause of the raised fibrinogen?
Acute phase response
c) On day 10 in intensive care, he develops a new fever, A full blood count and a septic screen are performed. The results of the full blood count are provided below. The septic screen results are awaited.
Hb |
76 |
g/L |
(130-175)* |
WCC |
15.8 |
x 109/L |
(4.0-11.0) |
Platelets |
1211 |
x 109/L |
(150-450) |
Reticulocytes |
220 |
x 109/L |
(10-80)* |
Neutrophils |
10.4 |
x 109/L |
(1.8-7.5) |
Lymphocytes |
2.06 |
x 109/L |
(1.5-4.0) |
Monocytes |
2.54 |
x 109/L |
(0.2-0.8) |
Eosinophils |
0.48 |
x 109/L |
(0.0-0.4) |
Haematocrit |
0.26 |
(0.4-0.52)* |
|
MCV |
92 |
fl |
(82-98) |
MCH |
29.9 |
pg |
(27.0-34.0) |
MCHC |
326 |
g/L |
(310-360) |
Film review: Moderate anisocytosis. Moderate polychromasia. Moderate number of target cells. Occasional Howell-Jolly bodies. Increased rouleaux formation. Marked thrombocytosis
c). What is the explanation for the blood picture?
Post splenectomy
d)Based on this explanation , what additional therapy will you consider ?
Immunization for HIB. Meningococcus and pneumococcus.
Penicillin or other antibiotic prophylaxis
e) As a consequence of the head injury, he develops a hydrocephalus which requires a ventriculo-peritoneal shunt. He is discharged home 4 weeks later. Six months after discharge, he presents with fever, headache and seizures.
List the 2 most likely differential diagnoses.
a) Shunt infection / blocked shunt
b) Meningitis from encapsulated bacteria.
c) Consideration should be given to other causes such as viral and bacterial meningitis, however they will carry a lesser mark.
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:
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:
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.
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.
Examine the list of blood or plasma products listed in the table below. Indicate in your answer,
a) whether crossmatch is essential with the use of each of these products
b) one major indication for the use of each of these products.
Need for crossmatch |
One major indication for use |
|
Packed red blood cells |
||
Platelets |
||
Fresh frozen |
||
Cryo precipitate |
||
Prothrombin concentrate |
||
Granulocyte concentrate |
||
Intravenous immunoglobulin |
c) List one contraindication to the use of
i) Platelet transfusion
ii) IV immunoglobulin infusion
d) Very briefly, outline the role of erythropoietin in the management of anaemia of critical illness?
Examine the list of blood or plasma products listed in the table below. Indicate in your answer,
a) whether crossmatch is essential with the use of each of these products
b) one major indication for the use of each of these products.
Need for crossmatch |
One major indication for use |
|
Packed red blood |
Yes |
a) Acute blood loss |
Platelets |
No |
Platelets < 20,000 or <50,000 with bleeding, or pending interventional/surgicalprocedure, bone marrow failure - <10,000 in absence of risk factors, <20,000 in presence of risk factors |
Fresh frozen |
No |
Warfarin overdose, coagulopathy post transfusion, post bypass bleeding |
Cryo precipitate |
No |
DIC, coagulopathy post transfusion with low fibrinogen, hereditary hypofibrinogenemia, Hemophilia,Von willebrand’s disease |
Prothrombin |
No |
Warfarin overdose where FFP may be difficult to administer because of volume considerations |
Granulocyte |
Yes |
Neutropenic sepsis |
Intravenous |
No |
LGB syndrome, |
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.
his question closely resembles other questions where one is expected to match a blood product with a need for transfusion.
These questions are:
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:
The indications are as follows:
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.
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.
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.
54 year old male presents with a right deep vein thrombosis and haemoptysis. These blood results are from his admission.
Test |
Value |
Normal range |
PT |
12 sec |
(12-14) |
APTT |
69 sec |
(34-38) |
Thrombin time |
16 sec |
(14-18) |
APTT mixing test |
60 sec |
a) What is the APTT mixing test and its significance in this patient?
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
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.
Hunt, Beverley J. "Bleeding and coagulopathies in critical care." New England Journal of Medicine 370.9 (2014): 847-859.
62 year old with a prosthetic mitral valve was noted to have the following coagulation profile
Test |
Value |
Normal range |
PT |
101 sec |
(12-14) |
APTT |
45 sec |
(34-38) |
INR |
8.7 |
(0.8-1.2) |
a) What is the likely diagnosis?
b) Outline your management of this patient
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
This question closely resembles Question 15.1 from the second paper of 2011.
Hunt, Beverley J. "Bleeding and coagulopathies in critical care." New England Journal of Medicine 370.9 (2014): 847-859.
A 24 year old female has the following haematology and coagulation profile post admission to the intensive care unit following post partum haemorrhage.
Test |
Value |
Normal range |
WCC |
5.6 |
(4.0-11.0) |
Hb |
60* |
(115-165G/L) |
Platelets |
30* |
(150-400 X 109/L) |
PT |
30.6* |
(10.5-13.5 sec) |
APTT |
>150* |
(21-36 sec) |
D Dimer |
>10* |
(<0.4 microgram/ml FEU) |
Fibrinogen |
0.8* |
(1.1-3.2G/L) |
a) What is the likely cause of these coagulation abnormalities?
b) In this context, list 3 likely causes of this coagulation profile.
c) What does an elevated D-dimer indicate ?
a) What is the likely cause of these coagulation abnormalities?
DIC
b) In this context, list 3 likely causes of this coagulation profile.
c) What does an elevated D-dimer indicate ?
Tests fibrinolysis. It measures the break down of the X linked fibrin
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:
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.
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.
A 54 year old lady presented to the emergency department after having been unwell for 4 days. Her Full Blood Count (FBC) report is provided below.
Hb |
* 128 g/L |
(130 – 180) |
WBC | * 56.51 X109/L | (3.50 - 11.00) |
Platelet | 347 X109/L | (150 - 450) |
RBC |
5.27 X1012/L |
(4.50 - 6.50) |
HCT |
0.414 |
(0.40 - 0.54) |
MCV |
82.6 fL |
(80 – 100) |
MCH |
* 26.3 pg |
(26.5 - 33.0) |
MCHC |
310 g/L |
(310 – 360) |
NEUTROPHIL |
(96.3 %) * 54.40 X10^9/L |
(1.7 - 7.0) |
LYMPHOCYTE |
(2.8 %) 1.60 X10^9/L |
(1.5 - 4.0) |
MONOCYTE |
(0.7 %) 0.44 X10^9/L |
(0.1 - 0.8) |
EOSINOPHIL |
(0.1 %) 0.05 X10^9/L |
(0.04 - 0.44) |
BASOPHIL |
(0.1 %)0.02 X10^9/L |
(0.00 - 0.20) |
Moderate rouleaux. Marked neutrophilia. Dohle bodies present, toxic granulation present
a. What likely haematological process is revealed by the abnormal white cell and neutrophil count?
b. Cite 3 features on this FBC which support your answer in (a)
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
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.
|
|
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.
A previously well 54 year old man presents with confusion. On examination a rash is noted ( a clinical photograph provided). Temperature 37.1 The initial blood results are provided below.
Venous biochemistry
Na |
135 |
mmol/L |
(135-145) |
|
K |
3.8 |
mmol/L |
(3.5-4.5) |
|
Urea |
18 |
mmol/L |
(2.9-8.2) |
* |
Cr |
177 |
mol/L |
(70-120) |
* |
Bilirubin |
45 |
mol/L |
(<20) |
* |
Haematology |
||||
Hb |
99 |
g/L |
(135-180) |
* |
WBC |
10.8 |
x 109/L |
(4.0-11.0) |
|
Plt |
26 |
x 109/L |
(140-400) |
* |
Blood film: Schistocytes
Coagulation |
|||
PT |
10 |
s |
(9-12) |
APTT |
29 |
s |
(24-39) |
Fibrinogen |
3.0 |
g/L |
(1.7-4.5) |
30.2 |
a) What is the most likely diagnosis?
b) What treatment needs to be instituted urgently?
a) What is the most likely diagnosis?
Thrombotic thrombocytopenic purpura
b) What treatment needs to be instituted urgently?
• Plasmapheresis
This question closely resembles Question 7.2 from the second paper of 2009.
A previously healthy 34 year old woman is transferred to your hospital intubated and ventilated with a history of a prolonged generalized tonic-clonic convulsion. On arrival, she is deeply unconscious with a GCS of 3, fixed dilated pupils, absent tendon reflexes and bilateral up-going plantar reflexes. An admission CT scan shows bilateral intracerebral haemorrhages. A full blood count report is as follows:
1) Hb 78 g/l (130-150),
2) WCC 14.5 x 106/mm3 (4.0-11.0),
3) Platelets 43 x 106 /mm3 (150-300)
Blood picture: Thrombocytopaenia, fragmented cells and reticulocytosis
Based on the history, CT scan and the hematology report, provide three possible differential diagnoses
Eclampsia
Thrombotic thrombocytopaenic purpura
HUS
Meningococcal meningitis with DIC …(although big bleed is unlikely)
Vasculitis.
This question is identical to Question 15.2 from the second paper of 2011.
A 56 year old man was admitted to your ICU for monitoring of his deteriorating conscious state following an acute thrombotic stroke involving the carotid territory. Over the next 6 hours, the patient’s conscious state has improved significantly. However, you are notified of an abnormal coagulation result from a sample taken at 6 hours after admission to intensive care. There are no signs of bleeding.
PT |
Baseline 13 |
6 hours 27 |
(12-16 sec) |
APTT |
34 |
120 |
(32-36 sec) |
INR |
1.1 |
2.1 |
|
TT |
12 |
34 |
(12-14 sec) |
Platelets |
146 |
148 |
(150-300 X 109/L) |
Fibrinogen |
3.6 |
0.9 |
(2.5-4 G/L) |
a) Suggest a reason for the abnormal blood result.
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.
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:
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.
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.
A 57 year old female has the following haematology and coagulation profile post admission to the intensive care unit after a laparotomy for intraabdominal sepsis with significant blood loss.
WCC | *2.77 | (3.5 – 11.00 x109/L) |
Hb |
*65 |
(115 –165 g/L) |
Platelets |
*14 |
(150-400 x109/L) |
PT |
*28.9 |
(12.0 – 15 Sec) |
INR |
*2.7 |
(0.8 – 1.1) |
APTT |
*122.5 |
(25.0 – 37.0 Sec) |
Fibrinogen |
*1.1 |
(2.20-4.30g/L) |
a) What is the most likely cause of the coagulation abnormalities?
b) How would you correct the coagulopathy and briefly provide a reason for your choice of therapy or therapies?
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
This question is virtually identical to Question 13.1 from the second paper of 2013.
A 44 year old male presents with dyspnoea and is diagnosed as having multiple pulmonary emboli on Computerised tomography pulmonary angiogram (CTPA). He is commenced on 1000 units of heparin per hour after a 5000 unit bolus. During the night his heparin has steadily increased to 1500 units per hour.
These blood results are from the next morning.
Test |
Value |
Normal range |
PT |
12 sec |
12-16 |
APTT |
*38.3sec |
25.0-37.0 |
Fibrinogen |
3.8 g/ L |
2.20-4.30 |
D-DIM LIA |
*>20.0 mcg/ml |
<0.5 |
a) Give 2 reasons for the relatively low APTT despite heparin therapy
b) List 4 causes for an increased predisposition to venous thromboembolic disease
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
This question is identical to Question 13.2 from the second paper of 2013.
A 58 year old male is admitted with haematemesis. His coagulation profile is shown below. List 2 likely causes of his coagulation abnormalities?
Test |
Value |
Normal range |
PT |
*25.9 sec |
(12-14) |
APTT |
*39 sec |
(34-38) |
INR |
*2.4 |
(0.8-1.2) |
1) Liver dysfunction due to alcoholic or viral liver disease.
2) Vit K deficiency
3) Patient on warfarin therapy.
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:
The whole spectrum of abnormal coagulation studies is discussed in greater detail elsewhere.
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.
A 45 year old man received an allogeneic bone marrow transplant for Acute Lymphatic Leukaemia. 26 days after the transplant the patient developed severe gastroenteritis and a maculopapular skin rash and respiratory insufficiency.
The following investigations were performed:
Hb |
94 G/L |
(110-150 |
Na (mmol/L) |
132 |
135-145 |
|
WCC |
2.3 x 109/L |
(4.0-10.0) |
K ( mmol/L) |
3.4 |
3.5-.5.0 |
|
Platelets |
54 x 109/L |
(150-300) |
Urea (mmol/L) |
8.2 |
4.0-6.0 |
|
Creatinine (mmol/L) |
0.1 |
0.04-0.12 |
||||
Bilirubin (micromol/L) |
67 |
<25 |
||||
Alkaline phosphatase |
265 |
<125 |
||||
ALT |
51 |
<40 |
||||
AST |
40 |
<40 |
Coagulation profile - normal
Stool: Microscopy: WCC ++ Cultures: No growth
C.difficile toxin- Not detected
a) List 3 possible diagnoses.
Over the next 3 weeks, the patient developed generalized oedema predominantly in the trunk and lower extremities. An ultrasound Doppler study of the abdomen revealed dilated portal vein and inferior vena cava. The right atrial pressures were normal.
Portal pressure 18 mm Hg (8 – 10)
Infrahepatic IVC 20 mm Hg (9-11)
Hepatic vein 8 mm Hg (9-10)
Suprahepatic IVC 8 mm Hg (7-8)
Right atrium 6 mm Hg
b) What is the likely explanation for these findings?
c) Name 2 treatment measures for the diagnosis in b)
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
This question closely resembles Question 26.2 from the first paper of 2013.
Define tumour lysis syndrome. List the risk factors associated with its development. Outline measures to prevent it and provide a rationale for the use of each of those measures.
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.
This question is identical to Question 27 from the first paper of 2013.
Briefly outline the mode of action and half life of aspirin, tirofiban and clopidogrel.
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
The college answer is as detailed as one is expected to produce given that there is only about 90 seconds to think about it.
A slightly more detailed summary of antiplatelet agents is available. The following table is borrowed from there.
Drug |
Chemical properties |
Mechanism |
Clearance |
Half-life |
Duration of effect |
Aspirin |
Salycilate; |
Irreversible COX-1 inhibition, thus decreased production of the prothrombotic thromboxane A2 |
Renal |
1-2 hrs |
7-10 days |
Clopidogrel |
Thienopyridine |
Irreversible inhibition of P2Y12 ADP receptor, thus inhibition of cAMP-dependent platelet activation |
50% renal, |
0.5-1 hrs |
7-10 days |
Prasugrel |
Thienopyridine |
Irreversible inhibition of P2Y12 ADP receptor, thus inhibition of cAMP-dependent platelet activation |
Renal |
7 hrs |
7-10 days |
Ticagrelor |
Nucleoside (adenosine) analogue |
Reversible inhibition of P2Y12 ADP receptor, thus inhibition of cAMP-dependent platelet activation |
Biliary |
7-8 hrs |
3-5 days |
Abciximab |
Fab fragment of a human monoclonal antibody |
Glycoprotein IIb/IIIa inhibition, thus inhibition of platelet binding to fibrinogen and von Willebrand factor. |
Reticulo-endothelial system |
0.5 hr |
18-24 hours |
Tirofiban |
Small molecule non-peptide |
Glycoprotein IIb/IIIa inhibition, thus inhibition of platelet binding to fibrinogen and von Willebrand factor. |
Renal |
2 hrs |
4-8 hours |
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.
You review a 40 year old male with chest pain and shortness of breath. He had been admitted with a deep vein thrombosis in his right leg. His coagulation profile is shown below.
INR |
1 |
(0.9 TO 1.2) |
APTT |
61 seconds |
(24 to 39 sec) |
PT |
11.5 seconds |
(10.5 to 13.5 sec) |
A. List 5 causes of the abnormality in the coagulation profile
B. List 5 tests that could differentiate the cause of this abnormality
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
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:
Normal PT | Raised PT | |
Normal APTT |
|
Extrinsic pathway failure
|
Raised APTT |
Intrinsic pathway failureFactor deficiency or anticoagulant factor? This is answered by mixing studies.
|
Intrinsic and extrinsic pathway failure
|
In brief, the raised APPT could be caused by either an anticoagulant factor, or by a deficiency of the factors involved in the intrinsic or final common pathway.
Thus, it could be any of the following:
The tests one would wish to perform?
In their answer, the college also intelligently suggest that you repeat the APTT, as it could all be an artifact of sampling.
Hunt, Beverley J. "Bleeding and coagulopathies in critical care." New England Journal of Medicine 370.9 (2014): 847-859.
A 60 year old gentleman on subcutaneous enoxaparin 80 mg bd for deep vein thrombosis has the following blood results. The blood sample was taken prior to the dose of enoxaparin
INR 1.3 0.9 TO 1.2
APTT 38 SEC 24 to 39
D dimer <0.2 mg/l <0.2 mg/l
Anti Xa 1.8 IU/ml (therapeutic range 0.6 to 1.0 iu/ml)
List 2 likely causes of a raised Anti-Xa level in this patient?
a) If the patient has underlying renal failure
b) body weight is low / incorrect dose of enoxaparin
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 clearance mechanisms are inadequate:
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.
The following blood results are obtained in a patient post cardiac surgery.
a) What is the most likely cause of the abnormal coagulation profile ?
PT |
13.9 seconds |
10.5 to 13.5 |
INR |
1.4 |
0.9 to 1.2 |
APTT |
85 sec |
24 to 39 |
ACT |
240 seconds |
<150 seconds |
b) List 3 complications of the agent commonly used to correct the above coagulation abnormality.
Consistent with heparin
b) List 3 complications of the agent commonly used to correct the above coagulation abnormality.
Anaphylaxis Pulm HT Hypotension Bleeding Bradycardia
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.
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:
It also has antibacterial properties, mainly hitting the Gram-positives.
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.
List 3 causes of a massive splenomegaly.
° CML
° Myelofibrosis
° Chronic malaria
° Kala Azar
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:
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.
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.
A previously well 54 year old man presents with confusion. On examination a rash is noted (see photograph below). Temperature is 37.10 C. The initial blood results are provided on the next page.
Venous biochemistry |
||
Test |
Value |
Normal Range |
Sodium |
135 mmol/L |
135 -145 |
Potassium |
3.8 mmol/L |
3.5 - 4.5 |
Urea* |
18 mmol/L |
2.9 - 8.2 |
Creatinine* |
177 mol/L |
70 -120 |
Bilirubin* |
45 mol/L |
<20 |
Haematology |
||
Test |
Value |
Normal Range |
Hb* |
99 G/L |
135 -180 |
WBC |
10.8 x 109/L |
4.0 -11.0 |
Platelets* |
26 x 109/L |
140 - 400 |
Blood film: Schistocytes |
Coagulation |
||
Test |
Value |
Normal Range |
PT |
10 sec |
9 -12 |
APTT |
29 sec |
24 - 39 |
Fibrinogen |
3.0 G/L |
1.7 - 4.5 |
a) What is the most likely diagnosis? Provide 3 reasons.
b) What definitive treatment needs to be instituted urgently?
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
Thrombotic thrombocytopenic purpura is discussed in greater detail elsewhere.
Characteristic features of TTP are as follows:
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).
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.
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.
List 5 likely causes for the following coagulation profile.
Test |
Value |
Normal Range |
PT* |
35.4 Sec |
12.0 - 15.0 |
INR* |
3.5 |
0.8 - 1.1 |
APTT* |
>170.0 Sec |
25.0 - 37.0 |
FIBRINOGEN* |
0.9 G/L |
2.20 - 4.30 |
1) DIC
2) Primary fibrinolysis
3) Dilutional coagulopathy from massive transfusion
4) Post thrombolysis
5) Snake bite
This question is identical to Question 30.2 from the first paper of 2010.
Examine the coagulation profile from a patient in intensive care.
Test |
Value |
Normal Range |
Prothrombin ratio (INR) |
1.0 |
0.8 -1.2 |
APTT* |
65 sec |
24 -39 |
Platelets |
240 x 109/L |
150 - 400 |
Bleeding time |
4 min |
2 - 8 |
Fibrinogen |
2.8 G/L |
1.5 - 4.0 |
FDPs |
<10 mg/L |
0 -10 |
a) List 4 possible causes of this picture.
b) List 4 further tests which you will perform to identify the cause of the coagulopathy in question 23.2.
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
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:
Thus, to discriminate among all these causes, one would need to perform the following series of tests:
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.
A 62 year old lady has very significant bleeding following an uncomplicated total hip replacement. Her coagulation profile post blood transfusion is as follows:
Test |
Value |
Normal Range |
PT |
13.5 sec |
(12.0 – 15.0) |
INR |
1.0 |
(0.8 – 1.1) |
APTT* |
45 sec |
(25.0 – 37.0) |
APTT (After mixing with normal plasma) |
29 sec |
(25.0-37.0) |
Platelet count |
225 X109/L |
(150 – 450) |
(a) List two (2) likely causes of her deranged coagulation profile.
(b) List two (2) additional pieces of information from her history which might be of importance.
(c) Name two (2) further tests you will undertake to elucidate the cause of her coagulopathy and bleeding tendency.
(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.
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.
Normal PT | Raised PT | |
Normal APTT |
|
Extrinsic pathway failure
|
Raised APTT |
Intrinsic pathway failure
|
Intrinsic and extrinsic pathway failure
|
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:
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.
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.
List five (5) likely causes for the following coagulation profile:
Test |
Value |
Normal Range |
PT* |
35.4 sec |
(12.0 – 15.0) |
INR* |
3.5 |
(0.8 – 1.1) |
APTT* |
>170.0 sec |
(25.0 – 37.0) |
FIBRINOGEN* |
0.9 G/L |
(2.20 – 4.30) |
• DIC
• Primary fibrinolysis
• Dilutional coagulopathy from massive transfusion
• Post thrombolysis
• Snake bite
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:
Normal PT | Raised PT | |
Normal APTT |
|
Extrinsic pathway failure
|
Raised APTT |
Intrinsic pathway failure
|
Intrinsic and extrinsic pathway failure
|
So, the differentials for this sort of pan-coagulopathy are
Hunt, Beverley J. "Bleeding and coagulopathies in critical care." New England Journal of Medicine 370.9 (2014): 847-859.
A 78 year old man presented after a fall resulting in a bruised hip.
His Full blood count is the following:
Test |
Value |
Normal Range |
Hb |
120 G/L |
115 – 165 |
WBC* |
1.91 x 10^9/L |
3.50 – 11.00 |
PLT* |
28 X10^9/L |
150 – 450 |
RBC* |
3.01 X10^12/L |
3.80 – 5.80 |
HCT* |
0.358 |
0.37 – 0.47 |
MCV* |
118.9 fL |
80 – 100 |
MCH* |
39.9 pg |
26.5 – 33.0 |
MCHC |
335 G/L |
310 – 360 |
NEUTROPHIL 79.6% * |
1.5 x 10^9/L |
1.7 – 7.0 |
LYMPHOCYTE 17.3% * |
0.3 x 10^9/L |
1.5 – 4.0 |
MONOCYTE 3.1% * |
0.06 x 10^9/L |
0.1 – 0.8 |
EOSINOPHIL 0.0% * |
0.00 x 10^9/L |
0.04 –0.44 |
BASOPHIL 0.0% |
0.00 x 10^9/L |
0.00 – 0.20 |
Moderate anisocytosis. Marked macrocytosis.
(a) List four (4) causes for the raised MCV
• 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.
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:
There are also a few uncommon causes:
One can find a discussion of the many causes of macrocytosis in this article.
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.
A patient recovering from long term critical illness was found to have a Hb of 65G/L.
You request 3 units of packed RBCs. The blood bank informs you that the patient has an uncommon blood group and the only blood available although safe, is nearing the end of its storage life.
Outline the factors that may contribute to the reduced efficacy of such blood and what clinical consequences might be expected?
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:
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.
Storage lesions of packed red blood cells are discussed in greater detail in another chapter
One can also find an (out of date) Blood Service Policy on "The Age of Red Cells" from the Australian Red Cross.
Theoretical objections to the use of old PRBCs are raised by Aubron et al in their 2013 article.
In brief summary, the storage lesions are as follows:
Thus, the almost-expired blood has a number of disadvantages:
The clinical consequences of transfusing someone with such blood?
However, on meta-analysis, some of the other adverse effect risks were not supported:
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.
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.
Leukodepleted blood is being introduced into clinical practice in Australia. What are the perceived benefits of using such blood?
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.
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:
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.
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.
A 45 year old man was admitted with life threatening shock after being involved in a motor vehicle accident. He suffered extensive limb and thoracic injuries requiring emergency surgery. Intra operative course was complicated by major blood loss and haemodynamic instability. Post operatively following return to ICU, he was noted to become hypotensive and febrile and oozy from various drip and operative sites. Red urine was noted.
The following were the laboratory tests:
Test |
Value |
Normal Range |
Hb* |
87 G/L |
(130 – 150) |
WCC* |
18.9 x 109/L |
(4 – 11) |
Platelets* |
127 x 109/L |
(150 – 300) |
Urea* |
14.1 mmol/L |
(4 – 6) |
Creat* |
0.18 mmol/L |
(0.04 – 0.12) |
CK* |
2000 U/L |
(<50) |
Myoglobin |
Trace |
|
Urine Hemoglobin |
++ |
a) Based on his clinical history and the lab report, what is the likely cause of his post operative deterioration?
b) How will you confirm your diagnosis?
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
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:
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:
One may also wish to test the coags, given that this sort of reaction is often complicated by DIC.
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.
Examine the list of blood or plasma products listed in the table below. Indicate in your answer, whether cross match is essential with the use of each of these products.
Product |
Need for cross match |
Cryo precipitate |
|
Fresh frozen plasma |
|
Granulocyte concentrate |
|
Intravenous immunoglobulin |
|
Packed red blood cells |
|
Platelets |
|
Prothrombin concentrate |
Product |
Need for cross match |
Cryo precipitate |
No |
Fresh frozen plasma |
No |
Granulocyte concentrate |
Yes |
Intravenous immunoglobulin |
No |
Packed red blood cells |
Yes |
Platelets |
No |
Prothrombin concentrate |
No |
According to the college answer, only the red cells and granulocytes need crossmatching - the other blood products can apparently be given willy-nilly. This makes some sense in the context of the physiology of transfusion reactions; only RBCs and granulocytes are likely to have the relevant antigens on their surface. This refers to crossmatching specifically, where the compatibility between the patient and the donor product is tested by mixing samples to detect ABO incompatibility. The contrast between this and the "group and screen" is that the group and screen merely tests for blood group and screens for antibodies, whereas the crossmatch mixes samples to confirm compatibility and then the compatible PRBC bags are put aside for that specific patient.
As far as grouping and screening goes, the Australian Red Cross Blood Service also recommend that "where possible, patients should receive ABO-identical blood products". The main reason for this is not a lifethreatening transfusion reaction, but rather the immediate and frustrating destruction of the transfused platelets (for example). Additionally, though uncrossmatched plasma and plasma components are generally held to be safe, the ARCBS also recommends they be ABO group-compatible, because the transfused plasma may occasionally contain some antibodies to the recipient's native RBCs. The amount of antibodies transfused in this way will be very small, and the reaction will be on a smaller scale, but it is still an avoidable source of morbidity.
The ANZBT Guidelines for Pretransfusion Laboratory Practice reflect these issues, suggesting that for plasma transfusion a pretransfusion crossmatch is not required, but that products should ideally be compatible with the ABO group of the recipient's red cells. Additionally, they support the recommendation for the use of ABO-compatible platelets.
Thus, when amended with these recommendations, the college answer would look like this:
Product |
Need for cross match |
Need for group and antibody screen |
Cryo precipitate |
No |
Yes, ABO ideally |
Fresh frozen plasma |
No |
Yes, ABO ideally |
Granulocyte concentrate |
Yes |
Yes, always - ABO and RhD |
Intravenous immunoglobulin |
No |
No |
Packed red blood cells |
Yes |
Yes, always - ABO and RhD |
Platelets |
No |
Yes, ABO ideally |
Prothrombin concentrate |
No |
No |
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)
Examine the following haematology data set.
Test |
Value |
Normal Range |
WBC |
9.5 x 109/L |
(4.0 – 10.5) |
RBC* |
3 x 1012/L |
(4.3 – 5.7) |
Hb* |
88 G/L |
(130 – 170) |
PCV* |
0.36 |
(0.38 – 0.49) |
MCV* |
103fL |
(83 – 98) |
MCH |
30 pg/L |
(28 – 33) |
MCHC* |
370 |
(330 – 360) |
Platelets |
190 x 109/L |
(150 – 400) |
Reticulocytes 5%, Occasional erythroblast, spherocytes, Heinz bodies +++
a) Provide an explanation for the above set of results.
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
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
Unstable haemoglobins
Deranged RBC metabolism
Decreased clearance of defective RBCs
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.
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.
A 40 year old previously well male presents with a ruptured appendix and associated peritonitis (Day 0). He returns to theatre 3 days later with ischaemic colitis and requires a right hemicolectomy. At laparotomy, he is noted to have extensive thrombosis in his superior mesenteric vein and portal vein. Attempts to anticoagulate him postoperatively (day 5 onwards) with intravenous heparin have been unsuccessful.
His post op haematology results are as follows:
Day 0 |
Day 1 |
Day 3 |
Day 5 |
Day 7 |
Day 9 |
Range |
|
INR |
1.2 |
1.7 |
1.8 |
1.6 |
0.8 – 1.3 seconds |
||
APTT |
36 |
38 |
36 |
28* |
31* |
37* |
24 – 35 seconds |
Fibrinogen |
5.8 |
1.8 |
1.4 |
1.7 |
2.0 – 5.0 g/L |
||
INR mix |
1.9 |
0.8 – 1.3 seconds |
|||||
APTT mix |
32.5 |
30 – 40 seconds |
|||||
D dimer |
>4.0 |
< 0.5 mg/L |
* On I.V. heparin
APTT therapeutic range for I.V. heparin therapy: 60 – 90 seconds
Additional tests performed on Day 7
A. Tests of hypercoagulability (plasma)
Antithrombin (functional) 20% (Reference: 80 – 120%)
B. Factor assays (plasma)
Factor VIII 4.10 IU/ml (Reference: 0.5 – 1.5)
C. Anti-Factor Xa assay (plasma)
Anti-Factor Xa 0 IU/ml (Reference for IV heparin therapy: 0.3 – 0.7)
a) What are the possible factors preventing therapeutic anticoagulation in this patient?
b) List 2 strategies to effect anticoagulation with intravenous heparin.
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
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.
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.
A 28 year old man presented with a persistent epistaxis to the emergency department.
The coagulation profile was as follows:
Test |
Value |
Normal Range |
INR |
1.2 |
0.8 – 1.2 |
APTT |
50 seconds |
25 – 39 |
Platelets |
250 X 109 / L |
150 – 350 |
Bleeding time* |
16 minutes |
2 – 8 |
Fibrinogen |
3 g/L |
1.5 – 4 |
FDPs |
< 10 mg/L |
0 – 10 |
Thrombin clotting time |
15 seconds |
12 – 17 |
a) What is the most likely diagnosis?
b) What would you confirm your diagnosis
a) What is the most likely diagnosis?
Von Willebrand’s disease
b) What would you confirm your diagnosis
• History – easy bruising, mucosal bleeding
• Family history
• Plasma vWF levels
• Factor VIII levels /activity
There is only one situation in which one might have essentially normal APTT, but an elevated bleeding time. The APTT test would be slightly elevated because Factor 8 relies on vWF activity, and in the absence of vWF one is effectively Factor 8-deficient. The PT would be normal.
Pathophysiology
There are three main types of VWD:
History and examination
Blood biochemistry and coags
Management
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.
A 50 year old female presents with a right deep vein thrombosis and haemoptysis.
These blood results are from her admission:
Test |
Value |
Normal Range |
PT |
12 seconds |
12 – 14 |
APTT* |
69 seconds |
34 – 38 |
Thrombin time |
16 seconds |
14 – 18 |
APTT mixing test |
60 seconds |
a) What is the APTT mixing test and what is its significance in this patient?
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
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.
Hunt, Beverley J. "Bleeding and coagulopathies in critical care." New England Journal of Medicine 370.9 (2014): 847-859.
A 68-year-old male with chronic atrial fibrillation is noted to have the following coagulation profile
Parameter | Patient Value | Normal Range |
PT | 101 | 12-14 |
APTT | 45 | 34-38 |
INR | 8.7 | 0.8-1.2 |
a) What is the likely diagnosis?
b) Outline your management of this patient?
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
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:
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.
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.
A 34-year-old woman is intubated and ventilated following a prolonged generalized tonic-clonic seizure. Initial non-contrast CT brain shows bilateral intracerebral haemorrhages. Arterial blood gases and haematology results post intubation are as follows:
Parameter | Patient value | Normal range |
Arterial Blood Gas | ||
FiO2 | 0.5 | |
pH | 7.15 | 7.35 – 7.45 |
PaCO2 | 35 mmHg (4.6 kPa) | 35 – 45 (4.6 – 6.0) |
PaO2 | 105 mmHg | (14 kPa) |
HCO3 | 12* mmol/l | 22 – 26 |
Haematology | ||
Haemoglobin | 78 g/l | 130 – 150 |
WCC | 14.5 | l 4.0 – 11.0 |
Platelets | 43 | l 150 – 300 |
Blood picture: Thrombocytopaenia, fragmented cells and reticulocytosis
Coagulation profile: Normal
a) List the abnormalities on the arterial blood gas and give the most likely cause in each case
b) Give three possible diagnoses for her presentation based on the history and investigations
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
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.
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.
A 35-year-old woman (gravida 2, para 1), 34 weeks pregnant, has been admitted to your ICU with pre-eclampsia. Her blood pressure is 160/100, she has moderate proteinuria, normal liver function and a platelet count of 120 x 109 /L. There is no evidence of foetal distress. Her significant past history includes a Factor V Leiden mutation and a history of proximal vein thrombosis during her first pregnancy.
a) What pharmacological regimen would you recommend for DVT prophylaxis? Briefly outline your rationale.
b) List three other inherited thrombophilias that may predispose to DVT in pregnancy?
c) Despite appropriate DVT prophylaxis this patient develops clinical features suggestive of a proximal vein DVT. What investigations would you do to help establish the diagnosis and why?
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:
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?
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?
If iliac vein thrombosis suspected, consider:
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:
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.
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
A 24-year-old woman has the following haematology and coagulation profile post
admission to the intensive care unit following post partum haemorrhage.
Parameter | Patient Value | Normal Range |
White cell count | 5.6 x 109/l | 4.0 – 11.0 |
Haemoglobin | 60 g/l | 115 – 165 |
Platelets | 30 x 109/l | 150 – 400 |
PT | 30.6 sec | 10.5 – 13.5 |
APTT | >150 sec | 21 – 36 |
D-dimer | >10 µgm/ml | FEU <0.4 |
Fibrinogen | 0.8 g/l | 1.1 – 3.2 |
a) What does this pattern of coagulation abnormalities suggest?
b) List three likely causes of this coagulation profile in this patient
c) What does an elevated D-dimer indicate?
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
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:
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.
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.
A 64-year-old woman presents with lethargy, shortness of breath on exertion and jaundice.
Hb |
64 g/L |
(115-155) |
|
MCV |
102.4 fl |
(80.0-98.0) |
|
Platelets |
114 X 109/L |
(150-400) |
|
White Cell Count |
101 X 109/L |
(4.0-11.0) |
|
Neutrophils |
0.22% |
2.3 X 109/L |
(1.8-7.5) |
Lymphocytes |
97% |
98.7 X109/L |
(1.0-3.5) |
Monocytes |
0.0% |
0.0X109/L |
(0.20-0.80) |
Eosinophils |
0.0% |
0.0X109/L |
(0.02-0.50) |
Basophils |
0.0% |
0.0X109/L |
(0.0-0.10) |
Nucleated RBCs |
3.6 per 100 WBC |
||
Reticulocyte count |
280 X 109/L |
(20-150) |
Polychromasia. Poikilocytosis. Spherocytes. Smudge cells.
i. What is your interpretation of the leucocytosis?
ii. What is your interpretation of the anaemia?
iii. What additional test would you perform to help determine the underlying cause of the anaemia?
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
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:
Warm haemolytic anaemia | Cold haemolytic anaemia |
|
|
Additional tests:
Laboratory features common to all haemolytic anaemias
Laboratory features specific to autoimmune causes of haemolytic anaemia
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.
A 70-year-old man presents with a seven-day history of recurrent epistaxis, bruising and increasing haemoptysis. He has no significant past medical history other than a TIA for which he takes Aspirin. He does not have any epistaxis at present. His INR and APTT are normal.
Hb |
96 g/L * |
(135-175) |
RBC |
3.32 x 1012 /L* |
(4.50-6.00) |
PCV |
0.29 * |
(0.40-0.50) |
MCV |
86.7 fl |
(80.0-98.0) |
MCH |
28.9 pg |
(27.0-33.0) |
MCHC |
333g/L |
(315-355) |
Platelets |
2 x 109/L* |
(150-400) |
Immature Platelet Forms |
17%* |
(1.1-6.1) |
Reticulocytes |
0.6% |
(0.5-2.0) |
White Cell Count |
8.82 x 109/L |
(4.0-11.0) |
i. List 6 potential aetiologies for the above blood picture in this patient.
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.
Decreased platelet production
|
Increased platelet destruction
|
Pseudothrombocytopenia
|
Dilution of platelets
Sequestration
|
Stasi, Roberto. "How to approach thrombocytopenia." ASH Education Program Book 2012.1 (2012): 191-197.
UpToDate: Approach to the adult patient with thrombocytopenia.
List five likely causes for the following coagulation profile:
Parameter |
Result |
Normal Range |
PT |
35.4 secs* |
12.0 – 15.0 |
INR |
3.5* |
0.8 – 1.1 |
APTT |
>170.0 secs* |
25.0 – 37.0 |
Fibrinogen |
0.9 G/L* |
2.20 – 4.30 |
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.
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.
1) List the differential diagnoses of a low platelet count in the critically ill.
2) A 68-year-old man commenced on continuous renal replacement therapy for Acute Kidney Injury (AKI) following repair of a ruptured abdominal aortic aneurysm is noted to have a platelet count of 40 x 109/L. What is your management of this problem?
a)
Management consists of establishing the diagnosis and specific and supportive treatment.
The most likely causes in this patient are:
Other causes to be considered if indicated from history or examination
Treatment
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:
Decreased platelet production
|
Increased platelet destruction
|
Pseudothrombocytopenia
|
Dilution of platelets
Sequestration
|
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
Maximise platelet production
Protect the patient from complications of thrombocytopenia
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.
A 43-year-old woman is transferred to your Intensive Care Unit from a regional hospital following a motor vehicle crash. She is in haemorrhagic shock secondary to abdominal and pelvic trauma and received 3L crystalloid and 8 units O Rh(D) negative blood prior to arrival in your hospital.
a)
Risks common to all blood transfusions
(infection, allergy, haemolysis, TRALI, fluid overload, dilutional coagulopathy, etc)
Risks specific to O-ve uncrossmatched
Mixed field group and screen (unclear blood group)
Prolong group and cross match if specimen not taken before.
Non-ABO, non Rh (D) antigens/antibodies leading to allo-immunisation (sensitization) and delayed haemolytic reactions
b)
Blood Product |
Need for Crossmatch |
Packed red blood cells |
Yes |
Platelets |
No |
Fresh Frozen Plasma |
No |
Cryoprecipitate |
No |
Prothrombin concentrate |
No |
Granulocyte concentrate |
Yes |
Intravenous immunoglobulin |
No |
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:
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.
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.
The following is the haematological profile of a 22-year-old previously healthy female admitted to ICU with community acquired pneumonia:
Parameter |
Result |
Normal Range |
INR |
1.1 |
0.8 – 1.2 |
Prothrombin time |
11 seconds |
10 – 15 |
APTT |
73 seconds* |
35 – 45 |
APTT after protamine |
69 seconds* |
35 – 45 |
APTT with 50% normal plasma |
53 seconds* |
35 – 45 |
Fibrinogen |
3.4 G/L |
2.5 – 5 |
a)
b)
c)
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.
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.
A 72-year-old man is admitted to ICU post-operatively for multi-trauma following a motor vehicle crash. 10 days post admission he develops a new fever. Septic screen results are pending and the full blood count is as follows:
Parameter |
Result |
Normal Range |
Haemoglobin |
76 G/L* |
130 – 175 |
White Cell Count |
15.8 x 109/L* |
4.0 – 11.0 |
Platelets |
1211 x 109/L* |
150 – 450 |
Reticulocytes |
220 x 109/L* |
10 – 80 |
Neutrophils |
10.4 x 109/L* |
1.8 – 7.5 |
Lymphocytes |
2.06 x 109/L |
1.5 – 4.0 |
Monocytes |
2.54 x 109/L* |
0.2 – 0.8 |
Eosinophils |
0.48 x 109/L* |
0.0 – 0.4 |
Haematocrit |
0.26* |
0.4 – 0.52 |
MCV |
92 fl |
82 – 98 |
MCH |
29.9 pg |
27.0 – 34.0 |
MCHC |
326 g/L |
310 – 360 |
Comment on blood film: Moderate anisocytosis. Moderate polychromasia. Moderate number of target cells. Occasional Howell-Jolly bodies. Increased rouleaux formation. Marked thrombocytosis.
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.
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.
The following is the full blood count of a 66-year-old man admitted to the High Dependency Unit following a gastro-intestinal haemorrhage:
Parameter |
Result |
Normal Range |
Haemoglobin |
84 G/L* |
130 – 175 |
White Cell Count |
8.3 x 109/L |
4.0 – 11.0 |
Platelets |
240 x 109/L |
150 – 450 |
Reticulocytes |
220 x 109/L* |
10 – 80 |
Neutrophils |
5.8 x 109/L |
1.8 – 7.5 |
Lymphocytes |
1.5 x 109/L |
1.5 – 4.0 |
Monocytes |
0.4 x 109/L |
0.2 – 0.8 |
Eosinophils |
0.6 x 109/L* |
0.0 – 0.4 |
Haematocrit |
0.25* |
0.4 – 0.52 |
MCV |
88.4 fl |
82 – 98 |
MCH |
30.2 pg |
27.0 – 34.0 |
MCHC |
341 g/L |
310 – 360 |
What is the most likely cause of this haematological profile?
Acute blood loss
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.
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.
A 21-year-old African American female has been admitted with mild dyspnoea and severe back and abdominal pain. Pulse oximetry on room air is 94%.
Full Blood Count report is as follows:
Test |
Value |
Normal Adult Range |
White Cell Count* |
16.52 x 109/L |
4.0 – 11.0 |
Haemoglobin* |
82 g/L |
115 – 155 |
Platelets* |
529 x 109/L |
150 – 400 |
Haematocrit* |
0.23 |
0.40 – 0.54 |
Mean Corpuscular Volume |
93.5 fL |
79 – 99 |
Red Cell Count* |
2.47 x 1012/L |
4.5 – 6.5 |
Mean Corpuscular Haemoglobin |
33.2 pg |
27 – 34 |
Mean Corpuscular Haemoglobin Concetration |
355 g/L |
320 – 360 |
Neutrophils % |
58% |
40 – 80 |
Blood film comment:
Target cells – occasional
Spherocytes – occasional
Sickle cells – occasional
Neutrophilia with toxic granulation
a)
Sickle cell crisis
b)
Ensure adequate ABC – in particular supplemental oxygenation to keep saturations above 96%
IV fluids
Adequate analgesia
Investigate possible precipitants.
c)
Haemoglobinopathies
Iron deficiency
Spleen removal
Liver disease
Thalassaemia
Deficiency of enzyme lecithin cholesterol acyl transferase
This is a sickle cell crisis.
What makes it so? well, the sickle cells are a dead giveaway.
The precipitants?
Management of a sickle cell crisis depends somewhat on what sort of crisis it is. They come in vasoocclusive, aplastic and sequestration flavours.
All will require oxygen, analgesia and rehydration.
Most will require blood transfusion.
As for target cells:
You will see lots of target cells in
Fewer target cells are seen in
Okpala, Iheanyi E. "Sickle cell crisis." Practical Management of Haemoglobinopathies (2004): 63-71.
Walker, H. Kenneth, et al. "Peripheral blood smear." (1990). in Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition.
Bessis, Marcel. "Codocytes and Target Cells." Corpuscles. Springer Berlin Heidelberg, 1974. 59-64.
Jones, Kathy W. "Evaluation of Cell Morphology and Introduction to Platelet and White Blood Cell Morphology." I do not know which textbook this is form, but it is a chapter which is available for free online ... for now.
Bull, BRIAN S., J. Breton-Gorius, and E. Beutler. "Morphology of the erythron."New York, McGraw Hill (2001): 271-288. - this is an online re-posting of a chapter of Williams' Haematology, but without the figures.
A 72-year-old male has presented acutely unwell to the Emergency Department and found to be in acute renal failure. You have been asked to review him.
His Full Blood Count report is as follows:
Test |
Value |
Normal Adult Range |
White Cell Count |
6.45 x 109/L |
4.0 – 11.0 |
Haemoglobin* |
97 g/L |
130 – 180 |
Platelets |
181 x 109/L |
150 – 400 |
Haematocrit* |
0.282 |
0.40 – 0.54 |
Mean Corpuscular Volume* |
101.1 fL |
79 – 99 |
Red Cell Count* |
2.79 x 1012/L |
4.5 – 6.5 |
Mean Corpuscular Haemoglobin* |
34.8 pg |
27 – 34 |
Mean Corpuscular |
344 g/L |
320 – 360 |
Red Cell Distribution Width – Standard Deviation |
53.2 fL |
|
Red Cell Distribution Width – Coefficient Variation |
14.4% |
10.0 – 17.0 |
Neutrophils % |
64.1% |
a)
b)
This is macrocytic hypochromic anaemia.
One can find the many causes of macrocytosis in this article.
Four tests to rule them all?
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.
Aslinia, Florence, Joseph J. Mazza, and Steven H. Yale. "Megaloblastic anemia and other causes of macrocytosis." Clinical medicine & research 4.3 (2006): 236-241.
With respect to the peripheral blood film of an adult:
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.
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:
A 1958 article reports on a few more causes:
The college answer also includes the following causes, for which there is not much literature:
There are numerous others.
For instance, one article (recording the finding of peripheral plasmacytosis in a patient with Dengue fever) also mentions (and backs with references) the following causes:
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:
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:
Kyle, R. A., and S. V. Rajkumar. "Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma." Leukemia 23.1 (2009): 3-9.
Fadem, Robert S., and JOHN E. McBIRNIE. "PLASMACYTOSIS IN DISEASES OTHER THAN THE PRIMARY PLASMACYTIC DISEASES A REPORT OF SIX CASES." Blood 5.2 (1950): 191-200.
Aherne, W. A. "The differentiation of myelomatosis from other causes of bone marrow plasmacytosis." Journal of clinical pathology 11.4 (1958): 326-329.
Constantino, Benie T., and Bessie Cogionis. "Nucleated RBCs—significance in the peripheral blood film." Lab Medicine 31.4 (2000): 223-229.
SCHMIDT, JOHN J., HAROLD J. ROBINSON, and CHARLES S. PENNYPACKER. "Peripheral plasmacytosis in serum sickness." Annals of internal medicine 59.4 (1963): 542-546.
Bäumler, H., et al. "Basic phenomena of red blood cell rouleaux formation."Biorheology 36.5 (1999): 439-442.
Wagner, Christian, Patrick Steffen, and Saša Svetina. "Aggregation of red blood cells: From rouleaux to clot formation." Comptes Rendus Physique 14.6 (2013): 459-469.
REPLOGLE, ROBERT L., HERBERT J. MEISELMAN, and EDWARD W. MERRILL. "SPECIAL ARTICLE Clinical Implications of Blood Rheology Studies." Circulation 36.1 (1967): 148-160.
Ponder, Eric. "On sedimentation and rouleaux formation-I." Experimental Physiology 15.3 (1925): 235-252.
With respect to thrombotic thrombocytopaenic purpura (TTP):
a)
Thrombocytopaenia, Microangiopathic haemolytic anaemia, fever, neurological symptoms, renal failure.
b)
A trigger such as infection, surgery, pancreatitis, pregnancy, produces endothelial activation. ADAMTS 13 is a von Willebrand factor cleaving protein. When endothelial activation occurs and ADAMTS 13 activity is low (often due to an autoantibody inhibitor), large vWF multimers accumulate causing microvascular thrombosis and haemolysis
c)
In TTP daily exchanges of 1.5 plasma volumes are used until remission has occurs (platelet count > 150). Replacement with cryodepleted plasma has been recommended as it has less vWF than standard FFP and adequate amounts of ADAMTS 13, but there is no clearly demonstrated clinical advantage over replacement with standard FFP. Replacement with 4% albumin would be inappropriate.
In Guillain Barre Syndrome a course of treatment is given, typically 1.5 plasma volumes every second day for a total of 5 exchanges. The treatment is NOT continued until remission. Replacement with albumin has a lower complication rate than with FFP, and so is preferred.
d)
With plasmafiltration, the patient’s blood is pumped through a circuit similar to a renal replacement therapy circuit. The membrane used filters plasma off. The filtered plasma is replaced with a colloid such as 4% albumin or FFP.
With plasmapheresis, the patient’s blood drains into a reservoir where it is centrifuged into its compents. The non-plasma components are returned to the patient. The discarded plasma is replaced with a colloid such as 4% albumin or FFP
e)
Steroids such as methylprednisolone or prednisolone bind to steroid receptors in the cytoplasm, and are then translocated into the nucleus where they interaction with specific DNA sequences to either enhance or suppress gene transcription. This causes widespread effects on both innate and acquired immunity, suppressing the immune response.
Rituximab is an antibody against CD20 receptors on B cells, resulting killing of these cells, and hence suppressing the immune response.
With such succinct college answers it is difficult to find room for improvement. References for further reading will have to suffice.
A good NEJM review article is available from 2004, and within it one may be able to find the majority of the answers to the first parts of the question.
Characteristic features of TTP:
Underlying pathophysiological process of TTP:
Low ADAMTS-13 levels are clearly implicated. One could really get carried away with the details of pathogenesis here. A brief explanation would have to be limited to the statement that a loss of ADAMTS-13-mediated vWF destruction leads to an exccess of vWF and thus to a systemic prothrombotic state, with microvascular thrombosis responsile for all the organ system damage.
Plasma exchange regimens for TTP and for Guillain-Barre syndrome
Plasma exchange in TTP aims to remove the ADAMTS-13 inhbitor while replacing the missing ADAMTS-13 protein, and thus the replacement fluid needs to be FFP (as a pure albumin solution would have no ADAMTS-13 in it). One is obliged to continue the treatments until the microvascular thrombosis and thrombocytopenia are no longer posing a problem.
Plasma exchange for Guillain-Barre syndrome aims to clear the aetiological autoantibody from the bloodstream. In essence, we say "we have no idea which antibody is causing the demyelination, so we will get rid of all of them". The evidence seems to support a 5-treatment regimen; it seems that six treatments are no better than four. Because there is no missing proteins to replace, the exchanged plasma can be FFP or albumin - it does not seem to matter to the resolution of disease. However, because FFP has a slightly higher risk of transfusion reactions, so in general albumin is the recommended replacement solution, unless there are specific reasons to replace blood proteins.
The technique of plasmapheresis is discussed in a frustrating article of which only view the first two pages are available to the subscriptionless reader. It is at a basic level the centrifugal separation of blood components.
In contrast, a decent quality plasma filtration article is available to the pennyless public. It describes the process as being virtually identical to the hemofiltration of renal replacement therapy, with the main difference being the size of the membrane pores (they need to be large enough to allow the extrusion of all non-cellular blood components).
A good review of the immunosuppressant mechanism of corticosteroid therapy was published in 2011 in Molecular and Cellular Endocrinology. Its 35 pages are a wild excess of detail for the time-poor exam candidate. For a workmanlike understanding of the mechanism, the CICM answer will suffice.
As for Rituximab, the monoclonal CD20 antibody- one can avail oneself of the Roche propaganda pamphlet, or read about the mechanism of its effect in the 2010 article from the Seminars in Hematology. The pragmatic exam candidate will probably limit themselves to the understanding that an attack on the CD20 receptor results in a complement-mediated B cell holocaust.
Batlle, Daniel C., et al. "The use of the urinary anion gap in the diagnosis of hyperchloremic metabolic acidosis." New England Journal of Medicine 318.10 (1988): 594-599.
George, James N. "Thrombotic thrombocytopenic purpura." New England Journal of Medicine 354.18 (2006): 1927-1935.
Peyvandi, Flora, et al. "von Willebrand factor cleaving protease (ADAMTS‐13) and ADAMTS‐13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura." British journal of haematology 127.4 (2004): 433-439.
Tsai, Han-Mou. "Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura." Journal of the American Society of Nephrology 14.4 (2003): 1072-1081.
Zheng, X. Long, et al. "Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura." Blood103.11 (2004): 4043-4049.
McLeod, Bruce C. "Therapeutic apheresis: use of human serum albumin, fresh frozen plasma and cryosupernatant plasma in therapeutic plasma exchange."Best Practice & Research Clinical Haematology 19.1 (2006): 157-167.
Raphael, J. C., et al. "Plasma exchange for Guillain-Barré syndrome." Cochrane Database Syst Rev 2.2 (2002).
Reimann, P. M., and P. D. Mason. "Plasmapheresis: technique and complications." Intensive care medicine 16.1 (1990): 3-10.
Coutinho, Agnes E., and Karen E. Chapman. "The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights." Molecular and cellular endocrinology 335.1 (2011): 2-13.
A 45-year-old male received an allogeneic bone marrow transplant for acute lymphatic leukaemia (ALL). Twenty-six days after the transplant he developed severe gastroenteritis and a maculopapular skin rash and respiratory insufficiency.
The following investigations were performed:
Test |
Value |
Normal Adult Range |
Haemoglobin* |
94G/L |
110 – 150 |
WCC* |
2.3 x 109/L |
4.0–10.0 |
Platelets* |
54 x 109/L |
150 – 300 |
Sodium* |
132 mmol/L |
135 – 145 |
Potassium* |
3.4 mmol/L |
3.5–5.0 |
Urea* |
8.2 mmol/L |
4.0–6.0 |
Creatinine |
100 µmol/L |
40 – 120 |
Bilirubin* |
67 µmol/L |
<25 |
ALP* |
265 IU/L |
<125 |
AST |
40IU/L |
<40 |
ALT* |
51IU/L |
<40 |
Coagulation profile: Normal
Stool:
a) List three possible diagnoses.
Over the next 3 weeks, he developed generalized oedema predominantly in the trunk and lower extremities.
An ultrasound Doppler study of the abdomen revealed dilated portal vein and inferior vena cava and the following pressure measurements were obtained:
Test |
Value |
Normal Adult Range |
Portal pressure* |
18 mmHg |
8– 10 |
Infrahepatic IVC* |
20 mmHg |
9– 11 |
Hepatic vein* |
8 mmHg |
9– 10 |
Suprahepatic IVC |
8 mmHg |
7– 8 |
Right atrium |
6 mmHg |
5- 10 |
a)
Sepsis
CMV infection
Graft v Host disease
b)
Veno-occlusive disease of the liver
c)
TIPS procedure
Diuretics
Fluid restriction
Somewhat unfairly, the college has presented us with a patient suffering from some nonspecific symptoms. This young man is anaemic, thrombocytopenic, and has raised LFTs which may explain the high bilirubin. On the plus side, he seems to have engrafted.
Differentials would have to include GVHD (given the rash), CMV infection (given the gastroenteritis) and maybe sepsis - but DIC is ruled out by the absence of coagulopathy.
Generally speaking, the manifestatations of GVHD are as follows:
The college reminds us to think broad by throwing a sepsis and a CMV in there. Manifestations of CMV infection following bone marrow transplant are protean, and may include all of the features mentioned in the college question.
Is there an organ system it does not affect?
The suddenly increased portal pressure (normal is 5-10mmHg) is suggestive of veno-occlusive disease of the bone marrow transplant recipient. These pressure measurements are not diagnostic values, however. There are the Seattle criteria and there are the Baltimore criteria, neither of which actually mention any pressures at all - they demand hepatomegaly, ascites and raised bilirubin.
However, the pressure values are given for a reason.
The current BCSH/BSBMT guidelines suggest the following management options:
Baron, Frédéric, Manuel Deprez, and Yves Beguin. "The veno-occlusive disease of the liver." Haematologica 82.6 (1997): 718-725.
Dignan, Fiona L., et al. "BCSH/BSBMT guideline: diagnosis and management of veno‐occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation." British journal of haematology 163.4 (2013): 444-457.
Richardson, Paul G., et al. "Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial." Biology of Blood and Marrow Transplantation 16.7 (2010): 1005-1017.
Couriel, Daniel, et al. "Acute graft‐versus‐host disease: Pathophysiology, clinical manifestations, and management." Cancer 101.9 (2004): 1936-1946.
Ljungman, Per, Paul Griffiths, and Carlos Paya. "Definitions of cytomegalovirus infection and disease in transplant recipients." Clinical Infectious Diseases 34.8 (2002): 1094-1097.
Bearman, Scott I. "The syndrome of hepatic veno-occlusive disease after marrow transplantation." Blood 85.11 (1995): 3005-3020.
Coppell, Jason A., et al. "Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome." Biology of Blood and Marrow Transplantation 16.2 (2010): 157-168.
Mcdonald, George B., et al. "Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors."Hepatology 4.1 (1984): 116-122.
Jones, Richard J., et al. "Venoocclusive disease of the liver following bone marrow transplantation." Transplantation 44.6 (1987): 778-783.
Kumar, Ashish, Praveen Sharma, and Shiv Kumar Sarin. "Hepatic venous pressure gradient measurement: time to learn." Indian J Gastroenterol 27.2 (2008): 74-80.
A previously healthy 34-year-old female is transferred to your hospital intubated and ventilated with a history of a prolonged generalized tonic-clonic convulsion. On arrival, she is deeply unconscious with a GCS of 3, fixed dilated pupils, absent tendon reflexes and bilateral up-going plantar reflexes. An admission CT scan shows bilateral intracerebral haemorrhages.
A full blood count report is as follows:
Test |
Value |
Normal Adult Range |
Haemoglobin* |
78 G/L |
115 – 155 |
White Cell Count* |
14.5 x 109 / L |
4.0 – 11.0 |
Platelets* |
43 x 109 /L |
150 – 300 |
Blood picture:
Thrombocytopaenia, fragmented red cells and reticulocytosis.
The combination of thrombocytopenia, haemorrhage and a MAHA-like blood film all suggest the following differentials:
Define tumour lysis syndrome (TLS).
List the risk factors associated with the development of tumour lysis syndrome.
List the strategies used for the prevention and/or treatment of tumour lysis syndrome and provide a rationale for the use of each strategy.
a)
Definition
Tumor lysis syndrome (TLS) is an oncological emergency that is caused by massive tumor cell lysis with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation
b)
Risk factors
c)
Prevention
Treatment
Tumour lysis syndrome is a metabolic disorder characterized by hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia brought about by rapid tumor cell turnover. A good NEJM review article is available for the time-rich exam candidate. The current classification system demands at least two of the abovementioned electolyte abnormalities 2-7 days after the commencement of cancer therapy.
The same NEJM article contains within it Table 2, which lists the following risk factors:
Prevention and treatment are well covered by the college answer.
In brief summary:
Preventative measures:
Management strategies:
Tiu, Ramon V., et al. "Tumor lysis syndrome." Seminars in thrombosis and hemostasis. Vol. 33. No. 4. New York: Stratton Intercontinental Medical Book Corporation, c1974-, 2007.
Howard, Scott C., Deborah P. Jones, and Ching-Hon Pui. "The tumor lysis syndrome." New England Journal of Medicine 364.19 (2011): 1844-1854.
Cairo, Mitchell S., and Michael Bishop. "Tumour lysis syndrome: new therapeutic strategies and classification." British journal of haematology 127.1 (2004): 3-11.
A 57-year-old female has the following haematological and coagulation profile post admission to the ICU after a laparotomy for intra-abdominal sepsis with significant blood loss.
Parameter |
Patient Value |
Normal Adult Range |
Haemoglobin |
65 G/L* |
115 – 165 |
White cell count |
2.77 x 109/L* |
3.5 – 11.0 |
Platelets |
14 x 109/L |
150 – 400 |
Prothrombin Time |
28.9 seconds* |
12.0 – 15.0 |
International Normalised Ratio |
2.7* |
0.8 – 1.1 |
Activated Partial Thromboplastin Time |
122.5 seconds* |
25.0 – 37.0 |
Fibrinogen |
1.1 G/L* |
2.2 – 4.3 |
a) List two likely causes of the coagulation abnormalities.
b) State how you would correct the coagulopathy and give your reasoning.
a)
Haemodilution with inadequate replacement of blood and clotting factors
DIC.
b)
a) One does not need to degrade oneself with discussions of direct thrombin inhibitor toxicity and post-thrombolysis complications. The answer is obviously a massive transfusion associated with dilutional coagulopathy, with inadequate blood product replacement, and possibly also DIC.
b)
A structured approach would resemble the following:
A brief discussion of the clotting cascade and of the various factor replacement blood products is available elsewhere.
DeMuro, J. P., and A. F. Hanna. "Trauma Induced Coagulopathy: Prevention and Intervention."Scand J Trauma Resusc Emerg Med 20.47 (2014): 4.
A 44-year-old male presents with dyspnoea and is diagnosed as having multiple pulmonary emboli on a computerised tomography pulmonary angiogram (CTPA). He is commenced on 1000 units of heparin per hour IVI after a 5000 unit intravenous bolus. During the night his heparin infusion has steadily increased to 1500 units per hour.
These blood results are from the following morning:
Parameter |
Patient Value |
Normal Adult Range |
Prothrombin Time |
12 seconds |
12 – 16 |
Acivated Partial Thromboplastin Time |
38.3 seconds* |
25.0 – 37.0 |
Fibrinogen |
3.8 G/L |
2.2 – 4.3 |
D-Dimer |
> 20.0 mg/ml* |
< 0.5 |
a) Give two reasons for the relatively low APTT despite heparin therapy.
b) List four causes for an increased predisposition to venous thromboembolic disease.
a)
b)
Some discussion of the management of heparin resistance goes on in the end of my brief pharmacological entry on unfractionated heparin.
Reasons one might be resistant to heparin:
Anderson, J. A. M., and E. L. Saenko. "Editorial I Heparin resistance." British journal of anaesthesia 88.4 (2002): 467-469.
Young, E., et al. "Heparin binding to plasma proteins, an important mechanism for heparin resistance." Thrombosis and haemostasis 67.6 (1992): 639-643.
Hirsh, J., et al. "Heparin kinetics in venous thrombosis and pulmonary embolism." Circulation 53.4 (1976): 691-695.
Anderson, Frederick A., and Frederick A. Spencer. "Risk factors for venous thromboembolism." Circulation 107.23 suppl 1 (2003): I-9.
a) Define tumour lysis syndrome (TLS).
b) List the risk factors associated with the development of TLS.
c) List the strategies used for the prevention and/or treatment of TLS and provide a rationale for the use of each strategy.
a)
Definition
Tumor lysis syndrome (TLS) is an oncological emergency that is caused by massive tumor cell lysis with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation
b)
Risk factors
c)
Prevention
Treatment
Tumour lysis syndrome is a metabolic disorder characterized by hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia brought about by rapid tumor cell turnover. A good NEJM review article is available for the time-rich exam candidate. The current classification system demands at least two of the abovementioned electolyte abnormalities 2-7 days after the commencement of cancer therapy.
The same NEJM article contains within it Table 2, which lists the following risk factors:
Though it is described by the college as an oncological emergency, it could be pointed out that haematological malignancies are much more likely to cause tumour lysis syndrome, and it is less well known among solid tumours. This could be because of the increased vascular exposure of the haematological malignancy as compared to the relatively walled-off solid tumours. Mirrakhimov et al (2014) also suggest that the haematological malignancies are at the same time more aggressive and therefore more sensitive to chemotherapy, i.e. a larger proportion of the maligant cells will die with the first act of oncological chemoterrorism
Prevention and treatment are well covered by the college answer.
In brief summary:
Preventative measures:
Management strategies:
Tiu, Ramon V., et al. "Tumor lysis syndrome." Seminars in thrombosis and hemostasis. Vol. 33. No. 4. New York: Stratton Intercontinental Medical Book Corporation, c1974-, 2007.
Howard, Scott C., Deborah P. Jones, and Ching-Hon Pui. "The tumor lysis syndrome." New England Journal of Medicine 364.19 (2011): 1844-1854.
Cairo, Mitchell S., and Michael Bishop. "Tumour lysis syndrome: new therapeutic strategies and classification." British journal of haematology 127.1 (2004): 3-11.
Mirrakhimov, Aibek E., et al. "Tumor lysis syndrome in solid tumors: an up to date review of the literature." Rare tumors 6.2 (2014): 68-76.
A 50-year-old male patient is admitted to ICU following a laparotomy, splenectomy and partial hepatectomy for intra-abdominal bleeding following a high-speed motor vehicle crash with isolated abdominal trauma. He has had a massive transfusion in theatre. He continues to be fluid responsive with a falling haemoglobin concentration consistent with on-going intraabdominal bleeding.
a) Outline your management of this problem.
The International Normalised Ratio (INR) result is >10 and subsequent history reveals the patient was taking warfarin for recurrent deep vein thromboses.
b) List the steps you would take to correct the INR.
The INR corrects to 2.0 and a thromboelastometry is performed with the resultant graphs (Image A) as shown on page 11. (Graphs from a normal individual, Image B, are included for comparison.)
Image A: the patient
Image B: normal
c) What coagulopathy do the patient’s graphs represent and what therapy is indicated?
a)
Clinical examination:
Haemodynamics, abdominal examination, drain losses, exclude other sources of bleeding,
temperature, urine output.
Investigations:
Ensure blood cross-matched and available
FBC and Coagulation tests: aPTT, PR, Platelet count, D-Dimers, TEG, Fibrinogen
ABG
CXR
Resuscitation:
Volume replacement
Transfusion of blood products
Correction of electrolyte associated with massive transfusion; e.g. hypcalcaemia
Prevention and treatment of hypothermia
May consider haematology input and activation of a massive transfusion protocol or similar.
Discuss with the surgical team re returning to theatre.
The INR result is >10 and subsequent history reveals the patient was taking warfarin for recurrent
DVTs
b)
Prothrombin Complex concentrate dose 25-50units/kg
Vitamin K 10-20mg
Fresh frozen plasma if ongoing bleeding.(contains Factor VII which is not in PCC)
c)
Thrombocytopaenia / Platelet dysfunction
Platelet therapy +/- cryoprecipitate
Consider DDAVP
c) The ROTEM interpretation aspect of this question killed the mood for a lot of people in this exam. The college did not include their ROTEM images in the paper made public on their site, presumably because they plan to recycle them. However, in various ways people are able to get hold of the old papers. If one looks closely enough, one might discover that the college used this Haemoview powerpoint presentation slide for their "normal" image (go to slide 7) and this Haemoview training document for their example of a ROTEM with poor clot stability. Of course, I could have used the same images, but that would have been lazy (and possibly illegal). Instead, de novo synthesis of ROTEM graphs was performed.
Viscoelastic tests of clotting function (TEG and ROTEM) are discussed in greated detail elsewhere. Also, on the ROTEM data interpretation page there are examples of normal and abnormal ROTEM graphs for a series of coagulopathy scenarios. In order to simplify revision, I reproduce the table of normal variables below:
Test | CT | CFT | alpha-angle | MCF | A10 | LI30 | ML |
INTEM | 100-240 | 30-110 | 70-83 | 50-72 | 44-66 | 94-100 | <15 |
EXTEM | 38-79 | 34-159 | 63-83 | 50-72 | 43-65 | 94-100 | <15 |
HEPTEM | 100-240 | 30-110 | 70-83 | 50-72 | 44-66 | 94-100 | n/a |
APTEM | 38-79 | 34-159 | 63-83 | 50-72 | 43-65 | n/a | n/a |
FIBTEM | n/a | n/a | 30-70 | 9-25 | 7-23 | n/a | n/a |
To arrive at a sensible interpretation, let us go through the thromboelastometry data in systematic detail:
Practical Haemostasis - best explanation ever.
The following list refers to classes of oral anticoagulation regimens for use in chronic atrial fibrillation:
a) Give an example of a drug for each class of drug listed. (10% marks)
b) Compare and contrast these regimens specifically with respect to:
(You may tabulate your answer.) (90% marks)
Regimen / Agent | Advantages / Disadvantages | Assessment of coagulation status | Life-threatening bleeding |
Anti-platelet agentsAspirin, clopidogrel, ticagrelor |
A – Simple, no testing .D – Poor efficacy; prolonged action; limited reversibility, Minor increased risk of (non- traumatic) ICH |
APTT, INR, platelets Bleeding time, TEG/ROTEM, Platelet function tests | Platelet transfusion |
Vit K anatagonistsWarfarin |
A – Remains gold standard; easy reversibility. D – Requires frequent monitoring; multiple drug (and alcohol) interactions. 3-4% risk of (any) bleeding; 2-5x risk of ICH (absolute risk .3-0.8%) |
APTT, INR, platelets | Vit K / Prothrombin complex concentrate (Prothrombinex) / FFP |
Direct antithrombin agentsDabigatran |
A – No testing. D – Twice daily dosing; not suitable in severe renal impairment (80% renally cleared); no direct antidote; interacts with amiodarone. ICH risk lower than warfarin in some patient groups, but ischaemic stroke risk raised in prosthetic heart valves |
No specific tests | Activated charcoal if recent ingestionAntifibrinolytic (tranexamic acid)
Dialysis if co- existing renal impairment |
Anti Xa agentsRivaroxaban, apixaban |
A – No testing. D – Twice daily dosing for apixaban; no direct antidote (yet); dose modification in renal impairment (33% & 27% renally cleared) |
Anti-Xa levels |
Activated charcoal if recent ingestion Antifibrinolytic (tranexamic acid) |
Additional comments:
Some candidates included agents given by intravenous or subcutaneous routes instead of
focusing on oral agents as asked.
The college table is probably as succinct an answer as one can manage in under ten minutes. FOAM and non-FOAM resources to help answer this question include the following:
This bibliography is perhaps more extensive than is reasonable for a single SAQ. In order to answer the question, the table offered below has been reassembled from the following chapters:
Advantages | Disadvantages | Tests | Reversal |
Antiplatelet agents- aspirin, clopidogrel | |||
|
|
|
|
Vitamin K antagonists - warfarin | |||
|
|
|
|
Direct Thrombin Inhibitors - dabigatran | |||
|
|
|
|
Factor Xa inhibitors- apixaban, rivaroxaban | |||
|
|
|
|
But, let us say that instead of wanting to answer a fellowship exam question you actually wanted to anticoagulate somebody for AF. Which drugs are best? What do the guidelines say? AHA/ACC/HRS (2014) make some specific recommendations:
In this grand list of reversal agents, it is also worth mentioning idarucizumab (which already well known but not yet trialed in Phase II trails until August of 2015 by Pollack et al, well after this paper was sat and graded). Also in late 2015 the ANNEXA-A and ANNEXA-R trials (Siegal et al, 2015) demonstrated the efficacy of andexanet alfa in reversing rivaroxaban and apixaban. Future iterations of this question will expect these details. In coming years the availability of the "universal" reversal agent ciraparantag will likely render all this primitive witchcraft obsolete (Galliazzo et al, 2018) - this substance binds all the heparins and DOACS by hydrogen bonds, disabling them and neutralising their effects.
Tran, Huyen, et al. "New oral anticoagulants: a practical guide on prescription, laboratory testing and peri‐procedural/bleeding management." Internal medicine journal 44.6 (2014): 525-536.
Ansell, Jack, et al. "The pharmacology and management of the vitamin K antagonists." Chest 126.suppl 3 (2004): 204S-233S.
January, Craig T., et al. "2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary." J Am College Cardiol (2014).
Stangier, Joachim, and Andreas Clemens. "Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor." Clinical and Applied Thrombosis/Hemostasis (2009).
Kreutz, Reinhold. "Pharmacodynamic and pharmacokinetic basics of rivaroxaban." Fundamental & clinical pharmacology 26.1 (2012): 27-32.
Perzborn, Elisabeth, et al. "Reversal of rivaroxaban-induced anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant activated factor VII in vitro." Thrombosis research 133.4 (2014): 671-681.
Scaglione, Francesco. "New oral anticoagulants: comparative pharmacology with vitamin K antagonists." Clinical pharmacokinetics 52.2 (2013): 69-82.
Frost, Charles, et al. "Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects." British journal of clinical pharmacology 75.2 (2013): 476-487.
Ward, Christopher, et al. "Practical management of patients on apixaban: a consensus guide." Thromb J 11.1 (2013): 27.
Pollack Jr, Charles V., et al. "Idarucizumab for dabigatran reversal." New England Journal of Medicine 373.6 (2015): 511-520.
Siegal, Deborah M., et al. "Andexanet alfa for the reversal of factor Xa inhibitor activity." New England Journal of Medicine373.25 (2015): 2413-2424.
Galliazzo, S., M. P. Donadini, and W. Ageno. "Antidotes for the direct oral anticoagulants: What news?." Thrombosis research164 (2018): S119-S123.
The following data refer to a 34-year-old male admitted to ICU twenty days after an allogeneic stem cell transplant for acute myeloid leukaemia. Over the last few days he had been complaining of right upper quadrant abdominal pain, and observed to have gained several kilos in weight.
Parameter | Patient Value | Normal Adult Range |
Sodium | 142 mmol/L | 135 – 145 |
Potassium | 4.8 mmol/L* | 3.5 – 4.5 |
Chloride | 97 mmol/L | 95 – 105 |
Bicarbonate | 22 mmol/L | 22 – 26 |
Urea | 11.2 mmol/L* | 2.9 – 8.2 |
Creatinine | 134 μmol/L* | 70 – 120 |
Calcium | 2.13 mmol/L | 2.10 – 2.55 |
Phosphate | 1.21 mmol/L | 0.65 – 1.45 |
Total bilirubin | 342 μmol/L* | 0 – 25 |
Aspartate aminotransferase (AST) | 175 U/L* | < 40 |
Gamma glutamyl transferase (GGT) | 123 U/L* | < 40 |
Alanine aminotransferase (ALT) | 87 U/L* | < 40 |
a) Give the most likely diagnosis. (15% marks)
b) How would you confirm this? (15% marks)
a)
Veno-occlusive disease of the liver (sinusoidal obstruction syndrome)
b)
Liver USS showing ascites and reversal of portal vein flow
Let us dissect the results systematically.
The electrolytes look deceptively normal. However, an exam candidate accustomed to playing these games will recognise the presented panel as an invitation to calculate the anion gap. If one does this, one will discover that it is raised.
(142 + 4.8) - (97 + 22) = 27.8
There does not seem to be much of a metabolic acidosis associated with this, which is a little weird (delta ratio is very high, which could suggest that there is some sort of pre-existing metabolic alkalosis present).
The ure and creatinine are raised, but not to a significant degree. Certainly not by a degree that might explain this weight gain with renal-related fluid overload.
The calcium and phosphate are trivially deranged; the normal phosphate suggests that the accumulation of retained non-volatile acids of renal failure is probably not responsible for the high anion gap.
Liver enzymes are deranged. ALT AST and GGT are all elevated, and even though alkaline phosphatase is not reported one can generally comment that there is non-specific liver injury occurring (i.e. the right upper quadrant pain is probably not acute cholecystitis, but rather the feeling of a swollen liver distending its capsule). The liver injury also suggests that lactate could explain the raised anion gap.
In summary:
None of these are parfticularly specific and you'd be struggling to narrow your list of differentials, but the college helpfully threw in the story about a recent bone marrow transplant. That's a giveaway. In the pattern recognition algorithm of the exam candidate, liver injury + BMT = VOD. Veno-occlusive disease tends to occur in the first three weeks after the transplant, and typically manifests with weight gain and a painful liver. The major clinical criteria for diagnosis (Seattle criteria and Baltimore criteria) usually also demand ascites, hepatomegaly and a bilirubin level (which we were not supplied with; it would have to be over 34 mmol/L).
Diagnosis does not require ultrasound, but it is usually ordered in this context. The BCSH/BSBMT guidelines (2013) concluded that "the main role of ultrasound is to exclude the presence of other diagnoses" because the ultrasound findings which are usually associated with VOD are insufficiently sensitive and specific. In any case, here they are:
Mohty, M., et al. "Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation." Bone marrow transplantation 51.7 (2016): 906-912.
Baron, Frédéric, Manuel Deprez, and Yves Beguin. "The veno-occlusive disease of the liver." Haematologica 82.6 (1997): 718-725.
Dignan, Fiona L., et al. "BCSH/BSBMT guideline: diagnosis and management of veno‐occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation." British journal of haematology 163.4 (2013): 444-457.
Richardson, Paul G., et al. "Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial." Biology of Blood and Marrow Transplantation 16.7 (2010): 1005-1017.
Couriel, Daniel, et al. "Acute graft‐versus‐host disease: Pathophysiology, clinical manifestations, and management." Cancer 101.9 (2004): 1936-1946.
Ljungman, Per, Paul Griffiths, and Carlos Paya. "Definitions of cytomegalovirus infection and disease in transplant recipients." Clinical Infectious Diseases 34.8 (2002): 1094-1097.
Bearman, Scott I. "The syndrome of hepatic veno-occlusive disease after marrow transplantation." Blood 85.11 (1995): 3005-3020.
Coppell, Jason A., et al. "Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome." Biology of Blood and Marrow Transplantation 16.2 (2010): 157-168.
Mcdonald, George B., et al. "Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors."Hepatology 4.1 (1984): 116-122.
Jones, Richard J., et al. "Venoocclusive disease of the liver following bone marrow transplantation." Transplantation 44.6 (1987): 778-783.
Kumar, Ashish, Praveen Sharma, and Shiv Kumar Sarin. "Hepatic venous pressure gradient measurement: time to learn." Indian J Gastroenterol 27.2 (2008): 74-80.
Cheuk, D. K., et al. "Interventions for prophylaxis of hepatic veno-occlusive disease in people undergoing haematopoietic stem cell transplantation." The Cochrane database of systematic reviews 5 (2015): CD009311-CD009311.
Mohty, M., et al. "Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation." Bone marrow transplantation 51.7 (2016): 906-912.
The following data refer to a 67-year-old male 8 days following initiation of treatment for acute leukaemia:
Parameter | Patient Value | Normal Adult Range |
Haemoglobin | 102 g/L* | 130 – 180 |
White Cell Count | 111 x 109/L* | 4 – 11 |
Platelets | 21 x 109/L* | 150 – 350 |
Blasts | 100 x 109/L* | 0 |
Sodium | 136 mmol/L | 136 – 145 |
Potassium | 6.1 mmol/L* | 3.5 – 5.0 |
Chloride | 95 mmol/L* | 98 – 106 |
Bicarbonate | 17 mmol/L* | 23 – 28 |
Urea | 21.8 mmol/L* | 2.9 – 7.1 |
Creatinine | 209 μmol/L* | 60 – 120 |
Calcium (corrected) | 2.48 mmol/L | 2.20 – 2.60 |
Phosphate | 2.76 mmol/L* | 0.80 – 1.45 |
Magnesium | 0.81 mmol/L | 0.60 – 1.10 |
Urate | 0.84 mmol/L* | 0.20 – 0.42 |
Total protein | 59 g/L* | 60 – 78 |
Albumin | 27 g/L* | 35 – 55 |
Bilirubin | 9 μmol/L | < 20 |
Alkaline phosphatase (ALP) | 587 U/L* | 36 – 92 |
Alanine transferase (ALT) | 42 U/L* | < 35 |
Gamma glutamyl transferase (GGT) | 110 U/L* | < 30 |
Lactate dehydrogenase (LDH) | 7157 U/L* | 60 – 100 |
a) Give the underlying cause of the above abnormalities and give your reasoning to explain these findings. (20% marks)
b) List the treatment options for this condition. (30% marks)
a)
Tumour lysis syndrome
Renal impairment with hyperkalaemia, hyperphosphataemia, hyperuraecamia and increased LDH
b)
Resuscitation – Adequate IV hydration
Treatment of hyperkalaemia – Calcium chloride, bicarbonate if ECG changes, dextrose- insulin, dialysis, resonium
Renal replacement therapy – metabolic acidosis, hyperkalaemia and hyperphosphataemia Allopurinol
Rasburicase
Let us dissect the results systematically.
The abnormalities and their potential explanations are:
The patient also has a white cell count of 111. This gives rise the the supicion that the hyperkalemia may be "pseudohyperkalemia of malignancy". The presence of haematological malignancy generally means a high white cell count; these extra cells are immature blasts which are structurally unsound, being exempt from normal cellular quality control mechanisms. The very act of aspirating these fragile cells into a syringe or vacutainer may give rise to wholesale cellular destruction by shear stress. The result is a falsely elevated potassium level. Kintzel and Scott presented a case report of this (2012) where the potassium level was 9.8mmol/L in the badly lysed sample and 4.1 mmol/L in the heparinised tube.
The treatment options are:
Tiu, Ramon V., et al. "Tumor lysis syndrome." Seminars in thrombosis and hemostasis. Vol. 33. No. 4. New York: Stratton Intercontinental Medical Book Corporation, c1974-, 2007.
Howard, Scott C., Deborah P. Jones, and Ching-Hon Pui. "The tumor lysis syndrome." New England Journal of Medicine 364.19 (2011): 1844-1854.
Cairo, Mitchell S., and Michael Bishop. "Tumour lysis syndrome: new therapeutic strategies and classification." British journal of haematology 127.1 (2004): 3-11.
Locatelli, Franco, and Francesca Rossi. "Incidence and pathogenesis of tumor lysis syndrome." Hyperuricemic Syndromes: Pathophysiology and Therapy. Vol. 147. Karger Publishers, 2005. 61-68.
Hsu, Hsiang-Hao, Yi-Ling Chan, and Chiu-Ching Huang. "Acute spontaneous tumor lysis presenting with hyperuricemic acute renal failure: clinical features and therapeutic approach." Journal of nephrology 17.1 (2004): 50-56.
Tiu, Ramon V., et al. "Tumor lysis syndrome." Seminars in thrombosis and hemostasis. Vol. 33. No. 04. Copyright© 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA., 2007.
Oda, Masako, et al. "Loss of urate oxidase activity in hominoids and its evolutionary implications." Molecular biology and evolution 19.5 (2002): 640-653.
Kintzel, Polly E., and William L. Scott. "Pseudohyperkalemia in a patient with chronic lymphoblastic leukemia and tumor lysis syndrome." Journal of Oncology Pharmacy Practice 18.4 (2012): 432-435.
Izumi, Masakazu, et al. "Increased serum alkaline phosphatase activity originating from neutrophilic leukocytes." Clinical chemistry 51.9 (2005): 1751-1752.
The following data refer to a 65-year-old male admitted to ICU with septic shock on a background of active rheumatoid arthritis.
Parameter | Patient Value | Normal Adult Range |
Haemoglobin | 86 g/L* | 125 – 180 |
Serum ferritin | 298 μg/L | 15 – 300 |
Serum iron | 7 μmol/L* | 9 – 27 |
Total Iron Binding Capacity (TIBC) | 52 μmol/L | 47 – 70 |
Transferrin Saturation (Iron / TIBC x 100) | 28% | 16 – 40 |
Erythropoietin level | 15 U/L | 4 – 28 |
C-reactive protein (CRP) | 321 mg/L* | <8 |
a) What abnormality is demonstrated in this patient? Give your reasoning. (20% marks)
b) What is the pathogenesis of these changes? (20% marks)
c) What specific treatment strategy would correct the demonstrated abnormality? (10% marks)
a)
Anaemia of Inflammation demonstrated by:
b)
Inflammation -> cytokines (IL6) -> increased hepcidin -> decreased iron release from bone marrow, decreased iron release from macrophages, decreased absorption of iron -> suppressed erythopoeisis
c)
Control inflammation, no value to iron replacement, no value to the use of erythropoietin.
Local resources to help with such questions include the following chapters:
In the above, there is a table of typical findings which is reproduced below:
Condition | MCV | MCHC | Serum iron | Ferritin | Transferrin | Transferrin saturation |
TIBC |
Iron deficiency anaemia | low | low | low | low | high | <20% | high |
Anaemia of inflammation (chronic disease) | low | low | low | normal | low | normal | low or normal |
Acute phase response | normal | normal | low | high | low | low | low |
Iron overload | normal | normal | high | high | normal | high | high |
The college answer refers to "Anaemia of Inflammation", a nomenclature which has superseded "anaemia of chronic disease" as the description of the anaemia which has low serum iron in spite of normal body iron stores (i.e. normal ferritin). This "inflammation" could actually be anything proinflammatory, and so it would be difficult to comment whether the rheumatoid arthritis is more responsible then the sepsis, or vice versa. In either case, the biochemical picture would be more or less the same.
Alternative explanations for these laboratory results could also include the anaemia of decreased erythropoietin release associated with renal failure; but the college specifically gave us RA, sepsis and a raised CRP, clearly aiming the candidates at something inflammatory. Iron studies in anaemia of chronic renal failure tend to demonstrate iron deficiency, i.e. the ferritin is also low, but there is a group in whom there is a "functional" iron deficiency with normal ferritin levels and a failure of iron release from body stores (Babitt & Lyn, 2012). If the inflammatory elements were omitted from the story, this would be a legitimate alternative explanation
The mechanism of anaemia of inflammation can be summarised as follows:
Routine management of such an anaemia is therefore somewhat unexciting:
But let's say that for some reason you've lost interest in treating causes of things. Can we cosmetically make the iron study numbers look better? Turns out that yes, we can. There are several possible treatments for this sort of anaemia which specifically target the mechanism of its pathogenesis:
Hawkins, Stephen F., and Quentin A. Hill. "Diagnostic Approach to Anaemia in Critical Care." Haematology in Critical Care: A Practical Handbook (2014): 1-8.
Gross, I. "Laboratory Studies in the Diagnosis of Iron Deficiency, Latent Iron Deficiency and Iron Deficient Erythropoiesis". from http://iron.sabm.org
Pieracci, Fredric M., et al. "A Multicenter, Randomized Clinical Trial of IV Iron Supplementation for Anemia of Traumatic Critical Illness*." Critical care medicine 42.9 (2014): 2048-2057.
Litton, Edward, et al. "The IRONMAN trial: a protocol for a multicentre randomised placebo-controlled trial of intravenous iron in intensive care unit patients with anaemia." Crit Care Resusc 16 (2014): 285-290.
Corwin, Howard L., et al. "Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial." Jama 288.22 (2002): 2827-2835.
Mesgarpour, Bita, et al. "Safety of off-label erythropoiesis stimulating agents in critically ill patients: a meta-analysis." Intensive care medicine 39.11 (2013): 1896-1908.
Nemeth, Elizabeta, and Tomas Ganz. "Anemia of inflammation." Hematology/Oncology Clinics 28.4 (2014): 671-681.
Babitt, Jodie L., and Herbert Y. Lin. "Mechanisms of anemia in CKD." Journal of the American Society of Nephrology (2012): ASN-2011111078.
Nemeth, Elizabeta, and Tomas Ganz. "Anemia of inflammation." Hematology/Oncology Clinics 28.4 (2014): 671-681.
The following data refer to a 48-year-old female admitted electively to ICU following extensive pelvic surgery for invasive endometrial carcinoma. The patient has remained in ICU for 22 days because of complications including acute kidney injury.
Parameter | Patient Value | Normal Adult Range | ||||
Haemoglobin | 66 g/L* | 125 – 180 | ||||
Serum ferritin | 14 μg/L* | 15 – 300 | ||||
Serum iron | 3 μmol/L* | 9 – 27 | ||||
Total Iron Binding Capacity (TIBC) | 86 μmol/L* | 47 – 70 | ||||
Transferrin Saturation | 9%* | 16 – 40 | ||||
Erythropoietin level | 41 U/L* | 4 – 28 | ||||
C-reactive protein (CRP) | 60 mg/L* | <8 |
a) What abnormality is demonstrated in this patient? Give your reasoning. (20% marks)
b) Give two potential causative factors in this patient. (10% marks)
c) Briefly outline the available treatment options to correct the demonstrated abnormality including any disadvantages / risks. (20% marks)
a)
Iron deficiency anaemia as evidenced by:
b)
Blood loss
Pre-existing dietary deficiency
c)
IV iron replacement – no demonstrated benefit and risks of adverse effects (awaiting Ironman study)
Oral iron replacement
Erythropoeitin – expensive and no demonstrated benefit
Blood transfusion – risks of transfusion including immunosuppression
Nil – may have reduced oxygen carrying capacity for some time until correction of Hb
Local resources to help with such questions include the following chapters:
In the above, there is a table of typical findings which is reproduced below:
Condition | MCV | MCHC | Serum iron | Ferritin | Transferrin | Transferrin saturation |
TIBC |
Iron deficiency anaemia | low | low | low | low | high | <20% | high |
Anaemia of chronic disease | low | low | low | normal | low | normal | low or normal |
Acute phase response | normal | normal | low | high | low | low | low |
Iron overload | normal | normal | high | high | normal | high | high |
Following from this, the results in this SAQ are pretty clearly iron deficiency anaemia (low haemoglobin, low iron, high TIBC, etc). The erythropoietin level is appropriately elevated, but not essential to making the diagnosis. Apart from blood loss and dietary deficiency, there's not much that can be added to the "potential causative factors".
The available treatment options are:
The college also included "do nothing" as a management option, though one might object that conceptually this would be the very opposite of a management plan. They also included recombinant human EPO as one of the treatment options, but then they also gave us a serum EPO which is significantly elevated. This defies logic- adding more exogenous EPO to the already high EPO level is unlikely to achieve a glorious haemopoietic victory, as the haemoglobin was still low even with the EPO levels almost double the upper range of normal. Moreover, giving EPO is not going to do anything to replenish your iron stores.
The most logical solution would be to give iron, or actual blood. Blood transfusion is of course the last option. The pros and cons of blood transfusion in the ICU are discussed in greater detail elsewhere. Iron replacement is probably somewhat less toxic, and seems like a sensible solution to a condition where the deficiency of iron is the main problem. One should not be deterred from doing this, even though the IRONMAN trial did not find any improvement in the rate of blood transfusion in their iron-infused group. Those patients did end up with a significantly higher haemoglobin at discharge, even though they were not specifically selected for having iron deficiency.
The objection to the use of IV iron is based in the finding that the iron-infused group has an increased nosocomial infection rate (28.6% vs. 22.9%). Apart from this, there was no major difference in the adverse event rate between the two groups. In any case, you don't have to give the iron intravenously. Oral iron replacement is not without its charm, and only slightly less effective (Bonovas et al, 2016).
Hawkins, Stephen F., and Quentin A. Hill. "Diagnostic Approach to Anaemia in Critical Care." Haematology in Critical Care: A Practical Handbook (2014): 1-8.
Gross, I. "Laboratory Studies in the Diagnosis of Iron Deficiency, Latent Iron Deficiency and Iron Deficient Erythropoiesis". from http://iron.sabm.org
Pieracci, Fredric M., et al. "A Multicenter, Randomized Clinical Trial of IV Iron Supplementation for Anemia of Traumatic Critical Illness*." Critical care medicine 42.9 (2014): 2048-2057.
Litton, Edward, et al. "The IRONMAN trial: a protocol for a multicentre randomised placebo-controlled trial of intravenous iron in intensive care unit patients with anaemia." Crit Care Resusc 16 (2014): 285-290.
Corwin, Howard L., et al. "Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial." Jama 288.22 (2002): 2827-2835.
Mesgarpour, Bita, et al. "Safety of off-label erythropoiesis stimulating agents in critically ill patients: a meta-analysis." Intensive care medicine 39.11 (2013): 1896-1908.
Litton, Edward, et al. "Intravenous iron or placebo for anaemia in intensive care: the IRONMAN multicentre randomized blinded trial." Intensive care medicine 42.11 (2016): 1715-1722.
Bonovas, Stefanos, et al. "Intravenous versus oral iron for the treatment of anemia in inflammatory bowel disease: a systematic review and meta-analysis of randomized controlled trials." Medicine 95.2 (2016).
With respect to thromboelastography and haemostasis:
The image depicted in Figure 1 represents a normal thromboelastogram.
With reference to the parameters labelled in Figure 1:
i. CT (or R)
ii. CFT (or K)
iii. Alpha angle
iv. MCF (or MA)
v. LI30 (or LY30 or CL)
a) Explain what each parameter represents and what it measures. (60% marks)
Review the following thromboelastograms labelled A – E.
Diagram A represents a normal coagulation profile.
b) Describe the coagulation status indicated by diagrams B – E. (40% marks)
a)
R (reaction time or clotting time) is the time elapsed until first measurable clot forms (amplitude of 2mm) and indicates the initiation of haemostasis and is dependent on presence of clotting factors.
K (kinetics or clot formation time) is the time taken to achieve a certain level of clot firmness (amplitude of 20mm) and indicates amplification of the clotting process. Dependent on fibrinogen.
Alpha angle reflects the speed of fibrin accumulation. Dependent on fibrinogen.
MA/MCF is the maximum amplitude or maximum clot firmness and is the highest vertical amplitude of the TEG tracing. Dependent on platelets and fibrin.
LY30 /CL (clot lysis) is the percentage of amplitude reduction 30 min after maximum amplitude and is a measure of fibrinolysis.
b)
B – Anticoagulant therapy or factor deficiency
C – Platelet dysfunction or thrombocytopaenia or fibrinogen deficiency
D – Fibrinolysis e.g. use of t-PA
E – Hypercoagulable state
In short form:
With detail:
CT and R values:
CFT and K values:
The α-angle:
Maximum clot firmness (MCF) and maximum amplitude (MA):
LY30 and CL (or CLT)
As for the examples:
A is a normal-looking TEG
B has an extremely prolonged CT, but a normal α-angle and a reasonably normal MCF. One might surmise that either something is missing among the clotting factors, or there is some inhibitor present. The platelet count and fibrinogen levels are probably near normal. One might find such a picture in a patient on warfarin, heparin, or receiving a direct thrombin inhibitor.
C is a TEG of a patient who has plenty of clotting factors; the reaction starts quickly. The MCF is inadequate, suggesting that platelet dysfunction (or thrombocytopenia) are to blame. The college mention that there may also be a problem with the fibrinogen level, but the good α-angle would suggest otherwise.
D is a TEG of a patient with hyperfirbrinolysis from whatever cause.
E is a patient with a hypercoagulable state; the blood clots quickly, with a very firm clot generated in no time.
The LITFL page for TEG is ideal to answer this question: they have lovely TEG silhouettes available for the "important patterns".
Practical haemostasis - page on TEG and ROTEM
Sankarankutty, Ajith, et al. "TEG® and ROTEM® in trauma: similar test but different results." World J Emerg Surg 7.Suppl 1 (2012): S3.
Coakley, Margaret, et al. "Transfusion triggers in orthotopic liver transplantation: a comparison of the thromboelastometry analyzer, the thromboelastogram, and conventional coagulation tests." Journal of cardiothoracic and vascular anesthesia 20.4 (2006): 548-553.
Venema, Lieneke F., et al. "An assessment of clinical interchangeability of TEG® and ROTEM® thromboelastographic variables in cardiac surgical patients." Anesthesia & Analgesia 111.2 (2010): 339-344.
Nielsen, Vance G. "A comparison of the Thrombelastograph and the ROTEM." Blood Coagulation & Fibrinolysis 18.3 (2007): 247-252.
Wikkelsoe, A. J., et al. "Monitoring patients at risk of massive transfusion with Thrombelastography or Thromboelastometry: a systematic review." Acta Anaesthesiologica Scandinavica 55.10 (2011): 1174-1189.
A 60-year old male with no significant past medical history has been treated in your ICU for 21 days for severe staphylococcal sepsis and multi-organ failure, for which he is receiving linezolid.
He requires continuous renal replacement therapy (CRRT) and, despite therapeutic heparin to facilitate this, his filter keeps clotting. His platelet count has reduced from 154 x 106/L to 56 x 106/L from day 18 to day 21.
a) List the four most likely differential diagnoses for the thrombocytopenia. (20% marks)
b) Discuss your investigation for the thrombocytopenia. (40% marks)
c) Outline your immediate management of this problem. (40% marks)
a)
i. Linezolid
ii. Consumption coagulopathy (from clotting on renal replacement therapy)
iii. Pseudothrombocytopenia (i.e., platelet clumping)
iv. Sepsis induced including DIC
v. Heparin induced (HIT or HITTS)
vi. TTP/HUS (less likely)
b)
Exclude pseudothrombocytopaenia
Increased consumption
Decreased production
a. Drugs, sepsis, alcohol, bone marrow suppression
c)
Additional Examiners’ Comments:
Most candidates passed but there was overall a knowledge gap on the management of this clinical problem
Possible differentials for thrombocytopenia? There is a vast array. Observe:
Decreased platelet production
|
Increased platelet destruction
|
Pseudothrombocytopenia
|
Dilution of platelets
Sequestration
|
In order to simplify one's answer, one may be able to narrow this range to the causes which are relevant to the critically septic patient on dialysis. This exact list is also offered in the discussion section of Question 4 from the second paper of 2001, which offers an essentialy identical scenario.
In brief:
This is a more manageable list.
One would organise the following investigations in order to work through it:
The links point to brief explanatory notes for these tests, which one may find in the local chapter on thrombocytopenia.
The following list of generic steps applies to thrombocytopenia of any cause:
Minimise platelet destruction
Maximise platelet production
Protect the patient from complications of thrombocytopenia
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.
You are the Intensivist looking after a 30-year-old male, with no significant past medical history, who has been in the Intensive Care Unit for eight days with severe community acquired pneumonia and septic shock.
Although there are no overt signs of bleeding, his haemoglobin has slowly dropped and is now 65 g/L. He has been recommenced on low dose noradrenaline and you have decided to transfuse one unit of packed cells.
His wife has concerns about the “safety” of this and refuses to consent until she speaks to you.
Outline the key points of your discussion with the patient’s wife, including the pros and cons of, and alternatives to blood transfusion in this context.
Discussion should cover:
Pros:
Cons:
Non-transfusion strategies should be employed
Calman scale of risk useful in this context:
Negligible (less than 1 in a million or dying of lightning strike)
Minimal, Very low, Low (1 in a thousand to 1 in 10000 or dying in a road accident)
High (>1 in 1000)
Additional Examiners’ Comments:
Candidates were not expected to give this much detail and were given credit for valid points not included in the answer template
I love it when they invite you to give less detail.
A "routine transfusion" in this setting is the transfusion which has a "numeric trigger" as opposed to a clinical indication (i.e. the patient is asymptomatic).
Rationale for some sort of strategy
Arguments in support of routine transfusion to a Hb of >70
Arguments against the routine transfusion to a Hb of >70
Practical approach to a questionably indicated transfusion
Alternatives to transfusion
Spahn et al (2013) have done an excellent review of this for Lancet. In summary:
Goodnough, Lawrence T., Jerrold H. Levy, and Michael F. Murphy. "Concepts of blood transfusion in adults." The Lancet 381.9880 (2013): 1845-1854.
Spahn, Donat R., and Lawrence T. Goodnough. "Alternatives to blood transfusion." The Lancet 381.9880 (2013): 1855-1865.
There is also a rescinded document from the NHMRC (2001) which has been used to guide practice: Clinical Practice Guidelines on the Use of Blood Components.
To some extent this document has been superceded by the Australian and New Zealand Society of Blood Transfusion GUIDELINES FOR THE ADMINISTRATION OF BLOOD PRODUCTS.
The Patient Blood Management Guidelines from the National Blood Authority of Australia is another series of documents worth looking at - it contains several important modules which have been reviewed and which act as successors to the 2001 NHMRC guidelines.
Treleaven, Jennie, et al. "Guidelines on the use of irradiated blood components prepared by the British Committee for Standards in Haematology blood transfusion task force." British Journal of Haematology 152.1 (2011): 35-51.
Aoun, Elie, et al. "Transfusion‐associated GVHD: 10 years’ experience at the American University of Beirut—Medical Center." Transfusion 43.12 (2003): 1672-1676.
Heddle, Nancy M., and Morris A. Blajchman. "The leukodepletion of cellular blood products in the prevention of HLA-alloimmunization and refractoriness to allogeneic platelet transfusions [editorial]." Blood 85.3 (1995): 603-606.
Sharma, R. R., and Neelam Marwaha. "Leukoreduced blood components: Advantages and strategies for its implementation in developing countries."Asian journal of transfusion science 4.1 (2010): 3.
Dzik, Walter H. "Leukoreduction of blood components." Current opinion in hematology 9.6 (2002): 521-526.
Corwin, Howard L., and James P. AuBuchon. "Is leukoreduction of blood components for everyone?." JAMA 289.15 (2003): 1993-1995.
Blajchman, M. A. "The clinical benefits of the leukoreduction of blood products."Journal of Trauma-Injury, Infection, and Critical Care 60.6 (2006): S83-S90.
Rosenbaum, Lizabeth, et al. "The reintroduction of nonleukoreduced blood: would patients and clinicians agree?." Transfusion 51.12 (2011): 2739-2743.
Bilgin, Y. M., L. M. van de Watering, and A. Brand. "Clinical effects of leucoreduction of blood transfusions." Neth J Med 69.10 (2011): 441-450.
Australian Red Cross - Blood Service Policy on "The Age of Red Cells"
Hess, John R. "Red cell changes during storage." Transfusion and Apheresis Science 43.1 (2010): 51-59.
Bennett-Guerrero, Elliott, et al. "Evolution of adverse changes in stored RBCs."Proceedings of the National Academy of Sciences 104.43 (2007): 17063-17068.
Hébert, Paul C., et al. "A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care." New England Journal of Medicine340.6 (1999): 409-417.
Carson, Jeffrey L., Paul A. Carless, and Paul C. Hébert. "Outcomes using lower vs higher hemoglobin thresholds for red blood cell transfusion." Jama 309.1 (2013): 83-84.
Lelubre, C., J. L. Vincent, and F. S. Taccone. "Red blood cell transfusion strategies in critically ill patients: lessons from recent randomized clinical studies." Minerva anestesiologica (2016).
Spahn, Donat R., and Lawrence T. Goodnough. "Alternatives to blood transfusion." The Lancet 381.9880 (2013): 1855-1865.
A 70-year-old male presents to the ED with a 2-week history of increasing dyspnoea, cough with altered sputum and fever. Past history includes chronic obstructive airways disease (COPD), lung cancer seven years ago treated with chemotherapy and radiation therapy with no sign of recurrence since.
Examination findings included RR 30 breaths/min, BP 110/70mmHg, HR 145 bpm, Temp 37.4ºC, anxious and distress but tired and peripherally cold and cyanosed.
CXR shows findings consistent with COPD and right lower lobe infiltrate.
The following arterial blood gas is taken one hour after receiving 2 litres of fluid resuscitation, antibiotics and bi-level non-invasive ventilation (NIV), at FiO2 = 1.0.
Parameter |
Patient Value |
Normal Adult Range |
|||
FiO2 |
1.0 |
||||
pH |
7.16* |
7.35 |
– 7.45 |
||
PCO2 |
33 mmHg* (4.3 kPa)* |
35 |
– |
45 (4.6 – 6.0) |
|
PO2 |
272 mmHg (38.5 kPa) |
||||
Bicarbonate |
11 mmol/L* |
22 |
– |
30 |
|
Base Excess |
-17 mmol/L* |
-3 – +3 |
|||
Sodium |
138 mmol/L |
135 – 145 |
|||
Potassium |
4.3 mmol/L |
3.5 – 5.0 |
|||
Chloride |
121 mmol/L* |
95 |
– |
110 |
|
Glucose |
13.1 mmol/L* |
3.5 – 7.8 |
|||
Lactate |
6.4 mmol/L* |
0.6 – 2.4 |
|||
Haemoglobin |
131 g/L* |
135 – 175 |
|||
Creatinine |
150 micromol/L* |
70 |
– |
120 |
Six hours later the patient remains on NIV, is conscious, reports feeling slightly better, feet remain cyanosed, BP 105/72 mmHg, HR 108 bpm, RR 30 breaths/min, urine output 10 – 20 mL/hr and the following biochemistry profile is obtained:
Parameter |
Patient Value |
Normal Adult Range |
||||
Sodium |
139 mmol/L |
135 – 145 |
||||
Potassium |
5.5 mmol/L* |
3.5 – 5.2 |
||||
Chloride |
110 mmol/L |
95 |
– 110 |
|||
Bicarbonate |
12 mmol/L* |
22 |
– 32 |
|||
Urea |
20.0 mmol/L* |
2.7 – 7.8 |
||||
Creatinine |
220 μmol/L* |
70 |
– 120 |
|||
Estimated glomerular filtration rate (eGFR) |
25 mL/min/1.73 m2* |
> 90 |
||||
Anion gap |
22 mmol/L* |
8 – 18 |
||||
Total protein |
57 g/L* |
60 |
– 80 |
|||
Albumin |
27 g/L* |
35 |
– 50 |
|||
Total bilirubin |
24.9 μmol/L |
< 25 |
||||
Alkaline phosphatase (ALP) |
81 IU/L |
30 |
– 110 |
|||
Alanine transaminase (ALT) |
6138 IU/L* |
< 65 |
||||
Aspartate transaminase (AST) |
10122 IU/L* |
< 50 |
||||
g-Glutamyl transferase (GGT) |
88 IU/L |
< 90 |
||||
C-reactive protein (CRP) |
22.5 mg/L* |
< 8 |
The patient’s haematology results are as follows:
Parameter |
Patient Value |
Normal Adult Range |
|||||||||
Haemoglobin |
87 g/L* |
130 – 180 |
|||||||||
White cell count |
2.1 x 109/L |
4 – 11 |
|||||||||
Platelets |
54 x 109/L |
140 – 440 |
|||||||||
International normalised ratio (INR) |
2.4 |
0.8 – 1.2 |
|||||||||
Activated partial thromboplastin time (APTT) |
38 sec* |
25 – 35 |
c) What is your interpretation of these findings? (20% marks)
c)
Acute anaemia, acute or chronic leucopaenia, acute or chronic thrombocytopaenia, coagulopathy with raised INR
No unifying diagnosis
Acute drop in haemoglobin over 2 hours is most likely due to haemorrhage or massive fluid infusion. Massive haemolysis is less likely given the bilirubin is not raised
Sepsis most likely cause of leucopaenia, thrombocytopaenia and raised INR
Acute liver failure may explain raised INR
Bone marrow failure would explain leucopaenia and thrombocytopaenia if they are chronic.
Any cause of bone marrow failure also accepted.
This is the third part of this SAQ. Question 23.1 is an ABG interpretation question, and Question 23.2 is more about the differential diagnosis of deranged LFTs.
The following list of differentials can be reproduced from the pancytopenia chapter:
|
|
These are all forms of a "unifying diagnosis" which is perhaps not appropriate here. The college answer seems to tolerate an individual list of differentials for each individual blood test abnormality, rather than expecting the candidates to connect the dots and make a diagnosis of haemophagocytic lymphohistiocytosis or some such. However, the trainees might not be aware of this. Some readers of Deranged Physiology have been in correspondence regarding this matter, and their profanity-laced comments suggest that to have a unifying diagnosis for these sorts of SAQs is one of their expectations. When asked "what is your interpretation of the findings", the correct answer should not be "these findings defy interpretation" or "just about anything, or several things, could be the cause".
The following blood results are from a 51 -year-old female who presented with arthralgia, jaundice and dark urine.
Parameter |
Patient Value |
Normal Adult Ran e |
|||
Haemoglobin |
68 g/L |
115 - 160 |
|||
White Cell Count |
33.1 x 109/L |
4.0 — 11.0 |
|||
Platelets |
307 x 109/L |
150 - 400 |
|||
Red Cell Count |
2.22 x 1012/L * |
3.80 - 4.80 |
|||
Haematocrit |
0.19* |
0.37 - 0.47 |
|||
Mean Cell Volume |
88 fL |
80 - 100 |
|||
Mean Cell Haemoglobin |
30.7 |
27.0 - 32.0 |
|||
Mean Cell Haemoglobin Concentration |
350 g/L |
320 - 360 |
|||
Reticulocyes |
2.5%* |
0.2 - 2.0 |
|||
Reticulocytes Absolute |
56 x 109/L |
20 - 130 |
|||
Comment: The red cells show moderate numbers of spherocytes |
|||||
Serum Haptoglobins |
< 0.10 g/L |
0.30 - 2.00 |
|||
Serum Lactate Dehydrogenase |
948 U/L* |
140 - 280 |
|||
Total Protein |
69 g/L |
60 - 80 |
|||
Albumin |
33 g/L |
35 - 50 |
Globulins |
36 g/L |
25 - 42 |
|
Total Bilirubin |
119 mol/L* |
< 20 |
|
Alanine Aminotransferase |
276 U/L* |
< 35 |
|
Alkaline Phosphatase |
120 U/L* |
30 - 1 10 |
|
Gamma-GlutamyI Transferase |
114 U/L* |
< 40 |
|
Direct Antiglobulin Test: |
|||
IgG |
Positive |
||
C3d |
Positive |
a) What is the diagnosis? (20% marks)
b) List three treatment options. (15% marks)
a)
b)
a) The only possible answer is autoimmune haemolytic anaemia. Overall, the differential diagnosis of autoimmune haemolytic anaemias looks like this:
Warm haemolytic anaemia | Cold haemolytic anaemia |
|
|
In this scenario, the patient probably has one of the warm haemolytic anaemias, because both the IgG and C3d were found coating the red cells (IgM and C3d are found in cold haemolysis). The WCC is raised suggestive of a lymphoproliferative disorder as the cause. Arthralia may be due to some sort of autoimmune disease (SLE or RA), or it may be a subtle hint that the patient has been taking diclofenac to soothe her aching joints (which is a drug known to cause warm autoimmune haemolysis).
b)
Generic management of warm autoimmune haemolytic anaemia could have included any three of the following options:
Zeerleder, S. "Autoimmune haemolytic anaemia-a practical guide to cope with a diagnostic and therapeutic challenge." Neth J Med 69.4 (2011): 177-84.
Gehrs, Bradley C., and Richard C. Friedberg. "Autoimmune hemolytic anemia."American journal of hematology 69.4 (2002): 258-271.
Birgens, Henrik, et al. "A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia." British journal of haematology 163.3 (2013): 393-399.
Lechner, Klaus, and Ulrich Jäger. "How I treat autoimmune hemolytic anemias in adults." Blood 116.11 (2010): 1831-1838.
Salama, A., and B. Mayer. "Diagnostic pitfalls of drug-induced immune hemolytic anemia." Immunohematology 30.2 (2014): 80-4.
Zantek, Nicole D., et al. "The direct antiglobulin test: a critical step in the evaluation of hemolysis." American journal of hematology 87.7 (2012): 707-709.
Ma, Kim, and Stephen Caplan. "Refractory IgG Warm Autoimmune Hemolytic Anemia Treated with Eculizumab: A Novel Application of Anticomplement Therapy." Case reports in hematology 2016 (2016).
Pignon, Jean‐Michel, Emmanuelle Poirson, and Henri Rochant. "Danazol in autoimmune haemolytic anaemia." British journal of haematology 83.2 (1993): 343-345.
A 33-year-old male who is 4 weeks after gunshot wounds to his chest and abdomen has the following report on his blood film:
a) What is meant by the term 'polychromasia' and what is its significance? (10% marks)
b) What are Howell-Jolly bodies, and what is their significance? (15% marks)
c) List two other features you might expect to see on the blood picture of a patient with Howell-Jolly bodies. (10% marks)
a)
b)
c)
a)
Polychromasia is another one of those morphological RBC abnormalities which the college love so much. It is an abnormally large raneg of colour variation among the (usually, red) erythrotcytes. It indicates the presence of an increased number of morphologically immature RBCs which have RNA inside them (and which therefore stain grey-blue with the giemsa stain). The stolen image below has helpful arrows pointing at them.
These cells are significant, because they represent either increased bone marrow stress or a failure of normal regulatory mechanisms responsible for "quality control" of erythrocytes.
Possible causes of polychromasia include:
b)
Howell-Jolly bodies are bits of lefteover DNA in the erythrocytes. Normally, the spleen would view these as defective, and they would be removed. They are typically seen in patients who have had a splenectomy.
Other associations include the following conditions:
c)
In this patient, splenectomy is the most likely common unifying diagnosis. There is a history of trauma to a vaguely spleeny area, and he has rouleaux (which suggest he may have post-splenectomy thrombocytosis). This question therefore resembles Question 18 from the second paper of 2007, which asked for the features of a post-splenectomy blood film.
The typical post-splenectomy blood film abnormalities are as follows:
Davidson, E. "The significance of blue polychromasia." Journal of clinical pathology 12.4 (1959): 322.
Ponder, Eric. "On sedimentation and rouleaux formation-I." Experimental Physiology 15.3 (1925): 235-252.
Walker, H. Kenneth, et al. "Peripheral blood smear." (1990). in Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition.
73-year-old female with a background of rheumatoid arthritis has been admitted to your ICU with a history of acute shortness of breath and a fluctuating conscious state. She has been having severe headaches for the last three weeks.
The following investigations were obtained:
Parameter |
Patient Value |
Normal Adult Ran e |
|
Haemoglobin |
76 |
1 15 - 160 |
|
White Cell Count |
23.8 x 10 |
4.0 - 1 1.0 |
|
Platelets |
198 x 10 IL |
150 - 450 |
|
Blood Film |
2% Plasma cells and rolueaux formation |
Parameter |
Patient Value |
Normal Adult Range |
Sodium |
137 mmol/L |
135 - 145 |
Potassium |
4.3 mmol/L |
3.2 -4.5 |
Chloride |
106 mmol/L |
100 - 1 10 |
Bicarbonate |
25 mmol/L |
22 - 27 |
Urea |
15.0 mmol/L* |
3.0 - 8.0 |
Creatinine |
280 umol/L* |
70 - 120 |
Total Calcium |
2.75 mmol/L* |
2.15 - 2.60 |
Phosphate |
1.3 mmol/L |
0.7 — 1.4 |
Albumin |
26 g/L* |
33 — 47 |
Globulins |
92.3 g/L* |
25 — 45 |
a) Give the diagnosis. (20% marks)
b) What urgent treatment is indicated? (10% marks)
a)
b)
a)
This looks like a hyperviscosity syndrome due to hypergammaglobulinaemia, a complication of Waldenström's macroglobulinemia or (less likely) multiple myeloma or plasmacytoma.
Features of this presentation which suggest hyperviscosity:
Other clinical features of symptomatic hyperviscosity include:
Even though multiple myeloma is quoted by the college, Waldenström's macroglobulinemia is the disorder where clinically significant hyperviscosity occurs most frequently, according to this article by Mehta et al (2003). This is because Waldenström's macroglobulinemia is characterised by the excess production of IgM, which is a massive molecule. However, numerous other causes of plasmacytosis exist:
b) Plasmapheresis is the usual urgent treatment for this. You centrifuge away the monoclonal badness and replace with nice clean albumin.
Mehta, Jayesh, and Seema Singhal. "Hyperviscosity syndrome in plasma cell dyscrasias." Seminars in thrombosis and hemostasis. Vol. 29. No. 05. Copyright© 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.:+ 1 (212) 584-4662, 2003.
A 62-year-old male has been admitted to your ICU for routine post-operative monitoring after a vascular
surgical procedure.
His pre-operative full blood count is displayed below:
Parameter |
Patient Value |
Normal Adult Range |
Haemoglobin |
125 q/L* |
130 - 180 |
White Cell Count |
7.4 x 10 /L |
4.5 - 11.0 |
Platelets |
255 x 10 /L |
150 - 400 |
Mean Cell Volume |
110 fl* |
80 - 98 |
Mean Cell Haemoqlobin |
30 oa/cell |
27 - 33 |
Mean Cell Haemoglobin Concentration |
320 g/L |
310 - 360 |
Give six possible causes for the findings on his full blood count. (20% marks)
Liver disease (including alcoholism)
Folate deficiency B12 deficiency
Hypothyroidism
Myelodysplasia
Drug related (one example required for mark – methotrexate, AZT, trimethoprim, phenytoin, some chemotherapeutic agents, cyclophosphamide. Multiple examples do not gain more marks)
Reticulocytosis
Familial
This is macrocytosis, defined as a mean corpuscular volume (MCV) of over 100fl.
There are several common causes:
There are also a few uncommon causes:
One can find a discussion of the many causes of macrocytosis in the 2006 article by Aslinia et al.
Aslinia, Florence, Joseph J. Mazza, and Steven H. Yale. "Megaloblastic anemia and other causes of macrocytosis." Clinical medicine & research 4.3 (2006): 236-241.
Inspect the following full blood count:
Parameter |
Patient Value |
Normal Adult Range |
Haemoqlobin |
96 q/L* |
130 - 175 |
White Cell Count |
17.4 x 10 /L* |
4.0 - 11.0 |
Platelets |
168 x 109/L |
150 - 450 |
Neutrophils |
12.4 x 10 /L* |
1.8 - 7.5 |
Lymphocytes |
2.06 x 10 /L |
1.50 - 4.00 |
Monocytes |
0.5 x 10 /L |
0.2 - 0.8 |
Eosinophils |
0.3 x 10/L |
0.0 - 0.4 |
Film: Circulating nucleated red blood cells, immature granulocytes and band forms observed.
a) What is the term used to describe these findings on a blood film? (20% marks)
b) Give four possible reasons these findings may be observed in a critically ill patient.
(20% marks)
The key findings are anaemia, nucleated red cells, immature granulocytes and band forms.
These abnormalities can be described as a "leukoerythroblastic" blood film picture
In summary, the possible causes of leukoerythroblastosis are:
Shamdas, Glenn J., et al. "Leukoerythroblastic anemia in metastatic prostate cancer. Clinical and prognostic significance in patients with hormone‐refractory disease." Cancer 71.11 (1993): 3594-3600.
Weick, J. K., A. B. Hagedorn, and J. W. Linman. "Leukoerythroblastosis. Diagnostic and prognostic significance." Mayo Clinic Proceedings. Vol. 49. No. 2. 1974.
A 56-year-old male presents with one-month history of weight loss and shortness of breath.
The results of his blood tests are as follows:
Parameter |
Patient Value |
Normal Adult Range |
|
Haemoglobin |
128g/L* |
135 - 180 |
|
White Cell Count |
6.1 x 109/L |
4.0 - 11.0 |
|
Platelets |
35 x 10l;l/L* |
150 - 400 |
|
Prothrombin time |
23.3 sec* |
12.0 - 16.5 |
|
International normalised ratio |
2.0* |
0.9 - 1.3 |
|
Activated partial thrombop lastin time |
45.7 sec* |
27.0 - 38.5 |
|
Fibrinoqen |
0.7 q/L* |
2.0 - 4.0 |
|
Total Protein |
39 a/L* |
60 - 80 |
|
Albumin |
24 q/L* |
35 - 50 |
|
Total Bilirubin |
215 umol/L* |
< 20 |
|
Alanine aminotransferase |
202 U/L* |
< 40 |
|
Alkaline phosphatase |
243 U/L* |
30 - 110 |
|
y-Glutamvl transferase |
394 U/L* |
< 60 |
|
Ferritin |
120000 ua/L* |
30 - 620 |
|
Iron |
15 µmol/L |
9 - 30 |
|
Transferrin |
13 µmol/L* |
23 - 43 |
|
Transferrin saturation |
58%* |
14 - 45 |
a) Give the diagnosis indicated by these results. (20% marks)
b) Give three possible underlying causes. (15% marks)
a) Haemophagocytic lymphohistiocytosis (HLH)
b) Viral infection e.g. EBV, HSV, HINI influenza
Lymphoma
Malignancy
Immune deficiency states
Rheumatological disorders
Other infection – bacterial and fungal less likely
a)
The only thing ever to produce a serum ferritin level of 120, 000? Surely, the college wanted to hear "haemophagocytic syndrome", but there are a variety of possibilites:
b)
Causes of haemophagocytic syndrome:
Congenital:
Acquired causes
Moore Jr, Charles, Michelle Ormseth, and Howard Fuchs. "Causes and significance of markedly elevated serum ferritin levels in an academic medical center." JCR: Journal of Clinical Rheumatology 19.6 (2013): 324-328.
Lee, Mark H., and Robert T. Means. "Extremely elevated serum ferritin levels in a university hospital: associated diseases and clinical significance." The American journal of medicine 98.6 (1995): 566-571.
Hearnshaw, Sarah, Nick Paul Thompson, and Andrew McGill. "The epidemiology of hyperferritinaemia." World journal of gastroenterology 12.36 (2006): 5866. - ! WARNING ! this link will download the whole September issue, with the potential to fatally clog your internet hole.
Janka, Gritta E. "Hemophagocytic syndromes." Blood reviews 21.5 (2007): 245-253.
A 52-year-old female presents with bruising and a retroperitoneal haematoma five weeks after starting warfarin for a proximal deep vein thrombosis (DVT) with a target international normalised ratio (INR) of 2.5.
Her investigations are as follows:
Parameter |
Patient Value |
Normal Adult Range |
|
Haemoglobin White Cell Count |
122 q/L* |
135 - 180 |
|
10.1 x 109/L |
4.0 - 11.0 |
||
Platelets |
298 x 109/L |
150 - 400 |
|
Prothrombin time |
29.3 sec* |
12.0 - 16.5 |
|
International normalised ratio |
2.3* |
0.9 - 1.3 |
|
Activated partial thromboplastin time |
117.0 sec* |
27.0 - 38.5 |
|
Fibrinogen |
3.9 a/L |
2.0 - 4.0 |
a) Give the likely underlying cause for this coagulation profile. (20% marks)
b) Give a test you could do to confirm this. (15% marks)
a) Factor deficiency - either VIII, IX, XI or XII
b)
Mixing study (patient plasma mixed with normal plasma 1:1 should show correction of APTT if case of factor deficiency).
Factor levels.
a)
This patient has an appropriate therapeutic INR, and an unexplains raised APTT. The college asks for the "likely underlying cause", as if there was only one possibility.
Causes of raised APTT are in fact numerous, and can be divided into factor deficiencies and factor inhibitors:
This patient has no reported history of lupus, but this whole history of a proximal DVT raises the possibility of antiphospholipid syndrome, which could result in a raised APTT with a relatively normal warfarinised PT.
Alternatively, one could make the conceptual leap and discuss direct thrombin inhibitor toxicity (as these might have been used to manage the DVT instead of warfarin).
b)
The ideal test would be a mixing study (to discriminate between the abovelisted differentials). However, the college did not want that- they asked for a test to "confirm the diagnosis" .
So:
Hunt, Beverley J. "Bleeding and coagulopathies in critical care." New England Journal of Medicine 370.9 (2014): 847-859.
Kamal, Arif H., Ayalew Tefferi, and Rajiv K. Pruthi. "How to interpret and pursue an abnormal prothrombin time, activated partial thromboplastin time, and bleeding time in adults." Mayo Clinic Proceedings. Vol. 82. No. 7. Elsevier, 2007.
A 49-year-old female presents with confusion. The results of her blood tests are as follows:
Parameter |
Patient Value |
Normal Adult Range |
Haemoglobin |
86 q/L* |
135 - 180 |
White Cell Count |
11.2 x 109/L* |
4.0 - 11.0 |
Platelets |
23 x 109/L* |
150 - 400 |
Prothrombin time |
14.0 sec |
12.0 - 16.5 |
Activated partial thromboplastin time |
35.0 sec |
27.0 - 38.5 |
Fibrinogen |
2.1 q/L |
2.0 - 4.0 |
Thrombin time |
14.0 sec* |
11.5 - 13.5 |
Urea |
12.1 mmol/L* |
3.0 - 8.0 |
Creatinine |
356 µmol/L* |
45 - 90 |
Lactate dehydrogenase |
2342 U/L* |
140 - 280 |
a) Give the likely diagnosis. (20% marks)
b) Give an additional test to support your diagnosis. (10% marks)
a) Thrombotic thrombocytopaenic purpura
Haemolytic-uraemic syndrome
Systemic lupus erythromatosis
MAHA (1 mark only)
b) ADAMTS13 (TTP)
Positive Shiga toxin / Entero-haemorrhagic E coli test (HUS)
ANA / anti-dsDNA (SLE)
Blood film
Reticulocyte count
Haptoglobins
a)
The diagnosis of TTP/HUS suggests itself, even though the "pentad" of symptoms is incomplete:
The low-ish fibrinogen suggests that a TTP-related excess of vWF has produced a systemic prothrombotic state, with microvascular thrombosis consuming all the fibrinogen.
b)
ADAMTS-13 level is of course the most important supportive test. The relevanc of this protein is discussed in the chapter on TTP/HUS.
George, James N. "Thrombotic thrombocytopenic purpura." New England Journal of Medicine 354.18 (2006): 1927-1935.
The following blood results were obtained from a previously fit and well patient undergoing a prolonged respiratory wean following an episode of severe community acquired pneumonia one month earlier.
Parameter |
Patient Value |
Adult Normal Range |
|
Haemoglobin |
78 g/l |
115- 155 |
|
Haematocrit |
0.20 |
0.35 - 0.45 |
|
Mean Cell Volume |
85 fL |
80-99 |
|
Mean Cell Haemoglobin |
28 pg |
27 - 33 |
|
White Cell Count |
15.3 X 10 |
4.0 - 11.0 |
|
Neutrophils |
120 x 109/L |
1.9 -7.5 |
|
Platelets |
758 x |
150 - 400 |
|
Reticulocyte count |
40 x IO9/L |
30- 130 |
|
Iron |
8 mmol/L• |
10-30 |
|
Ferritin |
798 |
20 - 450 |
|
Transferrin saturation |
0.10 |
0.15 - 0.50 |
|
Vitamin BIZ |
700 pmol/L |
200 - 900 |
|
Folate |
1 5 nmol/L |
||
C-reactive rotein |
210 |
||
Albumin |
25 |
35 - 50 |
Interpret the abnormal results and justify your reasoning. (40% marks)
Normochromic normocytic anaemia of chronic disease with on-going inflammation NOT Fe deficiency anaemia because:
The abnormalities are as follows:
This is consistent with an anaemia of chronic disease, which is usually a microcytic hypochromic affair (i.e MCV and MCH is usually lower in those cases). The reticulocyte count is typically low, which indicates underproduction of red cells. This comes from the review article by Weiss and Goodnough (NEJM, 2005)
For each of these "interpret iron studies" questions, this table ends up in the discussion section:
Condition | MCV | MCHC | Serum iron | Ferritin | Transferrin | Transferrin saturation |
TIBC |
Iron deficiency anaemia | low | low | low | low | high | <20% | high |
Anaemia of chronic disease | low | low | low | normal | low | normal | low or normal |
Acute phase response | normal | normal | low | high | low | low | low |
Iron overload | normal | normal | high | high | normal | high | high |
Hawkins, Stephen F., and Quentin A. Hill. "Diagnostic Approach to Anaemia in Critical Care." Haematology in Critical Care: A Practical Handbook (2014): 1-8.
IRON STUDIES STANDARDISED REPORTING PROTOCOL - RCPA, 2013
Hearnshaw, Sarah, Nick Paul Thompson, and Andrew McGill. "The epidemiology of hyperferritinaemia." World journal of gastroenterology 12.36 (2006): 5866. - ! WARNING ! this link will download the whole September issue, with the potential to fatally clog your internet hole.
Janka, Gritta E. "Hemophagocytic syndromes." Blood reviews 21.5 (2007): 245-253.
Weiss, Guenter, and Lawrence T. Goodnough. "Anemia of chronic disease." New England Journal of Medicine 352.10 (2005): 1011-1023.
Koepke, J. F., & Koepke, J. A. (1986). Reticulocytes. Clinical & Laboratory Haematology, 8(3), 169–179.
List six causes of hepato-splenomegaly. (30% marks)
• Chronic liver disease with portal hypertension
• Viral infections e.g. viral hepatitis, EBV
• Myeloproliferative disease e.g. myelofibrosis
• Lymphoma
• Leukaemia
• Pernicious anaemia
• Amyloidosis
• Malaria
• Sarcoidosis
• Acromegaly
• Thyrotoxicosis
• SLE
• Metabolic storage disease
• Obesity
• Kala-Azar (visceral leischmaniasis)
Massive splenomegaly is also discussed in Question 24.3 from the first paper of 2009, but that time there was nothing hepato about it.
The lists of causes for hepatosplenomegaly and massive splenomegaly are actually quite similar. Here they are side by side:
Causes common to both | |
Massive splenomegaly | Hepato-splenomegaly |
|
|
Causes unique to one or the other: | |
|
|
Luo, Esther J., and Lee Levitt. "Massive splenomegaly." Hospital Physician 31 (2008).
Hoffbrand's Essential Haematolgy has a table with the causes of splenomegaly in chapter 10.
Johnson, H. A., and R. A. Deterling. "Massive splenomegaly." Surgery, gynecology & obstetrics 168.2 (1989): 131-137.
Poulin, E. C., J. Mamazza, and C. M. Schlachta. "Splenic artery embolization before laparoscopic splenectomy." Surgical endoscopy 12.6 (1998): 870-875.
Bedu-Addo, George, and Imelda Bates. "Causes of massive tropical splenomegaly in Ghana." The Lancet 360.9331 (2002): 449-454.
Raje, Noopur, and Judith A. Ferry. "Case 27-2001: A 50-Year-Old Man with Marked Splenomegaly and Anemia." New England Journal of Medicine 345.9 (2001): 682-687.
Wyler, David J., and Anthony R. Mattia. "Case 11-1994: A 35-Year-Old Ethiopian Man with Splenomegaly and Recurrent Fever." New England Journal of Medicine 330.11 (1994): 775-781.
Vick, Eric J., et al. "Proliferation through activation: hemophagocytic lymphohistiocytosis in hematologic malignancy." Blood advances 1.12 (2017): 779-791.
A 74 year old female has been admitted to your ICU with urosepsis. She is previously well with no previous hospital admissions. She was commenced on prophylactic subcutaneous heparin on day one of her admission and the following blood results were obtained:
Parameter | Patient Value | Adult Normal Range | ||||||||||||||||||||
Haemoglobin | 10.1 g/L* | 9.8 g/L* | 9.6 g/L* | 120.0 - 160.0 | ||||||||||||||||||
White Cell Count | 18.4 x 109/L* | 14.2 x 109/L* | 10.5 x 109/L | 4.0 - 11.0 | ||||||||||||||||||
Platelet count | 120 x 109/L* | 101 x 109/L* | 88 x 109/L* | 150 - 350 |
On day three, one of your trainees performs a "HITTS screen" which is reported as positive. The patient has remained clinically stable.
Describe your approach to this situation and give a rationale.
(70% marks)
Probability of HITTS is low due to:
Timing of onset is too fast with no history of previous exposure
The platelet fall is not greater than 50%
There is no associated thrombosis or skin necrosis
There is a likely alternative cause – sepsis
The HITTS ELISA test has is not very specific and may give false positives
Therefore:
Reasonable to stop heparin in short term (although not mandatory)
No requirement for commencing alternatives
Could repeat test in short term
More accurate test (SRA- serotonin release test) not likely to be immediately available but will guide future management
Let's reason through this:
So, the "4T" score is in fact 0. That's associated with the lowest possible pre-test probability for HIT.
(Here is the scoring system in case the reasoning above does not make sense)
The positive ELISA test for anti-PF4 antibodies is meaningless, because is screening studies only 2-15% of all positive patients went on to develop any sort of clinically significant HIT.
So, the approach to this situation would be:
Arepally, Gowthami M., and Thomas L. Ortel. "Heparin-induced thrombocytopenia." New England Journal of Medicine 355.8 (2006): 809-817.
Patel, Vipul P., Matthew Bong, and Paul E. Di Cesare. "Heparin-induced thrombocytopenia and thrombosis." AMERICAN JOURNAL OF ORTHOPEDICS-BELLE MEAD- 36.5 (2007): 255.
Greinacher, Andreas. "Heparin-induced thrombocytopenia." New England Journal of Medicine 373.3 (2015): 252-261.
Greinacher, A., I. Michels, and C. Mueller-"Heparin-associated thrombocytopenia: the antibody is not heparin specific."Eckhardt. "Heparin-associated thrombocytopenia: the antibody is not heparin specific." Thrombosis and haemostasis 67.5 (1992): 545-549.
Pravinkumar, Egbert, and Nigel Robert Webster. "HIT/HITT and alternative anticoagulation: current concepts." British journal of anaesthesia 90.5 (2003): 676-685.
Nanwa, Natasha, et al. "The direct medical costs associated with suspected heparin-induced thrombocytopenia." Pharmacoeconomics 29.6 (2011): 511-520
Kelton, John G., and Theodore E. Warkentin. "Heparin-induced thrombocytopenia: a historical perspective." Blood 112.7 (2008): 2607-2616.
Wartekin, T. E., B. H. Chong, and A. Greinacher. "Heparin-induced thrombocytopenia: towards consensus." Thromb Haemostas 79 (1998): 1-7.
Warkentin, Theodore E. "Heparin‐induced thrombocytopenia: pathogenesis and management." British journal of haematology121.4 (2003): 535-555.
Visentin, Gian Paolo, Chao Yan Liu, and Richard H. Aster. "Molecular immunopathogenesis of Heparin-induced thrombocytopenia." Heparin-induced Thrombocytopenia. New York: Marcel Dekker (2004): 179-196.
Lo, G. K., et al. "Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin‐induced thrombocytopenia in two clinical settings." Journal of Thrombosis and Haemostasis 4.4 (2006): 759-765.
Warkentin, Theodore E., et al. "Impact of the patient population on the risk for heparin-induced thrombocytopenia." Blood 96.5 (2000): 1703-1708.
A 45-year-old male was admitted with life threatening shock after being involved in a motor vehicle accident, requiring emergency surgery with large volume blood loss. Post-operatively following return to ICU, he was noted to become hypotensive, febrile and oozy from various drip and operative sites. Red urine was noted.
The following blood results were obtained:
Parameter | Patient Value | Adult Normal Range | |||||||||||||||||||
Haemoglobin | 87 g/L* | 120 - 160 | |||||||||||||||||||
White Cell Count | 18.9 x 109/L* | 4.0 - 11.0 | |||||||||||||||||||
Platelet count | 132 x 109/L* | 150 - 350 | |||||||||||||||||||
Sodium | 138 mmol/L | 135 - 145 | |||||||||||||||||||
Potassium | 4.3 mmol/L | 3.5 - 5.0 | |||||||||||||||||||
Chloride | 102 mmol/L | 95 - 105 | |||||||||||||||||||
Bicarbonate | 20.0 mmol/L* | 22.0 - 26.0 | |||||||||||||||||||
Glucose | 5.3 mmol/L . | 3.5 - 6.0 | |||||||||||||||||||
Urea | 15.2 mmol/L* | 3.0 - 8.0 | |||||||||||||||||||
Creatinine | 80 µmol/L | 45 - 90 | |||||||||||||||||||
Creatinine Kinase | 2000 U/L* | 55 - 170 |
Urine Myoglobin: trace
Urine Haemoglobin: ++
Based on his clinical history and the lab report (shown on page 7), what is the likely cause of his post-operative deterioration? How will you confirm your diagnosis?
(30% marks)
Mismatched transfusion.
Check patient’s and donor groups and re check cross match.
A systematic discussion of the results:
Overall everything points to an acute haemolytic transfusion reaction. It would have been nice for the college to offer a picture; the urine of haemoglobinuria is classically bright red but translucent, in contrast to the muddy clot-filled haematuria which might result from some sort of renal trauma.
To confirm the diagnosis, the Australian Red Cross recommends the following steps:
You have been asked to assess a 76-year-old male, scheduled to have a verv large incisional hernia repaired electively. He has a history of obstructive sleep apnoea (OSA) requiring nocturnal continuous positive airway pressure (CPAP). A recent echocardiogram, done to evaluate pedal oedema and newly diagnosed elevated creatinine, has revealed an ejection fraction of 55%, a right ventricular systolic pressure RVSP of 90 mmH , and moderate tricuspid regurgitation (TR). He has a history of recurrent deep venous thrombosis (DVT) and pulmonary embolism (PE) due to deficiency of Factor V Leiden and is currently on Rivaroxaban.
a) List the specific risks associated with his co-morbidities in the perioperative period.
(40% marks)
b) Outline strategies that could be used to minimize these risks in the perioperative period.
(60% marks)
a)
OSA:
• Acute respiratory failure,
• Cardiac arrhythmias,
• Cardiac ischaemia including cardiac arrest
• Risk of exacerbation by opiates may make analgesic management difficult
Pulm hypertension:
• Acute right heart failure during perioperative period related to hypoxia and pain, Severe hypoxaemia,
• Cardiac dysrhythmias,
• Renal failure
Renal dysfunction:
• Fluid overload,
• Electrolyte and acid base imbalance,
• Altered drug metabolism
DVTs, PE, Factor V Leiden deficiency:
• High risk of thrombotic events esp PE with exacerbation of RHF.
Anticoagulation:
• Bleeding risk,
• Thrombotic risk if ceased and not adequately covered.
b)
Preop:
• Consider need for surgery,
• Consider timing of surgery o Surgery should be done when co-morbidities are optimised
o Organisational factors: Surgery should be conducted when ICU support available, experienced surgical and anaesthetic team available, early on list (so not cancelled), in hospital with appropriate support (ICU and usual physicians)
• May be relevant to discuss goals of therapy with patient, surgical team and pre-existing physicians
• Optimise cardiac status especially with respect to pulmonary hypertension,? need for pulmonary vasodilators. Cardiology input would be valuable
• Optimise respiratory status especially with respect to nocturnal NIV; settings, interface
• Plan anticoagulation over perioperative period.
• OK to mention IVC filter if recent PE. But not necessary
• Optimise renal function; may need renal consult and exclusion of reversible causes
• Liase with surgeon, anaesthetist, treating physicians regarding management plan
Intra-operative
• Use of regional techniques / local blocks to reduce requirement for systemic analgesia
• Appropriate monitoring and lines
Post-operative If intubated:
o Early extubation and early mobilisation to avoid atelectasis if possible o Consider role of extubation to NIV o Continue usual nocturnal NIV
• Consider opiate sparing analgesic regimen, consider regional techniques (will need to consider anticoagulation issues)
o Avoid NSAIDS due to renal dysfunction
• Avoid fluid overload
o Maintain vascular tone with low dose noradrenaline
o Consider vasopressin if high dose pressor required due to less effect on pulmonary vasculature
• Restart anticoagulation as soon as safe, in keeping with pre-operative plan o Consider surveillance duplex monitoring if > 24-48hours off anticoagulation
• Avoid nephrotoxic medications
Organise follow-up with usual physicians on discharge to the ward.
a)
Lets list the problems and consider the risks associated with them, in order of their appearance.
Problem | Risks |
Expected extensive abdominal procedure |
|
OSA on CPAP |
|
Pulmonary hypertension |
|
Factors V Leiden deficiency |
|
Anticoagulation with DOAC |
|
b)
To mitigate some of these risks, the following strategies may be considered:
Risk | Strategy |
Increased risk of post-op atelectasis |
|
Significant analgesia requirements |
|
Long complex procedure |
|
Prolonged recovery from anaesthetic |
|
OSA: Propensity to somnolence and hypoxia with sedatives |
|
Worsening of pulmonary hypertension |
|
Thrombophilia and anticoagulation |
|
Interestingly, the college recommends to avoid fluid overload. That's probably accurate as the term "overload" implies "excessive load", which is by definition bad. You should avoid excessive bad fluid loading. But, the term "adequate fluid resuscitation" is good. Or at least adequate. Gille et al (2014) recommended the use of a "restrictive" strategy, guided by TOE or PA catheter.
Gross, Jeffrey B., et al. "Practice guidelines for the perioperative management of patients with obstructive sleep apnea: a report by the American Society of Anesthesiologists Task Force on Perioperative Management of patients with obstructive sleep apnea." Anesthesiology 104.5 (2006): 1081.
Donahue, Brian S. "Factor V Leiden and perioperative risk." Anesthesia & Analgesia 98.6 (2004): 1623-1634.
Gille, Jochen, et al. "Perioperative anesthesiological management of patients with pulmonary hypertension." Anesthesiology research and practice 2012 (2012).
A 34-year-old male, who was previously well, has been admitted to your ICU with vomiting, malaise and oliguria. He has a new diagnosis of diffuse large B cell lymphoma and received his first round of chemotherapy four days ago. The following blood results were obtained:
Parameter | Patient Value | Adult Normal Range | |||||||||||||||||||||||||
Sodium | 138 mmol/L - | 135 - 145 | |||||||||||||||||||||||||
Potassium | 6.2 mmol/L* | 3.5 - 5.0 | |||||||||||||||||||||||||
Bicarbonate | 17.0 mmol/L* | 22.0 - 26 .0 | |||||||||||||||||||||||||
Urea | 21.0 mmol/L* | 3.0 - 8.0 | |||||||||||||||||||||||||
Creatinine | 398 µmol/L* | 45 - 90 | |||||||||||||||||||||||||
Glucose | 5.3 mmol/L | 3.5 - 6.0 | |||||||||||||||||||||||||
Magnesium | 1.10 mmol/L* it- | 0.75 - 0.95 | |||||||||||||||||||||||||
Calcium corrected | 1.78 mmol/L* | 2.12 - 2.62 | |||||||||||||||||||||||||
Phosphate | 3.9 mmol/L* "t- | 0.8 - 1.5 | |||||||||||||||||||||||||
Urate | 10 mmol/L | 0.20 - 0.42 |
a) List a differential diagnosis for the kidney injury. (20% marks)
b) Outline your assessment and management of this patient. (80% marks)
a)
It is likely the patient has tumour lysis syndrome (10/20).
Other differentials of acute kidney injury should be considered turn into list
• pre-renal (e.g. hypovolaemia, reduced perfusion)
• renal (e.g. glomerulonephritis, interstitial nephritis, vasculitis, ATN, acute cortical necrosis, drugs, pyelonephritis)
• post-renal (e.g. obstruction for calculi, tumour, clot)
• Chronic kidney injury which would put the patient at greater risk of tumour lysis is possible, but not likely if he is previously well.
• Sepsis is possible although it would usually occur at a later stage
(Marking Guide: 1 Mark for TLS; 0.25 marks for each reasonable differential)
b)
Resuscitation as needed to ensure adequate oxygenation and tissue perfusion.
Exclude differential diagnoses (history, examination and investigation including renal ultrasound).
• ECG, and if ECG changes consistent with hyperkalaemia, consider early intervention with (1) CaCl2 or Ca gluconate for temporary ECG stabilisation (new broad QRS or arrhythmia)
• (2) shift K intracellularly with either B2 agonist therapy (e.g. ventolin neb), insulin dextrose, or NaHCO3 if indicated
Specific management of tumour lysis syndrome
• IV fluids to encourage a diuresis
• Once well hydrated diuretics could be considered to encourage a diuresis (frusemide is most widely used, acetazolamide may alkalinise the urine which will increase the solubility of uric acid but reduce the solubility of CaPO4 and hence is less widely used)
• Rasburicase (to break down uric acid) o Urine alkalinisation not recommended if rasburicase has been given
o If rasburicase not available allopurinol maybe given (however, this is not as effective and will not breakdown uric acid, it merely reduces further uric acid formation)
Haemodialysis and/or filtration is generally instituted for standard indications, although it maybe instituted earlier in tumour lysis syndrome or if the patient remains oliguric.
Treat hypocalaemia only if symptomatic (cramps, paraesthesia) as excessive Ca replacement may precipitate CaPO4.
Hyperphosphataemia is most efficiently treated with haemodialysis and/or filtration, insulin dextrose and oral phosphate binders have a limited role.
Seek and treat sepsis.
Consider excluding renal obstruction with US.
Routine supportive care
Optimise oxygenation (if fluid overloaded maybe need supplemental oxygen)
Optimise perfusion and blood pressure
Withhold nephrotoxic medications drugs (NSAIDS, ACE-I, ARBs)
Consider dose modification of renally excreted drugs
DVT prophylaxis
Single room/ neutropenic precautions
The college certainly seems to love tumour lysis syndrome. This is the fourth time it has come up in the exam. It is certainly the top differential in this context. Nothing else could ever give rise to a urate level of 10mmol/L.
The list of other differentials might include:
And there is no reason why all of these might not co-exist simultaneously.
Assessment will consist of:
Specific management will consist of:
Tiu, Ramon V., et al. "Tumor lysis syndrome." Seminars in thrombosis and hemostasis. Vol. 33. No. 4. New York: Stratton Intercontinental Medical Book Corporation, c1974-, 2007.
Howard, Scott C., Deborah P. Jones, and Ching-Hon Pui. "The tumor lysis syndrome." New England Journal of Medicine 364.19 (2011): 1844-1854.
Cairo, Mitchell S., and Michael Bishop. "Tumour lysis syndrome: new therapeutic strategies and classification." British journal of haematology 127.1 (2004): 3-11.
Compare and contrast heparin induced thrombotic thrombocytopaenia syndrome (HITTS) and thrombotic thrombocytopaenlc purpura (TTP) with respect to their pathogenesis, clinical features, relevant laboratory findings, and treatment.
Condition |
TTP |
HITTS |
Aetiology 1 mark each |
|
Autoantibodies to platelet factor 4 (PF4) complexed with heparin |
Clinical Features 1 mark each |
Small vessel thrombosis- Microangiopathic haemolytic anaemia with multisystem involvement but renal and CNS dominate- |
Occurs within 4-10 days of heparin administration- arterial and venous thrombosis, thrombocytopenia |
Laboratory 2 marks each |
Low platelets, intravascular haemolysis with evidence of micrangiopathic changes to RBC morphology. LDH, Haptoglobin, COOMBS test, ADAMTS 13 deficiency |
Ant PF4 antibody, Functional Assays- (serotonin release, Heparin induced platelet activation) |
Treatment 1 mark each |
Plasmapharesis is the mainstay of treatment for Acquired TTP, FFP for hereditary TTP |
Cessation heparin Non heparin based anticoagulation ( Lepuridin etc) |
A "compare and contrast" question is typically something that benefits from a tabulated answer.
Observe:
Domain | HITS | TTP-HUS |
Pathogenesis |
|
|
Clinical features |
|
Classic "pentad"
|
Laboratory findings |
|
|
Treatment |
|
|
George, James N. "Thrombotic thrombocytopenic purpura." New England Journal of Medicine 354.18 (2006): 1927-1935.
Peyvandi, Flora, et al. "von Willebrand factor cleaving protease (ADAMTS‐13) and ADAMTS‐13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura." British journal of haematology 127.4 (2004): 433-439.
Tsai, Han-Mou. "Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura." Journal of the American Society of Nephrology 14.4 (2003): 1072-1081.
Oh's Intensive Care manual: Chapter 97 (pp. 993) Therapeutic plasma exchange and intravenous immunoglobulin therapy by Ian Kerridge, David Collins and James P Isbister
Kakishita, Eizo. "Pathophysiology and treatment of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS)."International journal of hematology 71.4 (2000): 320-327.
Noris, Marina, and Giuseppe Remuzzi. "Hemolytic uremic syndrome." Journal of the American Society of Nephrology 16.4 (2005): 1035-1050.
Kappler, Shane, Sarah Ronan-Bentle, and Autumn Graham. "Thrombotic Microangiopathies (TTP, HUS, HELLP)." Emergency Medicine Clinics of North America (2014).
Moake, Joel L. http://www.danielyoung.net/articles/NEJM%20TTP-HUS%202002.pdf "Thrombotic microangiopathies." New England Journal of Medicine 347.8 (2002): 589-600.
Arepally, Gowthami M., and Thomas L. Ortel. "Heparin-induced thrombocytopenia." New England Journal of Medicine 355.8 (2006): 809-817.
Patel, Vipul P., Matthew Bong, and Paul E. Di Cesare. "Heparin-induced thrombocytopenia and thrombosis." AMERICAN JOURNAL OF ORTHOPEDICS-BELLE MEAD- 36.5 (2007): 255.
Greinacher, Andreas. "Heparin-induced thrombocytopenia." New England Journal of Medicine 373.3 (2015): 252-261.
The following results were obtained from a patient in the ICU
Parameter |
Patient Value |
Adult Norma' Range |
Prothrombin time |
15.0 s |
10.0 - 15.0 |
International normalised ratio (INR) |
1.20 |
0.80 - 1.20 |
Activated Partial Thromboplastin Time (APTT) |
40.8 s* |
25.0 -35 0 |
Fibrinogen |
2.0 g/L |
2.0 —4.0 |
a) List four possible causes. (20% marks)
This is somewhat unsatisfying, as no history is given other than the patient is in ICU.
In summary, the results are:
Of these results the only actually abnormal one is the APTT.
Four possible causes of a slightly raised APTT are:
Kamal, Arif H., Ayalew Tefferi, and Rajiv K. Pruthi. "How to interpret and pursue an abnormal prothrombin time, activated partial thromboplastin time, and bleeding time in adults." Mayo Clinic Proceedings. Vol. 82. No. 7. Elsevier, 2007.
DeMuro, J. P., and A. F. Hanna. "Trauma Induced Coagulopathy: Prevention and Intervention."Scand J Trauma Resusc Emerg Med 20.47 (2014): 4.
White, Julian. "Snake venoms and coagulopathy." Toxicon 45.8 (2005): 951-967.
Kashuk, Jeffry L., et al. "Primary fibrinolysis is integral in the pathogenesis of the acute coagulopathy of trauma." Annals of surgery 252.3 (2010): 434-444.
De Stefano, Valerio, Guido Finazzi, and Pier Mannuccio Mannucci. "Inherited thrombophilia: pathogenesis, clinical syndromes, and management [see comments]." Blood 87.9 (1996): 3531-3544.
Hunt, Beverley J. "Bleeding and coagulopathies in critical care." New England Journal of Medicine 370.9 (2014): 847-859.
A 32-year-old female has been admitted to the ICU following an emergency response call for generalised tonic clonic seizures and obtundation. No past history is available. Non-contrast CT brain scan is normal. The following results are obtained:
Parameter |
Patient Value |
Adult Normal Range |
Sodium |
143 mmol/L |
135 – 145 |
Potassium |
3.0 mmol/L* |
3.5 – 5.0 |
Chloride |
116 mmol/L* |
95 – 105 |
Bicarbonate |
15.0 mmol/L* |
22.0 – 26.0 |
Glucose |
5.2 mmol/L |
3.5 – 6.0 |
Urea |
12.4 mmol/L* |
3.0 – 8.0 |
Creatinine |
202 μmol/L* |
45 – 90 |
Magnesium |
0.75 mmol/L |
0.75 – 0.95 |
Albumin |
14 g/L* |
35 – 50 |
Protein |
49 g/L* |
60 – 80 |
Total bilirubin |
35 μmol/L* |
< 26 |
Aspartate aminotransferase (AST) |
58 U/L* |
< 35 |
Alanine aminotransferase (ALT) |
50 U/L* |
< 35 |
Alkaline phosphatase (ALP) |
145 U/L* |
30 – 110 |
-Glutamyl transferase (GGT) |
45 U/L* |
< 40 |
Ionised calcium |
1.90 mmol/L* |
1.10 – 1.35 |
Calcium corrected |
2.90 mmol/L* |
2.12 – 2.62 |
Phosphate |
1.8 mmol/L* |
0.8 – 1.5 |
Creatinine Kinase |
356 U/L* |
55 – 170 |
Lactate dehydrogenase |
450 U/L* |
120 – 150 |
Haemoglobin |
75 g/L* |
120 – 160 |
White Cell Count |
20.0 x 109/L* |
4.0 – 11.0 |
Platelet count |
60 x 109/L* |
150 – 350 |
a)
• Thrombotic thrombocytopenic purpura
• HELLP syndrome
• Septic -meningo-encephalitis
• Drug - induced
• Vasculitis
• Malignancy
b)
• Blood film for schistocytosis
• Blood cultures/lumbar puncture
• Vasculitic screen
• Serology for pneumococcus/meningococcus
• Pregnancy test
Examiners Comments:
Generally, these questions were answered well. Those candidates that failed, missed all or part of the question or misinterpreted what was being asked, reiterating how important it is to read the question and understand what is required before starting to answer.
The abnormalities in this set of results are:
So; this mixture of abnormalities has to play along with a history of being young, female and seizury. The differentials therefore need to explain a decreased level of consciousness, renal failure, haematological disturbance with anaemia and theromobocytopenia, and seizures.
It is hard to say how HELP syndrome could have attracted any marks here, as you're missing the EL. Also, none of the differentials (apart from malignancy) explain the hypercalcemia. Also, malar
Thus, one would order a broadside of tests:
The following data refer to a 65-year-old male admitted to ICU with septic shock on a background of active rheumatoid arthritis.
Parameter |
Patient Value |
Adult Normal Range |
Haemoglobin |
86 g/L* |
125 – 180 |
Serum ferritin |
298 µg/L |
15 – 300 |
Serum iron |
7 µmol/L* |
9 – 27 |
Total Iron Binding Capacity (TIBC) |
52 µmol/L |
47 – 70 |
Transferrin Saturation (Iron / TIBC x 100) |
28% |
16 – 40 |
Erythropoietin level |
15 U/L |
4 – 28 |
C-reactive protein (CRP) |
321 mg/L* |
< 8 |
a) What abnormality is demonstrated in this patient? Give your reasoning. (20% marks)
b) What is the pathogenesis of these changes? (20% marks)
c) What are the principles of management? (10% marks)
This question is essentially identical to Question 18.1 from the first paper of 2015, except in the older SAQ question (c) reads "what specific treatment strategy would correct the demonstrated abnormality" instead of "what are the principles of management". These two alternative wordings must surely mean the exact same thing, because the college answer was identical for both versions of the question.
Anyway: a generic iron studies interpretation rubrik looks like this:
Condition | MCV | MCHC | Serum iron | Ferritin | Transferrin | Transferrin saturation |
TIBC |
Iron deficiency anaemia | low | low | low | low | high | <20% | high |
Anaemia of inflammation (chronic disease) | low | low | low | normal | low | normal | low or normal |
Acute phase response | normal | normal | low | high | low | low | low |
Iron overload | normal | normal | high | high | normal | high | high |
The college answer refers to "Anaemia of Inflammation", a nomenclature which has superseded "anaemia of chronic disease" as the description of the anaemia which has low serum iron in spite of normal body iron stores (i.e. normal ferritin). This "inflammation" could actually be anything proinflammatory, and so it would be difficult to comment whether the rheumatoid arthritis is more responsible then the sepsis, or vice versa. In either case, the biochemical picture would be more or less the same.
Alternative explanations for these laboratory results could also include the anaemia of decreased erythropoietin release associated with renal failure; but the college specifically gave us RA, sepsis and a raised CRP, clearly aiming the candidates at something inflammatory. Iron studies in anaemia of chronic renal failure tend to demonstrate iron deficiency, i.e. the ferritin is also low, but there is a group in whom there is a "functional" iron deficiency with normal ferritin levels and a failure of iron release from body stores (Babitt & Lyn, 2012). If the inflammatory elements were omitted from the story, this would be a legitimate alternative explanation.
The erythropoietin level is a weird thing to add because it is expensive and not usually a part of the normal panel. The RPCA Manual lists it as one of the tests "occasionally indicated" to discriminate primary from secondary erythrocytosis. It is not essential to the diagnosis of anaemia.
The mechanism of anaemia of inflammation can be summarised as follows:
Routine management of such an anaemia is therefore somewhat unexciting:
But let's say that for some reason you've lost interest in treating causes of things. Can we cosmetically make the iron study numbers look better? Turns out that yes, we can. There are several possible treatments for this sort of anaemia which specifically target the mechanism of its pathogenesis:
Hawkins, Stephen F., and Quentin A. Hill. "Diagnostic Approach to Anaemia in Critical Care." Haematology in Critical Care: A Practical Handbook (2014): 1-8.
Gross, I. "Laboratory Studies in the Diagnosis of Iron Deficiency, Latent Iron Deficiency and Iron Deficient Erythropoiesis". from http://iron.sabm.org
Pieracci, Fredric M., et al. "A Multicenter, Randomized Clinical Trial of IV Iron Supplementation for Anemia of Traumatic Critical Illness*." Critical care medicine 42.9 (2014): 2048-2057.
Litton, Edward, et al. "The IRONMAN trial: a protocol for a multicentre randomised placebo-controlled trial of intravenous iron in intensive care unit patients with anaemia." Crit Care Resusc 16 (2014): 285-290.
Corwin, Howard L., et al. "Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial." Jama 288.22 (2002): 2827-2835.
Mesgarpour, Bita, et al. "Safety of off-label erythropoiesis stimulating agents in critically ill patients: a meta-analysis." Intensive care medicine 39.11 (2013): 1896-1908.
Nemeth, Elizabeta, and Tomas Ganz. "Anemia of inflammation." Hematology/Oncology Clinics 28.4 (2014): 671-681.
Babitt, Jodie L., and Herbert Y. Lin. "Mechanisms of anemia in CKD." Journal of the American Society of Nephrology (2012): ASN-2011111078.
Nemeth, Elizabeta, and Tomas Ganz. "Anemia of inflammation." Hematology/Oncology Clinics 28.4 (2014): 671-681.
The following data refer to a 48-year-old female admitted electively to ICU following extensive pelvic surgery for invasive endometrial carcinoma. The patient has remained in ICU for 22 days because of complications including acute kidney injury.
Parameter |
Patient Value |
Adult Normal Range |
Haemoglobin |
66 g/L* |
125 – 180 |
Serum ferritin |
14 µg/L* |
15 – 300 |
Serum iron |
3 µmol/L* |
9 – 27 |
Total Iron Binding Capacity (TIBC) |
86 µmol/L* |
47 – 70 |
Transferrin Saturation (Iron / TIBC x 100) |
9%* |
16 – 40 |
Erythropoietin level |
41 U/L* |
4 – 28 |
C-reactive protein (CRP) |
60 mg/L* |
< 8 |
a) What abnormality is demonstrated in this patient? Give your reasoning. (20% marks)
b) Give two potential causative factors in this patient. (10% marks)
c) Briefly outline the available treatment options to correct the demonstrated abnormality including any disadvantages / risks. (20% marks)
a)
Iron deficiency anaemia as evidenced by:
b)
Blood loss
Pre-existing dietary deficiency
c)
IV iron replacement – no demonstrated benefit and risks of adverse effects (infection risk- IRONMAN)
Oral iron replacement?
Erythropoeitin – expensive and no demonstrated benefit
Blood transfusion – risks of transfusion including immunosuppression?
No treatment – may have reduced oxygen carrying capacity for some time until correction of Hb
This question is essentially identical to Question 18.2 from the first paper of 2015, except in 2015 the results of the IRONMAN study were not yet available. Apart from including a mention of this 2016 trial by Litton et al, the college examiners made the curious choice of taking management recommendations from the 2015 version of the question and rewording them in the form of questions ("Oral iron replacement?").
Anyway. Local resources to help with such questions include the following chapters:
In the above, there is a table of typical findings which is reproduced below:
Condition | MCV | MCHC | Serum iron | Ferritin | Transferrin | Transferrin saturation |
TIBC |
Iron deficiency anaemia | low | low | low | low | high | <20% | high |
Anaemia of chronic disease | low | low | low | normal | low | normal | low or normal |
Acute phase response | normal | normal | low | high | low | low | low |
Iron overload | normal | normal | high | high | normal | high | high |
Following from this, the results in this SAQ are pretty clearly iron deficiency anaemia (low haemoglobin, low iron, high TIBC, etc). The erythropoietin level is appropriately elevated, but not essential to making the diagnosis. Apart from blood loss and dietary deficiency, there's not much that can be added to the "potential causative factors".
The available treatment options are:
The college also included "do nothing" as a management option, though one might object that conceptually this would be the very opposite of a management plan. They also included recombinant human EPO as one of the treatment options, but then they also gave us a serum EPO which is significantly elevated. This defies logic- adding more exogenous EPO to the already high EPO level is unlikely to achieve a glorious haemopoietic victory, as the haemoglobin was still low even with the EPO levels almost double the upper range of normal. Moreover, giving EPO is not going to do anything to replenish your iron stores.
The most logical solution would be to give iron, or actual blood. Blood transfusion is of course the last option. The pros and cons of blood transfusion in the ICU are discussed in greater detail elsewhere. Iron replacement is probably somewhat less toxic, and seems like a sensible solution to a condition where the deficiency of iron is the main problem. One should not be deterred from doing this, even though the IRONMAN trial did not find any improvement in the rate of blood transfusion in their iron-infused group. Those patients did end up with a significantly higher haemoglobin at discharge, even though they were not specifically selected for having iron deficiency.
The objection to the use of IV iron is based in the finding that the iron-infused group has an increased nosocomial infection rate (28.6% vs. 22.9%). Apart from this, there was no major difference in the adverse event rate between the two groups. In any case, you don't have to give the iron intravenously. Oral iron replacement is not without its charm, and only slightly less effective (Bonovas et al, 2016).
Hawkins, Stephen F., and Quentin A. Hill. "Diagnostic Approach to Anaemia in Critical Care." Haematology in Critical Care: A Practical Handbook (2014): 1-8.
Gross, I. "Laboratory Studies in the Diagnosis of Iron Deficiency, Latent Iron Deficiency and Iron Deficient Erythropoiesis". from http://iron.sabm.org
Pieracci, Fredric M., et al. "A Multicenter, Randomized Clinical Trial of IV Iron Supplementation for Anemia of Traumatic Critical Illness*." Critical care medicine 42.9 (2014): 2048-2057.
Litton, Edward, et al. "The IRONMAN trial: a protocol for a multicentre randomised placebo-controlled trial of intravenous iron in intensive care unit patients with anaemia." Crit Care Resusc 16 (2014): 285-290.
Corwin, Howard L., et al. "Efficacy of recombinant human erythropoietin in critically ill patients: a randomized controlled trial." Jama 288.22 (2002): 2827-2835.
Mesgarpour, Bita, et al. "Safety of off-label erythropoiesis stimulating agents in critically ill patients: a meta-analysis." Intensive care medicine 39.11 (2013): 1896-1908.
Litton, Edward, et al. "Intravenous iron or placebo for anaemia in intensive care: the IRONMAN multicentre randomized blinded trial." Intensive care medicine 42.11 (2016): 1715-1722.
Bonovas, Stefanos, et al. "Intravenous versus oral iron for the treatment of anemia in inflammatory bowel disease: a systematic review and meta-analysis of randomized controlled trials." Medicine 95.2 (2016).
a) List the risk factors, clinical features and relevant investigations for occlusive upper limb deep venous thrombosis (ULDVT) in critically ill patients. (50% marks)
b) Discuss the available management options. (50% marks)
a)
Risk factors: (20% Marks)
5-7 correct 1 mark
<5 correct 0.5 mark
Clinical Features: (20% Marks)
Investigations: (10% Marks)
Compression ultrasound is the diagnostic standard, with >95% sensitivity and specificity. (this detail not required)
Doppler and CT may be required to diagnosis intrathoracic/super vena cava (SVC) obstruction.
b)
Treatment: (50% Marks)
Treatments aim to alleviate the symptoms, prevent thrombin propagation and pulmonary embolism, and prevent post-thrombotic syndromes.
(Highlighted points in treatment section are required for a pass mark.)
Examiners Comments:
Topic was poorly understood, with little knowledge beyond superficial. It was suspected that that relates to poor exposure and experience of more advanced interventions (thrombolysis, possible radiology directed treatments). Little was mentioned around importance of lines in thrombosis and almost everyone who remembered wanted to pull the lines out without thought or consideration of the implications.
Risk factors for upper limb DVT from Kommareddy et al (2002):
Gene mutations
|
Acquired thrombophilias
|
Other factors
|
Specific difference between upper limb and lower limb DVT risk factor profiles, according to Cote et al (2017):
Clinical features:
Investigations:
Management:
Guidelines from the American College of Chest Physicians (Kearon et al, 2012) recommend the following anticoagulation regimen:
In addition to this (not instead of it), one may need acute intervention:
Cook, Deborah, et al. "Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors." Critical care medicine 33.7 (2005): 1565-1571.
Miri, MirMohammad, Reza Goharani, and Mohammad Sistanizad. "Deep vein thrombosis among intensive care unit patients; an epidemiologic study." Emergency 5.1 (2017).
Wheeler, H. B. "Diagnosis of deep vein thrombosis. Review of clinical evaluation and impedance plethysmography." American journal of surgery 150.4A (1985): 7-13.
Williams, Michael T., et al. "Venous thromboembolism in the intensive care unit." Critical care clinics 19.2 (2003): 185-207.
Hirsch, Denise R., Edward P. Ingenito, and Samuel Z. Goldhaber. "Prevalence of deep venous thrombosis among patients in medical intensive care." Jama 274.4 (1995): 335-337.
Hong, Kee Chun, et al. "Risk factors and incidence of deep vein thrombosis in lower extremities among critically ill patients." Journal of clinical nursing 21.13-14 (2012): 1840-1846.
MAl-Dorzi, Hasan, and Yaseen M. Arabi. "Venous Thromboembolism in Critically Ill Patients: Risk Stratification and Prevention." Critical Care Update 2019 (2019): 29.
García-Olivares, Pablo, et al. "PROF-ETEV study: prophylaxis of venous thromboembolic disease in critical care units in Spain." Intensive care medicine 40.11 (2014): 1698-1708.
Obi, Andrea T., et al. "Validation of the Caprini venous thromboembolism risk assessment model in critically ill surgical patients." JAMA surgery 150.10 (2015): 941-948.
Ellis, Martin H., Yosef Manor, and Moshe Witz. "Risk factors and management of patients with upper limb deep vein thrombosis." Chest 117.1 (2000): 43-46.
Cote, Lauren P., et al. "Comparisons between upper and lower extremity deep vein thrombosis: a review of the RIETE registry." Clinical and Applied Thrombosis/Hemostasis 23.7 (2017): 748-754.
Kommareddy, Aruna, Michael H. Zaroukian, and Houria I. Hassouna. "Upper extremity deep venous thrombosis." Seminars in thrombosis and hemostasis. Vol. 28. No. 01. Copyright© 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.:+ 1 (212) 584-4662, 2002.
Hill, Stephen L., and Robert E. Berry. "Subclavian vein thrombosis: a continuing challenge." Surgery 108.1 (1990): 1-9.
Saber, W., et al. "Risk factors for catheter‐related thrombosis (CRT) in cancer patients: a patient‐level data (IPD) meta‐analysis of clinical trials and prospective studies." Journal of Thrombosis and Haemostasis 9.2 (2011): 312-319.
Kinnison, Malonnie L., et al. "Upper-extremity venography using digital subtraction angiography." Cardiovascular and interventional radiology 9.2 (1986): 106-108.
HULL, RUSSELL D., et al. "Diagnostic efficacy of impedance plethysmography for clinically suspected deep-vein thrombosis: a randomized trial." Annals of Internal Medicine102.1 (1985): 21-28.
Houshmand, Sina, et al. "The role of molecular imaging in diagnosis of deep vein thrombosis." American journal of nuclear medicine and molecular imaging 4.5 (2014): 406.
Malato, Alessandra, et al. "The impact of deep vein thrombosis in critically ill patients: a meta-analysis of major clinical outcomes." Blood Transfusion 13.4 (2015): 559.
McKelvie, Penelope A. "Autopsy evidence of pulmonary thromboembolism." Medical journal of Australia 160.3 (1994): 127-128.
Tran, Huyen A., et al. "New guidelines from the Thrombosis and Haemostasis Society of Australia and New Zealand for the diagnosis and management of venous thromboembolism." Medical Journal of Australia 210.5 (2019): 227-235.
Noyes, ADAM M., and John Dickey. "The arm is not the leg: pathophysiology, diagnosis, and management of upper extremity deep vein thrombosis." RI Med J 100 (2017): 33-36.
Kearon, Clive, et al. "Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines." Chest 141.2 (2012): e419S-e496S.
Watson, Lorna, Cathryn Broderick, and Matthew P. Armon. "Thrombolysis for acute deep vein thrombosis." Cochrane Database of Systematic Reviews 11 (2016).
Vedantham, Suresh, et al. "Guidance for the use of thrombolytic therapy for the treatment of venous thromboembolism." Journal of thrombosis and thrombolysis41.1 (2016): 68-80.
Vedantham, Suresh, et al. "Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis." New England Journal of Medicine 377.23 (2017): 2240-2252.
Comerota, Anthony J. "The current role of operative venous thrombectomy in deep vein thrombosis." Seminars in vascular surgery. Vol. 25. No. 1. WB Saunders, 2012.
With respect to transfusion protocols for massive haemorrhage; discuss the advantages and disadvantages of using a protocol guided by thromboelastography (TEG guided) compared to one that uses a fixed ratio of product replacement (e.g. FFP : platelets : packed cells = 1 : 1 : 1).
Background
Heterogeneous nature of the critically bleeding trauma patient and the spectrum of trauma induced coagulopathy may mean fixed ratio protocol (FRP) is too simplistic to apply to all patients. Although a FRP may improve survival, the optimal ratio of packed cells to other blood components is unknown. TEG-guided algorithms allow rapid identification and correction of patient-specific coagulation abnormalities. Trauma induced coagulopathy in the critically bleeding patient is complex and changes throughout time of resuscitation, therefore TEG allows repeated assessment and correction throughout resuscitation period.
TEG-guided MHP algorithms, as compared to FRP may limit unnecessary blood product transfusion and the associated complications (e.g. TRALI, volume overload) of giving high volumes of plasma and other products, while ensuring appropriate clotting factors are replaced as required (i.e. allows targeted intervention to replace coagulopathy with fewer side effects)
Advantages of TEG compared with FRP
Patient specific – therefore may limit unnecessary blood product transfusion and the associated complications (e.g. TRALI, transfusion reaction, volume overload, TACO, immunomodulation, allergy)
Patient specific – therefore ensures appropriate clotting factors are replaced when required (i.e. allows rapid targeted intervention to replace coagulopathy with fewer side effects)
Aids rapid identification of when there is an ongoing medical cause of bleeding (i.e. ongoing coagulopathy) versus purely surgical bleeding with the need to progress surgical intervention.
Detects fibrinolysis and hyperfibrinolysis which may be particularly relevant in the critically bleeding trauma patient.
TEGs have a higher sensitivity than standard laboratory tests to detect trauma induced coagulopathy and are faster than lab-based tests.
Even a 1:1:1 (plasma:platelets:packed cells) delivers dilute coagulation factors compared with whole blood; ideal ratio of blood products to packed cells in FRP remains debated.
Disadvantages of TEG compared with FRP
Machine (ROTEM or TEG) not available in all centres;
More expensive than standard laboratory coagulation testing
Ability to manage MHPs in multiple trauma patients simultaneously limited by number of machines available
Requires adequate volume of blood sample to run test and can’t be performed on intraosseous sample; therefore, may not be able to be performed on critically unwell patient with difficult iv access.
May delay lab preparation (thawing) of blood products while awaiting result; compared with fixed ratio protocol where products immediately thawed and delivered. (i.e. FRP allows rapid delivery of blood products independent of test results)
Requires interpretation of values to guide blood product use.
Not valid to assess effects of platelet function, direct thrombin inhibitors, LMWH, warfarin
Evidence
Controversial; evidence exists to support TEG in identifying trauma induced coagulopathy, but limited RCT trials on role of TEG-guided MHP algorithms
STATA trial currently ongoing (FRP vs thromboelastometry guided MHP in trauma patients)
Single centre RCT reports reduced blood transfusion rates and improved-survival with TEG-guided MHP (Gonzalez 2016) (compared with MTP guided by conventional coagulation assays)
Systematic review (2014) – 55 observational studies on use of TEG to guide blood product use in trauma:
FRP:
Note: The level of detail in the evidence section was not expected.
Examiner Comments:
A very topical question that was generally answered in a very superficial way. Detailed reference to the weak evidence base was not required, but some recognition of this fact was expected. Better structure often ensured better marks.
The examiners referred to TEG specifically in the question and throughout the answer, but it is clear that they were using the term interchangeably with ROTEM, and so in the discussion to follow TEG is also used as a surrogate for all forms of global testing for clotting function. Though the question asked specifically for a discussion of advantages and disadvantages, the college answer was formulated in a "critically evaluate" fashion which typically calls for a description of the rationale and supporting evidence As such, some mutant combination of the two answer formats is offered here, as a compromise which satisfies the authors' unhealthy preoccupation with tabulated answers.
Rationale for TEG-guided massive transfusion
Advantages of TEG
|
Disadvantages of TEG
|
Advantages of fixed ratio massive transfusion
|
Disadvantages of fixed ratio massive transfusion
|
Evidence which compares TEG-guided protocols with fixed ratio transfusion
Practical haemostasis - page on TEG and ROTEM
Sankarankutty, Ajith, et al. "TEG® and ROTEM® in trauma: similar test but different results." World J Emerg Surg 7.Suppl 1 (2012): S3.
Coakley, Margaret, et al. "Transfusion triggers in orthotopic liver transplantation: a comparison of the thromboelastometry analyzer, the thromboelastogram, and conventional coagulation tests." Journal of cardiothoracic and vascular anesthesia 20.4 (2006): 548-553.
Venema, Lieneke F., et al. "An assessment of clinical interchangeability of TEG® and ROTEM® thromboelastographic variables in cardiac surgical patients." Anesthesia & Analgesia 111.2 (2010): 339-344.
Nielsen, Vance G. "A comparison of the Thrombelastograph and the ROTEM." Blood Coagulation & Fibrinolysis 18.3 (2007): 247-252.
Wikkelsoe, A. J., et al. "Monitoring patients at risk of massive transfusion with Thrombelastography or Thromboelastometry: a systematic review." Acta Anaesthesiologica Scandinavica 55.10 (2011): 1174-1189.
Hunt, Harriet, et al. "Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) for trauma‑induced coagulopathy in adult trauma patients with bleeding." Cochrane Database of Systematic Reviews 2 (2015).
Nielsen, Jorn Dalsgaard, and Galloway Gregg. "Monitoring novel anticoagulants dabigatran, rivaroxaban and apixaban by thrombelastography. Proof of concept." (2013): 4813-4813.
Wikkelsø, A., et al. "Thromboelastography (TEG) or rotational thromboelastometry (ROTEM) to monitor haemostatic treatment in bleeding patients: a systematic review with meta‐analysis and trial sequential analysis." Anaesthesia 72.4 (2017): 519-531.
Gonzalez, Eduardo, et al. "Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays." Annals of surgery 263.6 (2016): 1051.
Da Luz, Luis Teodoro, et al. "Effect of thromboelastography (TEG®) and rotational thromboelastometry (ROTEM®) on diagnosis of coagulopathy, transfusion guidance and mortality in trauma: descriptive systematic review." Critical Care 18.5 (2014): 518.
The following data refer to a 34-year-old male admitted to ICU twenty days after an allogeneic stem cell transplant for acute myeloid leukaemia. Over the last few days he has been complaining of right upper quadrant abdominal pain, and observed to have gained several kilograms in weight.
Venous Biochemistry |
||
Parameter |
Patient Value |
Adult Normal Range |
Sodium |
142 mmol/L |
135 – 145 |
Potassium |
4.8 mmol/L* |
3.5 – 4.5 |
Chloride |
97 mmol/L |
95 – 105 |
Bicarbonate |
22 mmol/L |
22 – 26 |
Urea |
11.2 mmol/L* |
2.9 – 8.2 |
Creatinine |
134 μmol/L* |
70 – 120 |
Calcium |
2.13 mmol/L |
2.10 – 2.55 |
Phosphate |
1.21 mmol/L |
0.65 – 1.45 |
Total bilirubin |
342 μmol/L* |
0 – 25 |
Aspartate aminotransferase (AST) |
175 U/L* |
< 40 |
Gamma glutamyl transferase (GGT) |
123 U/L* |
< 40 |
Alanine aminotransferase (ALT) |
87 U/L* |
< 40 |
a) Veno-occlusive disease of the liver (sinusoidal obstruction syndrome)
b) ascites and reversal of portal vein flow. (2 marks)
The stem gives us everything needed to make the diagnosis here. The biochemical abnormalities are:
The combination of these findings with a recent history of BMT suggests strongly that veno-occlusive disease has developed. Both the Seattle and Baltimore criteria need a recent BMT, raised bilirubin and weight gain:
Seattle criteria:
|
Baltimore criteria:
|
Diagnosis does not require ultrasound, but it is usually ordered in this context. The BCSH/BSBMT guidelines (2013) concluded that "the main role of ultrasound is to exclude the presence of other diagnoses" because the ultrasound findings which are usually associated with VOD are insufficiently sensitive and specific. In any case, here they are:
Baron, Frédéric, Manuel Deprez, and Yves Beguin. "The veno-occlusive disease of the liver." Haematologica 82.6 (1997): 718-725.
Dignan, Fiona L., et al. "BCSH/BSBMT guideline: diagnosis and management of veno‐occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation." British journal of haematology 163.4 (2013): 444-457.
Richardson, Paul G., et al. "Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial." Biology of Blood and Marrow Transplantation 16.7 (2010): 1005-1017.
Couriel, Daniel, et al. "Acute graft‐versus‐host disease: Pathophysiology, clinical manifestations, and management." Cancer 101.9 (2004): 1936-1946.
Ljungman, Per, Paul Griffiths, and Carlos Paya. "Definitions of cytomegalovirus infection and disease in transplant recipients." Clinical Infectious Diseases 34.8 (2002): 1094-1097.
Bearman, Scott I. "The syndrome of hepatic veno-occlusive disease after marrow transplantation." Blood 85.11 (1995): 3005-3020.
Coppell, Jason A., et al. "Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome." Biology of Blood and Marrow Transplantation 16.2 (2010): 157-168.
Mcdonald, George B., et al. "Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors."Hepatology 4.1 (1984): 116-122.
Jones, Richard J., et al. "Venoocclusive disease of the liver following bone marrow transplantation." Transplantation 44.6 (1987): 778-783.
Kumar, Ashish, Praveen Sharma, and Shiv Kumar Sarin. "Hepatic venous pressure gradient measurement: time to learn." Indian J Gastroenterol 27.2 (2008): 74-80.
Cheuk, D. K., et al. "Interventions for prophylaxis of hepatic veno-occlusive disease in people undergoing haematopoietic stem cell transplantation." The Cochrane database of systematic reviews 5 (2015): CD009311-CD009311.
Mohty, M., et al. "Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation." Bone marrow transplantation 51.7 (2016): 906-912.
A 27-year-old male presents to the ICU febrile, ill and bleeding with the following results:
Parameter |
Patient Value |
Adult Normal Range |
Prothrombin time (PT) |
60.7 sec* |
12.0 – 16.5 |
International normalised ratio (INR) |
4.7* |
0.9 – 1.3 |
Activated partial thromboplastin time (APTT) |
> 220.0 sec* |
27.0 – 38.5 |
Fibrinogen |
0.2 g/L* |
2.0 – 4.0 |
Platelet count |
12 x 109/L* |
150 – 350 |
Prothrombin time mixing study |
13.8 sec |
|
APTT mixing study |
33.5 sec |
a) List three differential diagnoses for this presentation. (20% marks)
"Febrile, ill and bleeding" with a mixing study which corrects all the parameters suggests that all the clotting factors are somehow missing. They could have been missing for some time, or this could be an acute thing. Moreover, the fibrinogen and platelets are also very low.
What could cause this sort of pan-coagulopathy?
Stein, Eytan, et al. "The coagulopathy of acute promyelocytic leukaemia revisited." Best practice & research Clinical haematology 22.1 (2009): 153-163.
Kamal, Arif H., Ayalew Tefferi, and Rajiv K. Pruthi. "How to interpret and pursue an abnormal prothrombin time, activated partial thromboplastin time, and bleeding time in adults." Mayo Clinic Proceedings. Vol. 82. No. 7. Elsevier, 2007.
DeMuro, J. P., and A. F. Hanna. "Trauma Induced Coagulopathy: Prevention and Intervention."Scand J Trauma Resusc Emerg Med 20.47 (2014): 4.
White, Julian. "Snake venoms and coagulopathy." Toxicon 45.8 (2005): 951-967.
Kashuk, Jeffry L., et al. "Primary fibrinolysis is integral in the pathogenesis of the acute coagulopathy of trauma." Annals of surgery 252.3 (2010): 434-444.
De Stefano, Valerio, Guido Finazzi, and Pier Mannuccio Mannucci. "Inherited thrombophilia: pathogenesis, clinical syndromes, and management [see comments]." Blood 87.9 (1996): 3531-3544.
Hunt, Beverley J. "Bleeding and coagulopathies in critical care." New England Journal of Medicine 370.9 (2014): 847-859.
The following results were obtained from a 55-year-old female following an uneventful cholecystectomy:
Parameter |
Patient Value |
Adult Normal Range |
Prothrombin time (PT) |
16.0 sec |
12.0 – 16.5 |
International normalised ratio (INR) |
1.2 |
0.9 – 1.3 |
Activated partial thromboplastin time (APTT) |
56.0 sec* |
27.0 – 38.5 |
Fibrinogen |
2.8 g/L |
2.0 – 4.0 |
Platelet count |
223 x 109/L |
150 – 350 |
APTT mixing study |
52 sec |
a) List three causes of these results. What further blood tests would help to differentiate between them? (20% marks)
Other tests:
The history (cholecystectomy, etc) does not seem to serve much of a purpose here, as it dis not appear to have factored into the college's answer. In summary, this is an isolated raised APTT which does NOT reverse with a mixing study. The patient's blood, as it is mixed with a normal sample, makes the normal sample coagulopathic. There must be some sort of anticoagulant factor in it. Which one?
The three major candidates are:
The following tests are reasonable:
Kamal, Arif H., Ayalew Tefferi, and Rajiv K. Pruthi. "How to interpret and pursue an abnormal prothrombin time, activated partial thromboplastin time, and bleeding time in adults." Mayo Clinic Proceedings. Vol. 82. No. 7. Elsevier, 2007.
DeMuro, J. P., and A. F. Hanna. "Trauma Induced Coagulopathy: Prevention and Intervention."Scand J Trauma Resusc Emerg Med 20.47 (2014): 4.
White, Julian. "Snake venoms and coagulopathy." Toxicon 45.8 (2005): 951-967.
Kashuk, Jeffry L., et al. "Primary fibrinolysis is integral in the pathogenesis of the acute coagulopathy of trauma." Annals of surgery 252.3 (2010): 434-444.
De Stefano, Valerio, Guido Finazzi, and Pier Mannuccio Mannucci. "Inherited thrombophilia: pathogenesis, clinical syndromes, and management [see comments]." Blood 87.9 (1996): 3531-3544.
Hunt, Beverley J. "Bleeding and coagulopathies in critical care." New England Journal of Medicine 370.9 (2014): 847-859.
What is a mixing study, how is it performed and what is it purpose? (20% marks)
Mixing studies distinguish between factor deficiencies and the presence of inhibitors. They are performed by measuring the clotting time of the patient’s plasma diluted serially with normally plasma. If the mixture yields a 10% near normal results the study is said to be corrected and factor deficiency is inferred.
The weird design of the second paper of 2019 put his SAQ (directly asking about mixing studies) together with a bunch of questions (Question 5.2 and Question 5.3) which, for their correct interpretation, required the trainees to be able to interpret mixing studies. Ergo, if the trainee knew nothing at all, they would have scored poorly in all three SAQs. It is difficult to guess what additional advantage was obtained by this direct question, as compared to another question testing the trainees' understanding of mixing studies by means a clinical scenario. Some might say the latter is positioned higher in Bloom's taxonomy pyramid.
Anyway. Lets say your sample of plasma is giving a high PT or aPTT - grab your suspicious plasma sample, and mix it with normal blood plasma, 50:50. Obviously, if some sort of "factor inhibitor" is present, the normal blood will also be affected, and the resulting mixture will give abnormal aPTT and PT results. However, if there is a factor deficiency, the mixed sample will result in a normal PT or aPTT because the missing factors were contributed in the normal sample.
In short exam-focused point form:
Miller, C.H. "Mixing Studies". Ch 130. in: Transfusion Medicine and Hemostasis (Third Edition), 2019, Pages 783-784
a) Outline the pathophysiology, clinical and diagnostic features of Thrombotic Thrombocytopenic Purpura (TTP). (70% marks)
b) Outline the specific management of TTP. (30% marks)
Pathophysiology (2 marks)
Severe deficient activity of ADAMTS13 protease resulting in ultralarge von Williebrand factor (VWF) multimers to accumulate on the endothelial surface causing platelet aggregation and clumping with microthrombi formation leading to microangiopathic haemolytic anaemia (MAHA) and organ dysfunction. ADAMTS13 deficiency usually acquired (inhibitory autoantibody) or hereditary (inherited ADAMTS13 mutation). Enzyme activity is reduced during sepsis, pancreatitis, liver disease, pregnancy (2nd and 3rd trimester)
Clinical and diagnostic features (5 marks)
May present with weakness, fatigue, dyspnoea, gastrointestinal symptoms (abdominal pain/nausea/vomiting), history of bruising or bleeding with clinical findings of a petechial rash
Clinical features
Fever
Neurological symptoms (headache, confusion, seizure, stroke, coma)
Acute Kidney Injury (more likely in Haemolytic Uremic Syndrome)
Diagnostic features:
FBC and peripheral smear – anaemia, thrombocytopenia Features of MAHA (schistocytes, spherocytes, polychromasia)
Haemolysis - markedly elevated LDH, elevated indirect bilirubin, reduced haptoglobins, negative Coombs testing
Severe ADAMTS13 deficiency
Renal parameters – urea and creatinine may be deranged
Specific Management (3 marks):
Plasma exchange:
Daily exchanges 1.5 times plasma volume until remission. Replacement with cryodepleted plasma or FFP. (Replacement with 4% albumin would be inappropriate.)
Corticosteroids – reduce production of the ADAMTS13 inhibitor (autoantibody), reduced cytokine production or decreased autoantibody-mediated clearance of ADAMTS13.
Rituximab– chimeric monoclonal antibody directed against CD20 (found on B cells) –immunosuppressive
TTP is much beloved by the examiners, and will continue to appear in the papers. The superb pass rate for this SAQ (80.7%) demonstrates that the trainees recognise this.
Pathophysiology of TTP
From the college answer to Question 21 from the first paper of 2013:
"A trigger such as infection, surgery, pancreatitis, pregnancy, produces endothelial activation. ADAMTS 13 is a von Willebrand factor cleaving protein. When endothelial activation occurs and ADAMTS 13 activity is low (often due to an autoantibody inhibitor), large vWF multimers accumulate causing microvascular thrombosis and haemolys
Characteristic clinical features of TTP from Scully et al (2008)
Diagnostic features:
Specific management of TTP (2012 British guidelines):
George, James N. "Thrombotic thrombocytopenic purpura." New England Journal of Medicine 354.18 (2006): 1927-1935.
Peyvandi, Flora, et al. "von Willebrand factor cleaving protease (ADAMTS‐13) and ADAMTS‐13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura." British journal of haematology 127.4 (2004): 433-439.
Tsai, Han-Mou. "Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura." Journal of the American Society of Nephrology 14.4 (2003): 1072-1081.
Oh's Intensive Care manual: Chapter 97 (pp. 993) Therapeutic plasma exchange and intravenous immunoglobulin therapy by Ian Kerridge, David Collins and James P Isbister
Kakishita, Eizo. "Pathophysiology and treatment of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS)."International journal of hematology 71.4 (2000): 320-327.
Noris, Marina, and Giuseppe Remuzzi. "Hemolytic uremic syndrome." Journal of the American Society of Nephrology 16.4 (2005): 1035-1050.
Kappler, Shane, Sarah Ronan-Bentle, and Autumn Graham. "Thrombotic Microangiopathies (TTP, HUS, HELLP)." Emergency Medicine Clinics of North America (2014).
Moake, Joel L. http://www.danielyoung.net/articles/NEJM%20TTP-HUS%202002.pdf "Thrombotic microangiopathies." New England Journal of Medicine 347.8 (2002): 589-600.
Page, Evaren E., et al. "Thrombotic thrombocytopenic purpura: diagnostic criteria, clinical features, and long-term outcomes from 1995 through 2015." Blood advances 1.10 (2017): 590-600.
Scully, Marie, et al. "Regional UK TTP registry: correlation with laboratory ADAMTS 13 analysis and clinical features." British journal of haematology 142.5 (2008): 819-826.
Blombery, P., et al. "Diagnosis and management of thrombotic thrombocytopenic purpura (TTP) in Australia: findings from the first 5 years of the Australian TTP/thrombotic microangiopathy registry." Internal medicine journal 46.1 (2016): 71-79.
Scully, Marie, et al. "Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies." British journal of haematology 158.3 (2012): 323-335.
A 47-year-old female with newly diagnosed acute myeloid leukaemia presents with the following blood results:
Parameter |
Patient Value |
Adult Normal Range |
Haemoglobin |
89 g/L* |
120 – 160 |
White Cell Count |
110.0 x 109/L* |
4.0 – 11.0 |
Platelet count |
32 x 109/L* |
150 – 350 |
Blast cells |
104 x 109/L |
a) What specific issues might you anticipate as a result of the white cell count, and what clinical problems might these cause?
What management strategies would you employ to prevent or treat these issues? (60% marks)
1. Leukostasis/Hyperviscosity syndrome: white cell plugs in the microvasculature.
Most commonly affects lungs (dyspnoea, hypoxia, CXR infiltrates) and brain (visual changes, headache, dizziness, tinnitus, confusion progressing to coma)
Can also affect Heart (ischaemia, failure), kidney (AKI), liver/bowel ischaemia.
2. Tumour lysis syndrome- either spontaneous or in response to chemotherapy
Electrolyte abnormalities including hyperkalaemia, hyperphosphataemia and hypocalcaemia. Can cause arrhythmias, seizures and sudden death.
3. Artifactually low PaO2 on ABG due to metabolically active blasts which continue to utilise O2 in the test tube (SpO2 more reliable)
Management:
Keep hydrated
Start allopurinol or rasburicase to prevent TLS
Monitor FBC. Avoid RBC transfusion if possible (increases viscosity)
If there is a delay or contraindication to starting chemotherapy immediately, consider leukapheresis if symptomatic of hyper-viscosity.
For ABGs – sample transported on ice, analyse immediately. Monitor SpO2.
Examiners Comments:
When asked for a specific number of responses (e.g. 'three causes of') please supply this number of responses. Extra responses will not gain extra marks. If there are more causes, then list the most likely. Many candidates did not appear to pay attention to the mark allocation and gave insufficient detail in sections of the question worth the most marks.
As a table, this answer makes more sense:
specific issues might you anticipate | Leukostasis | Tumour lysis syndrome |
What clinical problems might these cause? |
|
|
Management |
|
|
Strictly speaking, this patient has hyperleukocytosis rather than leukostasis. Ganzel et al (2012) define it as any WCC in excess of 100,000, admitting that this is a fairly arbitrary cut-off. Leukostasis per se is a clinical manifestation of hyperleukocytosis, characterised by vascular occlusion and tissue hypoxia. It is seen with high WCCs, but usually quite a lot higher than this one (usually 400,000-1,000,000).
One last interesting feature is the need to refrigerate the ABGs. An excess of highly metabolically active blasts in the blood sample gives rise to "leukocyte larceny", where the hungry cells metabolise all the gases while you wait for the ABG machine to self-calibrate. The result is a spurious hypoxia and hypoglycaemia.
Porcu, Pierluigi, et al. "Hyperleukocytic leukemias and leukostasis: a review of pathophysiology, clinical presentation and management." Leukemia & lymphoma 39.1-2 (2000): 1-18.
Ganzel, Chezi, et al. "Hyperleukocytosis, leukostasis and leukapheresis: practice management." Blood reviews 26.3 (2012): 117-122.
Tiu, Ramon V., et al. "Tumor lysis syndrome." Seminars in thrombosis and hemostasis. Vol. 33. No. 4. New York: Stratton Intercontinental Medical Book Corporation, c1974-, 2007.
Howard, Scott C., Deborah P. Jones, and Ching-Hon Pui. "The tumor lysis syndrome." New England Journal of Medicine 364.19 (2011): 1844-1854.
Cairo, Mitchell S., and Michael Bishop. "Tumour lysis syndrome: new therapeutic strategies and classification." British journal of haematology 127.1 (2004): 3-11.
Gartrell, Kevin, and W. Rosenstrauch. "Hypoxaemia in patients with hyperleukocytosis: true or spurious, and clinical implications." Leukemia research 17.11 (1993): 915-919.
A previously well 24-year-old male presents with fevers, malaise and jaundice. Microbiological cultures are negative, and despite treatment with broad spectrum antibiotics he continues to deteriorate. The following results are obtained:
Parameter |
Patient Value |
Adult Normal Range |
Sodium |
129 mmol/L* |
135 – 145 |
Potassium |
5.1 mmol/L* |
3.5 – 5.0 |
Chloride |
105 mmol/L |
95 – 105 |
Bicarbonate |
14.0 mmol/L* |
22.0 – 26.0 |
Urea |
16.3 mmol/L* |
3.0 – 8.0 |
Creatinine |
659 µmol/L* |
45 – 90 |
Glucose |
7.0 mmol/L* |
3.5 – 6.0 |
Magnesium |
1.49 mmol/L* |
0.75 – 0.95 |
Albumin |
27 g/L* |
35 – 50 |
Protein |
45 g/L* |
60 – 80 |
Total bilirubin |
148 µmol/L* |
< 26 |
Conjugated bilirubin |
143 µmol/L |
|
Aspartate transferase |
2250 U/L* |
< 35 |
Alanine transferase |
1218 U/L* |
< 35 |
Alkaline phosphatase |
43 U/L |
30 – 110 |
g-Glutamyl transferase |
68 U/L* |
< 40 |
Ionised calcium |
0.97 mmol/L* |
1.10 – 1.35 |
Calcium corrected |
1.95 mmol/L* |
2.12 – 2.62 |
Phosphate |
1.11 mmol/L |
0.80 – 1.50 |
Creatinine Kinase |
500 U/L* |
55 – 170 |
Iron Level |
34 µmol/L |
6 – 35 |
Ferritin |
181,900 µg/L* |
30 – 400 |
Transferrin |
0.6 g/L* |
2.0 – 3.6 |
Ammonia |
78 µmol/L* |
16 – 60 |
Parameter |
Patient Value |
Adult Normal Range |
Haemoglobin |
132 g/L |
120 – 160 |
White Cell Count |
5.2 x 109/L |
4.0 – 11.0 |
Platelet count |
24 x 109/L* |
150 – 350 |
Parameter |
Patient Value |
Adult Normal Range |
Prothrombin time |
20.0 sec* |
12.0 – 16.5 |
International normalised ratio (INR) |
1.8* |
0.9 – 1.3 |
Activated partial thromboplastin time (APTT) |
77.0 sec* |
27.0 – 38.5 |
Fibrinogen |
0.7 g/L* |
2.0 – 4.0 |
D-Dimer |
66.0 mg/L* |
< 0.5 |
a) Interpret the abnormalities (30% marks)
b) What is the most likely diagnosis? (10% marks)
c) What are precipitants of this condition? (10% marks)
a)
Interpret the abnormalities.
Mild hyponatraemia and hyperkalaemia
AKI: Rise in creatinine out of proportion to rise in urea (ratio urea: creatinine < 100:1) – due to intrinsic renal dysfunction or associated severe liver injury
Reduced bicarbonate and normal anion gap metabolic acidosis Hyperbilirubinaemia – mostly conjugated
Acute hepatocellular liver injury: ratio AST:ALT increased but not quite 2:1 indicative of alcoholic hepatitis (also not supported by only slightly elevated GGT) but suggestive other acute liver injury Other synthetic liver dysfunction: INR 1.8; Ammonia mildly elevated
Mildly elevated CK - ? muscle injury
Severely elevated ferritin with normal iron levels. Normal Hb/ Wcc
Markedly deranged coagulation: severe thrombocytopaenia, low fibrinogen, markedly elevated APTT and severely elevated D-Dimer – Suggestive of DIC type pathology
b)
What is the most likely diagnosis?
Given the severity of the elevated ferritin and multiorgan involvement, Haemphagocytic lymphohistioctyosis (haemophagocytic syndrome)
c)
What are precipitants of this condition?
Viral infections particularly EBV/CMV/HSV/VZC/Parvovirus Malignancy especially lymphoma and leukaemia Rheumatologic conditions
First, let's list the abnormalities, and briefly digress on their meaning:
So, the only thing this could be is haemophagocytic syndrome. The causes of this rare disease can be found in the review article by Gritta Janka (2008):
Congenital:
Acquired causes
Lee, Mark H., and Robert T. Means. "Extremely elevated serum ferritin levels in a university hospital: associated diseases and clinical significance." The American journal of medicine 98.6 (1995): 566-571.
Hearnshaw, Sarah, Nick Paul Thompson, and Andrew McGill. "The epidemiology of hyperferritinaemia." World journal of gastroenterology 12.36 (2006): 5866. - ! WARNING ! this link will download the whole September issue, with the potential to fatally clog your internet hole.
Janka, Gritta E. "Hemophagocytic syndromes." Blood reviews 21.5 (2007): 245-253.
A 61-year-old male is diagnosed with a large haemothorax after a fall. He has a history of atrial fibrillation and takes rivaroxaban. He becomes increasingly hypoxic and hypotensive and a decision is made to urgently correct the coagulopathy and insert a chest drain.
His first set of coagulation tests are as follows:
Parameter |
Patient Value |
Adult Normal Range |
International normalised ratio (INR) |
2.0* |
0.9 – 1.3 |
Activated partial thromboplastin time (APTT) |
37.0 sec |
27.0 – 38.5 |
Fibrinogen |
5.4 g/L* |
2.0 – 4.0 |
a) What is the mechanism of action of rivaroxaban? (10% marks)
b) What other information do you need from history and investigations to make an assessment of his coagulation status? (40% marks)
c) What steps will you take to correct his coagulopathy? (50% marks)
Not available.
a) Mechanism of action
b)
Additional history:
Additional investigations:
c)
Correction of coagulopathy:
Kreutz, Reinhold. "Pharmacodynamic and pharmacokinetic basics of rivaroxaban." Fundamental & clinical pharmacology 26.1 (2012): 27-32.
Almegren, Mosaad. "Reversal of direct oral anticoagulants." Vascular health and risk management 13 (2017): 287.
Cohen, Oliver, Lucy-Anne Frank, and Susan Bradley. "Reversal of direct oral anticoagulants." British Journal of Hospital Medicine 79.5 (2018): C70-C73.
Siegal, Deborah M., et al. "Andexanet alfa for the reversal of factor Xa inhibitor activity." New England Journal of Medicine373.25 (2015): 2413-2424.
Galliazzo, S., M. P. Donadini, and W. Ageno. "Antidotes for the direct oral anticoagulants: What news?." Thrombosis research164 (2018): S119-S123.
A 75-year-old male patient presented with bone pain. His biochemical profile is shown below:
Parameter |
Patient Value |
Adult Normal Range |
Sodium |
140 mmol/L |
135 – 145 |
Potassium |
5.1 mmol/L* |
3.5 – 5.0 |
Chloride |
108 mmol/L* |
95 – 105 |
Bicarbonate |
21.0 mmol/L* |
22.0 – 26.0 |
Glucose |
6.0 mmol/L |
3.5 – 6.0 |
Urea |
25.0 mmol/L* |
3.0 – 8.0 |
Creatinine |
250 μmol/L* |
45 – 90 |
Magnesium |
1.10 mmol/L* |
0.75 – 0.95 |
Albumin |
25 g/L* |
35 – 50 |
Protein |
95 g/L* |
60 – 80 |
Total bilirubin |
26 μmol/L* |
< 26 |
Aspartate transferase |
60 U/L* |
< 35 |
Alanine transferase |
60 U/L* |
< 35 |
Alkaline phosphatase |
250 U/L* |
30 – 110 |
g-Glutamyl transferase |
40 U/L* |
< 40 |
Ionised calcium |
1.50 mmol/L* |
1.10 – 1.35 |
Calcium corrected |
2.90 mmol/L* |
2.12 – 2.62 |
Phosphate |
1.8 mmol/L* |
0.8 – 1.5 |
Lactate Dehydrogenase |
350 U/L* |
50 – 150 |
Beta2 microglobulin |
6 mg /L* |
< 1 |
a) Give the most likely diagnosis. (10% marks)
b) List the factors that may predispose to infection in this patient. (20% marks)
Not available.
Bone pain. He presents with bone pain.
a)
The abnormalities are:
So, this is multiple myeloma.
b)
Factors which increase the susceptibility to infection in myeloma and plasmacytoma are:
Kalambokis, G. N., L. Christou, and E. V. Tsianos. "Multiple myeloma presenting with an acute bacterial infection." International journal of laboratory hematology 31.4 (2009): 375-383.
A 62-year-old male has been admitted to your ICU for routine post-operative monitoring after a vascular surgical procedure.
His pre-operative full blood count (FBC) is displayed below:
Parameter |
Patient Value |
Adult Normal Range |
Haemoglobin |
125 g/L* |
130 – 180 |
White Cell Count |
7.4 x 109/L |
4.5 – 11 |
Platelets |
255 x 109/L |
150 – 400 |
Mean Cell Volume |
110 fL* |
80 – 98 |
Mean Cell Haemoglobin |
30 pg/cell |
27 – 33 |
Mean Cell Haemoglobin Concentration |
320 p/L |
310 – 360 |
a) Give six possible causes for the findings on his FBC. (30% marks)
Not available.
The abnormalities are:
The cell haemoglobin content is normal, i.e. this is a macrocytic normochromic anaemia.
There are several common causes:
There are also a few uncommon causes:
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.
A 52-year-old female presents with bruising and a retroperitoneal haematoma five weeks after starting warfarin for a proximal deep vein thrombosis (DVT) with a target international normalised ratio (INR) of 2.5.
Her investigations are as follows:
Parameter |
Patient Value |
Adult Normal Range |
Haemoglobin |
122 g/L* |
135 – 180 |
White Cell Count |
10.1 x 109/L |
4.0 – 11.0 |
Platelets |
298 x 109/L |
150 – 400 |
Prothrombin time |
29.3 sec* |
12.0 – 16.5 |
International normalised ratio (INR) |
2.3* |
0.9 – 1.3 |
Activated partial thromboplastin time (APTT) |
117.0 sec* |
27.0 – 38.5 |
Fibrinogen |
3.9 g/L |
2.0 – 4.0 |
a) Give the likely underlying cause for this coagulation profile. (20% marks)
b) List two confirmatory tests. (20% marks)
Not available.
The abnormalities are:
So: the extrinsic pathway is working normally (for a warfarinised lady), but the intrinsic pathway is broken. Why would that be? Naturally, you'd classify these abnormalities into two broad groups:
Factor deficiency seems less plausible given the history. So: what anticoagulant factors can there be? Or rather; what anticoagulant factor can you think of w, which might give rise to a bleeding propensity but at the same time predispose somebody to having clots? Antiphospholipid syndrome comes to mind.
b)
You would want to order:
Theoretically you could also order thrombin time and reptilase time, as antiphospholipid syndrome would have a normal; TT and RT.
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.
Hunt, Beverley J. "Bleeding and coagulopathies in critical care." New England Journal of Medicine 370.9 (2014): 847-859.
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.
A blood film from a patient is reported as showing a left shift and toxic changes.
a) What is the likely diagnosis?
b) What is meant by a left shift?
c) What constitutes ‘toxic changes’?
(25% marks)
Not available.
"Left shift and toxic changes" is some anachronistic terminology still used to describe the morphological changes which occur in neutrophils in response to a variety of (usually infectious) stressors.
Causes of this picture:
Left shift is an increased proportion of immature granulocytes, predominantly neutrophils.
"Toxic changes" are morphological changes seen in neutrophils, which occur as a part of widespread neutrophil activation (usually in response to systemic infection). To call "toxic changes" on a blood film, the laboratory scientist needs to find at least two out of three of the following morphological changes:
Zieve, Philip D., et al. "Vacuolization of the neutrophil: an aid in the diagnosis of septicemia." Archives of internal medicine 118.4 (1966): 356-357.
Zini, G. "Abnormalities in leukocyte morphology and number." Blood and bone marrow pathology. Churchill Livingstone Philadelphia, 2011. 247-261.
Schofield, K. P., et al. "Quantitative cytochemistry of the toxic granulation blood neutrophil." British journal of haematology 53.1 (1983): 15-22.
Weiner, W., and Elizabeth Topley. "Döhle bodies in the leucocytes of patients with burns." Journal of clinical pathology 8.4 (1955): 324-328.
Kulkarni, M., T. Agrawal, and V. Dhas. "Histopathologic bodies: An insight." Journal of the International Clinical Dental Research Organization 3.1 (2011): 43.
Easton, J. A., and Ch Fessas. "The incidence of Döhle bodies in various diseases and their association with thrombocytopenia." British journal of haematology 12.1 (1966): 54-60.
Cawley, J. C., and F. G. J. Hayhoe. "The Inclusions of the May‐Hegglin Anomaly and Dohle Bodies of Infection: an Ultrastructural Comparison." British journal of haematology 22.4 (1972): 491-496.
Nierhaus, Axel, et al. "Revisiting the white blood cell count: immature granulocytes count as a diagnostic marker to discriminate between SIRS and sepsis-a prospective, observational study." BMC immunology 14.1 (2013): 1.
A patient returns for review 8 weeks following severe gunshot injuries to the chest and abdomen. His blood film is reported as showing Howell Jolly bodies.
a) What is the significance of this finding?
b) What other changes associated with this problem may be noted on blood film?
c) What specific infections is this patient at risk from (requiring vaccination)?
d) If the blood film for this patient also reported basophilic stippling of the red cells, what might be the cause?
(25% marks)
Not available.
This is a lot of esoteric knowledge for a question that asks four things for 25% of the total mark. Each thing is therefore worth 6.25%, i.e. 0.6 marks out of a total 10. Applying the typical exam panic calculus, that means you have 36 seconds to process and compose the answer for each section.
a) The significance of the Howel-Jolly bodies:
This finding suggests the patient has had a trauma-related splenectomy. Howell-Jolly bodies are bits of leftover DNA in the erythrocytes. Normally, the spleen would view these as defective, and they would be removed. They are typically seen in patients who have had a splenectomy, or who are functionally asplenic for some other reason. Other associations include the following conditions:
b) Other abnormalities associated with splenectomy:
c) "What specific infections is this patient at risk from (requiring vaccination)?" is a weird way to phrase the question, which clearly wants to ask "what vaccinations should this patient have?", but still: let's answer it the way it was asked. The specific infections (requiring vaccination) are mainly from encapsulated organisms, and include:
d) Basophilic stippling of the red cells is the presence of altered ribosomes in the red cell cytoplasm, which is usually associated with lead toxicity. Could this mean that this trauma patient still has bits of lead somewhere in his body? Yes, it definitely does mean that. No joke: this happens all the time in those sorts of places in the world where gun violence is prevalent.
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.
Garcés, Juan Bernardo Gerstner, and Rafael Ignacio Manotas Artuz. "Lead poisoning due to bullets lodged in the human body." Colombia Médica: CM 43.3 (2012): 230.
A blood film from a patient is reported as showing a “dimorphic population of red cells”.
a) What is meant by dimorphic population?
b) Give four causes of this picture.
(25% marks)
Not available.
Dimorphic population of red cells is the presence of two or more morphologically distinct red cell populations in the same bloodstream. This is a finding usually reported on the basis of a strongly bimodal red cell volume histogram which is produced by automated blood cell analysers (Constantino, 2011). The term is somewhat misleading, as the histogram may have more than two discrete red cell populations sharing the bloodstream. However, usually there's only two cell populations; typically a group from before some sort of illness or treatment, and a group from after that event. Examples include:
Following from this, numerous possibilities exist to explain the concurrent presence of several morphologically distinct red cell variants, some of which are totally predictable. This representative list is cut-and-pasted from Constantino (2011):
Constantino, Benie T. "The red cell histogram and the dimorphic red cell population." Laboratory Medicine 42.5 (2011): 300-308.
Regarding COVID-19 vaccine induced immune thrombotic thrombocytopaenia (VITT):
a) Outline the pathophysiology and risk factors. (20% marks)
b) Outline the clinical presentation. (35% marks)
c) List three differential diagnoses. (15% marks)
d) Outline the supportive and specific management. (30% marks)
Not available.
Bucking the conventional wisdom that CICM Fellowship Exam questions follow their subject with a lag of 12-18 months, this one brings up a topic of considerable contemporary importance in the latter half of 2021, when the Australian population were working hard on developing herd immunity. For this SAQ from August 2021, the most effective revision resource would have to be the TSANZ statement on VITT from August 2021.
Pathophysiology and risk factors:
Clinical presentation:
Three differential diagnoses:
Supportive and specific management:
A 66-year-old male presents to hospital with hypotension, having had intermittent chest pain throughout the day. He develops runs of broad complex bradycardia requiring adrenaline boluses to maintain output. He is alert, and not in respiratory distress. His blood pressure is 90/40 mmHg, and his heart rate is 113 beats/min.
Past medical history includes Type 2 diabetes mellitus (T2DM) with end stage kidney disease. Baseline blood tests include K+ 5.8 mmol/L, urea 20 mmol/L, creatinine 430 μmol/L, Hb 96 g/L. Further questioning reveals a 4-day history of loose, dark bowel motions.
Blood gas results are shown below:
Parameter | Admission value | Adult Normal Range | ||||||||||||
FiO2 | 0.28 | |||||||||||||
pH | 7.14* | 7.35 – 7.45 | ||||||||||||
pO2 | 78 mmHg | |||||||||||||
pCO2 | 31.0 mmHg* | 35.0 – 45.0 | ||||||||||||
SpO2 | 94% | |||||||||||||
Bicarbonate | 10.3 mmol/L* | 22.0 – 26.0 | ||||||||||||
Base Excess | -14 mmol/L* | -2.0 – +2.0 | ||||||||||||
Lactate | 3.1 mmol/L* | 0.5 – 1.6 |
Parameter | Patient Value | Adult Normal Range | ||||||||||||
Sodium | 133 mmol/L* | 135 – 145 | ||||||||||||
Potassium | 6.9 mmol/L* | 3.5 – 5.0 | ||||||||||||
Chloride | 109 mmol/L* | 95 – 105 | ||||||||||||
Glucose | 16.8 mmol/L* | 3.5 – 6.0 | ||||||||||||
Urea | 41.5 mmol/L* | 3.0 – 8.0 | ||||||||||||
Creatinine | 489 μmol/L* | 45 – 90 | ||||||||||||
Magnesium | 0.95 mmol/L | 0.75 – 0.95 | ||||||||||||
Albumin | 35 g/L | 35 – 50 | ||||||||||||
Calcium corrected | 2.40 mmol/L | 2.12 – 2.62 | ||||||||||||
Phosphate | 1.5 mmol/L | 0.8 – 1.5 | ||||||||||||
Creatinine Kinase | 1692 U/L* | 55 – 170 | ||||||||||||
Hs troponin | 6501 ng/L* | 0 – 34 | ||||||||||||
Cortisol | 438 nmol/L | 170 – 500 | ||||||||||||
CRP | < 3 | < 5 | ||||||||||||
Parameter | Patient Value | Adult Normal Range | ||||||||||||
Haemoglobin | 66 g/L* | 120 – 160 | ||||||||||||
Mean Cell Volume | 93 fL | 80 – 99 | ||||||||||||
White Cell Count | 14.2 x 109/L* | 4.0 – 11.0 | ||||||||||||
Platelet count | 258 x 109/L | 150 – 350 | ||||||||||||
Parameter | Patient Value | Adult Normal Range | ||||||||||||
Prothrombin time | 14.5 sec | 12.0 – 16.5 | ||||||||||||
INR | 1.1 | 0.9 – 1.3 | ||||||||||||
APTT | 32.0 sec | 27.0 – 38.5 | ||||||||||||
Fibrinogen | 4.1 g/L* | 2.0 – 4.0 |
a) List the abnormalities and explain the potential cause of each. (60% marks)
The patient’s ECG (ECG 4.1) is shown on page 5. (Image removed from paper.)
b) List the abnormal ECG findings and list the likely diagnosis. (20% marks)
c) List how you would confirm this diagnosis. (20% marks)
Not available.
Without official college answers to refer to, the (broad) differentials presented by this SAQ were entirely to the imagination of the author, with predictably disastrous consequences.
First, let us list the abnormalities. The question does not specify where to get them from (just the bloods?), or how many to list; but this is for 60% of the marks, so the response needs to be comprehensive.
Thus, from the stem:
From the gas:
From the rest of the bloods:
The rest of the bloods are essentially normal.
"List the abnormal ECG findings" and "list the likely diagnosis" is a much harder task, even if one assumes the second half of the question asked to give the likely diagnosis instead (it is of course possible that "list the likely diagnosis" actually meant "give a list of differentials").
The college had removed the ECG from their paper, so this ECG comes from Falk (2005). Its main feature is a low-voltage QRS, with poor R wave progression. Addiitonal possible findings which might have appeared in the college EC could have been AV conduction abnormalities (eg. a first degree heart block) or a "pseudoinfarct" pattern (Cheng et al, 2013). Why was this ECG chosen to replace the one in the paper? Because the fascinating forensic task of reconstituting this SAQ has led the author to look for some kind of a grand unifying diagnosis which is associated with renal failure, one which produces ECG-detectable cardiac abnormalities, and which could be related to the upper GI blood loss. This winding path had led to amyloidosis. This is supported by uneducated Google searches:
This, of course, could be completely wrong. But the reader should note that listing ECG abnormalities and interpreting the data was worth most of the marks, and the diagnosis was one tiny fraction (perhaps 10% of the total). It is of course possible that "list the likely diagnosis" actually meant "give a list of differentials"
The investigations to confirm or exclude this disease would be:
Falk, Rodney H. "Diagnosis and management of the cardiac amyloidoses." Circulation 112.13 (2005): 2047-2060.
John, Roy M. "Arrhythmias in cardiac amyloidosis." The Journal of Innovations in Cardiac Rhythm Management 9.3 (2018): 3051.
Cheng, Zhongwei, et al. "The findings of electrocardiography in patients with cardiac amyloidosis." Annals of Noninvasive Electrocardiology 18.2 (2013): 157-162.
Chan, Rachael, and Stephanie Carpentier. "Gastric amyloidosis presenting as acute upper gastrointestinal bleeding: a case report." BMC gastroenterology 21.1 (2021): 1-4.
The following blood tests are obtained for a newly admitted patient in the ICU, who is intubated and mechanically ventilated.
Parameter | Patient Value | Adult Normal Range | |||||||||||||
FiO2 | 0.5 | ||||||||||||||
pH | 7.17* | 7.35 – 7.45 | |||||||||||||
pO2 | 93 mmHg (12.2 kPa) | ||||||||||||||
pCO2 | 40.0 mmHg (5.2 kPa) | 35.0 – 45.0 (4.6 – 6.0) | |||||||||||||
SpO2 | 95% | ||||||||||||||
Bicarbonate | 14.0 mmol/L* | 22.0 – 26.0 | |||||||||||||
Base Excess | -13.8 mmol/L* | -2.0 – +2.0 | |||||||||||||
Lactate | 1.4 mmol/L | 0.5 – 1.6 | |||||||||||||
Glucose | 7.3 mmol/L* | 3.5 – 6.0 | |||||||||||||
Parameter | Patient Value | Adult Normal Range | |||||||||||||
Sodium | 129 mmol/L* | 135 – 145 | |||||||||||||
Potassium | 5.5 mmol/L* | 3.5 – 5.0 | |||||||||||||
Chloride | 96 mmol/L | 95 – 105 | |||||||||||||
Bicarbonate | 14.0 mmol/L* | 22.0 – 26.0 | |||||||||||||
Urea | 16.3 mmol/L* | 3.0 – 8.0 | |||||||||||||
Creatinine | 659 μmol/L* | 45 – 90 | |||||||||||||
Albumin | 27 g/L* | 35 – 50 | |||||||||||||
Protein | 45 g/L* | 60 – 80 | |||||||||||||
Total bilirubin | 148 μmol/L* | < 26 | |||||||||||||
Aspartate transferase | 1,945 U/L* | < 35 | |||||||||||||
Alanine transferase | 1,218 U/L* | < 35 | |||||||||||||
Alkaline phosphatase | 43 U/L | 30 – 110 | |||||||||||||
g-Glutamyl transferase | 68 U/L* | < 40 | |||||||||||||
Ionised calcium | 0.97 mmol/L* | 1.10 – 1.35 | |||||||||||||
Phosphate | 1.11 mmol/L | 0.80 – 1.50 | |||||||||||||
Ferritin | 181,900 mg/L* | 30 – 400 |
Parameter | Patient Value | Adult Normal Range | |||||||||||||||
Haemoglobin | 132 g/L | 120 – 160 | |||||||||||||||
White Cell Count | 5.2 x 109/L | 4.0 – 11.0 | |||||||||||||||
Platelet count | 24 x 109/L* | 150 – 350 | |||||||||||||||
Parameter | Patient Value | Adult Normal Range | |||||||||||||||
Prothrombin time | 20.0 sec* | 12.0 – 16.5 | |||||||||||||||
INR | 1.8* | 0.9 – 1.3 | |||||||||||||||
APTT | 77.0 sec* | 27.0 – 38.5 | |||||||||||||||
Fibrinogen | 0.7 g/L* | 2.0 – 4.0 | |||||||||||||||
D-Dimer | 66.7 mg/L* | < 0.5 |
a) List the abnormalities. (60% marks)
b) List the most likely diagnosis. (10% marks)
c) List appropriate further investigations, and the initial specific pharmacological treatments of this condition. (30% marks)
Not available.
Let's go through his systematically:
So, there's a triple disorder: a respiratory acidosis, as well as a mixed high and normal anion gap metabolic acidosis. Also:
That's right, this question is a basically unchanged version of Question 24.1, except the stem in 2020 had read, "A previously well 24-year-old male presents with fevers, malaise and jaundice. Microbiological cultures are negative, and despite treatment with broad spectrum antibiotics he continues to deteriorate." This time, the examiners have removed this history from the stem, perhaps because one could make the potent argument that with a ferritin of almost 200,000, there's really nothing else this could be.
b) This is haemophagocytic syndrome, or haemophagocytic lymphohstiocytosis (HLH).
c)
Appropriate further investigations would have to include some additional tests, as what results we have been given do not yet fit the diagnostic criteria for HLH. From Henter et al (2004),
The diagnosis of HLH can be established if Criterion 1 or 2 is fulfilled. 1. A molecular diagnosis consistent with HLH 2. Diagnostic criteria for HLH fulfilled (5 of the 8 criteria below) Fever Splenomegaly Cytopenias (affecting ≥2 of 3 lineages in the peripheral blood) Hemoglobin <90 g/L (hemoglobin <100 g/L in infants <4 wk) Platelets <100 × 109/L Neutrophils <1.0 × 109/L Hypertriglyceridemia and/or hypofibrinogenemia Fasting triglycerides ≥3.0 mmol/L (ie, ≥265 mg/dL) Fibrinogen ≤1.5 g/L Hemophagocytosis in bone marrow or spleen or lymph nodes. No evidence of malignancy. Low or no NK cell activity (according to local laboratory reference) Ferritin ≥500 μg/L sCD25 (ie, soluble IL-2 receptor) ≥2400 U/mL
So, we don't have a molecular diagnosis, and zero history (so we can't confirm fever or splenomegaly). We do have low platelets, low fibrinogen, and raised ferritin. We need a few more criteria to be satisfied. Thus, the tests we need to send are as follows:
Initial specific pharmacological treatments, from La Rosée et al (2019):
Henter, Jan‐Inge, et al. "HLH‐2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis." Pediatric blood & cancer 48.2 (2007): 124-131.
La Rosée, Paul, et al. "Recommendations for the management of hemophagocytic lymphohistiocytosis in adults." Blood, The Journal of the American Society of Hematology 133.23 (2019): 2465-2477.
A 38-year-old female presents to the Emergency Department with complaints of lower abdominal pain and vaginal bleeding. On examination, she is confused and, with cool peripheral perfusion and patchy ecchymoses over her extremities. Vaginal examination reveals clots, with tissue resembling products of conception. She is tachypneic, tachycardic with a non-invasive blood pressure of 88/42 mmHg.
(Parts 24.1 and 24.2 of the question are related to the initial blood results obtained from this patient.)
Full blood count and coagulation results are shown below:
Parameter | Patient Value | Adult Normal Range | |||||||||||||||
Haemoglobin | 93 g/L* | 120 – 160 | |||||||||||||||
Mean Cell Volume | 85 fL | 80 – 100 | |||||||||||||||
Mean Corpuscular Haemoglobin (MCH) |
28.0 pg | 27.5 – 33.0 | |||||||||||||||
White Cell Count | 24.0 x 109/L* | 4.0 – 11.0 | |||||||||||||||
Platelet count | 25 x 109/L* | 150 – 350 | |||||||||||||||
Parameter | Patient Value | Adult Normal Range | |||||||||||||||
Prothrombin time | 24.0 sec* | 12.0 – 16.5 | |||||||||||||||
INR | 2.2* | 0.9 – 1.3 | |||||||||||||||
APTT | > 200.0 sec* | 27.0 – 38.5 | |||||||||||||||
Fibrinogen | < 0.4 g/L* | 2.0 – 4.0 |
a) Explain the abnormalities for the full blood count and coagulation parameters, and list one likely pathological diagnosis. (20% marks)
b) This patient continues to have ongoing vaginal bleeding along with ooze from invasive lines. Outline your principles of management. (20% marks)
Not available.
Explain the abnormalities:
List one likely pathological diagnosis:
Principles of management of DIC(SIC):
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.
A 39-year-old female has just been admitted to your unit with severe multiple injuries following a motor vehicle accident. Her injuries are right sided frontal intra-cerebral haemorrhage (ICH), multiple rib fractures with bilateral flail segments and lung contusions, grade III liver laceration, bilateral pubic rami and sacral fractures. She has a BMI of 39.
a) Outline the advantages and disadvantages of methods available to reduce the risks of pulmonary embolism (PE) in this patient. (40% marks)
On day 4 of the patient’s ICU admission, they develop multiple pulmonary emboli.
b) Outline the rationale of inserting an IVC filter in this patient. (30% marks)
c) List the advantages and disadvantages of using an IVC filter in this patient. (30% marks)
Not available.
VTE prophylaxis in the bleeding-prone trauma patient is always challenging, especially in this situation where the head is involved (thus raising the stakes), further surgery may be required (eg. rib fixation), and the liver is involved (thus lowering the clotting factor levels).
The methods-advantages-disadvantages answer would probably work better as a table:
Advantages | Disadvantages | |
Unfractionated heparin |
|
|
Low molecular weight heparin |
|
|
Compression stockings |
|
|
Sequential pneumatic compression devices |
|
|
b) Rationale for IVC filter insertion:
c)
Advantages of the IVC filter
Disadvantages of the IVC filter
Jacobs, Benjamin N., et al. "Unfractionated heparin versus low-molecular-weight heparin for venous thromboembolism prophylaxis in trauma." The journal of trauma and acute care surgery 83.1 (2017): 151.
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.
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