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)

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College answer

  • Sepsis/DIC,
  • Malignancy (especially acute promyelocytic leukemia)
  • Liver failure
  • Envenomation

Discussion

"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?

  • DIC, due to sepsis or heat stroke
  • After thrombolysis which is less likely (febrile, etc)
  • Liver failure, eg. a few days following paracetamol overdose (but then, why febrile?)
  • Warfarin overdose (again, no fever would be expected)
  • Anticoagulation with direct thrombin inhibitors in which case thrombin time should be prolonged, but reptilase time should be normal, and ... also, you would not be febrile, and you probably wouldn't feel particularly ill.
  • After a massive transfusion, without adequate factor replacement
  • After a snake bite - which can be pro or anti-coagulant. One might be unlucky enough to be bitten by Russell's Viper .
  • Primary fibrinolysis (eg. in trauma) - this 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. Also, platelet count should be normal in primary fibrinolysis, as they are not being consumed. Also, the patient would not be febrile.
  • Acute leukaemia: in fact, massive pan-coagulopathy is one of the defining characteristics of acute promyelocytic leukaemia specifically. Stein et al (2009) reviewed the subject and concluded that everything is the fault of blast cells whcih express a large number of annexin-II molecules on their surface, which is a high-affinity plasminogen activator. 

References

References

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.