Question 3.2

A 66-year-old patient was admitted to ICU post-emergency coronary artery bypass grafts (CABGs). The early post-operative course is complicated by ongoing oozing from lines and surgical sites. The coagulation profile post-ICU arrival is below:

Parameter

Patient Value

Adult Normal Range

Prothrombin time

12 sec

12.0-16.5

INR international normalized ratio

0.9

0.9-1.3

APTT activated partial thromboplastin time

119 sec*

27.0-38.5

Fibrinogen

1.6 g/L*

2.0-4.0

Platelets

137 x109/L*

150-350

Thrombin Time

>100 sec*

11-17

1. List four potential causes for the prolongation of the APTT (2 marks)

2. Explain the significance of the prolongation of the thrombin time. (1 mark)

3. List two tests that would help to confirm the differential diagnosis and explain your answer.

(1 mark)

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College Answer

Syllabus topic/section:

2.1.21 Applied Pharmacology in Intensive Care.

Aim:
To identify, assess and manage common coagulation abnormalities of critically ill patients.

Discussion:
Candidates should be commended for the depth of knowledge displayed here. Causes of thrombocytopenia were correctly noted and prioritised, Investigations including BMAT, SRA, PF4 ELISA test and were correctly identified.
Coagulation tests, Heparin resistance and the corresponding treatment strategies were explained well.
 

Discussion

If it was not for the thrombin time, this would be a straghtforward case of an isolated raised APTT. Thrombin time is discussed in greater detail in the primary exam section. It is a test that measures the final step of the clotting cascade, where fibrinogen is converted into fibrin by thrombin. 

1) Four potential causes for the prolongation of the APTT:

  • Factor deficiency or dysfunction:
    • Dilutional /consumptive coagulopathy (though PT should also be raised)
  • Factor inhibition
    • Heparin therapy (incompletely reversed)
    • Antiphospholipid syndrome (presence of lupus anticoagulant)
    • Direct thrombin inhibitor (eg. dabigatran)
  • Less likely (so, probably don;t include these in the list of four)
    • Factors 8, 9 11 or 12 deficiency
    • von Willebrand's disease (which is still essentially Factor 8 deficiency)

2) The significance of the prolongation of the thrombin time:

  • Thrombin time is elevated in 

    • Low fibrinogen levels
    • Poor fibrinogen function (i.e presence of dysfibrinogen)
    • The effect of thrombin inhibitors, eg. unfractinated heparin or dabigatran
  • It is not elevated due to warfarin,  Factor Xa inhibitors such as apixaban and rivaroxaban, or low molecular weight heparin

3) Two tests that would help to confirm the differential diagnosis:

  • Mixing studies (to detect the presence of an anticoagulant, i.e. the APTT and TT should correct with the addition of fresh plasma if factor deficiency is the only problem)
  • Reptilase time (like TT, but not affected by heparin or other thrombin inhibitors, which means it will only be elevated in the presence of fibrinogen dysfunction)

Theoretically, one could also have listed:

  • TEG or ROTEM using the heparinase cuvette (which would eliminate the effect of heparin on the APTT and TT)
  • Tests for antiphospholipid syndrome
  • Ecarin clotting time, which is a sensitive test to detect any direct thrombin inhibitors 

References

Jiritano, Federica, et al. "Platelets and extra-corporeal membrane oxygenation in adult patients: a systematic review and meta-analysis." Intensive care medicine 46 (2020): 1154-1169.

Warkentin, Theodore E., et al. "The platelet serotonin‐release assay.American journal of hematology 90.6 (2015): 564-572.