Question 8

Outline how the following tests assess coagulation: 
a) Prothrombin Time (PT) 
b) Activated Partial Thromboplastin Time (APTT) 
c) Activated Clotting Time (ACT) 
d) Thromboelastogram (TEG or ROTEM) 

[Click here to toggle visibility of the answers]

College Answer

It was expected candidates would cover all aspects of testing for each test listed. This would include normal, abnormal or therapeutic values, a comment on methods (either laboratory or point of care) and coagulation pathway assessment. General statements about the overall purpose of the test, collection methods, plasma vs whole blood as sample scored additional marks. Diagnoses or errors associated with abnormalities in each test would also have scored marks but were not mentioned in most answers. Overall there was a lack of depth of knowledge and incorrect facts. Many candidates knew about TEG, but did not know details about the other tests. 

Discussion

The content of the expected answer, if we are to take the examiner's comments literally, was completely unreasonable for a ten-minute effort. For one, "outline" does not mean "cover all aspects"; it means "provide a summary of the important points" if we are using the Syllabus Document.  Moreover, for each of the four tests mentioned, the examiners expected "normal, abnormal or therapeutic values, a comment on methods (either laboratory or point of care) and coagulation pathway assessment" as well as "statements about the overall purpose of the test, collection methods, plasma vs whole blood as sample" and "diagnoses or errors associated with abnormalities in each test". It is therefore not remarkable that 0% of the candidates passed this question. It would be easy to despair at the absurdity of these marking criteria, but the more productive reaction would be rage. They should be viewed as an instruction for future generations of CICM examiners to do better.

As an illustration, this is what an answer might look like if it were composed of specific direct statements to address the examiner's comments:

Prothrombin Time

Normal range 10-13 seconds
Therapeutic values 20-30 seconds for therapeutic warfarin anticoagulation (corresponds to INR 2.0 to 3.0)
Purpose Test for factor deficiency (II, VII, X) or warfarin therapy 
Coagulation pathway assessment

Extrinsic pathway (Factor VII)

Common pathway (Factors X and II)

Thus, PT captures most of the Vitamin K dependent factors
(Factor IX is also vitamin-K dependent, but is not tested.)

Collection method Citrated blood tube
Blood sample processing Sample is centrifuged; plasma is analysed
Laboratory or point of care method Laboratory method: recombinant tissue factor is added to the sample, a timer is started and the sample is observed manually or in an automated analyser until flow in the moving sample tube has stopped

Diagnoses or errors associated with abnormalitiers

Vit K-dependent factor problems: warfarin

FVII problems: warfarin, haemophilia

Factor Xa problems: apixaban, rivaroxaban

Thrombin problems: dabigatran,  lepirudin, heparin (yes, heparin)

activated Partial Thromboplastin Time

Normal range 30-40 seconds
Therapeutic values The aPTT target for systemic anticoagulation (eg. for PE or DVT) is usually 50-90 or 60-100 seconds
Purpose Test for factor deficiency (XII, XI, X, IX, II) or warfarin therapy 
Coagulation pathway assessment

Intrinsic pathway (Factor VII)

Common pathway (Factors X and II)

Thus, PT captures most of the Vitamin K dependent factors
(Factor IX is also vitamin-K dependent, but is not tested.)

Collection method Citrated blood tube
Blood sample processing Sample is centrifuged; plasma is analysed
Laboratory or point of care method Laboratory method: source of phospholipid (eg. cephalin) and negatively charged FXII activator (eg. kaolin) are added. Timer starts when calcium is added to reverse the citrate.
Diagnoses or errors associated with abnormalitiers

Factor deficiencies (except Factor VII), eg. liver disease

Factor Xa problems: apixaban, rivaroxaban

Thrombin problems: dabigatran,  lepirudin, heparin 

Antiphospholipid: an antibody to the phospholipid source, eg. lupus anticoagulant

Activated Clotting Time

Normal range 110-130 seconds
Therapeutic values

For ECMO, 200 seconds

For bypass, 400 seconds

Purpose Rapid test of all clotting function parameters, eg. to make adjustments to critically important therapeutic anticoagulation
Coagulation pathway assessment Whole clotting cascade: intrinsic, extrinsic, common pathway and platelet function
Collection method Whole fresh blood 
Blood sample processing Sample does not require processing
Laboratory or point of care method

Point of care automated test. A contact activator (eg. kaolin) is added to the whole blood sample. Endogenous platelets are used as the source of phospholipid. 

Diagnoses or errors associated with abnormalitiers

Any coagulopathy could give rise to an elevated ACT, i.e. it is not specific for any source of clotting dysfunction. 

Most useful when there is one single predictable source of clotting dysfunction (eg. heparinisation), in which case it can be used to titrate the heparin dose to effect

Viscoelastic Tests of Clotting Function

Normal range Multiple variables are measured by each test, including times and amplitudes
 
Therapeutic values At this stage there are no guidelines for the use of TEG or ROTEM to routinely monitor therapeutic anticoagulation
Purpose Simultaneous assessment of multiple domains of clotting function
Coagulation pathway assessment

Intrinsic, extrinsic, common protease pathways;
Fibrinogen (amount and function)

Platelet function

Collection method Whole blood
Blood sample processing Sample does not require processing
Laboratory or point of care method Point of care automated test. Sample is added to a viscometer which assesses clot formation indirectly by the changing deformability of the sample in different reagents
Diagnoses or errors associated with abnormalitiers

Factor deficiency, fibrinogen deficiency, poor platelet function (or thrombocytopenia), hyperfibrinolysis

So, that's 566 words, or 3,934 characters. Considering that the highest possible rate of writing handwritten characters is approximately 190 characters per minute, this table would take a 1980s police interviewer 20.7 minutes to answer.  

So, what would the answer look like if you didn't know about the examiners'  hidden expectations? Probably something like this:

  • Prothrombin Time (PT)
    • Laboratory test for the extrinsic and common pathways 
    • Centrifuged plasma sample is activated with tissue factor
    • Normal = 10-13 sec; therapeutic = 20-30 sec (corresponds to INR 2.0-3.0)
    • Abnormal in:
      • factor deficiency (Vit K sensitive factors II, VII, X)
      • warfarin therapy 
      • direct thrombin inhibitor therapy
      • direct Xa inhibitor therapy
  • activated Partial Thromboplastin Time (aPTT)
    • Laboratory test for the intrinsic and common pathways 
    • Normal = 30-40 sec; therapeutic = 50-90 sec 
    • Centrifuged plasma sample is activated with kaolin (negatively charged surface) and phospholipid (to replace platelets)
    • Abnormal in:
      • factor deficiency (XII, XI, X, IX, II)
      • heparin therapy 
      • direct thrombin inhibitor therapy
      • direct Xa inhibitor therapy
      • antiphospholipid syndrome
  • Activated Clotting Time (ACT)
    • Point of care test for whole clotting system
    • Whole fresh blood activated by kaolin
    • Normal 110-130, target ~200 for ECMO, ~400 for bypass
    • Abnormal in any coagulopathy (i.e. nonspecific)
  • TEG and ROTEM
    • ​​​​​​​Point of care test for whole clotting system
    • Whole fresh blood activated in presence of selected reagents (eg. heparinase)
    • Tests for a large range of variables, including:
      • Factor deficiency or presence of factor inhibitor
      • Fibrinogen deficiency
      • Poor platelet function (or thrombocytopenia)
      • Hyperfibrinolysis

References

Curry, Andy NG, and JM Tom Pierce. "Conventional and near-patient tests of coagulation." Continuing Education in Anaesthesia, Critical Care and Pain 7.2 (2007): 45-50.

Raber, Martin N. "Coagulation tests." Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition (1990).

Hardcastle, R. A., and C. J. Matthews. "Speed of writing." Journal of the Forensic Science Society 31.1 (1991): 21-29.

Hood, Joshua L., and Charles S. Eby. "Evaluation of a prolonged prothrombin time." Clinical chemistry 54.4 (2008): 765-768.

van den Besselaar, Antonius MHP, et al. "Paving the way for establishing a reference measurement system for standardization of plasma prothrombin time: harmonizing the manual tilt tube method." Journal of Thrombosis and Haemostasis 18.8 (2020): 1986-1994.

Kim, Joonseok, et al. "Coagulopathy and extremely elevated PT/INR after dabigatran etexilate use in a patient with end-stage renal disease." Case reports in medicine 2013 (2013).

Chin, Paul KL, et al. "A proposal for dose‐adjustment of dabigatran etexilate in atrial fibrillation guided by thrombin time." British journal of clinical pharmacology 78.3 (2014): 599-609.