Interpretation of abnormal coagulation studies

The college loves coagulopathy, and the number of questions concerned with the interpretation of coagulation studies is only exceeded by the cardiology ECG questions and arterial blood gases.

The following is a list of SAQs on the theme of “What’s wrong with these coags?”

Question 6.2 from the second paper of 2024 (fibrinogen) Question 3.2 from the second paper of 2023 (thrombin time) Question 25.3 from the second paper of 2020 (raised APTT) Question 19.1 from the second paper of 2019 (raised PT) Question 5.2 from the second paper of 2019 (pan-coagulopathy) Question 22.2 from the second paper of 2016 (raised APTT) Question 13.1 from the second paper of 2013 (DIC) Question 12.1 from the second paper of 2012 (antiphospholipid syndrome) Question 12.4 from the second paper of 2012 (total coagulation failure) Question 15.1 from the second paper of 2012 (warfarin overdose) Question 29.1 from the second paper of 2012 (DIC) Question 8.3  from the first paper of 2011 (mixing studies) Question 30.1 from the first paper of 2010 (factor deficiency) Question 30.2 from the first paper of 2010 (total coagulation failure)

Question 23.1 from the second paper of 2009 (total coagulation failure) Question 23.2 from the second paper of 2009 (causes of a high APTT) Question 17.1 from the first paper of 2009 (causes of a high APTT) Question 17.2 from the first paper of 2009 (raised anti-Xa level) Question 17.3 from the first paper of 2009 (heparin overdose) Question 6.1 from the second paper of 2008 (DIC) Question 6.2 from the second paper of 2008 (heparin resistance) Question 6.3 from the second paper of 2008 (warfarin overdose) Question 28.2  from the second paper of 2008 (post thrombolysis) Question 3.1 from the first  paper of 2008 (mixing studies) Question 3.2 from the first  paper of 2008 (warfarin overdose) Question 3.3 from the first  paper of 2008 (DIC) Question 29 from the first  paper of 2007 (antiphospholipid syndrome)

This is a fascinating topic, and one which has surprising amount of herpetology in it. A more indepth discussion of the reptilian contribution to coagulation tests is available elsewhere. Also, there is an excellent article which details a stepwise approach to the coagulopathic patient, and the manner in which the diagnosis of an isolated coagulation abnormality should be approached. An even greater depth of explanation (and more detailed references) can be found at Practical-Haemostasis.com.

A summary of the evaluation of a patient with prolonged bleeding time can be tabulated for easy digestion. This table is initially based on a similar (and better) table from a recent NEJM article, Bleeding and coagulopathies in critical care by Beverley Hunt.

Assessment of Prolonged Clotting Times

	Normal PT	Raised PT
Normal APTT	von Willebrand's disease Platelet dysfunction Fibrinolysis disorder Thus: perform platelet function studies or go straight for TEG / ROTEM	Extrinsic pathway failure Warfarin therapy Vitamin K deficiency Liver disease Isolated Factor VII deficiency
Raised APTT	Intrinsic pathway failure Factor deficiency or anticoagulant factor? This is answered by mixing studies. Anticoagulant factor: Normal TT and RT: antiphospholipid antibodies High TT, normal RT: Heparin therapy (heparinase assay) heparin-like anticoaguants (malignancy) High TT, high RT: Low fibrinogen Abnormal fibrinogen Paraproteinaemia Excessive fibrin degradation products Amyloidosis Factor deficiency von Willebrand's disease (de facto Factor 8 deficiency) Factor 8 deficiency (Haemophilia A) Factor 9 deficiency (Haemophilia B) Factor 11 deficiency (Haemophilia C, 8% of Ashkenazi Jews) Factor 12 deficiency (which is freakishly rare, and usually totally asymptomatic)	Intrinsic and extrinsic pathway failure DIC Massive transfusion Massive warfarin overdose Primary fibrinolysis Post thrombolysis Snake bite Direct thrombin inhibitor toxicity Severe liver failure

Causes of an isolated prolonged prothrombin time:

These would be rare. Essentially, this list of differentials is limited to situations which for one reason or another diminish the availability of Vitamin K for clotting factor synthesis

• Vitamin K nutritional deficiency
• Liver disease (impaired vitamin K storage)
• Warfarin therapy

Discriminating between causes of a raised PT

Is it a true deficiency of vitamin K dependent factors, or are the factors present and merely inactive to to a lack of carboxylation? One can use another snake for this. Echis carinatus is a venomous viper from the Middle East, and it happens to secrete a venom which can bypass the vitamin K dependent clotting factors to activate prothrombin. In severe liver disease, there is not enough thrombin being synthesis, and the ECT will be prolonged; but during warfarin therapy the ECT should be normal, as it bypasses the defective factors.

Causes of an isolated rise in APTT

APTT - but not PT - will increase if , or if there is an inhibition of the intrinisic pathway.

The causes include factor deficiencies:

• Factor deficiency or dysfunction:
  • Factors 8, 9 11 or 12 deficiency
  • von Willebrand's disease (which is still essentially Factor 8 deficiency)
  • Dilutional coagulopathy (though PT should also be raised)
• Factor inhibition
  • Heparin therapy
  • Antiphospholipid syndrome (presence of lupus anticoagulant)

So, is it a factor deficiency, or is it a factor inhibitor? One performs mixing studies when one tries to distinquish one from the other.

Discriminating between causes of a raised APTT: Causes of abnormal mixing studies

Mixing studies distinguish between factor deficiencies and factor inhibitors.

Lets say your sample of plasma is giving a high PT or aPTT - grab your suspicious plasma sample, and mix it with normal blood, 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. If there is a factor deficiency, the mixed sample will result in a normal PT or aPTT.

Discriminating between causes of a raised APTT with abnormal mixing studies

An abnormal mixing study result implies that in spite of the addition of normal plasma, the coagulopathy persists. This suggests that a factor inhibitor is present. The objective of further investigations is to figure out what is being inhibited, and how.

The three major candidates:

• Heparin
• Heparin-like anticoagulants (eg. in malignancy)
• Antiphospholipid syndrome
• Multiple myeloma
• Thrombolytic therapy and DIC, due to the presence of large amounts of fibrin degradation products which interfere with the polymerisation of fibrin

Thus, one may wish to go though the following steps:

• Test antiphospholipid antibodies
• Heparinase assay:
  • The heparinase enzyme rapidly degrade heparin. If there is heparin in the sample and it is responsible for the raised APTT, the heparinase will reverse the coagulopathy.
• If the patient has had no heparin, order a thrombin time and reptilase time.
  • Heparin will affect thrombin time but not reptilase time.
  • Heparin-like anticoagulants will also affect thrombin time but not reptilase time.
  • Weird disturbances of fibrinogen cleavage will elevate both thrombin and reptilase time, and these include excessive fibrin degradation byproducts, paraprotein, amyloidosis, and so forth.

Discriminating between causes of a raised APTT with normal mixing studies

Normal mixing studies (i.e. a coagulopathy totally reversed by the addition of enough normal plasma) suggest that a factor deficiency of some sort if present.

Sensibly, one would proceed from here by performing a factor assay. Even if you have 50% less of any given factor, your PT and aPTT should remain roughly normal, so subtle deficiencies would not be identified by APTT or mixing studies. One would need to perform a formal factor assay. This means, ordering specific factor levels.

Discriminating between causes of a raised APTT with thrombin time (TT)

Thrombin time is discussed in greater detail in the primary exam section, and in even greate detail at the Practical Haemostasis website.  Its a test of the ability of thrombin to convert fibrinogen into fibrin, which is usually quite a brisk reaction (normal range is 13-15 seconds). The test is performed by adding some thrombin to the blood sample. It is therefore sensitive to several possible causes of raised APTT:

• Low fibrinogen levels
• Poor fibrinogen function (i.e presence of dysfibrinogen)
• The effect of thrombin inhibitors, such as
  • heparin
  • dabigartan
  • lepirudin
  • D-dimers
  • lupus anticoagulant
• Something that immediately degrades the formed fibrin (eg. thrombolysis agents)
• Something that interferes in fibrin polymerisation in some crude mechanical way (eg. gelatins, starches, paraprotein)

Things that don't cause an elevated TT are also worth knowing:

• Warfarin and Factor Xa inhibitors such as apixaban and rivaroxaban do not affect thrombin time, as they interefere with the clotting cascade at various points upstream
• Low molecyular weight heparins usually do not cause a prolonged TT, except in overdose

Causes of an unexpectedly normal or unusually shortened APTT

Say, you expect somebody to have a raised APTT because of reasons (eg. they are being anticoagulated). An unexpectedly normal APTT in the face of heparinisation could be the consequence of heparin resistance, which can be caused by:

• Increased heparin-binding protein levels (all of them are acute phase reactants)
• Low antithrombin-III levels (i.e. nothing for heparin to bind)
• Increased heparin clearance (eg. due to splenomegaly in liver disease)
• High Factor VIII levels
• Factitious heparin resistance (eg. the heparin is not even connected to the line)

Kitchen (2000) suggests that in some of these situations (eg. FVIII excess) the monitoring of anti-Xa levels can be used to observe the "real" heparin effect, when the APTT is falesely depressed. 

Causes of total coagulopathy

This is a situation when everything is abnormal. The PT, the APTT, the fibrinogen level - everything is disturbed.

This pan-coagulation disturbance occurs in the following scenarios:

• DIC
• After thrombolysis
• Warfarin overdose
• Anticoagulation with direct thrombin inhibitors in which case thrombin time should be prolonged, but reptilase time should be normal
• 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.
• 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. 

Causes of hyperfibrinogenaemia

Why would the fibrinogen be high? Is there anything to even be concerned about? Surely this acute phase reactant is supposed  to be elevated in critical illness? Kamath & Lip (2003) and Lowe et al (2004) list several possible acute/subacute causes:

• Infection/inflammation (basically anything that increases your ESR)
• Physical exertion
• Trauma
• Pregnancy (especially later stages)
• Ischaemia (eg. MI, stroke, mesenteric ischaemia)
• Catecholamines (specifically, it seems, adrenaline)
• Nephrotic syndrome (Kendall et al, in 1971, found this to be the case, and it did not seem associated to any acutye phase state)

Chronically elevated fibrinogen is more likely due to:

• Malignancy
• Smoking
• Menopause
• High cholesterol
• Advanced age
• Oral contraception
• Obesity
• Physical inactivity
• G-455A polymorphism

Additionally, it varies seasonally (highest in the winter), which does not seem to have any relationship to outdoor temperature, and which remains unexplained.

Tests which would would launch, upon discovering a patient with an unexplained but raised fibrinogen level, would have to include:

• Blood cultures, as well as cultures of whatever other fluids look gross at the time
• Inflammatory markers, including CRP ESR and procalcitonin
• β-HCG
• Specific tumour markers (CA125, CA-19.9, CA15-3, α-foetoproetin, etc)