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?”
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.
|Normal PT||Raised PT|
Thus: perform platelet function studies or go straight for TEG / ROTEM
Extrinsic pathway failure
Intrinsic pathway failure
Factor deficiency or anticoagulant factor? This is answered by mixing studies.
Intrinsic and extrinsic pathway 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-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 deiciency of some sort if present.
Sensibly, one would proceed from here by performing a factor assay.
THE APTT WILL NOT PICK UP FACTOR VII DEFICIENCY. Additionally, 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.
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:
- 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.