Interpreting Coagulation Studies
- Coagulation testing is useful for assessing patients' ability to clot; for investigating the cause of a patient's coagulopathy; and for therapeutic monitoring of certain anticoagulant medications. The classical coagulation profile includes the prothrombin time and activated partial thromboplastin time, though other tests may be performed as required.
- Prothrombin time - 11 - 15 sec
- INR - 0.9 - 1.3
- APTT - 25 - 40 sec
- Thrombin time - <24 sec
- Fibrinogen - 1.5 - 4.5 g/L
The Coagulation Cascade
- Coagulation pathways are a complex set of interactions that result in the formation of a fibrin mesh in order to achieve secondary haemostasis. The coagulation cascade is a traditional representation of these processes that is useful in understanding and interpreting the coagulation profile.
- The extrinsic pathway is activated by tissue factor, produced within subendothelial tissue and exposed to the circulation in the setting of endothelial damage. Tissue factor activates factor VII which in turn activates factor X in the common pathway.
- The intrinsic pathway is activated primarily by collagen. XIIa and HMW activate factor XI, which then activates factor IX. Factor IXa acts with factor VIII to then activate factor X in the common pathway. Von Willebrand factor is a glycoprotein that stabilises factor VIII in the circulation.
- The common pathway involves the formation of the fibrin clot via thrombin activation. Factor Xa, activated through either the extrinsic or intrinsic pathway, converts prothrombin (factor II) to thrombin (IIa). Thrombin then converts fibrinogen to fibrin and activates factor XIII. Factor XIIIa creates fibrin closslinks that are incorporated into a platelet plug and stabilise the clot.
Measures of Coagulation
- The PT/INR and APTT are the most commonly measured screening tests to assess a patient's coagulative state.
- Prothrombin time (PT) is a test of the extrinsic and common pathways including factors VII, V, X, II and fibrinogen. It is performed by adding calcium and thromboplastin to a plasma sample and measuring the time to clot. The international normalised ratio (INR) is a correction of the PT to account for variation of reagents between laboratories, to allow for standardisation of values internationally.
- Activated partial thromboplastin time (APTT) is a test of the intrinsic and common pathways including kininogen, prekallikrein, XII, XI, IX, VIII, X, V, II and fibrinogen. This test is performed by contact activation, and the method varies between labs.
- Thrombin time (TT) tests only the final step of fibrin clot formation, and is not routinely performed as part of a coagulation screen. The test is performed by adding thrombin to a patient's plasma sample. If the TT is prolonged, a reptilase test is also performed to distinguish between fibrinogen disorders and defects higher up in the coagulation cascade.
- Fibrinogen is not routinely measured as part of a coagulation screen, though a ‘derived' (and inaccurate) fibrinogen level is often reported. A dedicated fibrinogen assay should be performed to determine the true fibrinogen concentration. Reduced fibrinogen may be due to consumption (e.g. in DIC), liver impairment, haemodilution or congenital deficiency. Fibrinogen is also an acute phase reactant whose levels will rise with infection, inflammation, malignancy and pregnancy.
Causes of Reduced Fibrinogen
- Consumption - DIC, cancers, thrombolytic therapy, snake bite
- Reduced synthesis - liver impairment
- Haemodilution - massive transfusion
- Congenital deficiency - hypofibrinogenaemia, afibrinogenaemia, dysfibrinogenaemia
Aetiology of Coagulopathy
- Isolated INR prolongation is most commonly seen in patients on warfarin, though high doses of warfarin can also prolong the APTT.
- Isolated APTT prolongation is commonly seen in patients on unfractionated heparin. Heparin can also prolong the PT/INR, and as such heparin neutralisers are added to PT/INR samples. Excess heparin (such as in heparin-locked lines) can overcome these neutralisers and produce a prolonged PT/INR.
- Prolongation of INR (and often APTT) is commonly seen in liver disease, and this should be considered as a cause of coagulopathy depending on the patient's risk profile, past medical history, examination and other relevant investigations. It is important to note that the INR does not correspond to the coagulative status of patients with liver disease, and most often these patients are also coagulopathic.
- Disseminated intravascular coagulation (DIC) is an important differential diagnosis in patients with prolonged PT/INR and APTT, and suspicion should be high in systemically unwell patients with coagulopathy and thrombocytopaenia.
- Factor deficiencies and the presence of specific factor inhibitors are less common and may cause prolonged INR, APTT or both. Hereditary factor deficiencies include haemophilia A (factor VIII) and haemophilia B (factor XI)
Causes of Abnormal Coagulation Profile
Isolated Prolonged PT/INR
- Warfarin (low dose)
- Mild vitamin K deficiency
- Factor VII deficiency
Isolated Prolonged APTT
- Unfractionated heparin - therapeutic or contamination
- Overcoagulation with low molecular weight heparin
- Factor deficiency - VIII, IX, VI, XII
- Factor inhibitors
- Von Willebrand disease
- Lupus anticoagulant (antiphospholipid antibody)
Prolonged PT/INR and APTT
- Artefactual - high haematocrit
- Liver disease
- Disseminated intravascular coagulation (DIC)
- Common pathway deficiency - X, V, II, fibrinogen
- Severe vitamin K deficiency
- Excess heparin (line contamination)
- Factor IIa inhibitors (dabigatran)
- Factor Xa inhibitors (rivaroxaban, apixaban)
- Start by checking whether the patient is on anticoagulants such as unfractionated / low molecular weight heparin, warfarin, direct thrombin or factor Xa inhibitors.
- Check the patient’s haematocrit - if elevated this can falsely elevate the PT/INR and APTT.
- Look for evidence of chronic liver disease in the history, exam and investigations.
- Consider DIC as a differential, especially in septic patients with thrombocytopaenia
- If unsure about the cause of abnormal coagulation profile, mixing studies can be performed to further evaluate the cause.
- Overall, the prolongation of PT/INR and/or APTT may be caused by either factor deficiencies or the presence of factor inhibitors. Mixing studies may be performed to distinguish between these two broad groups of causes.
- Mixing studies are performed by mixing the patient's plasma 50:50 with control plasma, and then measuring the PT/INR and/or the APTT.
- If the patient's coagulopathy (e.g. prolonged APTT) corrects with addition of control plasma, then factor deficiency is the cause of coagulopathy. If it does not correct, then factor inhibitors are present in the sample.
- Unfractionated heparin can be monitored by regularly testing APTT values. Consult local guidelines for heparin bolusing, rates and titration. Do not take a sample for APTT testing from the same limb through which the patient is recieving heparin. Patients with antiphospholipid syndrome who are on a heparin infusion cannot be monitored using APTT as levels are uninterpretable, and as such heparin anti-Xa levels should be used for monitoring.
- Low molecular weight heparins (such as enoxaparin and dalteparin) may be monitored by measuring factor Xa levels, though these are rarely performed except in specific circumstances such as obesity, pregnancy or renal dysfunction.
- Warfarin can be monitored through regular INR measurement, to ensure that patients are recieving a therapeutic dose. Consult local guidelines when commencing warfarin, and keep in mind that changes in warfarin dosing will take several days to have an effect on the INR, so dose titration should rely on the trend rather then being immediately reactive.
Common INR Targets
- AF, DVT/PE: 2.0 - 3.0
- Mechanical heart valve: 2.5 - 3.5
- Factor Xa inhibitors (such as apixaban and rivaroxaban) are not monitored, though drug-specific factor Xa levels may be performed under haematology guidance to estimate whether these drugs are therapeutic. Factor Xa inhibitors prolong the APTT and PT/INR, though this is in an unpredictable way.
- Direct thrombin inhibitors (such as dabigatran) may be monitored by measuring the dilute thrombin time, though this is rarely performed except in specific circumstances as guided by a haematologist. Direct thrombin inhibitors will also prolong the APTT and PT/INR, though this is in an unpredictable way and as such these measures cannot be used to monitor these medications.