the 50:50 mix. ▲ If the PT prolongation corrects on mixing (due to replacement of factor(s) from the normal plasma) the prolongation is likely due to a factor deficiency. If it does not correct the prolongation is likely due to an inhibitor. A partial correction may represent multiple factor deficiencies or an inhibitor. Prolonged APTT with normal PT / INR If the APTT is prolonged but the PT is not, the probable cause is related to the intrinsic pathway – either Factors VIII, IX, XI or the contact factors (Factor XII, Prekallikrein or High Molecular Weight Kininogen). What is the differential diagnosis? ▲ Congenital deficiency of Factors VIII, IX, XI or contact factors – usually a single factor deficiency. • Deficiencies of Factors VIII and IX are generally associated with bleeding • von Willebrand’s disease can have low factor VIII and be variably associated with bleeding • Factor XI deficiency is variably associated with bleeding • Contact factor deficiencies can profoundly elevate the APTT but do not result in a bleeding tendency ▲ Acquired causes of prolonged APTT may be due to inhibitors – either specific or non-specific. • Non-specific inhibitors may be drugs like heparin or antiphospholipid antibodies that target coagulation proteins bound to phospholipids (also known as lupus anticoagulants) – The PTT may also be elevated in patients on direct thrombin inhibitors • Specific inhibitors are directed to specific factors (usually Factor VIII) To distinguish between factor deficiency and inhibitor ▲ Perform a 50:50 mix: This test is performed by combining 1 part patient’s sample with 1 part normal plasma. An APTT is performed on the 50:50 mix. ▲ If the APTT prolongation corrects on mixing (due to replacement of factor(s) from the normal plasma) the prolongation is likely due to a factor deficiency. If it does not correct the prolongation is likely due to an inhibitor. A partial correction may represent multiple factor deficiencies or an inhibitor. 4. Evaluating Abnormal Coagulation Tests 27 Fibrinogen Common V II X VIII IX XI VII XII Pathway Fibrin Clot Intrinsic Pathway Extrinsic Pathway Fibrinogen Common V II X VIII IX XI VII XII Pathway Fibrin Clot Intrinsic Pathway Extrinsic Pathway 28 4. EVALUATING ABNORMAL COAGULATION TESTS Prolonged APTT and PT / INR If the PT / INR and the APTT are both prolonged, there could be multiple factors affected in the intrinsic and extrinsic pathways or a single factor deficiency in the common pathway – Factors X, V, II (prothrombin) or fibrinogen. What is the differential diagnosis? ▲ Congenital deficiency of Factors X, V, II or fibrinogen – usually a single factor deficiency. • Deficiencies of Factors X, V, II or fibrinogen may be associated with bleeding depending on the severity of the phenotype • Even if the fibrinogen is quantitatively normal, a qualitative abnormality may exist called dysfibrinogenemia ▲ Acquired causes. • Non-specific inhibitors - drugs (e.g. excessive doses of heparin, direct thrombin inhibitors or direct Xa inhibitors) or antiphospholipid antibodies that target coagulation proteins bound to phospholipid (also known as lupus anticoagulants) • Specific inhibitors directed to a factor within the common pathway • Severe vitamin K deficiency (low vitamin K dependent factors II, VII, IX and X) • Supratherapeutic warfarin therapy (low vitamin K dependent factors II, VII, IX and X) • Severe liver disease (due to impaired production of multiple coagulation factors) • Disseminated intravascular coagulation (due to increased consumption of multiple coagulation factors) • Isolated Factor X deficiency associated with systemic amyloidosis • Severe depletion of fibrinogen due to massive hemorrhage or fibrinolysis • Hemodilution (post operative sample, massive transfusion, pre-analytical causes) As previously discussed, the 50:50 mix may help in providing clues as to whether the cause of the prolongation is due to a factor deficiency or an inhibitor. However, specific factor levels and inhibitor studies will be more informative. 4. Evaluating Abnormal Coagulation Tests 29 Prolonged Thrombin time (TT) with normal or prolonged APTT and PT / INR If the Thrombin time is prolonged, the probable cause is related to either thrombin (Factor IIa) or fibrinogen. The PT / INR and APTT are not