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Q1: Definition and classification (2 min)
Define inherited thrombophilia. Name the five major defects and classify them as common/lower-risk versus rare/higher-risk. How does inherited thrombophilia differ from acquired thrombophilia (antiphospholipid syndrome)? Model answer: Inherited thrombophilia = a group of genetic defects shifting the haemostatic balance toward venous thrombosis. Common lower-risk: factor V Leiden (APC resistance, commonest in Europeans), prothrombin G20210A. Rare higher-risk: antithrombin, protein C, protein S deficiency. Acquired thrombophilia (APS) is antibody-mediated, gives arterial AND venous thrombosis with pregnancy loss, and a prolonged APTT that does not correct on mixing.
Q2: Pathophysiology (3 min)
Explain WHY factor V Leiden and prothrombin G20210A cause thrombosis. Explain the natural-anticoagulant pathway and why protein C/S deficiency causes warfarin-induced skin necrosis. Model answer: Factor V Leiden (Arg506Gln) resists cleavage by activated protein C, so procoagulant factor Va persists -> increased thrombin. Prothrombin G20210A raises prothrombin (factor II) levels -> more thrombin. The protein C/S system: thrombin bound to thrombomodulin activates protein C (cofactor protein S), which inactivates factors Va and VIIIa. Antithrombin directly inhibits thrombin and factor Xa. On starting warfarin, protein C has the SHORTEST half-life and falls first, creating a transient procoagulant window -> skin necrosis in deficient patients; hence bridge with heparin.
Q3: Whom to test and how to interpret (2 min)
When would you test for inherited thrombophilia, and what pitfalls distort the results? Model answer: Test selectively: VTE under 50, unusual site (cerebral, mesenteric, portal, hepatic), recurrent unprovoked, strong family history, OCP/pregnancy-related VTE, warfarin-induced skin necrosis, recurrent fetal loss. Do NOT test routinely — a low-risk defect rarely changes duration. Pitfalls: testing during acute thrombosis or on heparin/warfarin gives false-low protein C/S/antithrombin; pregnancy, liver disease, nephrotic syndrome and sepsis cause acquired deficiency. Time testing off anticoagulation and repeat abnormals.
Q4: Management and special populations (2 min)
How does anticoagulation choice and duration differ by defect? What is specific to pregnancy and to antithrombin deficiency? Model answer: The thrombotic event is treated with standard anticoagulation (DOAC or warfarin; LMWH in cancer). Duration is driven by the defect: low-risk defects get standard duration; high-risk defects (antithrombin deficiency, homozygous FVL, double defects), recurrent or unprovoked VTE get extended/lifelong therapy. Pregnancy: LMWH throughout and 6 weeks postpartum (warfarin teratogenic, DOACs avoided). Antithrombin deficiency causes heparin resistance (APTT fails to rise) -> give antithrombin concentrate and monitor anti-Xa. Counsel on OCP avoidance and offer cascade family screening.
Q5: Exam pearl (1 min)
Give the one-line association an examiner wants to hear for warfarin-induced skin necrosis, and for heparin resistance. Model answer: Warfarin-induced skin necrosis = protein C or S deficiency. Heparin resistance (APTT not rising) = antithrombin deficiency.