Hematology · Coagulation Disorders
The facts most likely to be tested
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Factor V Leiden, which resists inactivation by activated protein C, is the most common inherited thrombophilia.
Antiphospholipid syndrome is the key acquired thrombophilia, causing venous and arterial thrombosis plus recurrent fetal loss, and is the only thrombophilia worth testing after a first clot.
APL paradoxically prolongs the aPTT in vitro (that fails to correct on a mixing study) while causing clotting in vivo; lupus anticoagulant is confirmed by the Russell viper venom time.
Antiphospholipid syndrome requires lifelong anticoagulation even after a single clot, whereas most thrombophilias use warfarin to INR 2-3 for 6 months.
Heparin-induced thrombocytopenia presents 5-10 days after heparin with a >50% platelet drop, PF4 antibodies, and new thrombosis rather than bleeding.
For HIT, immediately stop all heparin (do not switch to LMWH), start a direct thrombin inhibitor (argatroban) or fondaparinux, and never transfuse platelets.
Suspect thrombophilia with recurrent, unprovoked, young-age, or unusual-site venous thromboembolism; inherited factor levels are best measured remote from the acute clot.
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A 32-year-old woman presents with her second unprovoked deep vein thrombosis and a history of two second-trimester miscarriages. Laboratory studies show a prolonged aPTT that fails to correct when her plasma is mixed with normal plasma. A Russell viper venom time is prolonged and confirmatory testing for anticardiolipin antibodies is positive on two occasions twelve weeks apart.
Which of the following is the most appropriate long-term management?
Lifelong anticoagulation with warfarin
Antiphospholipid syndrome, confirmed by a non-correcting aPTT mixing study and persistent antiphospholipid antibodies, requires lifelong anticoagulation even after a single thrombotic event because of its high recurrence risk. The in-vitro aPTT prolongation paradoxically coexists with an in-vivo prothrombotic state.
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Etiology / Epidemiology
Inherited or acquired predisposition to clot; factor V Leiden is the most common cause. Antiphospholipid syndrome is the key acquired form.
Clinical Manifestations
Recurrent or unprovoked venous thromboembolism, clots at young age, or unusual sites; APL also causes recurrent fetal loss.
Diagnosis
APL syndrome is the only one to test after a first clot; it elevates the aPTT that fails to correct on mixing study.
Treatment
Warfarin to INR 2-3 for 6 months for most; APL needs lifelong anticoagulation after one clot.
Prognosis
Recurrence risk rises with unprovoked or APL-associated clots, often requiring indefinite anticoagulation.
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Epidemiology & Etiology
Thrombophilias are inherited or acquired conditions predisposing to thrombosis. The most common inherited cause is factor V Leiden mutation; others include the prothrombin gene mutation and deficiencies of antithrombin, protein C, and protein S. The most important acquired form is antiphospholipid (APL) syndrome (lupus anticoagulant and anticardiolipin antibody). Acquired risk also rises with malignancy, pregnancy, estrogen, surgery, and immobility. Notably the natural anticoagulants protein C, protein S, and antithrombin can be lost in the urine in nephrotic syndrome, producing a hypercoagulable state.
Pertinent Anatomy
Thrombosis occurs predominantly in the deep venous system of the legs and pelvis, with embolization to the pulmonary arteries. Antiphospholipid syndrome and certain disorders also cause arterial thrombosis and placental vascular thrombosis leading to fetal loss. Some states (PNH) characteristically clot in unusual sites such as mesenteric and hepatic veins.
Pathophysiology
Inherited thrombophilias tip Virchow's balance toward clotting: factor V Leiden resists inactivation by activated protein C, and deficiencies of antithrombin, protein C, or protein S remove natural anticoagulant brakes. In antiphospholipid syndrome antibodies against phospholipid-binding proteins promote both venous and arterial thrombosis and recurrent miscarriage; paradoxically they prolong the aPTT in vitro while causing clotting in vivo. Heparin-induced thrombocytopenia is an acquired prothrombotic antibody (anti-PF4) state.
Clinical Manifestations
Patients present with venous thromboembolism, DVT or pulmonary embolism, that may be recurrent, unprovoked, at a young age, or in unusual locations. Antiphospholipid syndrome additionally causes arterial thrombosis (stroke), recurrent spontaneous abortions, and may produce a false-positive VDRL. Heparin-induced thrombocytopenia presents 5-10 days after starting heparin with a platelet drop over 50% and new venous or arterial thrombosis rather than bleeding.
Diagnosis
Indiscriminate thrombophilia testing after a first clot is discouraged; the only thrombophilia worth testing after a first clot is APL syndrome. APL is the single thrombophilia that elevates the aPTT; the best initial test is a mixing study, in which the aPTT remains prolonged because a circulating inhibitor is present, and the most accurate test for lupus anticoagulant is the Russell viper venom time. HIT is confirmed by ELISA for PF4 antibodies or the serotonin release assay. Inherited factor levels are best measured remote from acute clot and anticoagulation.
Treatment
For most thrombophilias there is no difference in anticoagulation intensity: use warfarin to an INR of 2 to 3 for 6 months after a provoked or first clot. Antiphospholipid syndrome typically requires lifelong anticoagulation even after a single clot. For HIT, immediately stop all heparin products (do not switch to LMWH) and start a direct thrombin inhibitor (argatroban, bivalirudin) or fondaparinux, adding warfarin only after platelets recover; do not transfuse platelets in HIT.
Prognosis
Recurrence risk depends on the trigger and disorder. Provoked clots have low recurrence after a finite anticoagulation course, whereas unprovoked events and antiphospholipid syndrome carry high recurrence, often justifying indefinite therapy. Untreated HIT can cause limb-threatening or fatal thrombosis.
Differential Diagnosis
Disseminated intravascular coagulation: consumptive coagulopathy with bleeding, low platelets, prolonged PT/aPTT, and low fibrinogen, not isolated thrombosis.
Heparin-induced thrombocytopenia: acquired prothrombotic state with platelet drop 5-10 days after heparin and PF4 antibodies.
Nephrotic syndrome: secondary hypercoagulability from urinary loss of antithrombin, protein C, and protein S.
Malignancy (Trousseau): occult cancer causing migratory thrombophlebitis and unprovoked VTE.
Paroxysmal nocturnal hemoglobinuria: thrombosis in unusual sites with hemolysis and low CD55/CD59.