Thrombophilia: Inherited and Acquired

Hypercoagulable states — factor V Leiden, prothrombin mutation, natural anticoagulant deficiencies, and antiphospholipid syndrome — when to test and how to anticoagulate

Key Points

• Thrombophilia is an inherited or acquired predisposition to venous (and sometimes arterial) thrombosis; it modifies risk but rarely changes acute treatment of a first provoked clot.
• The most common inherited thrombophilias are factor V Leiden and the prothrombin G20210A mutation; deficiencies of antithrombin, protein C, and protein S are rarer but more thrombogenic.
• Antiphospholipid syndrome (APS) is the most important acquired thrombophilia — it causes venous and arterial thrombosis and pregnancy morbidity, and it changes anticoagulant choice.
• Thrombophilia testing is frequently overused; test only when the result will change management, and never during acute thrombosis or while on anticoagulation, when many assays are unreliable.
• Triple-positive antiphospholipid syndrome should be anticoagulated with a vitamin K antagonist (warfarin), not a DOAC — DOACs were inferior in randomized trials (notably for arterial events).
• The decision on duration of anticoagulation is driven more by whether the first event was provoked or unprovoked than by the presence of a heterozygous common thrombophilia.

Overview and Pathophysiology

Thrombophilia refers to a hypercoagulable state — an inherited or acquired tendency to form pathologic thrombi, predominantly venous thromboembolism (VTE: deep vein thrombosis and pulmonary embolism). Thrombosis is best understood through Virchow's triad — hypercoagulability, venous stasis, and endothelial injury — and thrombophilias tip the balance of the first component. Most thrombotic events occur when an underlying thrombophilia coincides with an acquired trigger (surgery, immobility, hospitalization, estrogen therapy, pregnancy, malignancy, or infection). **Inherited thrombophilias**…

Inherited Thrombophilias

**Factor V Leiden (FVL):** The most common inherited thrombophilia in people of European ancestry (~3–8% carrier frequency). A point mutation (Arg506Gln) renders factor Va resistant to inactivation by activated protein C ("APC resistance"), sustaining thrombin generation. Heterozygotes have a ~3–8× increased VTE risk; homozygotes considerably higher. Screening test: activated protein C resistance assay, confirmed by genetic testing. **Prothrombin G20210A mutation:** A gain-of-function mutation in the 3' untranslated region of the prothrombin gene that raises plasma prothrombin (factor II)…

Antiphospholipid Syndrome (APS)

Antiphospholipid syndrome is the most clinically important **acquired** thrombophilia — an autoimmune disorder in which antiphospholipid antibodies promote both venous and arterial thrombosis and cause pregnancy morbidity. It may be primary or associated with systemic lupus erythematosus. **Clinical criteria (thrombosis and/or pregnancy morbidity):** - Vascular thrombosis: venous, arterial (including stroke in young patients), or small-vessel. - Pregnancy morbidity: ≥3 unexplained consecutive early miscarriages, ≥1 fetal death ≥10 weeks, or premature birth from severe preeclampsia/placental…

When (and When Not) to Test

Thrombophilia testing is one of the most overused and misapplied panels in medicine. A positive result rarely changes acute management of a provoked first clot, and inappropriate testing generates anxiety, unnecessary cost, and sometimes harm (unwarranted lifelong anticoagulation). **Testing may be reasonable when the result will change management, for example:** - Unprovoked VTE in a younger patient with a strong family history, where confirming a high-risk thrombophilia might support extended anticoagulation (though unprovoked status often already justifies this). - Suspected…

Management and Anticoagulation

**Acute VTE:** Treatment of the acute clot is the same regardless of most thrombophilias — a therapeutic anticoagulant (low-molecular-weight heparin/fondaparinux bridging to warfarin, or a direct oral anticoagulant such as apixaban, rivaroxaban, edoxaban, or dabigatran). Cancer-associated thrombosis is treated with LMWH or select DOACs per guidelines. **Choice of anticoagulant with thrombophilia:** - Most inherited thrombophilias do **not** contraindicate DOACs. - **Antithrombin deficiency:** heparin may be less effective ("heparin resistance") because it depends on antithrombin;…