Inherited Thrombophilia: Factor V Leiden, Prothrombin Mutation, and Antithrombin Deficiency

Core Idea

Factor V Leiden (activated protein C resistance), prothrombin G20210A, and antithrombin/protein C/protein S deficiency increase thrombosis risk by impairing coagulation feedback inhibition or enhancing thrombin generation. These traits predispose to spontaneous or provoked venous thromboembolism, especially when combined with acquired risk factors.

Explainer

From the coagulation cascade, you know that the tissue factor pathway generates a burst of thrombin — the enzyme that converts fibrinogen to fibrin and amplifies its own production by activating factors V, VIII, and XI. But you may have noticed a tension: if thrombin amplifies itself, what stops the clot from growing indefinitely and occluding the entire circulation? The answer is a set of anticoagulant feedback loops that normally contain clot formation to the site of injury. Inherited thrombophilias are mutations that selectively break these brakes without disrupting forward coagulation — the result is a system biased toward clotting.

The most common is Factor V Leiden, a single point mutation (Arg506Gln) that makes Factor Va resistant to cleavage by activated protein C (APC). In normal physiology, thrombomodulin on endothelial cells converts thrombin into an anticoagulant enzyme that activates protein C; protein C then cleaves and inactivates Factors Va and VIIIa, switching off the amplification loop. Factor V Leiden interferes with the off-switch: Va remains active longer, thrombin generation is prolonged, and the clot-forming tendency is amplified. Heterozygotes have ~3–5x increased venous thrombosis risk; homozygotes have ~50–80x increased risk.

Prothrombin G20210A works differently: it is a variant in the 3' untranslated region of the prothrombin gene that increases mRNA stability and leads to elevated prothrombin levels in plasma. More substrate means more thrombin can be generated from any given coagulation stimulus. Antithrombin deficiency removes a different brake entirely — antithrombin normally inactivates thrombin and Factor Xa directly, and heparin works by binding antithrombin and dramatically accelerating this inactivation. People with antithrombin deficiency are also relatively resistant to heparin therapy, which has practical treatment implications. Protein C and protein S deficiencies impair the same APC pathway as Factor V Leiden, but from the opposite direction: the brake is intact, but there isn't enough of it.

The key clinical insight is that these mutations are risk modifiers, not deterministic disease causes. Most heterozygous carriers live without a thrombotic event for decades — the inherited defect merely shifts the threshold. What precipitates a clinical DVT or pulmonary embolism is usually a combination of the inherited background with an acquired trigger from Virchow's triad: immobility (stasis), surgery or trauma (endothelial injury), or pregnancy and oral contraceptives (hypercoagulable state). A young woman with Factor V Leiden who starts combined oral contraceptives has a synergistic risk increase — estrogen independently increases coagulation factors while the mutation impairs the compensatory protein C response. Recognizing this multiplicative interaction guides decisions about anticoagulation and contraceptive choice.