Resistance to activated protein C caused by the R 506 Q mutation in the gene for factor V is a common risk factor for venous thrombosis

The protein C system is an important natural anticoagulant pathway. Protein C is the key component of the system and it is activated by thrombin bound to thrombomodulin on the surface of endothelial cells. Activated protein C (APC) inhibits coagulation by cleaving and inactivating coagulation factors factor Va and factor Villa. Until recently, the major genetic causes of familial venous thrombophilia were inherited deficiencies of protein C, protein S or antithrombin, but together they were found in less than 5‐10% of patients with thrombosis. In 1993, the situation changed drastically with the description of inherited APC‐resistance as a novel risk factor for venous thrombosis. APC‐resistance is characterized by a poor anticoagulant response to APC. Inherited APC‐resistance is the most common genetic risk factor for this disease and it is found in 20‐60% of patients. The condition is caused by a single point mutation in the gene for factor V which predicts substitution of arginine (R) at position 506 with a glutamine (Q). Mutated factor V (FVR 506 Q, FV:Q 506 or FV Leiden) expresses normal procoagulant properties but is partially resistant to APC. The resulting hypercoagulable state confers a life‐long increased risk of venous but not arterial thrombosis. The FVR 506 Q mutation is common in Caucasians with a prevalence of 1‐15%, whereas it is not found in other human races. The FVR 506 Q mutation may, due to its high prevalence, be an additional risk factor in individuals carrying other inherited defects such as deficiency of protein S, protein C or antithrombin. Such individuals have a high incidence of thrombosis and severe thrombophilia is a multigenetic disease. The high prevalence of inherited APC‐resistance and the availability of easy functional and genetic tests will stimulate the development of prophylactic regimens and hopefully result in a decreased incidence of thrombosis.