Resistance to activated protein C caused by the R506Q 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 VIIIa. 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 (FVR506Q, FV:Q506 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 506Q mutation is common in Caucasians with a prevalence of 1-15%, whereas it is not found in other human races. The FVR 506Q 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.