Activated protein C resistance: Clinical implications

The discovery of inherited resistance to activated protein C (APC) as a major risk factor for venous thrombosis has dramatically improved our understanding of the pathogenesis of venous thrombosis. In a majority of cases, APC resistance is associated with a single point mutation in the factor V gene (FV) that results in substitution of arginine, R, at position 506 by glutamine, Q, (FV:Q(506)). The mutation renders factor Va partially resistant to degradation by APC. A functional APC resistance test, which includes predilution of the patient plasma with factor V-deficient plasma, is found to be 100% sensitive and specific for the presence of FV:Q(506) and is useful as a screening assay. Carriers of the FV:Q(506) allele have increased thrombin generation, resulting in hypercoagulability and a lifelong increased risk of venous thrombosis. In Western countries, APC resistance due to the FY mutation is present in 20-60% of thrombosis patients and in 1-15% of healthy controls, whereas the mutation is virtually absent from ethnic groups other than Caucasians. This may explain the high incidence of venous thrombosis in Western countries. The thrombotic risk in APC-resistant individuals may be further increased by other genetic defects, e.g., protein C or protein S deficiency, and by exposure to circumstantial risk factors, e.g., oral contraceptives, pregnancy, immobilization, and surgery. The question is thus raised as to whether general screening for APC resistance before circumstantial risk factors occur is warranted in Western countries.