Resistance to activated protein C due to mutated factor V as a novel cause of inherited thrombophilia

Abstract

Inherited resistance to activated protein C (APC) was recently recognized as a novel cause underlying venous thrombophilia. In most cases APC-resistance is due to a single point mutation in the factor V gene leading to a replacement of Arg506 with Gln (factor V Leiden). Amino acid substitution occurs at one of the APC cleavage sites of factor Va, rendering it resistant to APC inactivation. Plasma anticoagulant response to exogenous APC as a simple diagnostic assay of APC- resistance shows good sensitivity and specificity as compared to gene analysis, yet standardization of the results needs to be improved. The APC-resistance trait is present in 2%-6% of the general population and was found to be associated with venous thrombophilia in about 20% of patients with unexplained thrombosis. Clinical features are substantially similar to other congenital plasma abnormalities predisposing to thrombosis (antithrombin III, protein C, protein S deficiencies); yet the overall clinical penetrance of the defect seems lower, at least for the heterozygous condition. Preliminary data suggest a higher risk of thrombosis in APC-resistant homozygous individuals or in patients exhibiting APC-resistance together with other thrombophilic genetic defects. To date, genetically determined APC-resistance does not seem to play a significant role in the development of arterial thrombotic disease.