Factor V gene mutation causing inherited resistance to activated protein C as a basis for venous thromboembolism

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Abstract
Venous thromboembolism is often familial, suggesting that genetic risk factors are involved. Until recently, genetic defects known to predispose for thrombosis (deficiencies of antithrombin III, protein C, and protein S) had not been shown to account for more than 5-10% of the cases. Inherited resistance to the anticoagulant function of activated protein C (APC) in the last year has been identified as a major basis for familial thrombosis. Unlike other genetic risk factors for thrombosis, APC resistance is highly prevalent in the general population (2-5%). In more than 90% of cases, the APC-resistance phenotype is associated with a point mutation in the factor V gene, which predicts replacement of arginine at position 506 with a glutamine. As APC inhibits factor Va by cleavage at arginine 506, mutated factor V is resistant to APC. In its heterozygous state, the mutation is associated with a 5-10-fold increased risk of thrombosis. Homozygocity is associated with more severe APC resistance, and with a higher risk of thrombosis. Because of its high prevalence in the population, individuals with deficiencies of other anticoagulant proteins occasionally carry the factor V gene mutation. People with such combinations of mutations have a higher risk of thrombosis than those with the single mutations. In conclusion, in the majority of familial thrombosis cases it is now possible to identify an underlying genetic risk factor. APC resistance caused by a single, factor V gene mutation, is the most frequent risk factor and it is at least ten times more common than any of the other genetic defects associated with thrombosis.