New molecular insights into the genetics of thrombophilia. Resistance to activated protein C caused by Arg506 to Gln mutation in factor V as a pathogenic risk factor for venous thrombosis.

Genetic risk factors are important in the pathogenesis of venous thrombosis, as demonstrated by the familial clustering of the disease. However, well defined genetic defects were until recently found in less than 10% of the thrombosis patients. In 1993, inherited resistance to activated protein C (APC) was reported as a novel pathogenetic risk factor for thrombosis. It is found in 20-60% of patients with venous thrombosis. APC-resistance is in more than 90% of the cases caused by a single point mutation in the gene for factor V (G to A transition at nucleotide position 1691), which predicts replacement of Arg(R)506 in the APC-cleavage site with a Gln(Q). After activation, mutated factor V, FV:Q506, is less efficiently degraded by APC than normal factor V, which results in increased thrombin generation and a hypercoagulable state. The FV:Q506 mutation is highly prevalent in the general population (5-10%). Heterozygosity for FV:Q506 is associated with a 5-10-fold increased risk of thrombosis, whereas homozygous cases have 50-100-fold increased risk of thrombosis.