Mutation in blood coagulation factor V associated with resistance to activated protein C

Abstract

Activated protein C (APC) is a serine protease with potent anticoagulant properties, which is formed in blood on the endothelium from an inactive precursor. During normal haemostasis, APC limits clot formation by proteolytic inactivation of factors Va and VIIIa (ref. 2). To do this efficiently the enzyme needs a nonenzymatic cofactor, protein S (ref. 3). Recently it was found that the anticoagulant response to APC (APC resistance) was very weak in the plasma of 21% of unselected consecutive patients with thrombosis and about 50% of selected patients with a personal or family history of thrombosis; moreover, 5% of healthy individuals show APC resistance, which is associated with a sevenfold increase in the risk for deep vein thrombosis. Here we demonstrate that the phenotype of APC resistance is associated with heterozygosity or homozygosity for a single point mutation in the factor V gene (at nucleotide position 1,691, G-->A substitution) which predicts the synthesis of a factor V molecule (FV Q506, or FV Leiden) that is not properly inactivated by APC. The allelic frequency of the mutation in the Dutch population is approximately 2% and is at least tenfold higher than that of all other known genetic risk factors for thrombosis (protein C (ref. 8), protein S (ref. 9), antithrombin10 deficiency) together.

Factor VLeiden

“…In factor Va, these are R306, R506, and less importantly, R679. The molecular basis of FV Leiden is a missense mutation in the factor V (FV) gene at G1691A, resulting in R506 being changed to glutamine (R506Q) [8][9][10]. This change slows the inactivation of factor Va by APC, that is, factor V "resists" being degraded by APC, thereby creating a genetic risk factor that in association with environmental risk factors causes an increased risk for venous thrombosis.…”

“…APC resistance laboratory testing will not be described in detail here, because the topic was recently reviewed [46]. When factor V Leiden was first discovered, DNA testing involved cumbersome manual PCR followed by MnlI enzyme digestion [8]. Since then, many easier and/or more automated methods have been developed.…”

The factor VR506Q mutation causing APC resistance is highly prevalent amongst unselected outpatients with clinically suspected deep venous thrombosis

“…It is caused by a single point mutation in the factor V gene (FV : R506Q or factor V Leiden) [4][5][6][7]. The FV : R506Q mutation results in replacement of arginine (R) by glutamine (Q) at position 506.…”

Prevalence of activated protein C resistance and analysis of clinical profile in thromboembolic patients. A Belgian prospective study

“…The modification of one of the three activated protein-C cleavage sites located on the heavy chain renders factor V Leiden less sensitive to inactivation by APC. As factor V procoagulant activity is left unchanged, the mutation unbalances the procoagulant and the anticoagulant properties leading to a hypercoagulable state [3,5].…”