Prothrombin activation is increased among asymptomatic carriers of the prothrombin G20210A and factor V Arg506Gln mutations

The risk of venous thrombosis is increased in individuals who carry specifi c genetic abnormalities in blood coagulation proteins. Among Caucasians, th e prothrombin G20210A and factor V Arg506Gln (FV R506Q) mutations are the m ost prevalent defects identified to date. We evaluated their influence on m arkers of coagulation activation among participants in the Second Northwick Park Heart Study, which recruited healthy men (aged 50-61 years) from nine general medical practices in England and Wales. They were free of clinical vascular disease and malignancy at the lime of recruitment. Genotypes for the two mutations were analyzed using microplate array diagonal gel electro phoresis, and coagulation markers (factor XIIa; activation peptides of fact or IX, factor X, and prothrombin; fibrinopeptide A) were measured by immuno assay. Factor VII coagulant activity and factor VIIa levels were determined by a functional clotting assay. Among 1548 men genotyped for both mutation s, 28 (1.8%) and 52 (3.4%) were heterozygous for prothrombin G20210A and FV R506Q, respectively. The only coagulation marker that was significantly as sociated with the two mutations was prothrombin activation fragment F1+2 [m ean +/- SD, 0.88 +/- 0.32 nmol/L in men with prothrombin G20210A (p = 0.002 ) and 0.89 +/- 0.30 in men with FV R506Q (p = 0.0001) versus 0.72 +/- 0.24 among non-carriers for either mutation]. This data provides conclusive evid ence that heterozygosity for the prothrombin G20210A as well as the FV R506 Q mutations in the general population leads to an increased rate of prothro mbin activation in vivo.