title: Prothrombin activation is increased among asymptomatic carriers of the prothrombin G20210A and factor V Arg506Gln mutations.
abstract: The risk of venous thrombosis is increased in individuals who carry specific genetic abnormalities in blood coagulation proteins. Among Caucasians, the prothrombin G20210A and factor V Arg506Gln (FV R506Q) mutations are the most prevalent defects identified to date. We evaluated their influence on markers 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 time of recruitment. Genotypes for the two mutations were analyzed using microplate array diagonal gel electrophoresis, and coagulation markers (factor XIIa; activation peptides of factor IX, factor X, and prothrombin; fibrinopeptide A) were measured by immunoassay. Factor VII coagulant activity and factor VIIa levels were determined by a functional clotting assay. Among 1548 men genotyped for both mutations, 28 (1.8%) and 52 (3.4%) were heterozygous for prothrombin G202 IOA and FV R506Q, respectively. The only coagulation marker that was significantly associated with the two mutations was prothrombin activation fragment FI+2 [mean +/- 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 mutationl. This data provides conclusive evidence that heterozygosity for the prothrombin G20210A as well as the FV R506Q mutations in the general population leads to an increased rate of prothrombin activation in vivo.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Boston VA Healthcare System, Harvard Medical School, Boston, MA 02115, USA. bauer.kenneth@med.va.gov
authors.forename: K A
authors.initials: KA
authors.lastname: Bauer
authors.forename: S
authors.initials: S
authors.lastname: Humphries
authors.forename: B
authors.initials: B
authors.lastname: Smillie
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: J A
authors.initials: JA
authors.lastname: Cooper
authors.forename: S
authors.initials: S
authors.lastname: Barzegar
authors.forename: R D
authors.initials: RD
authors.lastname: Rosenberg
authors.forename: G J
authors.initials: GJ
authors.lastname: Miller
mesh_terms: D001779:Blood Coagulation Factors / Q000378:metabolism; D005165:Factor V / Q000235:genetics*; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology / Q000235:genetics; D010446:Peptide Fragments / Q000097:blood* / Q000235:genetics; D017354:Point Mutation / Q000502:physiology*; D011516:Prothrombin / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D019851:Thrombophilia / Q000097:blood / Q000235:genetics; D006113:United Kingdom / Q000453:epidemiology; D020246:Venous Thrombosis / Q000209:etiology / Q000235:genetics
chemical_list: D001779:Blood Coagulation Factors; D010446:Peptide Fragments; C045879:prothrombin fragment 1.2; D005165:Factor V; D011516:Prothrombin