Functional properties of factor V and factor Va encoded by the R2-gene.
Carriership of the factor V (FV) gene marked by the R2-haplotype, a series of linked polymorphisms encoding several amino acid changes in FV, is associated with mild resistance to activated protein C (APC) and with an increased risk of thrombosis. We compared the functional properties of normal FV(a) and R2-FV(a) in model systems and in plasma. FV and R2-FV were equally well activated by thrombin and expressed identical cofactor activities in prothrombin activation. Rate constants of APC-catalyzed inactivation of FVa and R2-FVa were similar both with and without protein S. However, significant differences were observed between haemostatic parameters determined in plasma from homozygous carriers of the R2-gene (n = 5) and age-matched non-carriers (n = 19). Plasma from R2-carriers contained significantly lower FV levels and the ratio of the two FV isoforms (FV1 and FV2) was shifted in favor of FV1. The FV2/FV1 ratio was 1.4 (95% CI = 1.3-1.5) in homozygous carriers of R2 and 2.8 (95% CI = 2.5-3.1) in controls (p < 0.00001). In an APC resistance test which quantifies the cofactor activity of FV in APC-catalyzed FVIII(a) inactivation, homozygous R2-carriers had significantly lower (p < 0.00001) APC sensitivity ratios (APCsr = 1.54, 95% CI = 1.48-1.60) than controls (APCsr = 2.17, 95% CI = 2.05-2.28). This indicates that R2-FV has reduced cofactor activity in APC-catalyzed FVIII(a) inactivation. The changes of the relative amounts of FV1 and FV2 in carriers of the R2-gene will result in increased thrombin formation in the presence of APC and may provide a mechanistic explanation for the increased thrombotic risk associated with the R2-haplotype.
Hoekema
L
L
Department of Biochemistry, Cardiovascular Research Institute, Maastricht, Maastricht University, The Netherlands.
Castoldi
E
E
Tans
G
G
Girelli
D
D
Gemmati
D
D
Bernardi
F
F
Rosing
J
J
D020016:Activated Protein C Resistance / Q000097:blood; D000328:Adult; D001780:Blood Coagulation Tests; D004305:Dose-Response Relationship, Drug; D005165:Factor V / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015943:Factor Va / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015951:Factor Xa / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D017293:Protein S / Q000494:pharmacology; D011516:Prothrombin / Q000494:pharmacology; D013927:Thrombosis / Q000209:etiology / Q000235:genetics
D020033:Protein Isoforms; D017293:Protein S; D015943:Factor Va; D005165:Factor V; D011516:Prothrombin; D015951:Factor Xa