Plasma factor VII-activating protease is increased by oral contraceptives and induces factor VII activation in-vivo

Abstract

Oral contraceptive (OC) use influences the hemostatic system significantly and is a risk factor for development of cardiovascular disease. Factor VII-activating protease (FSAP) has potential effects on hemostasis. The 1601GA genotype of the 1601 G/A polymorphism in the FSAP gene expresses a FSAP alloenzyme with reduced pro-fibrinolytic activity. Presently, we address whether OC use and OC formulation affect FSAP measures in human blood. Healthy women (n = 588) were allocated to six cycles of OCs with estrogen contents of 20 μg (n = 158), 30 μg (n = 284), 35 μg (n = 79) or 50 μg (n = 67) combined with various progestins. FSAP genotypes, FSAP and factor VII (FVII) plasma measures were assessed at baseline and after 6 cycles of OC. The 1601GA genotype was present in 49 (8.3%) of the women and was associated with significantly reduced levels of FSAP (P ≤ 0.001). OC use increased FSAP antigen by 25% and FSAP activity by 59% (P < 0.001). The FSAP increase was comparable in the seven different OC treatment groups (P > 0.05). The relative increase in FSAP activity was significantly higher in women carrying the 1601GG genotype (63%) than in women carrying 1601GA genotype (50%) (P = 0.01) and was associated with an increased activation of FVII. In conclusion: OC use increases the plasma measures of FSAP. The increase in FSAP is comparable in the seven OC-groups studied but is more significant in women carrying the 1601GG genotype than in women with the 1601GA genotype and results in increased activation of FVII suggesting that FSAP-induced activation of FVII takes place in-vivo and not only in-vitro as hitherto described.