Effects of oral contraceptives on hemostasis and thrombosis

OBJECTIVE: The object of the study was to determine the effects of oral con traceptives on blood coagulation, in particular on the protein C pathway. STUDY DESIGN: Plasma samples from healthy men, from healthy female users an d nonusers of oral contraceptives, and from heterozygous and homozygous mal e and female carriers of the factor V Leiden mutation (some of whom used or al contraceptives) were tested far their sensitivity to activated protein G by means of a new activated protein C resistance test developed in our lab oratory. This assay is based on measurement of the effect of activated prot ein C on the endogenous thrombin potential, the time integral of thrombin g eneration initiated in plasma through the extrinsic coagulation pathway. RESULTS: The normalized activated protein G sensitivity ratio ([ETP+APC/ETP -APC](plasma/)[ETP+APC/ETP-APC](normal) (plasma), where ETP is endogenous t hrombin potential, +APC is with activated protein C, and -APC is without ac tivated protein C) of men was lower than that of healthy female nonusers of oral contraceptives. The normalized activated protein C sensitivity ratio of the users of oral contraceptives was significantly higher than that of n onusers of oral contraceptives. The normalized activated protein C sensitiv ity ratio of women who were using oral contraceptives with third-generation progestogens was higher than that of users of oral contraceptives with sec ond-generation progestogens. Furthermore, the normalized activated protein C sensitivity ratio of 80% of the users of third-generation preparations fe ll within the 5th to 95th percentile of the normalized activated protein C sensitivity ratio of female carriers of factor V Leiden, a mutation that is associated with hereditary resistance to activated protein C and with an i ncreased risk of Venous thromboembolism. CONCLUSION: Acquired activated protein C resistance may explain the increas ed risk of venous thromboembolism among users of oral contraceptives report ed in epidemiologic studies and the higher risk of venous thromboembolism a mong users of oral contraceptives with third-versus second-generation proge stogens.