Objective: The object of the study was to determine the effects of oral contraceptives on blood coagulation, in particular on the protein C pathway.
Study design: Plasma samples from healthy men, from healthy female users and nonusers of oral contraceptives, and from heterozygous and homozygous male and female carriers of the factor V Leiden mutation (some of whom used oral contraceptives) were tested for their sensitivity to activated protein C by means of a new activated protein C resistance test developed in our laboratory. This assay is based on measurement of the effect of activated protein C on the endogenous thrombin potential, the time integral of thrombin generation initiated in plasma through the extrinsic coagulation pathway.
Results: The normalized activated protein C sensitivity ratio ([ETP+APC/ETP-APC]plasma/[ETP+APC/ETP-APC]normal plasma, where ETP is endogenous thrombin potential, +APC is with activated protein C, and -APC is without activated 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 nonusers of oral contraceptives. The normalized activated protein C sensitivity ratio of women who were using oral contraceptives with third-generation progestogens was higher than that of users of oral contraceptives with second-generation progestogens. Furthermore, the normalized activated protein C sensitivity ratio of 80% of the users of third-generation preparations fell 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 increased risk of venous thromboembolism.
Conclusion: Acquired activated protein C resistance may explain the increased risk of venous thromboembolism among users of oral contraceptives reported in epidemiologic studies and the higher risk of venous thromboembolism among users of oral contraceptives with third- versus second-generation progestogens.
PIP: The studies described in this review were designed to examine the in vitro effects of oral contraceptives (OCs) on blood coagulation, particularly their effects on the protein C pathway. The sensitivity to activated protein C was tested using a new developed activated protein C resistance. Data showed that the use of OCs is associated with acquired activated protein C resistance; also, plasma samples of women who use third-generation OCs show more resistance than those of second-generation OC users. There appears to be a remarkable correlation between the normalized activated protein C sensitivity ratio determined with the endogenous thrombin potential-based assay and the increased risks of venous thromboembolism. The normalized activated protein C sensitivity ratio of OC users was significantly higher than in non-OC users. It is shown that 80% of users of third-generation OCs had normalized activated protein C sensitivity ratios, which fell within the 5th-95th percentile for the factor V Leiden heterozygous carriers. Moreover, OC use and factor V Leiden mutation appears to intensify and affects the activity of protein C pathway. This review indicates that the acquired activated protein C resistance explains the increase in venous thromboembolism among users of OCs with third- vs. second-generation progestogens.