Effects of oral contraceptives on hemostasis and thrombosis.
OBJECTIVE
The object of the study was to determine the effects of oral contraceptives on blood coagulation, in particular on the protein C pathway.


METHODS
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.


CONCLUSIONS
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.
Rosing
J
J
Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
Tans
G
G
D003276:Contraceptives, Oral / Q000009:adverse effects*; D004351:Drug Resistance; D005165:Factor V / Q000235:genetics; D005260:Female; D006487:Hemostasis / Q000187:drug effects*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D011486:Protein C / Q000502:physiology; D013927:Thrombosis / Q000139:chemically induced*
D003276:Contraceptives, Oral; D011486:Protein C; C095381:factor V Leiden; D005165:Factor V