The impact of protein S and tissue factor pathway inhibitor on coagulation, assessed with thrombin generation, in women starting combined oral contraceptives

Background: Combined oral contraceptives (COCs) are associated with an increased risk of venous thromboembolism. Several changes are induced in both coagulant and anticoagulant factors, of which the impact on protein S (PS) and tissue factor pathway inhibitor (TFPI) may be especially important. The global thrombin generation (TG) assay, which accounts for all pro- and anticoagulant factors, can be used to evaluate the effect of the changes of PS and TFPI using antibodies to eliminate the effect of these inhibitors. Objectives: The aim of this study was to investigate the effect of PS, TFPI, and activated protein C (APC) on coagulation, as assessed with the TG assay in individuals before and after starting COCs. Methods: Twenty-four women between 15 and 34 years of age who were starting COC treatment were included in the study. Blood samples were drawn at baseline, before first COC dose, and at follow-up, approximately 3 to 4 months later. TG assays were performed on all samples, with the addition of anti-PS, anti-TFPI, and APC, to evaluate their impact on TG. Results: A reduction in APC sensitivity was demonstrated after COC start, reflected in a twofold increased normalized APC sensitivity ratio. TG potential increased significantly after addition of anti-PS and anti-TFPI, both at baseline and after 3 months of COC treatment, but increased relatively less at follow-up. Conclusion: While we previously found only modest COC-induced decreases in PS activity and TFPI levels in this population, indicated a substantial reduction of anticoagulant activity after 3 months of COC use.