Endogenous thrombin potential changes during the first cycle of oral contraceptive use

Objectives: Venous thromboembolism (VTE) risk increases within months of combination oral contraceptive (COC) initiation. Because elevated endogenous thrombin potential (ETP) has been found in several studies to be a VTE risk factor, we evaluated the extent of ETP changes during the initial cycle of an ethinyl estradiol (EE) and levonorgestrel (LNG) COC. We also assessed the relationship between ETP changes and systemic EE and LNG concentrations.

Study design: Participants provided multiple blood samples during a first 21-day cycle of a 30-mcg EE/150-mcg LNG COC and after a further 7 days without an active COC. Thrombin generation measured with and without addition of activated protein C (APC) yielded ETP_+APC and ETP_-APC and the normalized APC sensitivity ratio (nAPCsr). EE and LNG pharmacokinetic analyses were conducted over 24 h after the first COC tablet and again at steady state.

Results: Thrombin generation was determined in 16 of the 17 women who completed the study. Mean ETP_-APC increased steadily to 21% above baseline at 24 h after the 6th COC tablet (COC6₂₄; p<.001) and to 28% above baseline at steady state (COC21; p<.001). The percentage increase in mean ETP_+APC was considerably more - 54% at COC6₂₄ and 79% at steady state. Mean nAPCsr increased by 28% at COC6₂₄ and by 41% at steady state. Higher concentrations of EE or LNG were not correlated with greater increases in ETP.

Conclusions: ETP increases during the first COC cycle were substantial.

Implications: The early increases in ETP may provide biological support for the rapid increase in VTE risk during initial COC use. The lack of association between this clotting system perturbation and the systemic EE concentration is surprising and deserves further study.