Different effects of oral contraceptives containing different progestogens on protein S and tissue factor pathway inhibitor

Summary Background:Oral contraceptives (OC) containing different types of progestogens induce different sensitivities to activated protein C (APC) measured with the thrombin generation-based APC-resistance test. These differences in APC resistance may be the biological explanation for the differences in thrombotic risk of the various pills. The mechanistic basis of APC resistance observed in OC users is unknown. Our objective was to study the effect of OC on the two main determinants of the APC-resistance test, free protein S and free tissue factor pathway inhibitor (TFPI). Patients/methods:We measured free protein S and free TFPI in 156 users of various types of OC. Results:Users of desogestrel-containing OC, known to double the risk of thrombosis compared with levonorgestrel-containing OC, had lower free protein S (24 vs. 33 U dL−1) and TFPI free antigen (2.9 vs. 3.6 ng mL−1) levels than users of OC containing levonorgestrel. Women using cyproterone acetate-containing OC, known to confer a high thrombotic risk, had the lowest free protein S (19 U dL−1) and free TPFI antigen (2.5 ng mL−1) levels. Users of OC containing drospirenone had lower free protein S (23 U dL−1) and TFPI antigen levels (3.2 ng mL−1) than users of levonorgestrel-containing OC. Low free protein S and low free TFPI antigen levels were associated with an increased resistance to APC, an established risk factor for thrombosis. Conclusions:This study observed that the differences in APC resistance induced by OC containing different progestogens can at least in part be explained by different effects of OC on free protein S and TFPI.