Objective: Compared to non-users, the risk of venous thromboembolism (VTE) has been reported to be increased several fold in women using combined oral contraceptives (COC) or hormonal replacement therapy (HRT). This increase in risk is explained, at least in part, by activated protein C resistance (APCr) induced by the estrogenic moieties [1–2]. APCr has also been observed in carriers of the factor V Leiden mutation, where heterozygosity imparts an approximately 8-fold increased risk of VTE . Factor Va inactivation by APC is crucial in down-regulating thrombin formation. Impaired factor Va inactivation increases the risk of VTE both in carriers and in non-carriers of the factor V Leiden mutation . A global measure of the clotting capacity of plasma is the endogenous thrombin potential (ETP), which is determined by the thrombin generation test (TGT). The TGT quantifies thrombin generation after triggering the extrinsic pathway of the coagulation cascade with tissue factor in the presence of phospholipids. To assess APC resistance, the amounts of thrombin generated in the absence and presence of exogenous APC are compared. The relative resistance compared to that of individuals without thrombophilia and who are not receiving COCs or HRT, provides the normalized APC sensitivity ratio (nAPCsr). Estetrol (E4) acts as an estrogen agonist in stimulating the endometrium, and when administered to postmenopausal women, reverses vaginal atrophy while decreasing vasomotor symptoms [4-5]. Unlike other estrogens, E4 blocks the membrane Estrogen Receptor α (ERα), has tissue specific activity, and acts differently than Selective Estrogen Receptor Modulators (SERMs). Crystalline structure studies confirm that E4 interacts with the nuclear ERα in a fashion similar to other estrogens and not SERMs . In contrast to other estrogens administered orally, E4 exhibits only minimal first-pass metabolism and hepatic effects on triglycerides, sex hormone-binding globulin, corticosteroid-binding globulin, and angiotensinogen. In this study, we sought to determine the effects of E4 on coagulation factors, including the ETP-based nAPCsr in postmenopausal women. Design: In this multicenter, randomized, placebo-controlled, double-blind, dose-finding study, changes from baseline of coagulation factors, hemostasis biomarkers and ETP-based nAPCsr were assessed in 257 postmenopausal women who received 2.5; 5; 10; or 15 mg E4, or placebo once daily for 12 weeks. Results: During E4 use in postmenopausal women, the hemostasis markers including fibrinogen, prothrombin, prothrombin fragment 1+2, D-dimer, factor VIII activity, protein C, antithrombin, and tissue factor pathway inhibitor, did not show significant changes from baseline. A small statistically significant, but non- clinically meaningful decrease of free protein S (5.9%) was observed at the highest E4 dose. Relative changes from baseline of the ETP-based nAPCsr were -27.6% (n=34) for placebo, and -12.3% (n=39), 14.0% (n=35), 11.1% (n=32), and 40.0% (n=32) for 2.5, 5, 10, and 15 mg E4, respectively. This was similar to the 30% increase observed in younger women receiving 15 mg E4/DRSP, but is in marked contrast to the increases on EE/DRSP (219%) and EE/LNG (165%). Conclusion: The observed changes with E4 and E4/DRSP in the old and younger populations included in postmenopausal and contraceptive trials can be considered as clinically non-significant. These hemostasis changes were less than those observed with other HRT products containing estradiol or conjugated equine estrogens. These data on ETP-based nAPCsr and the other hemostasis data from previous trials support the notion that E4 may be associated with a lower risk of thrombosis strengthening the position of E4 as a promising new treatment option for postmenopausal women.