Low Thrombin Generation in Users of a Contraceptive Containing Estetrol and Drospirenone

Abstract

Objective To compare the impact on thrombin generation of the new combined oral contraceptive containing 15 mg estetrol and 3 mg drospirenone with ethinylestradiol (30 or 20 mcg) associated either with 150 mcg levonorgestrel or with 3 mg drospirenone. Methods Data were collected from the “E4/DRSP Endocrine Function, Metabolic Control and Hemostasis Study” (NCT02957630). Overall, the per protocol set population included 24 subjects in the ethinylestradiol/levonorgestrel arm, 28 subjects in the ethinylestradiol/drospirenone and 34 subjects in the estetrol/drospirenone arm. Thrombograms and thrombin generation parameters (lag time; peak; time to peak; endogenous thrombin potential [ETP] and mean velocity rate index [mVRI]) were extracted for each subject at baseline and after 6 cycles of treatment. Results After 6 cycles of treatment, ethinylestradiol-containing products arms show a mean thrombogram outside the upper limit of the reference range, that is the 97.5th percentile of all baseline thrombograms. On the other hand, the mean thrombogram of estetrol/drospirenone is within this reference interval. After 6 cycles of treatment, all thrombin generation parameters are statistically less impacted by estetrol/drospirenone than ethinylestradiol-containing products. Conclusions In conclusion, an association of 15 mg estetrol with 3 mg drospirenone does not have an impact on thrombin generation compared to ethinylestradiol-containing products which, either associated with levonorgestrel or drospirenone, are able to increase the production of procoagulant factors and decrease the production of anticoagulant ones, shifting the patient to a prothrombotic state. Ethinylestradiol-containing products thus generate prothrombotic environments contrary to estetrol which demonstrates a neutral profile on hemostasis.

The benefits of estetrol addition to drospirenone for contraception

“…EE-containing products increase the production of procoagulant factors and decrease the production of anticoagulants to a level that favors clot formation. 25 , 38 , 39 , 79 E4-DRSP has less impact on thrombin generation than EE-containing OCs associated with LNG or DRSP, which either increase the production of procoagulant factors or decrease the production of anticoagulant ones, shifting the patient to a prothrombotic state. EE-containing OCs thus generate prothrombotic environments, whereas the E4 containing OCs demonstrate a neutral profile on these hemostasis markers.…”

“…The characterization of the hemostatic profile of E4-DRSP is well documented. 1 , 38 , 39 , 66 , 77 , 78 Its impact on the entire coagulation process has been determined using the endogenous thrombin potential–based APC resistance assay, the thrombin generation assay, and several hemostasis markers, suggesting the absence of a clinically relevant impact on hemostasis when compared with EE-containing products ( Figures 3 and 4 ). EE-containing products increase the production of procoagulant factors and decrease the production of anticoagulants to a level that favors clot formation.…”

“…EE-containing OCs thus generate prothrombotic environments, whereas the E4 containing OCs demonstrate a neutral profile on these hemostasis markers. 39

Figure 4 Endogenous thrombin potential(ETP)-based activated protein C(APC) resistance assay The ETP-based APC resistance assay permits the evaluation of congenital and acquired APC resistance by using data from thrombin generation curves. Thrombin generation curves (thrombograms) reflect the amount of thrombin produced over time in a measurement well.

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“…Overall, unlike other estrogens, the unique metabolism of E4 leads to a low impact on the liver and breast and on hemostasis parameters 38 , 39 while maintaining beneficial effects on the endometrium, vagina, cardiovascular system, bone, and brain. 24 …”

Response to paper by Binkowska et al. Risk of venous thromboembolism during the use of oral estrogen-progestogen hormone therapies in light of most recent research findings. Commentary: Oestradiol is not the holy grail in the quest for the ideal oestrogen therapy

“…These data show that E 4 , either associated with DRSP or alone, has a negligible and not clinically relevant impact on thrombin generation, a global coagulation test sensitive to the changes induced by oestrogenic compounds ( Fig. 1 B, C) [ 15 , 20 ]. Added to its low impact on APC resistance and the accumulating evidence that these biological changes are associated with the increased risk of VTE observed in women on HT or combined hormonal contraceptives, E 4 represents an oestrogen with an expected low risk of VTE.…”