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  • MK2 Inhibitor IV br Progestogens and venous thromboembolism

    2021-02-22


    Progestogens and venous thromboembolism: clinical data
    Progestogens and haemostatis: biological studies For many years, the effect of HT on haemostatis has been largely investigated in observational studies as well as in high evidence level studies among users of oral and transdermal estrogens [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52]. However, few studies, which most of them were randomized controlled trials, were adequately designed for assessing the effect of progestogens or for comparing the effect of a specific progestogen to each other on APCr, a validated surrogate marker of VTE and on F1+2 or Ddimers, first-generation biomarkers of coagulation and fibrinolysis [29], [33], [40], [41], [43], [47], [48], [49], [50], [51], [53] (Table 2). In addition, because postmenopausal women using progestogens are also prescribed estrogens, it is important to note that the influence of progestogens on haemostasis among postmenopausal women has been only investigated in a context of estrogens use. On one hand, some data allowed assessing the main effect of some progestogens by comparing the changes in haemostasis between users of oral estrogens alone or combined with either micronized MK2 Inhibitor IV [51], dydrogesterone [33], [40], MPA [29], [47], [51], trimegestone [33], [40] or gestodene [43]. Micronized progesterone, dydrogesterone, MPA and trimegestone may not induce significant changes in F1+2, DDimers and APCr related to oral estrogens use. As part of the investigation regarding MPA, these biological data are not in accordance with the clinical results which show an increased VTE risk among users of CEE+MPA as compared with CEE alone users. However, since oral estrogens activate blood coagulation and induce APCr, a potential influence of progestogen on haemostasis could be diluted by oral estrogens effect and partly explain why little or no variation was detected. With regard to gestodene, data remained inconclusive with a higher increase in DDimers but a lower one in APCr among gestodene users [43]. On the other hand, some studies compared the effect of two different progestogens on haemostasis in the context of either oral estrogen users [29], [33], [40], [48], [49], [51], [54] or transdermal estrogens users [53]. Among oral estrogens users, no clear differences have been highlighted. While a randomized controlled trials showed no significant difference in blood coagulation activation and APCr between trimegestone and dydrogesterone [33], [40], another study showed that trimegestone was associated with a significantly higher increase in DDimers concentration as compared to dydrogesterone [49]. When compared to other progestogen, MPA could have similar [51] or more deleterious effect [41], [50] on haemostasis, suggesting a potential detrimental impact of progestogens with androgenic properties on coagulation. Because transdermal estrogens, contrary to oral estrogens, have little or no effect on blood coagulation activation [43], studying the impact of progestogens on haemostasis seems to be more relevant among postmenopausal women using transdermal ET. The Study of NorpregnAnes of Coagulation (SNAC) provided the only data comparing the impact of micronised progesterone and norpregnane derivatives on haemostasis among transdermal estrogens users [53]. In the study, norpregnane derivatives, but not micronized progesterone, were associated with an increase in F1+2 concentrations and an APCr induction. These results were concordant with clinical data showing an association between norpregnane derivatives but not micronized progesterone with the VTE risk. However, the SNAC study was a cross-sectional study and a selection bias might have occurred, as described in the clinical data. In conclusion, no clear evidence for a differential effect of progestogens on haemostasis has been highlighted but norpregnane derivatives could activate blood coagulation and induce APCr [53], providing a biological support to the clinical results [6], [7].