Estradiol provokes hypercoagulability and affects fibrin biology: A mechanistic exploration of sex dimorphisms in coagulation

Abstract

In support of improving patient care, this activity has been planned and implemented by CineMed and the American Association for the Surgery of Trauma. CineMed is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. AMA PRA Category 1 Credits™CineMed designates this enduing material for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. ObjectivesAfter reading the featured articles published in the Journal of Trauma and Acute Care Surgery, participants should be able to demonstrate increased understanding of the material specific to the article. Objectives for each article are featured at the beginning of each article and online. Test questions are at the end of the article, with a critique and specific location in the article referencing the question topic.

Sex dimorphisms in coagulation: Implications in trauma‐induced coagulopathy and trauma resuscitation

“…55 The higher levels and activity of coagulation factors in females are likely partially driven by circulating sex hormone levels, with shorter clotting times in women on in vitro fertilization treatment during high estrus 22 and increased coagulation factors in both women on oral contraceptive pills 56 and females during peak estrus of the menstrual cycle. 57 Interestingly, oral contraceptives not only promote thrombin formation in females by upregulation of coagulation factors but also via decreased antithrombin levels 58 which further drive thrombin generation. These in vivo changes can be recapitulated in vitro such that blood from healthy volunteers spiked with physiologic concentrations of estradiol displays pronounced hypercoagulability, with shorter time to clot formation and increased thrombin generation.…”

“…These in vivo changes can be recapitulated in vitro such that blood from healthy volunteers spiked with physiologic concentrations of estradiol displays pronounced hypercoagulability, with shorter time to clot formation and increased thrombin generation. 57 These sex-specific differences in enzymatic hemostasis resulting in increased thrombin generation have clinical relevance, as thrombin generation is impaired in the setting of TIC and is strongly predictive of the need for massive transfusion and mortality. 59,60 Previous work has linked traumatic injury and release of histone-complexed DNA fragments and extracellular vesicles which drive endotheliopathy and coagulopathy related to thrombin generation.…”

“…83 Like other coagulation contributors, these sex dimorphisms appear to be at least partially driven by sex hormones, with estradiol provoking increased functional fibrinogen and increased fibrinogen contribution to clot strength in vitro and in vivo. 8,57,75 In a rat model examining the effects of surgically induced menopause on fibrinolysis, Topcuoglu et al demonstrate that ovariectomized rats have higher relative levels of fibrinolytic activity, which can then be reduced with hormonal treatment. 84 These same correlative changes are seen in humans-premenopausal females have higher circulating levels of PAI-1 as compared to their older, less hormonally active counterparts, 85 and in the setting of oral contraceptive therapy, there are robust increases in PAI-1 and subsequent decreases in endogenous fibrinolytic activity.…”

“…Interestingly, oral contraceptives not only promote thrombin formation in females by upregulation of coagulation factors but also via decreased antithrombin levels 58 which further drive thrombin generation. These in vivo changes can be recapitulated in vitro such that blood from healthy volunteers spiked with physiologic concentrations of estradiol displays pronounced hypercoagulability, with shorter time to clot formation and increased thrombin generation 57 …”

“…Like other coagulation contributors, these sex dimorphisms appear to be at least partially driven by sex hormones, with estradiol provoking increased functional fibrinogen and increased fibrinogen contribution to clot strength in vitro and in vivo 8,57,75 . In a rat model examining the effects of surgically induced menopause on fibrinolysis, Topcuoglu et al demonstrate that ovariectomized rats have higher relative levels of fibrinolytic activity, which can then be reduced with hormonal treatment 84 .…”