Estrogen and thrombosis: A bench to bedside review

Abstract

Estrogen, in the clinical setting is used primarily for contraception and hormone replacement therapy. It has been well established that estrogen increases the risk of both arterial and venous thrombosis. While estrogen is known to induce a prothrombotic milieu through various effects on the hemostatic pathways, the exact molecular mechanism leading to those effects is not known. The most common clinical presentation of estrogen-related thrombosis is venous thromboembolism (VTE) of the deep veins of the legs or pulmonary vessels, usually within the first few months of use. Estrogen has also been associated with increased risk of "unusual site" thromboses, as well as arterial thrombosis. Women at high-risk of thrombosis need careful evaluation and counseling for contraception, pregnancy, menopausal hormonal therapy and other estrogen-related conditions or treatments in order to lower the risk of thromboses. We review the most recent evidence on management of high-estrogen states in women at high-risk of thrombosis, as well as emerging data on unique populations such as transgender women. More studies are needed to better understand the pathophysiology of hormone-related thrombosis, as well as more comprehensive techniques to stratify risks for thrombosis so as to enable tailoring of recommendations for each individual.

Figure 1 -

Timeline displaying the chronology of the various scientific discoveries that have shaped our understanding of the physiological mechanisms of estrogen. [, –40] ERα: Estrogen Receptor-alpha ERβ: Estrogen Receptor-beta

Figure 2 -

This diagram demonstrates our current understanding of the effects of estrogen on hemostasis & thrombosis. 1) The exact effect of estrogen on platelet activation and aggregation remains unclear, with conflicting reports in the literature showing altered platelet behavior. Estrogen is known to increase VWF levels which plays a central role in platelet adhesion and activation. 2) Estrogen leads to increased thrombin generation and fibrin clot formation by increasing the levels of variable coagulation proteins (green arrowheads) and decreasing the levels of anticoagulant proteins (red arrowheads). 3) Conversely, estrogen has also been shown to be associated with increased fibrinolysis due to decreased PAI-1 levels, which does not seem to balance out the increase in coagulation. Thus the net effect overall, has been shown to be prothrombotic. aPC = activated Protein C AT = anti-thrombin PAI-1 = plasminogen activator inhibitor 1 PL = phospholipid TM = thrombomodulin tPA = tissue plasminogen activator VWF = von Willebrand Factor * In different studies, estrogen has been shown to increase Protein C antigen levels but also increase Protein C resistance

Figure 3 -

Proposed algorithm to guide contraceptive management for women at high risk of VTE based authors’ opinion. *These include: uncontrolled hypertension, ischemic heart disease, stroke, migraine with aura, smoking in women of age 35 or older, or multiple cardiovascular comorbidities.

Figure 4 -

We summarize the 2018 American Society of Hematology recommendations on ante-partum and post-partum anticoagulation in pregnant women with hereditary thrombophilias without personal history of thrombosis in this algorithm. AT: Anti-thrombin FVL: Factor V Leiden PGM: Prothrombin gene mutation *Regardless of family history †With the exception of homozygous PGM without family history, where antepartum anticoagulation was not recommended.