Estrogen and Thrombosis: A Bench to Bedside Review Original paper

What was studied?

The study reviewed estrogen’s role in thrombosis, particularly focusing on how estrogen therapy, used in hormone replacement therapy (HRT) and contraception, affects the risk of thrombosis, including venous thromboembolism (VTE) and arterial thrombosis. It explored the mechanisms by which estrogen influences hemostasis and coagulation pathways, contributing to a prothrombotic environment. The paper also discussed estrogen’s effects on various hemostatic and fibrinolytic variables, platelets, von Willebrand factor (vWF), and the coagulation cascade, providing a thorough overview of how estrogen administration, whether endogenous or exogenous, impacts thrombosis risk. The research emphasizes the clinical relevance of assessing individual risks when prescribing estrogen-based therapies, including in specific populations like transgender women and women with a high risk of thrombosis.

Who was studied?

The study focuses on women of reproductive age using hormonal contraceptives, postmenopausal women undergoing HRT, and those at a higher risk for thromboembolic events. The research also includes transgender women using estrogen therapy for gender-affirming care. It emphasizes populations using different estrogen formulations, such as combined oral contraceptives (COCs) and HRT containing either estrogen alone or combined with progestin. The study draws on data from animal models, clinical trials, and epidemiological studies that explore the effects of estrogen therapy across different age groups, health conditions, and genetic backgrounds, particularly those predisposed to thrombosis.

Most important findings

The study identifies estrogen’s prothrombotic effects, notably its influence on the coagulation cascade, platelet function, and fibrinolysis. Estrogen significantly alters hemostatic factors, increasing plasma levels of procoagulant proteins such as factor II, factor VII, factor VIII, and fibrinogen, while reducing levels of protein S and tissue factor pathway inhibitor. These changes contribute to an increased risk of thrombosis, particularly in women using oral contraceptives or combined hormone replacement therapy (HRT). The study also highlights the dose-dependent effects of estrogen, noting that higher doses (e.g., early formulations of COCs with 150 µg of estrogen) are linked to a significantly higher risk of thromboembolic events compared to lower-dose formulations. Transdermal estrogen, which avoids the first-pass effect through the liver, was found to have a lower associated risk of thrombosis compared to oral estrogen. Additionally, the review discusses the role of progestins in exacerbating thrombosis risk, particularly with third and fourth-generation progestins, which further increase the risk when combined with estrogen. Finally, emerging data suggest that individualized risk assessments are essential, particularly for populations such as transgender women, who may have unique estrogen exposure patterns.

Key implications

The findings underscore the importance of individualized treatment plans for patients using estrogen-containing therapies. Clinicians should assess thrombosis risk in patients before initiating estrogen therapy, particularly those with pre-existing cardiovascular or clotting risks. The route of administration (oral vs. transdermal) plays a critical role in determining the level of risk, with transdermal estrogen being the safer option for women with cardiovascular concerns. For women with an intact uterus, the addition of progestin is necessary to prevent endometrial hyperplasia, but careful consideration should be given to the type of progestin used due to its potential contribution to thrombosis risk. Low-dose oral contraceptives and HRT formulations with estrogen alone may be appropriate for postmenopausal women who do not have contraindications, but long-term use should be carefully monitored. For high-risk women, such as those with a history of thrombosis or BRCA1/2 mutations, the study suggests alternative therapies or non-hormonal treatments may be warranted to minimize thrombosis risk.