Elsevier

Thrombosis Research

Volume 192, August 2020, Pages 40-51
Thrombosis Research

Review Article
Estrogen and thrombosis: A bench to bedside review

https://doi.org/10.1016/j.thromres.2020.05.008Get rights and content

Highlights

  • Estrogen affects the hemostatic pathway through various mechanisms.

  • The overall effect of estrogen is prothrombotic.

  • The dose and route of estrogen impacts its prothrombotic effect.

  • Evaluation of prothrombotic risk factors before contraception or pregnancy is needed

  • We present emerging data on unique populations such as transgender women.

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.

Introduction

Worldwide, hundreds of millions of women use exogenous estrogens either as contraceptives or as post-menopausal hormonal replacement. There is significant evidence that estrogen use in both these situations is associated with an increased risk of thrombosis, both arterial and venous. The increased risk is dependent both on the dose and well as the mode of delivery of the hormone, and studies identify alterations in numerous aspects of the hemostatic and fibrinolytic pathways that contribute to the generation of a prothrombotic milieu. This review summarizes the mechanisms identified, the various clinical situations predisposing to the increased risk of estrogen-associated thrombosis and the management thereof.

Section snippets

Discovery of estrogens

In 1896, a young Austrian researcher excised the ovaries of adult rabbits, re-implanted pieces of the ovaries in different locations and noted that unlike oophorectomized rabbits, there was an absence of uterine atrophy. Based on this, he postulated that the ovaries must likely send some substance via the blood stream to the uterus.[1] By 1924, the estrus cycle and its effects on the uterus was well established. [2] In 1929, pure oestrone crystals called “theelin”, were purified by Doisy from

Physiology of estrogen

The term estrogen is coined from the Greek word “Oistros” meaning “mad desire” and “andgennan” meaning “to produce”. It is a generic term for a family of hormones that affect the female reproductive system[7]. The female body naturally produces three forms of endogenous estrogen, which have many physiologic functions. 17β estradiol (E2) is a steroid hormone synthesized from cholesterol. E2 is the most potent form of estrogen produced by the ovary and has the highest affinity for the estrogen

Mechanisms

Although estrogen is known to affect multiple hemostatic variables, the exact molecular mechanism of estrogen-induced thrombosis remains unclear. Given the delicate balance between hemostasis and thrombosis, it is possible that small changes induced by hormonal therapy may increase the overall risk of thrombosis [50]. In the paragraphs below, we summarize the animal and human studies that identify pathways/factors altered with estrogen treatment and that are likely to affect the risk for

Venous thrombosis

The most common sites of thrombosis related to high estrogen states are the deep veins of the legs and the pulmonary veins. Consistently, approximately 80% of thromboses occurring in pregnancy are venous [90]. CHC use has also been associated with “unusual” sites of thrombosis. Multiple studies show an increase in the risk of cerebral venous sinus thrombosis, with an OR of 5.59 (95% CI 3.95–7.91) and 7.59 (95% CI 3.82—15.09) in two separate meta-analyses [91,92]. However, the absolute risk

Contraceptive management in women with high risk of thrombosis

Determining the thrombotic risk in women takes into consideration several factors, such as age, comorbidities, smoking history, family history, and history of thrombosis. Furthermore, while routine screening for hereditary thrombophilias remains controversial due to the rarity of these conditions, their presence can increase the risk of thrombosis.

The Medical Eligibility Criteria for contraceptive use by the World Health Organization lists history of VTE, surgery with prolonged immobilization,

Antiphospholipid antibodies

Women with anti-phospholipid syndrome (APS) on anticoagulation are continued on therapeutic anticoagulation with LMWH during pregnancy. There is a lack of robust data to guide the management of pregnancy or contraception in women with positive anti-phospholipid (aPL) antibodies without a history of thrombosis. A study by Lynch et al. measured aPL antibody levels in 451 low-risk nulliparous women during early pregnancy, and found that 24.4% had positive aPL antibodies. The rate of fetal loss in

Conclusion

CHCs are widely used and are safe and effective for regulation of fertility in the majority of women. Although thrombotic complications are the most important side effect, some clinical implications appear to be evident. The choice of a contraceptive method depends on a personal and family history of thrombosis, and those with a risk of thrombotic disease should be recommended alternatives to CHCs. Screening for prothrombotic mutations before initiating CHCs is not cost effective, and it is not

Author contributions

MAI and DS wrote manuscript and contributed the figures and tables; LN edited all versions of the manuscript.

Acknowledgements

LN's work is supported by National Heart, Lung and Blood Institute grants HL142647-01, HL121131-01, and U01 HL143402.

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