CoChat
Sign Up
Cited by 261Venous Thromboembolism Diagnosis and ManagementBlood Coagulation and Thrombosis MechanismsPlatelet Disorders and Treatments

Estrogen and thrombosis: a bench to bedside review

Open access
Abou-Ismail, Mouhamed Yazan, Citla Sridhar, Divyaswathi, Nayak, Lalitha·2020·Thrombosis Research
DOI 10.1016/j.thromres.2020.05.008PMC PMC7341440
Open this paper in CoChat — free account

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.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review summarizes mechanisms, clinical presentations, and management of estrogen-associated arterial and venous thrombosis across contraception, menopausal hormone therapy, pregnancy, and special populations including transgender women. Estrogen increases thrombotic risk in a dose-, route-, progestogen-, and context-dependent manner, but the exact molecular mechanism remains unclear.

Key findings

  • Combined oral contraceptive (CHC) use raises VTE risk: absolute VTE risk is reported at 0.19–0.37 per 1,000 woman-years in non-users versus 0.55–1.41 per 1,000 woman-years in users, with higher risk among users of third- and fourth-generation progestogens.
  • In postmenopausal women, oral estrogen therapy was associated with higher risk of first VTE (RR 1.63; 95% CI 1.40–1.90) and DVT (RR 2.09; 95% CI 1.35–3.23) compared with transdermal estrogen, though the evidence level is low because studies were observational.
  • The Women’s Health Initiative found increased VTE risk with menopausal hormone therapy (HR 2.06; 95% CI 1.6–2.7), with notably higher risk in women with prior thromboembolic event (HR 3.9) and a 6-fold increase in VTE in women with factor V Leiden on CHC (HR 6.7; 95% CI 3.1–14.5).
  • In transgender women, estrogen use was associated with higher VTE incidence than in cisgender men (adjusted HR 3.2; 95% CI 1.5–6.5) and cisgender women (adjusted HR 2.5; 95% CI 1.2–5.0), with risk increasing over duration of use; ischemic stroke risk was also elevated after 6 years.

Methods

  • Narrative “bench to bedside” review; no primary data collection or systematic search strategy is described.
  • Synthesizes animal and human studies, randomized trials, observational studies, meta-analyses, and clinical guidelines on estrogen physiology, hemostatic mechanisms, thrombosis presentation, and management.
  • Main analysis is qualitative synthesis, including proposed management algorithms for contraception and pregnancy in high-risk women and discussion of special populations such as antiphospholipid antibodies, inherited thrombophilias, myeloproliferative neoplasms, and transgender women.

Limitations

  • The paper states that the exact molecular mechanism of estrogen-induced thrombosis remains unclear and that more studies are needed to understand hormone-related thrombosis pathophysiology and to develop comprehensive risk-stratification tools.
  • The paper repeatedly notes insufficient or conflicting data, including for platelet effects, clinical implications of fibrinolysis changes, optimal route of estrogen administration, management of antiphospholipid antibodies without thrombosis, myeloproliferative neoplasms, and anticoagulation in transgender women; many recommendations rest on low-certainty or observational evidence.
  • Evident from the text: as a narrative review, it lacks a systematic search and formal quality assessment, and it relies heavily on observational studies, surrogate endpoints, and extrapolation across populations.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.thromres.2020.05.008

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 98 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Women on estrogen-containing therapy have a significantly higher risk of retinal vein occlusion compared to women who do not use them.

    “Using a nationwide database study, we found a significantly higher risk of retinal vein occlusion in women on estrogen-containing therapy as compared to women who do not use them [94].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Citla Sridhar D, Gollamudi J, Cao S, Fu P, Nayak L, Incidence of retinal vein occlusion in women of reproductive age on estrogen. 2019, Haemophilia.

      Not checked in the free run.

  • Findingown data

    In a nationwide database, increased risk of retinal vein occlusion in patients on CHCs was highest within the first 30 days of initiation.

    “We used a nation-wide data base and reported an increased risk of RVO in patients on CHCs that was highest within the first 30 days of initiation [94].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Citla Sridhar D, Gollamudi J, Cao S, Fu P, Nayak L, Incidence of retinal vein occlusion in women of reproductive age on estrogen. 2019, Haemophilia.

      Not checked in the free run.

  • Premisecitation

    The increased risk of estrogen-associated thrombosis depends on both the dose and the mode of delivery of the hormone.

    “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.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [82] DeLoughery TG, Estrogen and thrombosis: controversies and common sense. Reviews in Endocrine and Metabolic Disorders, 2011 12(2): p. 77– 84. 21559819 source

      Not checked in the free run.

    • cites [86] Tepper NK,, Nonoral combined hormonal contraceptives and thromboembolism: a systematic review. Contraception, 2017 95(2): p. 130– 139. 27771476 PMC11025291 source

      Not checked in the free run.

    • cites [89] Mohammed K,, Oral vs Transdermal Estrogen Therapy and Vascular Events: A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab, 2015 100(11): p. 4012– 20. 26544651 source

      Not checked in the free run.

  • Premisecitation

    Estrogen increases factor VII levels in postmenopausal women.

    “Another study in post-menopausal women showed that estrogen increased factor VII levels, and overall resulted in a pro-thrombotic state [64].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Cosman F,, Short-term effects of estrogen, tamoxifen and raloxifene on hemostasis: a randomized-controlled study and review of the literature. Thromb Res, 2005 116(1): p. 1– 13. 15850603 source

      Not checked in the free run.

  • Premisecitation

    Estrogen is associated with increased risk of unusual site thromboses.

    “Estrogen has also been associated with increased risk of “unusual site” thromboses, as well as arterial thrombosis.”
    • Also stated in: § Venous Thrombosis · plain
      “CHC use has also been associated with “unusual” sites of thrombosis.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [91] Dentali F, Crowther M, and Ageno W, Thrombophilic abnormalities, oral contraceptives, and risk of cerebral vein thrombosis: a meta-analysis. Blood, 2006 107(7): p. 2766– 73. 16397131 source

      Not checked in the free run.

    • cites [92] Amoozegar F,, Hormonal Contraceptives and Cerebral Venous Thrombosis Risk: A Systematic Review and Meta-Analysis. Front Neurol, 2015 6. PMC4313700 25699010 source

      Not checked in the free run.

    • cites [94] Citla Sridhar D, Gollamudi J, Cao S, Fu P, Nayak L, Incidence of retinal vein occlusion in women of reproductive age on estrogen. 2019, Haemophilia.

      Not checked in the free run.

  • May combine two claims. 19
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Premisecitation

    Combined oral contraceptives increase plasma levels of factors II, VII, VIII, X, and fibrinogen, and decrease factor V levels.

    “A randomized cross over study among women showed that combined oral contraceptives affect the coagulation cascade by increasing plasma levels of factors II, VII, VIII, X, and fibrinogen, and by decreasing factor V levels [62, 63].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [62] Middeldorp S,, Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross-over study. Thromb Haemost, 2000 84(1): p. 4– 8. 10928461

      Not checked in the free run.

    • cites [63] Tans G,, A randomized cross-over study on the effects of levonorgestreland desogestrel-containing oral contraceptives on the anticoagulant pathways. Thromb Haemost, 2000 84(1): p. 15– 21. 10928463 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Estrogen use is associated with an increased risk of both arterial and venous thrombosis.

    “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.”
    • Also stated in: § Introduction · boosted
      “There is significant evidence that estrogen use in both these situations is associated with an increased risk of thrombosis, both arterial and venous.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [82] DeLoughery TG, Estrogen and thrombosis: controversies and common sense. Reviews in Endocrine and Metabolic Disorders, 2011 12(2): p. 77– 84. 21559819 source

      Not checked in the free run.

    • cites [83] de Bastos M,, Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev, 2014(3): p. Cd010813. 24590565 PMC10637279

      Not checked in the free run.

    • cites [99] Roach RE,, Combined oral contraceptives: the risk of myocardial infarction and ischemic stroke. Cochrane Database Syst Rev, 2015(8): p. Cd011054. 26310586 PMC6494192

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The effect of estrogen on the cardiovascular system is not entirely understood.

    “The effect of estrogen on the cardiovascular system is not entirely understood, and continues to be studied.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A 2015 meta-analysis of 24 studies by Roach et al showed a 1.6-fold increased risk of MI or ischemic stroke in women on CHCs, which appeared to increase with higher estrogen doses.

    “A 2015 meta-analysis of 24 studies by Roach et al showed a 1.6-fold increased risk of MI or ischemic stroke in women on CHCs, which appeared to increase with higher estrogen doses [99].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Roach RE,, Combined oral contraceptives: the risk of myocardial infarction and ischemic stroke. Cochrane Database Syst Rev, 2015(8): p. Cd011054. 26310586 PMC6494192

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the Women's Health Initiative study, the risk of VTE due to MHT was highest in the first year of therapy, but persisted for the five years of follow-up.

    “In the Women’s Health Initiative (WHI) study, the risk of VTE due to MHT was highest in the first year of therapy, but persisted for the five years of follow-up [102].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Cushman M,, Estrogen plus progestin and risk of venous thrombosis. Jama, 2004 292(13): p. 1573– 80. 15467059 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The absolute risk of VTE in women who do not use OCPs is 0.19 to 0.37 per 1,000 woman-years, and with OCP use ranges from 0.55 to 1.41 per 1,000 woman-years, with higher risk among users of third and fourth generation progesterones.

    “While The absolute risk of VTE in women who do not use OCPs is reported at 0.19 to 0.37 per 1,000 woman-years, that of of VTE with OCP use ranges from 0.55 to 1.41 per 1000 woman years, with higher risk among users of third and fourth generation progesterones.[83]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] de Bastos M,, Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev, 2014(3): p. Cd010813. 24590565 PMC10637279

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oral estrogen therapy is associated with a higher risk of first episode of VTE (RR, 1.63; 95% CI, 1.40-1.90) and deep venous thrombosis (RR, 2.09; 95% CI, 1.35-3.23) compared to transdermal estrogen therapy in postmenopausal women.

    “Finally, a meta-analysis of 15 observational studies showed that oral estrogen therapy was associated with a higher risk of first episode of VTE (RR, 1.63; 95% CI, 1.40–1.90) and deep venous thrombosis (DVT) (RR, 2.09; 95% CI, 1.35–3.23) when compared to transdermal estrogen therapy in post menopausal women.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Mohammed K,, Oral vs Transdermal Estrogen Therapy and Vascular Events: A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab, 2015 100(11): p. 4012– 20. 26544651 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Short-duration E2 treatment (2-6 hours) has an anti-inflammatory effect, while chronic administration over 60 days is associated with a pro-inflammatory response.

    “Similarly, a short duration of E2 treatment (2–6 hours) has an anti-inflammatory effect [78, 79], while chronic administration over 60 days is associated with a pro-inflammatory response [77].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [77] Calippe B,, Chronic estradiol administration in vivo promotes the proinflammatory response of macrophages to TLR4 activation: involvement of the phosphatidylinositol 3-kinase pathway. J Immunol, 2008 180(12): p. 7980– 8. 18523261 source

      Not checked in the free run.

    • cites [78] Pelekanou V,, Estrogen anti-inflammatory activity on human monocytes is mediated through cross-talk between estrogen receptor ERalpha36 and GPR30/GPER1. J Leukoc Biol, 2016 99(2): p. 333– 47. 26394816 source

      Not checked in the free run.

    • cites [79] Vegeto E,, Regulation of the lipopolysaccharide signal transduction pathway by 17beta-estradiol in macrophage cells. J Steroid Biochem Mol Biol, 2004 91(1–2): p. 59– 66. 15261308 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Low-dose E2 exposure (doses consistent with oral contraceptive pills) is associated with increased pro-inflammatory cytokine expression, while high doses (pregnancy levels) tend to generate an anti-inflammatory response.

    “Both in vitro and in vivo studies show that while low dose exposure to E2 (doses consistent with oral contraceptive pills) is associated with increased pro-inflammatory cytokine expression [74, 76, 77], high doses (pregnancy levels) tend to generate an anti-inflammatory response [74].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [74] Straub RH, The complex role of estrogens in inflammation. Endocr Rev, 2007 28(5): p. 521– 74. 17640948 source

      Not checked in the free run.

    • cites [76] Calippe B,, 17Beta-estradiol promotes TLR4-triggered proinflammatory mediator production through direct estrogen receptor alpha signaling in macrophages in vivo. J Immunol, 2010 185(2): p. 1169– 76. 20554954 source

      Not checked in the free run.

    • cites [77] Calippe B,, Chronic estradiol administration in vivo promotes the proinflammatory response of macrophages to TLR4 activation: involvement of the phosphatidylinositol 3-kinase pathway. J Immunol, 2008 180(12): p. 7980– 8. 18523261 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CHCs decrease plasminogen activator inhibitor (PAI-1) and increase tissue plasminogen activator (tPA), but these changes are counteracted by higher levels of thrombin activatable fibrinolysis inhibitor.

    “CHCs also affect fibrinolysis by decreasing levels of plasminogen activator inhibitor (PAI −1) and increasing levels of tissue plasminogen activator (tPA). However, these changes are shown to be counteracted by higher levels of thrombin activatable fibrinolysis inhibitor in women taking CHCs [67].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Meijers JC,, Increased fibrinolytic activity during use of oral contraceptives is counteracted by an enhanced factor XI-independent down regulation of fibrinolysis: a randomized cross-over study of two low-dose oral contraceptives. Thromb Haemost, 2000 84(1): p. 9– 14. 10928462

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In an international case-control study across 21 centers, the World Health Organization reported in 1995 that increased risk of VTE was apparent within 4 months of starting CHCs, was unaffected by the duration of current type of CHC use, and returned to baseline within 3 months of discontinuing CHCs.

    “In an international case-control study across 21 centers, the World Health Organization reported in 1995 that increased risk of VTE was apparent within 4 months of starting CHCs, was unaffected by the duration of current type of CHC use, and returned to baseline within 3 months of discontinuing CHCs [100].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet, 1995 346(8990): p. 1575– 82. 7500748 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Approximately 80% of thromboses occurring in pregnancy are venous.

    “Consistently, approximately 80% of thromboses occurring in pregnancy are venous [90].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] ACOG Practice Bulletin No. 196: Thromboembolism in Pregnancy. Obstet Gynecol, 2018 132(1): p. e1– e17. 29939938 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The most recent and compelling data suggests an increased risk of MI and stroke due to estrogen, however, the absolute risk remains low.

    “In summary, the most recent and compelling data suggests an increased risk of MI and stroke due to estrogen, however, the absolute risk remains low.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the WHI trial, VTE risk was increased with a hazard ratio of 2.06 (95% CI 1.6-2.7), similar for both DVT and PE.

    “In the trial, VTE risk was increased with HR of 2.06 (95% CI, 1.6–2.7), which was similar for both DVT and PE [102].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Cushman M,, Estrogen plus progestin and risk of venous thrombosis. Jama, 2004 292(13): p. 1573– 80. 15467059 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The levonorgestrel-releasing IUD is preferred over the progestin-only implant since IUD effects are primarily local.

    “The levonorgestrel-releasing IUD is preferred over the progestin-only implant since IUD effects are primarily local (Table 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The rate of fetal loss was higher in women with anti-phospholipid antibodies (15.8%) than in those without (6.5%), with a relative risk of 2.44 (95% CI 1.29-4.62).

    “The rate of fetal loss in these women was higher in those with aPL antibodies (15.8%) than in those without (6.5%), with a relative risk of 2.44 (95% CI, 1.29–4.62).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lynch et al

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The ASH 2018 guidelines strongly recommend both antepartum and postpartum thromboprophylaxis in women with prior VTE related to high estrogen states, based on low-certainty evidence.

    “The ASH 2018 guidelines strongly recommend both antepartum and postpartum thromboprophylaxis in these patients, although this is based on low-certainty evidence [109].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Bates SM,, American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy, in Blood Adv. 2018 p. 3317– 59. 30482767 PMC6258928 source

      Not checked in the free run.

    • Rests on an assumption: Pregnancy increases the risk of VTE due to hypercoagulable state, venous stasis, and endothelial injury.
    • Rests on an assumption: The risk of VTE in pregnancy is increased throughout all trimesters but is highest during the post-partum period.
    • Rests on an assumption: Additional risk factors for pregnancy-associated VTE include a prior history of VTE, hospitalization for an acute illness or cesarean-section delivery, and the presence of an inherited thrombophilia.

  • May combine two claims.

    Premisecitation

    In the same study, CHC use was associated with a threefold increase of VTE and a fivefold increased risk of splanchnic thrombosis.

    “However, CHC use was associated with a threefold increase of VTE (HR), and a fivefold increased risk of splanchnic thrombosis (HR) [115]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [115] Gangat N,, Estrogen-based hormone therapy and thrombosis risk in women with essential thrombocythemia. Cancer, 2006 106(11): p. 2406– 11. 16628652 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In CHC users, mild thrombophilia increased the risk of VTE almost 6-fold and severe thrombophilia almost 7-fold.

    “A systematic review and meta-analysis by Van Vlijmen et al, in 2017, showed that in CHC-users, mild or severe thrombophilia increased the risk of VTE almost 6-fold and 7-fold respectively.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [111] van Vlijmen EF,, Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost, 2016 14(7): p. 1393– 403. 27121914 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The adjusted HR for VTE with estrogen use in transgender women was 3.2 (95% CI 1.5-6.5) compared to cisgender men and 2.5 (1.2-5.0) compared to ciswomen.

    “The adjusted HR for VTE with estrogen use in transgender women was 3.2 (95% CI: 1.5–6.5) compared to cisgender men, and 2.5 (1.2–5.0) compared to ciswomen, which increased with longer duration of use.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Getahun D,, Cross-sex Hormones and Acute Cardiovascular Events in Transgender Persons: A Cohort Study. Ann Intern Med, 2018 169(4): p. 205– 213. 29987313 PMC6636681 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The increasing risk of VTE with duration of estrogen use in transgender women contrasts with menopausal hormone therapy, where risk is highest in the first year and decreases with time.

    “The increasing risk of VTE with duration of estrogen use is in contrast with menopausal hormonal therapy, where the risk is highest in the first year of use and decreases with time. [122]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] Canonico M,, Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. Bmj, 2008 336(7655): p. 1227– 31. 18495631 PMC2405857 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    CHCs are safe and effective for regulation of fertility in the majority of women.

    “CHCs are widely used and are safe and effective for regulation of fertility in the majority of women.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Screening for prothrombotic mutations before initiating CHCs is not cost effective.

  • May combine two claims.

    Premisecitation

    In a U.S. database study of 2,842 transwomen and matched cisgender men and women, transwomen had a higher incidence of VTE than both reference populations, and risk increased over time.

    “The researchers found that transwomen had a higher incidence of VTE than both reference populations, and that risk increased over time.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Getahun D,, Cross-sex Hormones and Acute Cardiovascular Events in Transgender Persons: A Cohort Study. Ann Intern Med, 2018 169(4): p. 205– 213. 29987313 PMC6636681 source

      Not checked in the free run.

23 of 23

  • The authors state this as an assumption.

    The factors used in this review to identify women at high risk of thrombosis (previous VTE, severe thrombophilias, strong family history of VTE, and other comorbidities) reliably identify high risk.

    “In this review, we consider the following to be associated with a high risk of thrombosis: Previous history of VTE“Severe” thrombophilias: such as homozygous or double heterozygous FVL or prothrombin mutation, severe deficiencies in Protein C, S or antithrombin, anti-phospholipid syndrome.”

  • The paper relies on this without support.

    The risk of thrombosis in patients on therapeutic anticoagulation is lowered by anticoagulant therapy.

    “An argument for their use is that these patients risk of thrombosis is lowered by anticoagulant therapy.”

  • The paper relies on this without support.

    Findings from animal models and changes in hemostatic biomarkers translate to clinical thrombosis risk in humans.

    “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 thrombosis.”

  • The paper relies on this without support.

    The etonogestrel subdermal implant is the most effective contraceptive option available for women.

    “The etonogestrel subdermal implant has a similar mechanism of contraception as well as suppressing ovulation, and is the most effective contraceptive option available for women.”

  • The paper relies on this without support.

    The etonogestrel subdermal implant causes irregular bleeding in approximately 20% of patients.

    “However, it can cause alteration in menstrual flow leading to irregular bleeding in ~20% of patients.”

  • The paper relies on this without support.

    The levonorgestrel IUD has a more favorable bleeding profile compared with the other two LARCs.

    “In comparison with the other two LARCS, it has a more favorable bleeding profile.”

  • The paper relies on this without support.

    Pregnancy increases the risk of VTE due to hypercoagulable state, venous stasis, and endothelial injury.

    “Pregnancy increases the risk of VTE due to hypercoagulable state, venous stasis, and endothelial injury.”

  • The paper relies on this without support.

    The risk of VTE in pregnancy is increased throughout all trimesters but is highest during the post-partum period.

    “The risk is increased throughout all trimesters but highest during the post-partum period.”

  • The paper relies on this without support.

    Additional risk factors for pregnancy-associated VTE include a prior history of VTE, hospitalization for an acute illness or cesarean-section delivery, and the presence of an inherited thrombophilia.

    “Additional risk factors include a prior history of VTE, hospitalization for an acute illness or cesarean-section delivery, and the presence of an inherited thrombophilia (e.g. factor V Leiden mutation, prothrombin gene mutation, or antithrombin III, protein C, or protein S deficiencies).”

  • The paper relies on this without support.

    Women with inherited thrombophilias are at increased risk of VTE.

    “Women with inherited thrombophilias, such as FVL, Protein C or S deficiency, antithrombin deficiency, or prothrombin gene mutation, are at increased risk of VTE.”

  • The paper relies on this without support.

    The VTE risk of inherited thrombophilias is further exacerbated by increased estrogen levels due to medications or pregnancy.

    “This risk is further exacerbated by increased levels of estrogen due to medications or pregnancy.”

  • The paper relies on this without support.

    Screening for prothrombotic mutations before initiating CHCs is not cost effective.

    “Screening for prothrombotic mutations before initiating CHCs is not cost effective”
12 of 12

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • HERS treatment is described as both MHT and CHC

    Minor

    The paper describes HERS participants as receiving menopausal hormone therapy in one section, but attributes a HERS VTE result to CHC in another.

  • Norgestimate is assigned to two progestogen generations

    Minor

    The text calls norgestimate a third-generation progestogen, but later lists it as second-generation.

  • Van Vlijmen meta-analysis has conflicting publication years

    Minor

    The text dates the cited meta-analysis to 2017, while its reference entry gives 2016.

  • WHI participants' treatment is described as both MHT and CHC

    Minor

    The section identifies the WHI trial as evidence about menopausal hormone therapy, then describes women in that trial as taking combined hormonal contraceptives.

4 of 4

The citation lists haven’t been fetched yet

References 129 · Cited by 261

Research works printed but not linked: 4

  1. Doisy, 1929, Folliculin from urine of pregnant women, American Journal of Physiology, 90, 329
  2. Canez, 1992, Progestogens and estrogens, Infertil Reprod Med Clin North Am, 3, 59
  3. Birkhauser, 1996, Chemistry, physiology, and pharmacology of sex steroids, J Cardiovasc Pharmacol, 28, S1
  4. Citla Sridhar, 2019, Incidence of retinal vein occlusion in women of reproductive age on estrogen, Haemophilia.

Authors
Abou-Ismail, M. Y., Citla Sridhar, D., & Nayak, L.
Affiliations
University Hospitals of Cleveland (US)
Corresponding author
Nayak, Lalitha
ORCID
Nayak, Lalitha
Venue
Thrombosis Research
Publisher
Elsevier BV
Published
2020-08
Volume
192
Pages
40-51
ISSN
0049-3848 (ISSN-L)
DOI
10.1016/j.thromres.2020.05.008
PMC
PMC7341440
OpenAlex
W3020862479
Cited by
261
References
129
Citations by year
2026: 40 · 2025: 74 · 2024: 56 · 2023: 53 · 2022: 25 · 2021: 10 · 2020: 2
FWCI
4.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Thrombosis Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Heart, Lung, and Blood Institute (HL142647-01, U01 HL143402, HL121131-01)
Topics
  • Health Sciences › Medicine › Internal Medicine › Venous Thromboembolism Diagnosis and Management
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
Keywords
estrogen, thrombosis, venous thromboembolism, arterial thrombosis, hormone replacement therapy, contraception, hypercoagulability, hemostasis, thrombosis risk stratification, transgender women, pregnancy, menopause
MeSH terms
Contraception, Estrogens, Female, Humans, Risk Factors, Thrombosis, Estrogen Replacement Therapy, Venous Thrombosis, Venous Thromboembolism

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review