Women's and Transgender Issues in Thrombosis and Hemostasis: Laboratory Parameters of Coagulation and Fibrinolysis Influenced by Hormones, Including Pregnancy and Postpartum.

There are an estimated 700,000 to 1 million transgender individuals living in the United States alone.1, 2 Although these individuals require the same, if not greater, level of surgical care due to the importance of gender-affirming surgery, they often require medical treatment involving cross-sex hormone therapy or medications, which block the effects of endogenous hormones. For transfeminine (male-to-female transgender) individuals, patients are typically counseled to hold medications such as exogenous estrogens due to the concern of increased risk of venous thromboembolism (VTE). This practice is not without risks as stopping treatment can increase dysphoria and lead to symptoms such as hot flashes and mood disruption. Indeed, recent studies have brought to light controversies regarding the appropriateness of stopping medical therapy. This review aims to answer whether or not exogenous estrogens should be stopped prior to surgery in male-to-female transgender individuals. Asscheman et al. performed a 2013 review of the risk of developing VTE in transgender women receiving hormone therapy.1 They found 10 studies reporting VTE in male-to-female subjects treated with cross-sex hormones between 1980 and 2012. They described the decrease in the prevalence and incidence rates of VTE among transgender women over the course of 40 years, likely attributed to safer practices in the formulation and administration of exogenous estrogens, such as the use of transdermal estrogens in patients >40 years of age. Regarding postoperative VTE, the authors compared 1989 and 1997 studies of postoperative VTE prevalence. The later study reported a lower prevalence (<1.0% vs. 1.7%), attributed to the widespread use of perioperative low molecular weight heparin. Although noting that oral contraception (OC) is typically not discontinued by cisgender women before surgery due to the risk of unplanned pregnancy, the authors recommended discontinuing hormonal therapy in transgender women 2 weeks before surgery as they did not carry this risk. They also recommended waiting 3 to 4 weeks before resuming hormonal treatment. Both recommendations were acknowledged as not supported by evidence. Nonetheless, cessation of hormones 2 weeks prior to surgery has become the generally accepted protocol. Similarly, Shatzel et al. conducted a 2017 review of thrombotic issues in transgender medicine, reviewing hormonal interventions and related hematologic complications. Like many reviews on the risks of VTE in transgender individuals, the authors noted the limited data on the thrombotic complications for transfeminine persons. They therefore applied studies on menopausal hormone replacement therapy (HRT) and OC in cisgender women as a biologic correlate. The increased risk of VTE in cisgender women taking these hormone formulations has been well described. For instance, in menopausal therapy, HRT has been shown in pooled prospective and randomized controlled trials to increase the rates of VTE in cisgender women about fourfold, with the greatest risk occurring within the first year of therapy and among smokers.3 The few studies (11 total) that examined VTE risk in transgender patients were all retrospective in nature. The authors further clarified the differences in the rates of thrombosis based on the route and form of estrogen used. The rate of VTE was highest with oral estrogen supplementation, particularly ethinylestradiol, and lowest with transdermal estrogen.3 As with cisgender women, the risk of VTE in transgender women was highest in the first year after starting estrogen supplementation and among smokers. However, the increased risk in the postoperative period is less clear. Guidelines regarding holding HRT in cisgender women are varied with some recommending cessation prior to surgery and others stressing only thromboprophylaxis. Nonetheless, the authors recommended cessation of exogenous estrogens for 2 weeks prior to surgery in transgender women.1, 3 Although the authors also acknowledged the lack of data supporting this practice, they cited the lack of side effects and pregnancy risk with holding hormonal therapy. More recently, in a 2019 systemic review by Boskey et al., 18 articles were reviewed examining how medications used in cross-sex hormone treatment affect perioperative risk.2 Among them, 12 studied the impact of estrogens on perioperative risk ranging from as far back as the 1970s. Due to the lack of robust studies on the effects of hormone therapy on transgender women, all studies investigated the role of exogenous estrogen in cisgender women. Six of the 12 studies, comprising a total of 1,706 total women, demonstrated an increased risk of VTE. Among these, the highest level of evidence was a large prospective study comprising 817 women undergoing spine surgery, which reported that estrogen therapy significantly increased postoperative VTE risk (univariate relative risk, 6.2).4 In contrast, the six remaining studies, comprising a total of 6,598 patients found no difference in increased postoperative VTE risk. For instance, a case–control study of 318 women undergoing hip and knee arthroplasty found no difference in VTE between women undergoing HRT and those who were not.5 Although there exists evidence demonstrating the thrombogenic potential of exogenous estrogens in cisgender women, the authors noted that researchers have questioned whether estrogen increases the risk of VTE in the postoperative period beyond that of undergoing surgery. They also cited the lack of studies and difficulty obtaining data on the perioperative safety of estrogen in transgender women due to their routine discontinuation of hormones despite a lack of evidence supporting the practice.2 Furthermore, as progestins used in combined OCs and HRT may also affect thrombogenic risk and transgender women are generally prescribed unopposed estrogens, they cautioned that extrapolating the results of hormone studies on cisgender women may not be generalizable. While it is true that transgender women do not have to balance the risk of discontinuing hormone therapy with the risk of pregnancy, the authors emphasized the physical and behavioral side effects of discontinuing estrogen, including emotional lability, anxiety, depression, and perimenopausal-like symptoms. Due to the inconsistency of evidence and the lack of studies examining the perioperative risk in transgender women, the authors concluded that decisions on discontinuing estrogen treatment should keep individual risk factors and concerns in mind.2 In the senior author's practice, hormones are held for 2 weeks before surgery unless the patient's endocrinologist states that hormone use may continue. We permit resumption of hormones once the patient returns home and feels their daily activity comfort has reached the preoperative level. Recognizing the lack of transgender-specific evidence regarding the cessation of estrogen, the practice of discontinuing estrogen therapy for 2 weeks prior to surgery should be weighed against individual risk factors, mode of administration, and side effects. Robust transgender-specific prospective studies evaluating the postoperative risks and side effects of discontinuing estrogen therapy are necessary. These recommendations are based on three reviews, which include prospective cohort studies, retrospective cohort studies, case control, and case series studies (level 4 evidence; Table I).

primary prophylaxis with direct oral anticoagulants (DOACs) for transwomen taking estrogen is not cost-effective

Perioperative considerations for transgender women undergoing routine surgery: a narrative review

In 1993, individuals with a hereditary predisposition to venous thromboembolism whose plasmas exhibited a poor response to activated protein C (APC) in an activated partial thromboplastin time assay were identified.1 The molecular basis for this laboratory phenotype of resistance to APC was a guanine to adenine mutation at nucleotide 1691 in the factor V gene.2 This results in the replacement of arginine (R) at position 506 by glutamine in the resulting protein, a defect which has been termed factor V Leiden. R506 is the first of three sites at which APC normally cleaves and inactivates procoagulant factor Va. The Q506 substitution causes factor Va to be inactivated approximately l0-fold more slowly than normal, thereby making the cofactor relatively resistant to the anticoagulant action of APC.3 This allows for increased factor Va availability within the prothrombinase complex, thereby enhancing thrombin generation and the development of a hypercoagulable state. See page 1012 Factor V Leiden is the most common inherited risk factor for venous thromboembolism, increasing the risk of venous thrombosis by 4- to 10-fold in heterozygotes and 50- to 100-fold in homozygotes.4,5⇓ Heterozygosity can be identified in 12% to 20% of unselected white patients presenting with venous thrombosis and 40% to 50% of patients with a strong positive family history. Approximately 3% to 7% of normal white patients are heterozygous carriers of factor V Leiden, but the mutation is rare in …

Insights from outside BJOG

Despite great strides in hormone therapy (HT) research, clinical trial data on the benefit-to-risk profile of different formulations, doses, and routes administration of HT remain lacking. Most of the large-scale clinical trials1–3 have tested oral conjugated equine estrogens with or without medroxyprogesterone acetate, and data on nonoral routes and different types and doses of estrogens and progestogens have been limited. The evidence is mounting that route of delivery and possibly type and dose of HT are important factors, particularly for venous thromboembolism (VTE). Results of clinical trials4,5 and observational studies6 have been concordant in demonstrating an increased risk of VTE with oral exogenous HT. Recent studies suggest that VTE risk may be lower with transdermal than oral estrogen7 and with estrogen alone than with combined therapy.4 However, in the absence of rigorous evidence from large-scale clinical trials on differential effects by hormone formulation or route of delivery, should these findings influence clinical practice? Article p 840 The Estrogen and Thromboembolism Risk (ESTHER) study,7 published in the current issue of Circulation , adds important, relevant data to bolster the case that HT type and route of delivery do indeed make a difference. This well-designed, French, multicenter case-control study of VTE enrolled 271 consecutive cases of VTE in women (age, 45 to 70 years) and matched them to hospital and community controls. Current HT use was present in 46% of the VTE cases compared with 37% of controls. Oral HT users had 4-fold-increased odds of VTE; however, there was no increased risk among transdermal hormone users (odds ratio, 0.9). Previous randomized trials have suggested that the risk of VTE may …

Introduction: Venous thromboembolism (VTE) is a potential risk of estrogen therapy. However, data show an improvement in the quality of life for transgender people who use feminizing hormone therapy. With few transgender-specific data, guidance may be drawn from cisgender (nontransgender) data, with a focus on hormonal birth control and postmenopausal hormone replacement therapy (HRT). The aim of this review is to examine the degree to which routes of administration, patient comorbidities, and type of hormone utilized affect the safety of estrogen therapy.Methods: We identified 6,349 studies by searching PubMed with the terms “transgender”, “estrogen”, “VTE”, and “HRT”. Of these, there were only 13 studies between 1989 and 2018 that investigated the effects of hormone therapy, including types of estrogens used, in transgender women and men.Results: The data suggest that the route of hormone administration, patient demographics, and patient comorbidities all affect estrogen’s link with VTE. For example, avoiding ethinyl estradiol might make the use of hormone therapy in trans feminine individuals safer than oral birth control. Data from both cis and trans groups suggest additional VTE risk associated with the use of progestins. While transdermal estrogens dosed up to 0.1 mg/day or below appear lower risk for VTE than other forms of estrogen, it is unclear whether this is related to the delivery method or a dose effect. Finally, even if the risk from exogenous estrogen use remains significant statistically, the absolute clinical risk remains low.Conclusion: Clinicians should avoid the use of ethinyl estradiol. Additionally, data suggest that progestins should be avoided for transgender individuals. Further study of the relationship between estrogen use and the risk of VTE will serve to inform the safest care strategies for transgender individuals.

e Renal Vein Thrombosis, Oral Contraceptive Use, and Hyperhomocysteinemia

Interventions to prevent venous thrombosis after air travel, are they necessary? Yes.

Reflections and recommendations on the COVID-19 pandemic: Should hormone therapy be discontinued?

Risk assessment for recurrent venous thrombosis

It is well established that estrogens increase the risk of both arterial and venous thrombosis. Abnormally high levels of some coagulation factors combined with a decrease in anticoagulation factors contribute to thrombotic risk. Although estrogens are known to affect multiple hemostatic markers, the exact molecular mechanism of estrogen-induced thrombosis is unclear. However, small changes in these markers with different types, doses, and/or routes of estrogens may increase thrombotic risk. Most studies on the effect of estrogens have been carried out in premenopausal women using combined oral contraceptives (COCs); studies in postmenopausal women using hormone therapy (HT) are scarce. Short-term studies comparing hemostatic parameters in women receiving either ethinyl estradiol (EE) or estradiol (E2), each combined with a different progestin, generally show that EE- and E2-based COCs have minimal hemostatic effects on most markers and weaker effects on some markers with E2. The novel estrogen estetrol (E4), emerging as a promising option for both hormonal contraception and postmenopausal HT, appears to have a neutral hemostatic effect. The increased procoagulant factors and decreased anticoagulatory mechanisms observed with estrogen use have been linked to an increased venous thromboembolism (VTE) risk and have been studied in women using hormonal contraception or HT. In contraceptive studies, it has been shown that estrogen dosage plays a role in VTE risk, as EE increases this risk in a dose-dependent manner. Although some studies suggest that the progestin type in COCs may affect VTE risk, other studies have found no difference in risk between androgenic and non-androgenic progestins. As for the E4-based COC, it is currently being evaluated for VTE risk in post-marketing studies. Regarding postmenopausal HT, both the CEE-alone and CEE/MPA arms of the Women's Health Initiative trial showed an increased risk of VTE. However, the results are mixed regarding the impact of oral E2 on VTE risk. Although some data suggest a lesser impact of transdermal HT on this risk, further studies are needed to confirm this finding.

This study aims to investigate venous thromboembolism (VTE) risk in relation to age at menopause, age at menarche, parity, bilateral oophorectomy, and time since menopause, as well as any interaction with randomized hormone therapy (HT) assignment, among postmenopausal women. Using pooled data from the Women's Health Initiative HT clinical trials including 27,035 postmenopausal women aged 50 to 79 years who had no history of VTE, we assessed the risk of VTE in relation to age at menopause, age at menarche, parity, bilateral oophorectomy, and time since menopause by Cox proportional hazards models. Linear trends, quadratic relationships, and interactions of reproductive life characteristics with HT on VTE risk were systematically tested. During follow-up, 426 women reported a first VTE, including 294 non-procedure-related events. No apparent interaction of reproductive life characteristics with HT assignment on VTE risk was detected, and there was not a significant association between VTE and age at menarche, age at menopause, parity, oophorectomy, or time since menopause. However, analyses restricted to non-procedure-related VTE showed a U-shaped relationship between age at menopause and thrombotic risk that persisted after multivariable analysis (P < 0.01). Compared with women aged 40 to 49 years at menopause, those who had early menopause (age <40 y) or late menopause (age >55 y) had a significantly increased VTE risk (hazard ratio [95% CI]: 1.8 [1.2-2.7] and 1.5 [1.0-2.4], respectively). Reproductive life characteristics have little association with VTE and do not seem to influence the effect of HT on thrombotic risk among postmenopausal women. Nevertheless, early and late onset of menopause might be newly identified risk factors for non-procedure-related VTE.

Oral estrogen therapy increases venous thromboembolism risk among postmenopausal women. Although recent data showed transdermal estrogens may be safe with respect to thrombotic risk, the impact of the route of estrogen administration and concomitant progestogens is not fully established. We used data from the E3N French prospective cohort of women born between 1925 and 1950 and biennially followed by questionnaires from 1990. Study population consisted of 80 308 postmenopausal women (average follow-up: 10.1 years) including 549 documented idiopathic first venous thromboembolism. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional models. Compared to never-users, past-users of hormone therapy had no increased thrombotic risk (HR=1.1; 95% CI: 0.8 to 1.5). Oral not transdermal estrogens were associated with increased thrombotic risk (HR=1.7; 95% CI: 1.1 to 2.8 and HR=1.1; 95% CI: 0.8 to 1.8; homogeneity: P=0.01). The thrombotic risk significantly differed by concomitant progestogens type (homogeneity: P<0.01): there was no significant association with progesterone, pregnanes, and nortestosterones (HR=0.9; 95% CI: 0.6 to 1.5, HR=1.3; 95% CI: 0.9 to 2.0 and HR=1.4; 95% CI: 0.7 to 2.4). However, norpregnanes were associated with increased thrombotic risk (HR=1.8; 95% CI: 1.2 to 2.7). In this large study, we found that route of estrogen administration and concomitant progestogens type are 2 important determinants of thrombotic risk among postmenopausal women using hormone therapy. Transdermal estrogens alone or combined with progesterone might be safe with respect to thrombotic risk.

Disclosure: I. Yaish: None. G. Keltch: None. Y. Greenman: None. K.M. Tordjman: None. Background:- Sex hormones have far-reaching effects on the brain, both emotionally and cognitively. - Varying levels of sex hormones are associated with altered emotional states and cognitive abilities. -No longitudinal study has assessed the impact of cross-sex hormone on these issues in young transgender people. Aim:•To prospectively evaluate the effect of gender-affirming hormonal therapy (GAHT) on cognition and emotional state in transgender men and women initiating therapy Subjects and Methods:- Transgender men (TM) aged 24.6±7.8 y (18-37), and 11 transgender women (TW) 27.3±9.4 (19-46).- Mood questionnaires (PHQ9 and GAD-7), and cognitive tests (short-term logical memory test, sub-tests of knowledge, forward and backward digit recall, number-coding and random learning from WAIS-III, a verbal fluency test and CTMT test) were administered prior to GAHT, and 3-6 months into treatment. - Scores were calculated for emotional stress, memory, attention, and executive functions. - Wilcoxon tests for paired samples assessed the impact of GAHT on these variables. Results - In TM, GAHT significantly improved executive functions but had no effect on memory, attention, and emotional stress. - In TW, GAHT significantly improved memory but had no effect on attention, executive functions, and emotional stress. - Despite a trend for improved emotional stress with GAHT in both groups, over this short study period, this was not significant. Conclusions:- - In keeping with the literature, this short preliminary study showed that estrogen contributes to memory, and testosterone to executive functions.-- This is the first time this has been shown in transgender individuals. -The lack of effect on emotional stress is probably due to the small sample size and short duration, larger studies should elucidate this point. Presentation: Saturday, June 17, 2023