Risk and management of congenital thrombophilia in transgender individuals undergoing gender-affirming hormone therapy

Risk and management of congenital thrombophilia in transgender individuals undergoing gender-affirming hormone therapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Risk and management of congenital thrombophilia in transgender individuals undergoing gender-affirming hormone therapy Elena Campello, Alberto Scala, Cristiana Bulato, Andrea Benetti, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6573735/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Gender-affirming hormone therapy (GAHT), particularly estrogen-based regimens, is associated with an increased risk of venous thromboembolic events (VTE), which may be exacerbated in individuals with hereditary thrombophilia. Despite this risk, the prevalence and clinical implications of hereditary thrombophilia in transgender individuals remain underexplored. We screened 114 transgender individuals (54 AMAB, 60 AFAB) at the University Hospital of Padua (Italy) for hereditary thrombophilia, including factor V Leiden (FVL), prothrombin G20210A (PT20210A), antithrombin (AT), protein C (PC), and protein S (PS) deficiencies, as well as antiphospholipid antibodies. Hereditary thrombophilia was identified in 9.6% of participants, including two cases of severe thrombophilia. No participants tested positive for antiphospholipid antibodies. Individuals with thrombophilia had a higher prevalence of personal and family history of VTE. Three thrombotic events were recorded prior to GAHT: one transgender woman (heterozygous FVL) with unprovoked lower limb VTE, one transgender man (PC deficiency) with neonatal cerebral ischemia, and one transgender man (heterozygous FVL) with subclavian VTE during chemotherapy. A multidisciplinary approach involving coagulation specialists and endocrinologists was implemented to optimize risk reduction strategies, including tailored GAHT regimens and anticoagulation when necessary. No VTE occurred during follow up. These findings highlight the importance of thrombophilia screening to enable individualized care and enhance the safety of GAHT protocols. Health sciences/Cardiology Health sciences/Endocrinology gender incongruence thrombosis thrombophilia anticoagulation hormones Figures Figure 1 Highlights Hormone therapy in transgender people has been linked to a higher risk of venous thrombosis. Thrombophilia screening is recommended in case of a personal or family history of thrombosis. Hereditary thrombophilia affects 9.6% of transgender people, similar to the general population. Risk reduction strategies and tailored hormone therapy can help prevent thrombosis. INTRODUCTION Transgender and gender-diverse (TGD) individuals experience an incongruence between their gender identity and the sex assigned to them at birth. 1 Many TGD individuals seek gender-affirming medical treatments to align their physical characteristics with their gender identity, contributing to a growing demand for gender-affirming services in recent years. Gender-affirming programs should be tailored to the individual’s goals and may include psychological support, gender-affirming hormone therapy (GAHT), and gender-affirming surgeries. 1 , 2 In particular, testosterone therapy is used to promote masculinization in individuals assigned female at birth (AFAB). Conversely, feminizing hormone therapy involves the administration of estradiol and anti-androgens, such as cyproterone acetate (CPA), spironolactone, or gonadotropin-releasing hormone (GnRH) analogues in individuals assigned male at birth (AMAB). 1 , 2 Various studies have assessed the cardiovascular risk in the TGD population and its relation with GAHT. 3 , 4 Estrogen therapy has been linked to a significant increase in venous thromboembolic events (VTE) in TGD AMAB individuals, a risk also observed in cisgender women using hormonal contraception or hormone replacement therapy. 5 – 7 A meta-analysis estimates the incidence of VTE at 43 per 10,000 patient-years among TGD individuals undergoing estrogen therapy—higher than the incidence observed in cisgender women receiving hormone replacement therapy. 5 , 6 Additionally, VTE risk continues to increase even after eight years of feminizing hormone therapy. 5 This is particularly significant given that GAHT is typically a lifelong treatment. On the other hand, secondary erythrocytosis is a common adverse effect of testosterone therapy. 8 Primary erythrocytosis has been associated with arterial and venous thrombosis, but this effect has never been demonstrated in androgen-induced erythrocytosis. 9 – 11 The prothrombotic effects of exogenous hormones may be amplified in individuals with predisposing conditions such as hereditary thrombophilia. Hereditary thrombophilia are genetic conditions that increase the risk of hypercoagulability, including factor V Leiden (FVL) and prothrombin G20210A (PT20210A) mutations, and deficiencies of protein C (PC), protein S (PS), and antithrombin (AT). 12 These conditions contribute to an elevated baseline risk of VTE and can interact synergistically with environmental or pharmacologic factors to further increase thrombotic risk. 13 For instance, in cisgender women, the combination of estrogen-containing therapies and hereditary thrombophilia is associated with a significantly increased risk of VTE. 14 Despite these risks, there is limited research addressing the prevalence and clinical implications of hereditary thrombophilia in TGD individuals undergoing GAHT. Routine screening for thrombophilia is not universally recommended before initiating GAHT, leaving a critical gap in risk stratification and individualized care. In fact, international guidelines recommend to screen only individuals with a personal or family history of TVE. 1 , 2 Given the known thrombotic risks of hormone therapy and the potential for increased risk in patients with underlying thrombophilia, understanding the prevalence of these genetic conditions in the TGD population is essential, not because we expected it to differ from the general population, but because these data are lacking and are needed to inform individualized risk management strategies for GAHT. 15 This study investigates the prevalence of hereditary thrombophilia in a cohort of TGD individuals undergoing GAHT. By characterizing the distribution of thrombophilic conditions in this population, we aim to provide insights into the intersection of gender-affirming care and thrombotic risk management. MATERIALS AND METHODS The present investigation is part of the Hypergender study , a longitudinal study designed to evaluate the haematological effects of GAHT in TGD individuals. Participants were assessed at baseline and after 3, 6, and 12 months of GAHT. Data collection Adult TGD individuals who initiated GAHT at the University Hospital of Padova between December 2022 and December 2024 were enrolled. Inclusion criteria were being over 18 and below 50 years of age, a diagnosis of gender incongruence, and the intention to initiate GAHT. Exclusion criteria included refusal to provide informed consent or discontinuation of clinical follow-up. During the first endocrinological visit, clinical history was collected, including personal and family history of TVE and cardiovascular events, personal pathological history, cardiovascular risk factors, current pharmacological treatment, and previous use of GAHT. Physicians also performed a physical examination, including anthropometric measurements. Routine laboratory tests required for prescribing GAHT included a complete blood count, liver and kidney function tests, sex hormone profile, prolactin, glycaemia, and lipid profile. All participants underwent thrombophilia screening and provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the University Hospital of Padua (5990/AO/24). Thrombophilia screening All enrolled TGD individuals underwent a screening for thrombophilia before starting GAHT. Screening included tests for AT, PC, and PS deficiencies, FVL and PT20210A mutations, as well as rare inherited thrombophilia (pseudo-homozygous FVL and AT resistance). AT, PC, PS activity, and antigen levels as well as activated protein C resistance (aPCR) were measured as previously reported. 12,16,17 Reduced levels of anticoagulant factors (activity and/or antigen) were confirmed in 2 consecutive determinations and in at least 1 first-degree relative. AT activity was evaluated by a FIIa-based assay (Berichrom® Antithrombin III, Siemens Healthcare Diagnostics) using a BCS® XP coagulometer (Siemens Healthcare Diagnostics). PC chromogenic and coagulometric activities were measured on a BCS XP Coagulation analyser (Siemens Healthcare Diagnostics) using 2 commercial kits, Berichrom Protein C and Protein C Reagent (Siemens Healthcare Diagnostics), respectively. PC antigen was determined by a home-made sandwich ELISA using a sheep anti-human PC antibody (Affinity Biologicals) as the capture antibody and horseradish peroxidase conjugated sheep anti-human PC antibody (Affinity Biologicals) as the detection antibody. PS activity testing was performed on an ACL TOP 300 CTS analyser (Instrumentation Laboratory) with the HemosIL Protein S Activity kit (Instrumentation Laboratory). Total and free PS antigen were measured with a home-made ELISA. FVL and PT20210A were detected by GeneXpert HemosIL® F5 and F2 assay (Cepheid, Sunnyvale, CA, USA). Additionally, testing for select acquired thrombophilic conditions was performed, including screening for antiphospholipid antibodies (lupus anticoagulant, anticardiolipin IgG/IgM, and anti-beta-2-glycoprotein I IgG/IgM). Follow-up and study outcomes All enrolled TGD individuals underwent longitudinal evaluation in accordance with clinical practice, after 3, 6, 12 and 24 months of GAHT initiation. During follow-up, clinical data were recorded, including anthropometric parameters, smoking habit, GAHT regimens, occurrence of VTE or other major cardiovascular events. TGD individuals were instructed to report to our Center if they presented symptoms suggestive of thrombosis. Smoking status was defined as current use of tobacco or cessation within the previous 12 months. Study outcomes included the prevalence of hereditary thrombophilia and the occurrence of thrombotic events (venous and/or arterial) in individuals with thrombophilia during follow-up. Statistical Analysis Categorical variables are presented as total numbers and percentages, while quantitative variables are expressed as median and interquartile ranges [IQR]. Normal distribution was assessed using the Kolmogorov-Smirnov test. As most variables were not normally distributed, non-parametric tests were used for statistical analysis. Participants were compared based on sex assigned at birth and the presence or absence of hereditary thrombophilia. For quantitative variables, the Mann-Whitney test was used. For categorical variables, the Chi-square or Fisher’s exact test was performed, as appropriate. A p-value of less than 0.05 was considered statistically significant. The analysis was conducted using IBM SPSS Statistics, version 29 (IBM Corp., Armonk, NY). RESULTS We recruited 114 TGD individuals (60 AFAB, 54 AMAB) referring to the Regional Reference Center for Gender Incongruence (CRRIG) of Veneto Region during the study period. The median age was 23 [IQR 20–26] years. Among the TGD individuals, 17.5% reported a family history of VTE, and over one-third of the sample smoked tobacco. The characteristics of the population are summarized in Table 1. Table 1. Characteristics of the study population compared for sex assigned at birth. TOTAL AMAB AFAB P value Sample – n 114 54 (47.4%) 60 (52.6%) - Age - years 23 [19.8-26.3] 24 [20.8-32.3] 22.5 [19.0-25.0] 0.022 Height – cm 170 [165-175] 175 [170-181] 165 [162-170] <0.001 BMI – Kg/m 2 22.4 [19.8-26.5] 20.7 [19.6-24.8] 24.3 [20.9-27.3] 0.034 Thrombophilia – n 11 (9.6%) 6 (11.1%) 5 (8.3%) 0.426 Severe thrombophilia - n 2 (1.8%) 1 (1.9%) 1 (1.7%) 0.999 Smoke * – n 41 (36.0%) 20 (37%) 21 (35%) 0.457 CVD family history – n 55 (48.2%) 23 [42.6%] 32 (53.3%) 0.267 VTE family history – n 24 (17.5%) 8 (14.8%) 12 (20%) 0.471 Previous VTE – n 3 (2.6%) 1 (1.8%) 2 (3.3%) 0.540 Comorbidities – n Obesity Diabetes Hypertension Dyslipidaemia Anxiety/depression CVD 15 (13.2%) 1 (0.8%) 4 (3.5%) 22 (19.6%) 23 (21.1%) 3 (2.6%) 5 (9.6%) 0 3 (5.6%) 14 (26.9%) 10 (18.5%) 1 (1.9%) 10 (16.7%) 1 (2.8%) 1 (2.8%) 8 (13.3%) 13 (21.7%) 2 (3.3%) 0.209 0.526 0.270 0.059 0.413 0.540 *Smoking status was defined as current use of tobacco or cessation within the previous 12 months. AMAB: assigned male at birth; AFAB: assigned female at birth; n: numerosity; VTE: venous thrombo-embolic event; CVD: cardiovascular disease. Data are presented as median and interquartile range [IQR] or number and %, as appropriate. Prevalence of hereditary thrombophilia in the study population Eleven participants (9.6%, [95% confidence interval (CI) 4.2-15.1%]; 5 AFAB, 6 AMAB) were found to have congenital thrombophilia, namely 9 mild thrombophilia (6 cases of heterozygous FVL, 3 cases of heterozygous PT20210A), and 2 severe thrombophilia (1 PC deficiency, 1 homozygous PT20210A). No participants tested positive for antiphospholipid antibodies, confirming the absence of acquired thrombophilia in our cohort. Table 2 presents a comparison between individuals with and without hereditary thrombophilia. Participants with thrombophilia more frequently had a personal (18.2% vs 0%, p = 0.009) or family history of VTE (45.4% vs 14.7%, p = 0.024). Table 2. Characteristics of the study population comparing individuals with or without congenital thrombophilia Without thrombophilia With thrombophilia P value Sample – n 103 (90.4%) 11 (9.6%) - AMAB – n 48 (46.6%) 6 (54.5%) 0.754 Age - years 23 [19-26] 26 [22-31] 0.139 Height – cm 170 [165-175] 170 [165-175] 0.922 BMI – Kg/m 2 22.3 [19.7-26.1] 24.5 [21.0-29.7] 0.278 Smoke * – n 38 (37.3%) 3 (27.3%) 0.744 CVD family history – n 49 (47.6%) 6 (54.5%) 0.756 VTE family history - n 15 (14.7%) 5 (45.4%) 0.024 Previous VTE - n 0 3 (27.3%) <0.001 Comorbidities – n Obesity Diabetes Hypertension Dyslipidemia Anxiety/depression CVD 13 (12.9%) 1 (1%) 4 (3.9%) 20 (19.8%) 20 (20.4%) 2 (1.9%) 2 (18.2%) 0 0 2 (18.2%) 3 (27.3%) 0 0.641 0.904 0.663 0.630 0.421 0.816 *Smoking status was defined as current use of tobacco or cessation within the previous 12 months. AMAB: assigned male at birth; AFAB: assigned female at birth; n: numerosity; VTE: venous thrombo-embolic event; CVD: cardiovascular disease. Data are presented as median and interquartile range [IQR] or number and %, as appropriate. Three cases of thrombosis were recorded prior to the initiation of GAHT, all in individuals with hereditary thrombophilia. The first case involved a transgender woman (AMAB, 31 years) with heterozygous FVL, who experienced an unprovoked deep vein thrombosis in the left lower extremity 2 years before GAHT. Additional risk factors included smoking and obesity (BMI 30.4 kg/m²). Since the VTE, the patient has been continuously treated with direct oral anticoagulants (rivaroxaban). The second case concerned a transgender man (AFAB, 26 years) who experienced a neonatal cerebral ischemic event consistent with cerebral venous sinus thrombosis, although radiological confirmation was not available, resulting in mild cognitive impairment. This was the only thrombotic event recorded for this patient. At the time of study enrollment, he had a BMI of 36.9 and reported current tobacco use (5–10 cigarettes/day), with a prior history of heavy smoking (up to 60 cigarettes/day). The patient was not on anticoagulant therapy at the time of GAHT initiation. The third case involved a transgender man (AFAB, 23 years) with heterozygous FVL. During adolescence he was diagnosed with Hodgkin Lymphoma and underwent chemotherapy and radiotherapy. He developed deep vein thrombosis in the subclavian and internal jugular veins, likely catheter-associated, during chemotherapy. He was treated initially with low molecular weight heparin for one year, followed by 18 months of warfarin. Furthermore, he was later diagnosed with breast cancer. In agreement with the patient, he underwent bilateral mastectomy, hysterectomy and oophorectomy, both as part of his oncological treatment and for gender affirmation. Additional clinical information on TGD individuals with hereditary thrombophilia is presented in Table 3. Hormonal therapy and follow-up of TGD individuals with hereditary thrombophilia When hereditary thrombophilia was detected, AMAB individuals were referred to the Haemorrhagic and Thrombotic Diseases Unit before initiating GAHT. During this evaluation, the patients’ thrombotic risk was assessed based on factors such as age, BMI, smoking status, family history of VTE, comorbidities, concurrent medications, and type of thrombophilia. Patients received personalized counselling, including guidance on managing high-risk situations for thrombosis, such as surgery or immobilization. Additionally, the coagulation specialist and endocrinologist collaboratively determined the optimal hormonal therapy to minimize VTE risk. The six AMAB individuals with hereditary thrombophilia were treated with transdermal estradiol at a moderate dosage, preferably combined with spironolactone, a non-progestin anti-androgen. However, some patients on spironolactone experienced adverse effects (e.g., arterial hypotension, palpitations) or insufficient anti-androgenic effect (e.g., persistence of spontaneous erections). In these cases, endocrinologists switched the treatment to low-dose CPA (≤12.5 mg/day). One AMAB individual with heterozygous FVL and a history of VTE was on rivaroxaban at the time of GAHT initiation. Anticoagulant therapy was continued, and the endocrinologist prescribed transdermal estradiol alongside low-dose CPA. For AFAB individuals, those with thrombophilia received counselling to reduce VTE risk, but no specific modifications to hormone therapy were implemented. As reported, two AFAB individuals experienced thrombotic events and were referred to the Thrombotic and Haemorrhagic Diseases Unit for counselling. One AFAB individual with PC deficiency and a history of neonatal stroke was advised to address concomitant risk factors, such as smoking cessation and weight reduction. The second AFAB individual, who had heterozygous FVL and a history of VTE during chemotherapy, was advised to reintroduce low-dose anticoagulant therapy (rivaroxaban 10 mg) prior to initiating testosterone. To minimize oncological risk, testosterone therapy was combined with an aromatase inhibitor. Currently, this patient is receiving injectable testosterone undecanoate, rivaroxaban, and letrozole. Among AFAB thrombophilia group, only one individual (AFAB, 25 years) developed mild erythrocytosis (haematocrit – Hct 51%) after 24 months of testosterone therapy. In this case, the interval of testosterone undecanoate administration was extended from one vial every 11 weeks to every 12 weeks. Detailed hormonal and anticoagulant therapies for patients with thrombophilia are summarized in Table 3. Table 3. Clinical characteristic of transgender individuals with congenital thrombophilia. Sex assigned at birth (age) Thrombophilia type BMI (Kg/m 2 ) Smoke VTE family history Previous VTE Anticoagulant therapy GAHT regimen Follow-up (months) AFAB (22 years) het FVL 21.0 no no no - T gel 69 mg/day 18 AFAB (26 years) PC deficiency 36.9 yes no yes - T gel 46 mg/day 6 AFAB (23 years) het FVL 21.0 no no yes Rivaroxaban 10 mg/day TU 1000 mg every 12 weeks 24 AFAB (25 year) § het FVL 27.0 no yes no - TU 1000 mg every 12 weeks 24 AFAB (30 years) het FVL 17.0 no yes no - T gel 23 mg day 27 AMAB (39 years) hom G20210A 24.5 no no no - E2 patch 50 mcg day + spironolactone 50 mg/day 3 AMAB (49 years) hom G20210A 22.1 no no no - E2 gel 1.5 mg/day + CPA 12.5 mg/day 12 * AMAB (20 years) het FVL 29.7 no no no - E2 gel 2 mg/day + CPA 25 mg/3 day per week 12 * AMAB (18 years) het G20210A 20.9 yes yes no - E2 spray 6.12 mg day + spironolactone 50 mg day 12 AMAB (26 years) het G20210A 26.5 no yes no - E2V pills 4 mg + CPA 12.5 mg day* 15 ** AMAB (31 years) het FVL 30.4 yes no yes Rivaroxaban 20 mg/day E2 spray 6.12 mg/day + CPA 25 mg/ 3 days per week 38 T: testosterone; TU: testosterone undecanoate; E2: estradiol; E2V: estradiol valeriate; CPA: cyproterone acetate; GAHT: gender-affirming hormone therapy; FVL: Factor V Leiden; G20210A: prothrombin mutation G20210A; het: heterozygous; hom: homozygous. *Spironolactone was not tolerated or not effective. **Self-administered GAHT. § The patient developed mild erythrocytosis. In the overall TGD population, median follow-up after GAHT initiation was 15 [IQR 12-24] months. No case of VTE occurred during GAHT, neither in patients with thrombophilia nor in those without thrombophilia. DISCUSSION This study examines the intersection of hereditary thrombophilia and GAHT in TGD individuals, focusing on the prevalence of thrombophilia conditions and their management within this population. Our findings contribute to the limited body of literature, providing insights to help clinicians to personalize GAHT regimens and mitigate thrombotic risks. Prevalence of hereditary thrombophilia in our cohort In the general population, mild hereditary thrombophilia, including heterozygous FVL and PT20210A mutations, is present in approximately 5–7% of individuals. 14,18,19 Severe hereditary thrombophilia, such as homozygous FVL or PT20210A mutations and deficiencies in AT, PC, or PS is rarer, with a prevalence of approximately 0.02–0.2%. 16,18–20 In our cohort, the prevalence of hereditary thrombophilia was 9.6%, consistent with general population estimates, with mild thrombophilia accounting for 7.8% and severe thrombophilia for 1.7%. Notably, individuals with thrombophilia in our cohort reported higher rates of personal or family history of VTE, emphasizing the importance of detailed patient histories for individualized care. Although thrombophilia is not expected to be causally related to demographic or lifestyle variables such as age, BMI, or smoking status, we compared these characteristics to explore whether individuals with hereditary thrombophilia tend to accumulate additional thrombotic risk factors, which might be relevant in the setting of GAHT. Few studies have explored the prevalence of congenital thrombophilia in the TGD population. 21,22 A retrospective cohort study by Kerrebrouck et al. reported a lower rate of hereditary thrombophilia (11 carriers out of 1700 individuals), although thrombophilia screening in that study was limited to TGD individuals with a personal or family history of VTE. 21 Overall, these findings underscore that for individuals with a history of VTE or familial predisposition, consultation with a haematologist is critical to assess the need for screening for congenital thrombophilia and to better define individual VTE risks. When comprehensive screening is routinely performed, a higher prevalence of thrombophilia—including severe cases—becomes evident, aligning with general population data. This information is critical for evaluating thrombotic risk, particularly in situations requiring careful management. However, given the relatively small cohort and short follow-up, our findings should be interpreted with caution. The absence of VTE events is reassuring but not conclusive, and may reflect limited power rather than definitive safety. Management of thrombophilia risk in our cohort The type, formulation, and route of hormone administration are critical factors influencing VTE risk. 22,23 In general, feminizing GAHT involves the administration of oral or transdermal estradiol in combination with an antiandrogen (e.g., CPA, spironolactone, or GnRH analogues). Among estrogens, ethinyl estradiol is associated with a higher VTE risk compared to estradiol. 6,24–26 Additionally, transdermal estrogen formulations are safer than oral preparations, particularly regarding thrombotic risk. 6,27 As a result, current guidelines recommend against the use of ethinyl estradiol and conjugated estrogens in GAHT. For TGD individuals at higher VTE risk or those over 45 years of age, transdermal estradiol is the preferred option. 1 In regards to antiandrogen therapy, data on CPA have shown an increased thrombotic risk when used in combination with ethinyl estradiol in cisgender women. 28 This risk is also elevated in cisgender women with hereditary thrombophilia. 29 Additionally, in patients with prostate cancer, high-dose CPA has been associated with a higher thrombotic risk compared to GnRH analogues or orchiectomy. 30 However, metastatic prostate cancer independently increases VTE risk, complicating direct comparisons. GnRH agonists may be considered as an alternative for TGD individuals at higher thrombotic risk since they do not significantly impact coagulation. Studies support their safety profile. 31,32 Testosterone therapy does not appear to increase thrombotic risk. Retrospective studies that have examined VTE in this population report a low incidence, with cases often linked to predisposing thrombotic risk factors. 33 A retrospective review involving 1,358 TGD individuals receiving testosterone therapy found no increased risk of stroke or VTE compared to cisgender men and women. However, the study did report an increased risk of myocardial infarction (standardized incidence ratio 3.69; 95%CI, 1.94–6.42) compared to cisgender women, but not cisgender men. 25 A large case-crossover study by Walker et al. identified a higher VTE risk in cisgender men receiving testosterone therapy, both with (OR 2.32; 95%CI, 1.97–2.74) and without (OR 2.02; 95%CI, 1.47–2.77) hypogonadism. 33 Smaller studies also noted that cisgender men who developed VTE on testosterone therapy frequently had underlying hypercoagulable conditions. 34,35 However, meta-analyses and systematic reviews of hypogonadal cisgender men undergoing testosterone replacement therapy did not show an increased VTE risk. 9,36 On the other hand, secondary erythrocytosis is common during testosterone therapy. 8 In the transgender population, higher dosages of testosterone therapy, injectable formulations, and higher serum testosterone levels during therapy have been correlated with polycythaemia. 8,37 The clinical implications of polycythaemia in transgender individuals, including its potential association with VTE, cardiovascular, and cerebrovascular complications, remain incompletely investigated. 38 In our cohort, for AMAB individuals with hereditary thrombophilia, referral to the Haemorrhagic and Thrombotic Diseases Unit occurred prior to GAHT initiation. Risk stratification considered age, BMI, smoking habit, family history of VTE, comorbidities, medications, and type of thrombophilia. Tailored counselling was provided, emphasizing strategies for managing high-risk conditions such as surgery or immobilization. Collaboration between coagulation specialists and endocrinologists ensured that GAHT regimens were optimized to mitigate VTE risks. Typically, transdermal estradiol at moderate doses was combined with spironolactone (Figure 1). However, adverse effects or incomplete anti-androgenic effect with spironolactone prompted some patients to switch to low-dose CPA (≤12.5 mg per day). GnRH analogues (e.g., triptorelin, leuprolide) may also be considered, though data on their use in adult TGD populations remain limited. For AFAB individuals with hereditary thrombophilia, counselling focused on minimizing acquired risk factors and regular monitoring of Hct. In case of erythrocytosis, the endocrinologist followed the recommendations from the Endocrine Society for testosterone replacement therapy in hypogonadism. 39 In particular, testosterone dosage was lowered for Hct >50% and patients were advised to stop smoking. Furthermore, the use of transdermal testosterone seems to mitigate the risk of erythrocytosis. 8 In case of Hct >54%, testosterone therapy was suspended and the patient was referred to the Haematologist for phlebotomy. Among AFAB thrombophilia group, only one individual developed mild erythrocytosis (Hct 51%) after 24 months of testosterone therapy. In this case, we decided to extend the interval between testosterone undecanoate administrations from one vial every 11 weeks to every 12 weeks. Beyond thrombophilia and hormone therapy, additional risk factors for thrombosis should be considered. Many studies report a high prevalence of tobacco use among TGD individuals, which we observed in our cohort, with nearly one-third identified as smokers. 4 Additionally, TGD AFAB individuals tend to have a higher BMI, fat mass index, and prevalence of obesity compared to cisgender women. 40,41 A systematic review found that obesity is associated with a two-fold increase in VTE risk compared to individuals with normal weight. 42 Furthermore, anxiety, depression, and other psychiatric conditions are also more common in this population, likely as a result of gender minority stress. 43 Depression, in particular, has been linked to an increased risk of VTE. 44 Finally, many TGD individuals undergo gender-affirming surgeries, which carry an inherent risk of VTE due to perioperative factors. 45 These considerations underscore the need for comprehensive counselling, targeting reversible risk factors such as smoking and weight management. In our cohort, no VTEs were reported amongst TGD individuals with or without thrombophilia after GAHT initiation, after a median follow-up of 15 months. This favourable outcome may be attributed to the efficacy of a multidisciplinary approach integrating haematological evaluation, personalized GAHT regimens, and patient education. Our strategy suggests the need for routine screening for thrombophilia in TGD individuals with a personal or family history of VTE, as well as in those with multiple concomitant acquired risk factors, enabling informed risk stratification and management (Figure 1). [PLEASE, INSERT FIGURE 1 HERE. In print, the image can be in black&white] Management of patients with thrombophilia and previous thrombosis in our cohort Among three individuals with hereditary thrombophilia and prior thrombosis, a tailored approach was developed in a multidisciplinary setting. A transgender woman with unprovoked VTE of the lower limb was already on full anticoagulation therapy at the first endocrinological visit and therefore anticoagulation was continued during GAHT. Feminizing therapy included transdermal estradiol and CPA, as anticoagulation was expected to neutralize the additional thrombotic risks of this anti-androgenic progestogen. This approach was in line with findings from a sub-analysis of the EINSTEIN study. 46 The study showed that cisgender women continuing estrogen-progestin therapy during anticoagulation did not experience an increased rate of VTE recurrence compared to other women on anticoagulant therapy. A transgender man who experienced a VTE during chemotherapy was referred to the coagulation specialist before GAHT initiation. This patient was therefore advised to reintroduce low-dose anticoagulation when starting testosterone therapy. A transdermal testosterone formulation was selected; eventually, he switched to injectable testosterone undecanoate for personal preference. Lastly, a transgender man with PC deficiency and a neonatal stroke history was advised to minimize acquired risk factors (smoke cessation, weight loss) and to promptly refer to a physician in case of signs of VTE. Anticoagulation was not initiated, considering the absence of active risk factors at the time of GAHT initiation. With this strategy, no recurrent thrombotic events were detected during GAHT in individuals with thrombophilia and previous thrombosis. This favourable outcome may be attributed to the proactive use of anticoagulation therapy, where indicated, alongside tailored interventions targeting modifiable risk factors to optimize outcomes, as summarized in Figure 1. The continuation of rivaroxaban in individuals with prior VTE aligns with evidence supporting its effectiveness in preventing recurrent events, even when combined with estrogen therapy. 46 These cases underscore the importance of a multidisciplinary approach to ensuring the safety of gender-affirming treatments, particularly in complex situations with an increased thromboembolic risk. Gender-affirming treatments significantly improve mental health and quality of life, making their continuation essential for TGD individuals, even in case of prior thrombotic events. Clinicians must carefully weight these benefits against thrombotic risks, especially in patients with hereditary thrombophilia. Limitations Findings from the present study are limited by its small sample size and short follow-up period, which may underestimate the incidence of VTE. The absence of a control group also prevents direct comparisons on the thrombotic risk between TGD individuals undergoing GAHT and the general population undergoing hormonal therapy. However, with our strategy we did not detect thrombotic events even in non-thrombophilia individuals. Future studies with larger cohorts and longer follow-up are needed to better understand the long-term VTE risks of GAHT in individuals with and without hereditary thrombophilia. Conclusions Hereditary thrombophilia in TGD individuals is as common as in the general population, encompassing 9.6% of this population. Our study suggests that hormone therapy in TGD individuals with hereditary thrombophilia, even in cases of severe thrombophilia or previous thrombosis, may be feasible and safe, when supported by individualized, multidisciplinary management. This success was achieved through a meticulous, multidisciplinary approach encompassing risk assessment, personalized GAHT regimens, and ongoing risk management. The integration of coagulation expertise with endocrinological care allowed for GAHT adjustments to minimized thrombotic risk while maintaining therapeutic goals. Key strategies included the preferential use of transdermal estradiol and careful selection of anti-androgens for feminizing therapy, and tailored management of testosterone therapy in AFAB individuals. Additionally, addressing modifiable risk factors such as smoking and weight management, alongside the judicious use of anticoagulation when indicated, contributed to the favourable outcomes observed in our cohort. Future research should further investigate the long-term outcomes of risk reduction strategies and tailored GAHT regimens on thrombotic and cardiovascular risk in this unique population. Declarations Acknowledgements On behalf of the Interdisciplinary Group for Gender Incongruence (GIIG) of the University Hospital of Padua, Italy: Andrea Garolla, Anna Aprile, Anna Belloni Fortina, Annamaria Cattelan, Alberto Ferlin, Alberto Scala, Angela Favaro, Benedetta Tascini, Camillo Barbisan, Carlo Saccardi, Chiara Ceolin, Claudio Terranova, Corrado Marchese Ragona, Daniela Basso, Elena Campello, Elisa Varotto, Eleonora Vania, Fabrizio Dal Moro, Fabrizio Vianello, Francesco Francini, Francesca Venturini, Giancarlo Ottaviano, Giorgio De Conti, Giovanni Frattin, Giuseppe Sergi, Giulia Musso, Laura Guazzarotti, Lolita Sasset, Marina Bonato, Marina Miscioscia, Marta Ghisi, Massimo Iafrate, Maurizio Iacobone, Michela Gatta, Paolo Meneguzzo, Paolo Simioni, Rossana Schiavo, Rossella Perilli, Sandro Giannini, Tommaso Vezzaro. Author contributions E.C., A.S., P.S., and A.G. contributed to the conceptualization of the study. E.C. and C.B. developed the methodology. A.S. and E.C. performed the formal analysis. C.S., E.C., A.S., A.G., C.B., A.B., G.F., and F.T. carried out the investigation. P.S., A.F., and A.G. provided resources. A.S. and C.B. curated the data. A.S. and E.C. wrote the original draft. A.F., P.S., A.G., and L.D.T. reviewed and edited the manuscript. A.S. and E.C. prepared the visualizations. P.S., A.G., and A.F. supervised the project. E.C. administered the project and acquired funding. All authors reviewed the manuscript and approved the final version. Data availability statement Data are available from the corresponding author (E.C.) upon reasonable request. Financial support This study was funded by the Italian Ministry of University and Research (MUR) to E.C. under the project “Longitudinal thrombo-inflammatory profiling of individuals undergoing gender-affirming hormone therapy (Hyper-gender study)” (Project Code: P2022RWMFC, PRIN 2022 PNRR - DD 1409 of 14/09/2022) - CUP: C53D23009540001, within the framework of the National Recovery and Resilience Plan (PNRR), Mission 4, Component 2, Investment 1.1 'Project of Significant National Interest (PRIN). Conflicts of interest The authors have no competing interests to declare that are relevant to the content of this article. References Coleman, E. et al. Standards of Care for the Health of Transgender and Gender Diverse People, Version 8. Int. J. Transgender Heal. 23 , S1–S259 (2022). Hembree, W. C. et al. Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 102 , 3869–3903 (2017). Van Zijverden, L. 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Occurrence of Acute Cardiovascular Events in Transgender Individuals Receiving Hormone Therapy. Circulation 139 , 1461–1462 (2019). Toorians, A. W. F. T. et al. Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment in transsexual people. J. Clin. Endocrinol. Metab. 88 , 5723–5729 (2003). Wierckx, K. et al. Prevalence of cardiovascular disease and cancer during cross-sex hormone therapy in a large cohort of trans persons: a case-control study. Eur. J. Endocrinol. 169 , 471–478 (2013). Dragoman, M. V. et al. A systematic review and meta-analysis of venous thrombosis risk among users of combined oral contraception. Int. J. Gynaecol. Obstet. 141 , 287–294 (2018). Khialani, D. et al. The joint effect of genetic risk factors and different types of combined oral contraceptives on venous thrombosis risk. Br. J. Haematol. 191 , 90–97 (2020). Köhler, T. S. et al. A pilot study on the early use of the vacuum erection device after radical retropubic prostatectomy. BJU Int. 100 , 858–862 (2007). Asscheman, H. et al. Venous thrombo-embolism as a complication of cross-sex hormone treatment of male-to-female transsexual subjects: a review. Andrologia 46 , 791–795 (2014). Dittrich, R. et al. Endocrine treatment of male-to-female transsexuals using gonadotropin-releasing hormone agonist. Exp. Clin. Endocrinol. Diabetes 113 , 586–592 (2005). Walker, R. F. et al. Association of Testosterone Therapy With Risk of Venous Thromboembolism Among Men With and Without Hypogonadism. JAMA Intern. Med. 180 , 190–197 (2020). Glueck, C. J. et al. Testosterone therapy, thrombophilia-hypofibrinolysis, and hospitalization for deep venous thrombosis-pulmonary embolus: an exploratory, hypothesis-generating study. Clin. Appl. Thromb. Hemost. 20 , 244–249 (2014). Freedman, J., Glueck, C. J., Prince, M., Riaz, R. & Wang, P. Testosterone, thrombophilia, thrombosis. Transl. Res. 165 , 537–548 (2015). Klok, F. A. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb. Res. 191 , 145–147 (2020). Krishnamurthy, N. et al. Erythrocytosis Is Rare With Exogenous Testosterone in Gender-Affirming Hormone Therapy. J. Clin. Endocrinol. Metab. (2023) doi:10.1210/CLINEM/DGAD651. King, H., Kelley, T. P. & Shatzel, J. J. Gender-affirming hormone therapy in the transgender patient: influence on thrombotic risk. Hematol. Am. Soc. Hematol. Educ. Progr. 2024 , 652–663 (2024). Bhasin, S. et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 95 , 2536–2559 (2010). Ceolin, C. et al. Bone health and body composition in transgender adults before gender-affirming hormonal therapy: data from the COMET study. J. Endocrinol. Invest. 47 , 401–410 (2024). Santangelo, C. et al. Dietary Habits, Physical Activity and Body Mass Index in Transgender and Gender Diverse Adults in Italy: A Voluntary Sampling Observational Study. Nutrients 16 , (2024). Allman-Farinelli, M. A. Obesity and venous thrombosis: a review. Semin. Thromb. Hemost. 37 , 903–907 (2011). Mezza, F. et al. Minority stress and mental health in European transgender and gender diverse people: A systematic review of quantitative studies. Clin. Psychol. Rev. 107 , (2024). Kunutsor, S. K., Seidu, S. & Khunti, K. Depression, antidepressant use, and risk of venous thromboembolism: systematic review and meta-analysis of published observational evidence. Ann. Med. 50 , 529–537 (2018). Boskey, E. R., Taghinia, A. H. & Ganor, O. Association of Surgical Risk With Exogenous Hormone Use in Transgender Patients: A Systematic Review. JAMA Surg. 154 , 109–115 (2019). Martinelli, I. et al. Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use. Blood 127 , 1417–1425 (2016). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6573735","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":463286844,"identity":"3bae632f-db34-48bf-a6ff-dca0adbca73a","order_by":0,"name":"Elena Campello","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIiWNgGAWjYDACdgST8cADBhsGBmYGBgkGAzxamJHYBxIY0mBa8OhB03IYzJBgwGMNPzPzsQc/GOzkdWc3HziQUHE+cTs778EbDAV/cGqRbGZLN+xhSDbcdudYwoGEM7cTdzbzJVvgc5jBYR4zCR6GA4zbbuQYHEhsu524ASSCT4v9Yf5vkn8YDthvu5H/AajlHGEtBsw8bNJAWxKBtgDJtgOEtUgcZjOTljFITgb6xQDol2TjDYeBfkkwMMaphb+9+Znkmwo72223mx8++FBhJ7vh/NmDNz78kcOpBeo8BnBcQAEPA0MCAQ1QJyJrGQWjYBSMglGABABuxVTyuowXPAAAAABJRU5ErkJggg==","orcid":"","institution":"University of Padua","correspondingAuthor":true,"prefix":"","firstName":"Elena","middleName":"","lastName":"Campello","suffix":""},{"id":463286845,"identity":"ca7447bd-d3a3-49a0-aa7b-b7159ac1420f","order_by":1,"name":"Alberto Scala","email":"","orcid":"","institution":"University of Padua","correspondingAuthor":false,"prefix":"","firstName":"Alberto","middleName":"","lastName":"Scala","suffix":""},{"id":463286846,"identity":"0cd802c5-cd13-449a-a0bf-b5fea990a4ef","order_by":2,"name":"Cristiana Bulato","email":"","orcid":"","institution":"University of Padua","correspondingAuthor":false,"prefix":"","firstName":"Cristiana","middleName":"","lastName":"Bulato","suffix":""},{"id":463286847,"identity":"cc4fd80a-f6fc-4e6e-82b2-dd464edccfe0","order_by":3,"name":"Andrea Benetti","email":"","orcid":"","institution":"University of Padua","correspondingAuthor":false,"prefix":"","firstName":"Andrea","middleName":"","lastName":"Benetti","suffix":""},{"id":463286848,"identity":"34946247-0338-419d-9c52-9feb04714120","order_by":4,"name":"Giacomo Faggian","email":"","orcid":"","institution":"University of Padua","correspondingAuthor":false,"prefix":"","firstName":"Giacomo","middleName":"","lastName":"Faggian","suffix":""},{"id":463286849,"identity":"24728992-eaf5-4338-867a-31b53de782dc","order_by":5,"name":"Luca De Toni","email":"","orcid":"","institution":"University of Padua","correspondingAuthor":false,"prefix":"","firstName":"Luca","middleName":"","lastName":"De Toni","suffix":""},{"id":463286850,"identity":"cf9022bd-be15-4f63-91f0-42db98d53b33","order_by":6,"name":"Chiara Simion","email":"","orcid":"","institution":"University of Padua","correspondingAuthor":false,"prefix":"","firstName":"Chiara","middleName":"","lastName":"Simion","suffix":""},{"id":463286851,"identity":"e8e006fe-1a46-4723-905d-563fb00a9cc9","order_by":7,"name":"Francesco Torresan","email":"","orcid":"","institution":"University of Padua","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Torresan","suffix":""},{"id":463286852,"identity":"3cefb459-2fb6-4dc7-9666-78c15f370751","order_by":8,"name":"Andrea Ferlin","email":"","orcid":"","institution":"University of Padua","correspondingAuthor":false,"prefix":"","firstName":"Andrea","middleName":"","lastName":"Ferlin","suffix":""},{"id":463286853,"identity":"e4ef18c2-fc92-4dc6-9571-4827f2dfab50","order_by":9,"name":"Paolo Simioni","email":"","orcid":"","institution":"University of Padua","correspondingAuthor":false,"prefix":"","firstName":"Paolo","middleName":"","lastName":"Simioni","suffix":""},{"id":463286854,"identity":"7edbab15-3c56-4e6f-9c2b-335f123abe08","order_by":10,"name":"Andrea Garolla","email":"","orcid":"","institution":"University of Padua","correspondingAuthor":false,"prefix":"","firstName":"Andrea","middleName":"","lastName":"Garolla","suffix":""}],"badges":[],"createdAt":"2025-05-01 18:23:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6573735/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6573735/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83768387,"identity":"4985a4e2-e931-4b44-8714-8fefbfb7841d","added_by":"auto","created_at":"2025-06-02 11:45:36","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":157920,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProposal for clinical management of thromboembolic risk in transgender patients undergoing gender-affirming hormone therapy.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVTE: venous thromboembolism; BMI: body mass index; AMAB: assigned male at birth; AFAB: assigned female at birth; CPA: cyproterone acetate; GnRH: gonadotropin-releasing hormone (GnRH) analogues.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6573735/v1/42fc38569b92f32e26449ef6.jpg"},{"id":84547760,"identity":"d405bc1d-4907-44c9-a0a6-590410c61cd3","added_by":"auto","created_at":"2025-06-13 09:32:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1319046,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6573735/v1/a5377d27-fd24-4672-856c-ad195d7c156e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Risk and management of congenital thrombophilia in transgender individuals undergoing gender-affirming hormone therapy","fulltext":[{"header":"Highlights","content":"\u003cul class=\"decimal_type\"\u003e\n \u003cli\u003eHormone therapy in transgender people has been linked to a higher risk of venous thrombosis.\u003c/li\u003e\n \u003cli\u003eThrombophilia screening is recommended in case of a personal or family history of thrombosis.\u003c/li\u003e\n \u003cli\u003eHereditary thrombophilia affects 9.6% of transgender people, similar to the general population.\u003c/li\u003e\n \u003cli\u003eRisk reduction strategies and tailored hormone therapy can help prevent thrombosis.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003eTransgender and gender-diverse (TGD) individuals experience an incongruence between their gender identity and the sex assigned to them at birth.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Many TGD individuals seek gender-affirming medical treatments to align their physical characteristics with their gender identity, contributing to a growing demand for gender-affirming services in recent years. Gender-affirming programs should be tailored to the individual\u0026rsquo;s goals and may include psychological support, gender-affirming hormone therapy (GAHT), and gender-affirming surgeries.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e In particular, testosterone therapy is used to promote masculinization in individuals assigned female at birth (AFAB). Conversely, feminizing hormone therapy involves the administration of estradiol and anti-androgens, such as cyproterone acetate (CPA), spironolactone, or gonadotropin-releasing hormone (GnRH) analogues in individuals assigned male at birth (AMAB).\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eVarious studies have assessed the cardiovascular risk in the TGD population and its relation with GAHT.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Estrogen therapy has been linked to a significant increase in venous thromboembolic events (VTE) in TGD AMAB individuals, a risk also observed in cisgender women using hormonal contraception or hormone replacement therapy.\u003csup\u003e\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e A meta-analysis estimates the incidence of VTE at 43 per 10,000 patient-years among TGD individuals undergoing estrogen therapy\u0026mdash;higher than the incidence observed in cisgender women receiving hormone replacement therapy.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Additionally, VTE risk continues to increase even after eight years of feminizing hormone therapy.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e This is particularly significant given that GAHT is typically a lifelong treatment.\u003c/p\u003e \u003cp\u003eOn the other hand, secondary erythrocytosis is a common adverse effect of testosterone therapy.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Primary erythrocytosis has been associated with arterial and venous thrombosis, but this effect has never been demonstrated in androgen-induced erythrocytosis. \u003csup\u003e\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe prothrombotic effects of exogenous hormones may be amplified in individuals with predisposing conditions such as hereditary thrombophilia. Hereditary thrombophilia are genetic conditions that increase the risk of hypercoagulability, including factor V Leiden (FVL) and prothrombin G20210A (PT20210A) mutations, and deficiencies of protein C (PC), protein S (PS), and antithrombin (AT).\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e These conditions contribute to an elevated baseline risk of VTE and can interact synergistically with environmental or pharmacologic factors to further increase thrombotic risk.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e For instance, in cisgender women, the combination of estrogen-containing therapies and hereditary thrombophilia is associated with a significantly increased risk of VTE.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDespite these risks, there is limited research addressing the prevalence and clinical implications of hereditary thrombophilia in TGD individuals undergoing GAHT. Routine screening for thrombophilia is not universally recommended before initiating GAHT, leaving a critical gap in risk stratification and individualized care. In fact, international guidelines recommend to screen only individuals with a personal or family history of TVE.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Given the known thrombotic risks of hormone therapy and the potential for increased risk in patients with underlying thrombophilia, understanding the prevalence of these genetic conditions in the TGD population is essential, not because we expected it to differ from the general population, but because these data are lacking and are needed to inform individualized risk management strategies for GAHT.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis study investigates the prevalence of hereditary thrombophilia in a cohort of TGD individuals undergoing GAHT. By characterizing the distribution of thrombophilic conditions in this population, we aim to provide insights into the intersection of gender-affirming care and thrombotic risk management.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eThe present investigation is part of the \u003cem\u003eHypergender study\u003c/em\u003e, a longitudinal study designed to evaluate the haematological effects of GAHT in TGD individuals. Participants were assessed at baseline and after 3, 6, and 12 months of GAHT.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData collection\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAdult TGD individuals who initiated GAHT at the University Hospital of Padova between December 2022 and December 2024 were enrolled. Inclusion criteria were being over 18 and below 50 years of age, a diagnosis of gender incongruence, and the intention to initiate GAHT. Exclusion criteria included refusal to provide informed consent or discontinuation of clinical follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDuring the first endocrinological visit, clinical history was collected, including personal and family history of TVE and cardiovascular events, personal pathological history, cardiovascular risk factors, current pharmacological treatment, and previous use of GAHT. Physicians also performed a physical examination, including anthropometric measurements. Routine laboratory tests required for prescribing GAHT included a complete blood count, liver and kidney function tests, sex hormone profile, prolactin, glycaemia, and lipid profile.\u003c/p\u003e\n\u003cp\u003eAll participants underwent thrombophilia screening and provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the University Hospital of Padua (5990/AO/24).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThrombophilia screening\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll enrolled TGD individuals underwent a screening for thrombophilia before starting GAHT. Screening included tests for AT, PC, and PS deficiencies, FVL and PT20210A mutations, as well as rare inherited thrombophilia (pseudo-homozygous FVL and AT resistance). AT, PC, PS activity, and antigen levels as well as activated protein C resistance (aPCR) were measured as previously reported.\u003csup\u003e12,16,17\u003c/sup\u003e Reduced levels of anticoagulant factors (activity and/or antigen) were confirmed in 2 consecutive determinations and in at least 1 first-degree relative. AT activity was evaluated by a FIIa-based assay (Berichrom\u0026reg; Antithrombin III, Siemens Healthcare Diagnostics) using a BCS\u0026reg; XP coagulometer (Siemens Healthcare Diagnostics). PC chromogenic and coagulometric activities were measured on a BCS XP Coagulation analyser (Siemens Healthcare Diagnostics) using 2 commercial kits, Berichrom Protein C and Protein C Reagent (Siemens Healthcare Diagnostics), respectively. PC antigen was determined by a home-made sandwich ELISA using a sheep anti-human PC antibody (Affinity Biologicals) as the capture antibody and horseradish peroxidase conjugated sheep anti-human PC antibody (Affinity Biologicals) as the detection antibody. PS activity testing was performed on an ACL TOP 300 CTS analyser (Instrumentation Laboratory) with the HemosIL Protein S Activity kit (Instrumentation Laboratory). Total and free PS antigen were measured with a home-made ELISA. FVL and PT20210A were detected by GeneXpert HemosIL\u0026reg; F5 and F2 assay (Cepheid, Sunnyvale, CA, USA). Additionally, testing for select acquired thrombophilic conditions was performed, including screening for antiphospholipid antibodies (lupus anticoagulant, anticardiolipin IgG/IgM, and anti-beta-2-glycoprotein I IgG/IgM).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFollow-up and study outcomes\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll enrolled TGD individuals underwent longitudinal evaluation in accordance with clinical practice, after 3, 6, 12 and 24 months of GAHT initiation. During follow-up, clinical data were recorded, including anthropometric parameters, smoking habit, GAHT regimens, occurrence of VTE or other major cardiovascular events. TGD individuals were instructed to report to our Center if they presented symptoms suggestive of thrombosis. Smoking status was defined as current use of tobacco or cessation within the previous 12 months.\u003c/p\u003e\n\u003cp\u003eStudy outcomes included the prevalence of hereditary thrombophilia and the occurrence of thrombotic events (venous and/or arterial) in individuals with thrombophilia during follow-up. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCategorical variables are presented as total numbers and percentages, while quantitative variables are expressed as median and interquartile ranges [IQR]. Normal distribution was assessed using the Kolmogorov-Smirnov test. As most variables were not normally distributed, non-parametric tests were used for statistical analysis.\u003c/p\u003e\n\u003cp\u003eParticipants were compared based on sex assigned at birth and the presence or absence of hereditary thrombophilia. For quantitative variables, the Mann-Whitney test was used. For categorical variables, the Chi-square or Fisher\u0026rsquo;s exact test was performed, as appropriate. A p-value of less than 0.05 was considered statistically significant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe analysis was conducted using IBM SPSS Statistics, version 29 (IBM Corp., Armonk, NY).\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eWe recruited 114 TGD individuals (60 AFAB, 54 AMAB) referring to the Regional Reference Center for Gender Incongruence (CRRIG) of Veneto Region during the study period. The median age was 23 [IQR 20\u0026ndash;26] years. Among the TGD individuals, 17.5% reported a family history of VTE, and over one-third of the sample smoked tobacco. The characteristics of the population are summarized in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Characteristics of the study population compared for sex assigned at birth.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTOTAL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAMAB\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAFAB\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSample\u0026nbsp;\u003c/strong\u003e\u0026ndash; n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e54 (47.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e60 (52.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e - years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e23 [19.8-26.3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e24 [20.8-32.3]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e22.5 [19.0-25.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.022\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeight\u0026nbsp;\u003c/strong\u003e\u0026ndash; cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e170 [165-175]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e175 [170-181]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e165 [162-170]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI\u003c/strong\u003e \u0026ndash; Kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e22.4 [19.8-26.5]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e20.7 [19.6-24.8]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e24.3 [20.9-27.3]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.034\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eThrombophilia\u0026nbsp;\u003c/strong\u003e\u0026ndash; n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e11 (9.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e6 (11.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e5 (8.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e0.426\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSevere thrombophilia\u003c/strong\u003e - n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2 (1.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e1 (1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e1 (1.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoke\u003c/strong\u003e*\u0026nbsp;\u0026ndash; n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e41 (36.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e20 (37%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e21 (35%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e0.457\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCVD family history\u0026nbsp;\u003c/strong\u003e\u0026ndash; n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e55 (48.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e23 [42.6%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e32 (53.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e0.267\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVTE family history\u0026nbsp;\u003c/strong\u003e\u0026ndash; n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e24 (17.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e8 (14.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e12 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e0.471\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrevious VTE\u0026nbsp;\u003c/strong\u003e\u0026ndash; n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e3 (2.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e1 (1.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e2 (3.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e0.540\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eComorbidities\u003c/strong\u003e \u0026ndash; n\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Obesity \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Diabetes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Hypertension \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Dyslipidaemia\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Anxiety/depression\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;CVD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15 (13.2%)\u003c/p\u003e\n \u003cp\u003e1 (0.8%)\u003c/p\u003e\n \u003cp\u003e4 (3.5%)\u003c/p\u003e\n \u003cp\u003e22 (19.6%)\u003c/p\u003e\n \u003cp\u003e23 (21.1%)\u003c/p\u003e\n \u003cp\u003e3 (2.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 (9.6%)\u003c/p\u003e\n \u003cp\u003e0\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (5.6%)\u003c/p\u003e\n \u003cp\u003e14 (26.9%)\u003c/p\u003e\n \u003cp\u003e10 (18.5%)\u003c/p\u003e\n \u003cp\u003e1 (1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 19px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10 (16.7%)\u003c/p\u003e\n \u003cp\u003e1 (2.8%)\u003c/p\u003e\n \u003cp\u003e1 (2.8%)\u003c/p\u003e\n \u003cp\u003e8 (13.3%)\u003c/p\u003e\n \u003cp\u003e13 (21.7%)\u003c/p\u003e\n \u003cp\u003e2 (3.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.209\u003c/p\u003e\n \u003cp\u003e0.526\u003c/p\u003e\n \u003cp\u003e0.270\u003c/p\u003e\n \u003cp\u003e0.059\u003c/p\u003e\n \u003cp\u003e0.413\u003c/p\u003e\n \u003cp\u003e0.540\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Smoking status was defined as current use of tobacco or cessation within the previous 12 months.\u003c/p\u003e\n\u003cp\u003eAMAB: assigned male at birth; AFAB: assigned female at birth; n: numerosity; VTE: venous thrombo-embolic event; CVD: cardiovascular disease. Data are presented as median and interquartile range [IQR] or number and %, as appropriate.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePrevalence of hereditary thrombophilia in the study population\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eEleven participants (9.6%, [95% confidence interval (CI) 4.2-15.1%]; 5 AFAB, 6 AMAB) were found to have congenital thrombophilia, namely 9 mild thrombophilia (6 cases of heterozygous FVL, 3 cases of heterozygous PT20210A), and 2 severe thrombophilia (1 PC deficiency, 1 homozygous PT20210A). No participants tested positive for antiphospholipid antibodies, confirming the absence of acquired thrombophilia in our cohort. Table 2 presents a comparison between individuals with and without hereditary thrombophilia. Participants with thrombophilia more frequently had a personal (18.2% vs 0%, p = 0.009) or family history of VTE (45.4% vs 14.7%, p = 0.024).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Characteristics of the study population comparing individuals with or without congenital thrombophilia\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWithout thrombophilia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWith thrombophilia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSample\u0026nbsp;\u003c/strong\u003e\u0026ndash; n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e103 (90.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e11 (9.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAMAB\u003c/strong\u003e \u0026ndash; n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e48 (46.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e6 (54.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e0.754\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e - years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e23 [19-26]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e26 [22-31]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e0.139\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeight\u0026nbsp;\u003c/strong\u003e\u0026ndash; cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e170 [165-175]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e170 [165-175]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e0.922\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI\u003c/strong\u003e \u0026ndash; Kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e22.3 [19.7-26.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e24.5 [21.0-29.7]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e0.278\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoke\u003c/strong\u003e*\u0026nbsp;\u0026ndash; n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e38 (37.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e3 (27.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e0.744\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCVD family history\u0026nbsp;\u003c/strong\u003e\u0026ndash; n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e49 (47.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e6 (54.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e0.756\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVTE family history\u0026nbsp;\u003c/strong\u003e- n\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e15 (14.7%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5 (45.4%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.024\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrevious VTE\u0026nbsp;\u003c/strong\u003e- n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3 (27.3%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eComorbidities\u003c/strong\u003e \u0026ndash; n\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Obesity \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Diabetes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Hypertension \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Dyslipidemia\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Anxiety/depression\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; CVD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 30px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13 (12.9%)\u003c/p\u003e\n \u003cp\u003e1 (1%)\u003c/p\u003e\n \u003cp\u003e4 (3.9%)\u003c/p\u003e\n \u003cp\u003e20 (19.8%)\u003c/p\u003e\n \u003cp\u003e20 (20.4%)\u003c/p\u003e\n \u003cp\u003e2 (1.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 26px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 (18.2%)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e2 (18.2%)\u003c/p\u003e\n \u003cp\u003e3 (27.3%)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.641\u003c/p\u003e\n \u003cp\u003e0.904\u003c/p\u003e\n \u003cp\u003e0.663\u003c/p\u003e\n \u003cp\u003e0.630\u003c/p\u003e\n \u003cp\u003e0.421\u003c/p\u003e\n \u003cp\u003e0.816\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Smoking status was defined as current use of tobacco or cessation within the previous 12 months.\u003c/p\u003e\n\u003cp\u003eAMAB: assigned male at birth; AFAB: assigned female at birth; n: numerosity; VTE: venous thrombo-embolic event; CVD: cardiovascular disease. Data are presented as median and interquartile range [IQR] or number and %, as appropriate.\u003c/p\u003e\n\u003cp\u003eThree cases of thrombosis were recorded prior to the initiation of GAHT, all in individuals with hereditary thrombophilia. The first case involved a transgender woman (AMAB, 31 years) with heterozygous FVL, who experienced an unprovoked deep vein thrombosis in the left lower extremity 2 years before GAHT. Additional risk factors included smoking and obesity (BMI 30.4 kg/m\u0026sup2;). Since the VTE, the patient has been continuously treated with direct oral anticoagulants (rivaroxaban).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe second case concerned a transgender man (AFAB, 26 years) who experienced a neonatal cerebral ischemic event consistent with cerebral venous sinus thrombosis, although radiological confirmation was not available, resulting in mild cognitive impairment. This was the only thrombotic event recorded for this patient. At the time of study enrollment, he had a BMI of 36.9 and reported current tobacco use (5\u0026ndash;10 cigarettes/day), with a prior history of heavy smoking (up to 60 cigarettes/day). The patient was not on anticoagulant therapy at the time of GAHT initiation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe third case involved a transgender man (AFAB, 23 years) with heterozygous FVL. During adolescence he was diagnosed with Hodgkin Lymphoma and underwent chemotherapy and radiotherapy. He developed deep vein thrombosis in the subclavian and internal jugular veins, likely catheter-associated, during chemotherapy. He was treated initially with low molecular weight heparin for one year, followed by 18 months of warfarin. Furthermore, he was later diagnosed with breast cancer. In agreement with the patient, he underwent bilateral mastectomy, hysterectomy and oophorectomy, both as part of his oncological treatment and for gender affirmation. Additional clinical information on TGD individuals with hereditary thrombophilia is presented in Table 3.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eHormonal therapy and follow-up of TGD individuals with hereditary thrombophilia\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWhen hereditary thrombophilia was detected, AMAB individuals were referred to the Haemorrhagic and Thrombotic Diseases Unit before initiating GAHT. During this evaluation, the patients\u0026rsquo; thrombotic risk was assessed based on factors such as age, BMI, smoking status, family history of VTE, comorbidities, concurrent medications, and type of thrombophilia. Patients received personalized counselling, including guidance on managing high-risk situations for thrombosis, such as surgery or immobilization. Additionally, the coagulation specialist and endocrinologist collaboratively determined the optimal hormonal therapy to minimize VTE risk.\u003c/p\u003e\n\u003cp\u003eThe six AMAB individuals with hereditary thrombophilia were treated with transdermal estradiol at a moderate dosage, preferably combined with spironolactone, a non-progestin anti-androgen. However, some patients on spironolactone experienced adverse effects (e.g., arterial hypotension, palpitations) or insufficient anti-androgenic effect (e.g., persistence of spontaneous erections). In these cases, endocrinologists switched the treatment to low-dose CPA (\u0026le;12.5 mg/day).\u003c/p\u003e\n\u003cp\u003eOne AMAB individual with heterozygous FVL and a history of VTE was on rivaroxaban at the time of GAHT initiation. Anticoagulant therapy was continued, and the endocrinologist prescribed transdermal estradiol alongside low-dose CPA.\u003c/p\u003e\n\u003cp\u003eFor AFAB individuals, those with thrombophilia received counselling to reduce VTE risk, but no specific modifications to hormone therapy were implemented.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs reported, two AFAB individuals experienced thrombotic events and were referred to the Thrombotic and Haemorrhagic Diseases Unit for counselling. One AFAB individual with PC deficiency and a history of neonatal stroke was advised to address concomitant risk factors, such as smoking cessation and weight reduction. The second AFAB individual, who had heterozygous FVL and a history of VTE during chemotherapy, was advised to reintroduce low-dose anticoagulant therapy (rivaroxaban 10 mg) prior to initiating testosterone. To minimize oncological risk, testosterone therapy was combined with an aromatase inhibitor. Currently, this patient is receiving injectable testosterone undecanoate, rivaroxaban, and letrozole.\u003c/p\u003e\n\u003cp\u003eAmong AFAB thrombophilia group, only one individual (AFAB, 25 years) developed mild erythrocytosis (haematocrit \u0026ndash; Hct 51%) after 24 months of testosterone therapy. In this case, the interval of testosterone undecanoate administration was extended from one vial every 11 weeks to every 12 weeks. Detailed hormonal and anticoagulant therapies for patients with thrombophilia are summarized in Table 3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Clinical characteristic of transgender individuals with congenital thrombophilia.\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eSex assigned at birth (age)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003eThrombophilia type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003eBMI (Kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003eSmoke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8px;\"\u003e\n \u003cp\u003eVTE family history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003ePrevious VTE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eAnticoagulant therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003eGAHT regimen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003eFollow-up (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eAFAB\u003c/p\u003e\n \u003cp\u003e(22 years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003ehet FVL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e21.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14px;\"\u003e\n \u003cp\u003eT gel 69 mg/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAFAB\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(26 years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePC deficiency\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e36.9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eyes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eno\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eyes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT gel 46 mg/day\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAFAB\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(23 years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ehet FVL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e21.0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eno\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eno\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eyes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRivaroxaban 10 mg/day\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTU 1000 mg every 12 weeks\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e24\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eAFAB\u003c/p\u003e\n \u003cp\u003e(25 year)\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003ehet FVL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e27.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14px;\"\u003e\n \u003cp\u003eTU 1000 mg every 12 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10px;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eAFAB\u003c/p\u003e\n \u003cp\u003e(30 years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003ehet FVL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e17.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14px;\"\u003e\n \u003cp\u003eT gel 23 mg day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eAMAB\u003c/p\u003e\n \u003cp\u003e(39 years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003ehom G20210A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e24.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14px;\"\u003e\n \u003cp\u003eE2 patch 50 mcg day + spironolactone 50 mg/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eAMAB\u003c/p\u003e\n \u003cp\u003e(49 years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003ehom G20210A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e22.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14px;\"\u003e\n \u003cp\u003eE2 gel 1.5 mg/day + CPA 12.5 mg/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10px;\"\u003e\n \u003cp\u003e12 *\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eAMAB\u003c/p\u003e\n \u003cp\u003e(20 years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003ehet FVL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e29.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14px;\"\u003e\n \u003cp\u003eE2 gel 2 mg/day + CPA 25 mg/3 day per week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10px;\"\u003e\n \u003cp\u003e12 *\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eAMAB\u003c/p\u003e\n \u003cp\u003e(18 years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003ehet G20210A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e20.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14px;\"\u003e\n \u003cp\u003eE2 spray 6.12 mg day + spironolactone 50 mg day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003eAMAB\u003c/p\u003e\n \u003cp\u003e(26 years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003ehet G20210A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e26.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14px;\"\u003e\n \u003cp\u003eE2V pills 4 mg + CPA 12.5 mg day*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10px;\"\u003e\n \u003cp\u003e15 **\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAMAB\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(31 years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ehet FVL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e30.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eyes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eno\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eyes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRivaroxaban 20 mg/day\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eE2 spray 6.12 mg/day + CPA 25 mg/ 3 days per week\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e38\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eT: testosterone; TU: testosterone undecanoate; E2: estradiol; E2V: estradiol valeriate; CPA: cyproterone acetate; GAHT: gender-affirming hormone therapy; FVL: Factor V Leiden; G20210A: prothrombin mutation G20210A; het: heterozygous; hom: homozygous. *Spironolactone was not tolerated or not effective. **Self-administered GAHT. \u003csup\u003e\u0026sect;\u003c/sup\u003eThe patient developed mild erythrocytosis.\u003c/p\u003e\n\u003cp\u003eIn the overall TGD population, median follow-up after GAHT initiation was 15 [IQR 12-24] months. No case of VTE occurred during GAHT, neither in patients with thrombophilia nor in those without thrombophilia.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study examines the intersection of hereditary thrombophilia and GAHT in TGD individuals, focusing on the prevalence of thrombophilia conditions and their management within this population. Our findings contribute to the limited body of literature, providing insights to help clinicians to personalize GAHT regimens and mitigate thrombotic risks.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePrevalence of hereditary thrombophilia in our cohort\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn the general population, mild hereditary thrombophilia, including heterozygous FVL and PT20210A mutations, is present in approximately 5\u0026ndash;7% of individuals.\u003csup\u003e14,18,19\u003c/sup\u003e Severe hereditary thrombophilia, such as homozygous FVL or PT20210A mutations and deficiencies in AT, PC, or PS is rarer, with a prevalence of approximately 0.02\u0026ndash;0.2%. \u003csup\u003e16,18\u0026ndash;20\u003c/sup\u003e In our cohort, the prevalence of hereditary thrombophilia was 9.6%, consistent with general population estimates, with mild thrombophilia accounting for 7.8% and severe thrombophilia for 1.7%.\u003c/p\u003e\n\u003cp\u003eNotably, individuals with thrombophilia in our cohort reported higher rates of personal or family history of VTE, emphasizing the importance of detailed patient histories for individualized care. Although thrombophilia is not expected to be causally related to demographic or lifestyle variables such as age, BMI, or smoking status, we compared these characteristics to explore whether individuals with hereditary thrombophilia tend to accumulate additional thrombotic risk factors, which might be relevant in the setting of GAHT.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFew studies have explored the prevalence of congenital thrombophilia in the TGD population.\u003csup\u003e21,22\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eA retrospective cohort study by Kerrebrouck et al. reported a lower rate of hereditary thrombophilia (11 carriers out of 1700 individuals), although thrombophilia screening in that study was limited to TGD individuals with a personal or family history of VTE.\u003csup\u003e21\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eOverall, these findings underscore that for individuals with a history of VTE or familial predisposition, consultation with a haematologist is critical to assess the need for screening for congenital thrombophilia and to better define individual VTE risks. When comprehensive screening is routinely performed, a higher prevalence of thrombophilia\u0026mdash;including severe cases\u0026mdash;becomes evident, aligning with general population data. This information is critical for evaluating thrombotic risk, particularly in situations requiring careful management. However, given the relatively small cohort and short follow-up, our findings should be interpreted with caution. The absence of VTE events is reassuring but not conclusive, and may reflect limited power rather than definitive safety.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eManagement of thrombophilia risk in our cohort\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe type, formulation, and route of hormone administration are critical factors influencing VTE risk.\u003csup\u003e22,23\u003c/sup\u003e In general, feminizing GAHT involves the administration of oral or transdermal estradiol in combination with an antiandrogen (e.g., CPA, spironolactone, or GnRH analogues). Among estrogens, ethinyl estradiol is associated with a higher VTE risk compared to estradiol.\u003csup\u003e6,24\u0026ndash;26\u003c/sup\u003e\u0026nbsp; Additionally, transdermal estrogen formulations are safer than oral preparations, particularly regarding thrombotic risk.\u003csup\u003e6,27\u003c/sup\u003eAs a result, current guidelines recommend against the use of ethinyl estradiol and conjugated estrogens in GAHT. For TGD individuals at higher VTE risk or those over 45 years of age, transdermal estradiol is the preferred option.\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIn regards to antiandrogen therapy, data on CPA have shown an increased thrombotic risk when used in combination with ethinyl estradiol in cisgender women.\u003csup\u003e28\u003c/sup\u003e This risk is also elevated in cisgender women with hereditary thrombophilia.\u003csup\u003e29\u003c/sup\u003e Additionally, in patients with prostate cancer, high-dose CPA has been associated with a higher thrombotic risk compared to GnRH analogues or orchiectomy.\u003csup\u003e30\u003c/sup\u003e However, metastatic prostate cancer independently increases VTE risk, complicating direct comparisons. GnRH agonists may be considered as an alternative for TGD individuals at higher thrombotic risk since they do not significantly impact coagulation. Studies support their safety profile. \u003csup\u003e31,32\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eTestosterone therapy does not appear to increase thrombotic risk. Retrospective studies that have examined VTE in this population report a low incidence, with cases often linked to predisposing thrombotic risk factors.\u003csup\u003e33\u003c/sup\u003e A retrospective review involving 1,358 TGD individuals receiving testosterone therapy found no increased risk of stroke or VTE compared to cisgender men and women. However, the study did report an increased risk of myocardial infarction (standardized incidence ratio 3.69; 95%CI, 1.94\u0026ndash;6.42) compared to cisgender women, but not cisgender men.\u003csup\u003e25\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eA large case-crossover study by Walker et al. identified a higher VTE risk in cisgender men receiving testosterone therapy, both with (OR 2.32; 95%CI, 1.97\u0026ndash;2.74) and without (OR 2.02; 95%CI, 1.47\u0026ndash;2.77) hypogonadism.\u003csup\u003e33\u003c/sup\u003e Smaller studies also noted that cisgender men who developed VTE on testosterone therapy frequently had underlying hypercoagulable conditions.\u003csup\u003e34,35\u003c/sup\u003e However, meta-analyses and systematic reviews of hypogonadal cisgender men undergoing testosterone replacement therapy did not show an increased VTE risk.\u003csup\u003e9,36\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eOn the other hand, secondary erythrocytosis is common during testosterone therapy.\u003csup\u003e8\u003c/sup\u003e In the transgender population, higher dosages of testosterone therapy, injectable formulations, and higher serum testosterone levels during therapy have been correlated with polycythaemia.\u003csup\u003e8,37\u003c/sup\u003e The clinical implications of polycythaemia in transgender individuals, including its potential association with VTE, cardiovascular, and cerebrovascular complications, remain incompletely investigated.\u003csup\u003e38\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn our cohort, for AMAB individuals with hereditary thrombophilia, referral to the Haemorrhagic and Thrombotic Diseases Unit occurred prior to GAHT initiation. Risk stratification considered age, BMI, smoking habit, family history of VTE, comorbidities, medications, and type of thrombophilia. Tailored counselling was provided, emphasizing strategies for managing high-risk conditions such as surgery or immobilization. Collaboration between coagulation specialists and endocrinologists ensured that GAHT regimens were optimized to mitigate VTE risks. Typically, transdermal estradiol at moderate doses was combined with spironolactone (Figure 1). However, adverse effects or incomplete anti-androgenic effect with spironolactone prompted some patients to switch to low-dose CPA (\u0026le;12.5 mg per day). GnRH analogues (e.g., triptorelin, leuprolide) may also be considered, though data on their use in adult TGD populations remain limited.\u003c/p\u003e\n\u003cp\u003eFor AFAB individuals with hereditary thrombophilia, counselling focused on minimizing acquired risk factors and regular monitoring of Hct. In case of erythrocytosis, the endocrinologist followed the recommendations from the Endocrine Society for testosterone replacement therapy in hypogonadism.\u003csup\u003e39\u003c/sup\u003e In particular, testosterone dosage was lowered for Hct \u0026gt;50% and patients were advised to stop smoking. Furthermore, the use of transdermal testosterone seems to mitigate the risk of erythrocytosis.\u003csup\u003e8\u003c/sup\u003e In case of Hct \u0026gt;54%, testosterone therapy was suspended and the patient was referred to the Haematologist for phlebotomy. Among AFAB thrombophilia group, only one individual developed mild erythrocytosis (Hct 51%) after 24 months of testosterone therapy. In this case, we decided to extend the interval between testosterone undecanoate administrations from one vial every 11 weeks to every 12 weeks.\u003c/p\u003e\n\u003cp\u003eBeyond thrombophilia and hormone therapy, additional risk factors for thrombosis should be considered. Many studies report a high prevalence of tobacco use among TGD individuals, which we observed in our cohort, with nearly one-third identified as smokers.\u003csup\u003e4\u003c/sup\u003e Additionally, TGD AFAB individuals tend to have a higher BMI, fat mass index, and prevalence of obesity compared to cisgender women.\u003csup\u003e40,41\u003c/sup\u003e A systematic review found that obesity is associated with a two-fold increase in VTE risk compared to individuals with normal weight.\u003csup\u003e42\u003c/sup\u003e Furthermore, anxiety, depression, and other psychiatric conditions are also more common in this population, likely as a result of gender minority stress.\u003csup\u003e43\u003c/sup\u003e Depression, in particular, has been linked to an increased risk of VTE.\u003csup\u003e44\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eFinally, many TGD individuals undergo gender-affirming surgeries, which carry an inherent risk of VTE due to perioperative factors.\u003csup\u003e45\u003c/sup\u003e These considerations underscore the need for comprehensive counselling, targeting reversible risk factors such as smoking and weight management.\u003c/p\u003e\n\u003cp\u003eIn our cohort, no VTEs were reported amongst TGD individuals with or without thrombophilia after GAHT initiation, after a median follow-up of 15 months. This favourable outcome may be attributed to the efficacy of a multidisciplinary approach integrating haematological evaluation, personalized GAHT regimens, and patient education. Our strategy suggests the need for routine screening for thrombophilia in TGD individuals with a personal or family history of VTE, as well as in those with multiple concomitant acquired risk factors, enabling informed risk stratification and management (Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e[PLEASE, INSERT FIGURE 1 HERE. In print, the image can be in black\u0026amp;white]\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eManagement of patients with thrombophilia and previous thrombosis in our cohort\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAmong three individuals with hereditary thrombophilia and prior thrombosis, a tailored approach was developed in a multidisciplinary setting.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA transgender woman with unprovoked VTE of the lower limb was already on full anticoagulation therapy at the first endocrinological visit and therefore anticoagulation was continued during GAHT. Feminizing therapy included transdermal estradiol and CPA, as anticoagulation was expected to neutralize the additional thrombotic risks of this anti-androgenic progestogen. This approach was in line with findings from a sub-analysis of the EINSTEIN study.\u003csup\u003e46\u003c/sup\u003e The study showed that cisgender women continuing estrogen-progestin therapy during anticoagulation did not experience an increased rate of VTE recurrence compared to other women on anticoagulant therapy.\u003c/p\u003e\n\u003cp\u003eA transgender man who experienced a VTE during chemotherapy was referred to the coagulation specialist before GAHT initiation. This patient was therefore advised to reintroduce low-dose anticoagulation when starting testosterone therapy. A transdermal testosterone formulation was selected; eventually, he switched to injectable testosterone undecanoate for personal preference. \u0026nbsp;Lastly, a transgender man with PC deficiency and a neonatal stroke history was advised to minimize acquired risk factors (smoke cessation, weight loss) and to promptly refer to a physician in case of signs of VTE. Anticoagulation was not initiated, considering the absence of active risk factors at the time of GAHT initiation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWith this strategy, no recurrent thrombotic events were detected during GAHT in individuals with thrombophilia and previous thrombosis. This favourable outcome may be attributed to the proactive use of anticoagulation therapy, where indicated, alongside tailored interventions targeting modifiable risk factors to optimize outcomes, as summarized in Figure 1. The continuation of rivaroxaban in individuals with prior VTE aligns with evidence supporting its effectiveness in preventing recurrent events, even when combined with estrogen therapy.\u003csup\u003e46\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThese cases underscore the importance of a multidisciplinary approach to ensuring the safety of gender-affirming treatments, particularly in complex situations with an increased thromboembolic risk. Gender-affirming treatments significantly improve mental health and quality of life, making their continuation essential for TGD individuals, even in case of prior thrombotic events. Clinicians must carefully weight these benefits against thrombotic risks, especially in patients with hereditary thrombophilia.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLimitations\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFindings from the present study are limited by its small sample size and short follow-up period, which may underestimate the incidence of VTE. The absence of a control group also prevents direct comparisons on the thrombotic risk between TGD individuals undergoing GAHT and the general population undergoing hormonal therapy. However, with our strategy we did not detect thrombotic events even in non-thrombophilia individuals. Future studies with larger cohorts and longer follow-up are needed to better understand the long-term VTE risks of GAHT in individuals with and without hereditary thrombophilia.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eHereditary thrombophilia in TGD individuals is as common as in the general population, encompassing 9.6% of this population. Our study suggests that hormone therapy in TGD individuals with hereditary thrombophilia, even in cases of severe thrombophilia or previous thrombosis, may be feasible and safe, when supported by individualized, multidisciplinary management. This success was achieved through a meticulous, multidisciplinary approach encompassing risk assessment, personalized GAHT regimens, and ongoing risk management. The integration of coagulation expertise with endocrinological care allowed for GAHT adjustments to minimized thrombotic risk while maintaining therapeutic goals. Key strategies included the preferential use of transdermal estradiol and careful selection of anti-androgens for feminizing therapy, and tailored management of testosterone therapy in AFAB individuals. Additionally, addressing modifiable risk factors such as smoking and weight management, alongside the judicious use of anticoagulation when indicated, contributed to the favourable outcomes observed in our cohort.\u003c/p\u003e \u003cp\u003eFuture research should further investigate the long-term outcomes of risk reduction strategies and tailored GAHT regimens on thrombotic and cardiovascular risk in this unique population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOn behalf of the Interdisciplinary Group for Gender Incongruence (GIIG) of the University Hospital of Padua, Italy: Andrea Garolla, Anna Aprile, Anna Belloni Fortina, Annamaria Cattelan, Alberto Ferlin, Alberto Scala, Angela Favaro, Benedetta Tascini, Camillo Barbisan, Carlo Saccardi, Chiara Ceolin, Claudio Terranova, Corrado Marchese Ragona, Daniela Basso, Elena Campello, Elisa Varotto, Eleonora Vania, Fabrizio Dal Moro, Fabrizio Vianello, Francesco Francini, Francesca Venturini, Giancarlo Ottaviano, Giorgio De Conti, Giovanni Frattin, Giuseppe Sergi, Giulia Musso, Laura Guazzarotti, Lolita Sasset, Marina Bonato, Marina Miscioscia, Marta Ghisi, Massimo Iafrate, Maurizio Iacobone, Michela Gatta, Paolo Meneguzzo, Paolo Simioni, Rossana Schiavo, Rossella Perilli, Sandro Giannini, Tommaso Vezzaro.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eE.C., A.S., P.S., and A.G. contributed to the conceptualization of the study. E.C. and C.B. developed the methodology. A.S. and E.C. performed the formal analysis. C.S., E.C., A.S., A.G., C.B., A.B., G.F., and F.T. carried out the investigation. P.S., A.F., and A.G. provided resources. A.S. and C.B. curated the data. A.S. and E.C. wrote the original draft. A.F., P.S., A.G., and L.D.T. reviewed and edited the manuscript. A.S. and E.C. prepared the visualizations. P.S., A.G., and A.F. supervised the project. E.C. administered the project and acquired funding. All authors reviewed the manuscript and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are available from the corresponding author (E.C.) upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial support\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by the Italian Ministry of University and Research (MUR) to E.C. under the project \u0026ldquo;Longitudinal thrombo-inflammatory profiling of individuals undergoing gender-affirming hormone therapy (Hyper-gender study)\u0026rdquo; (Project Code: P2022RWMFC, PRIN 2022 PNRR - DD 1409 of 14/09/2022) - CUP: C53D23009540001, within the framework of the National Recovery and Resilience Plan (PNRR), Mission 4, Component 2, Investment 1.1 \u0026apos;Project of Significant National Interest (PRIN).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests to declare that are relevant to the content of this article. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eColeman, E. \u003cem\u003eet al.\u003c/em\u003e Standards of Care for the Health of Transgender and Gender Diverse People, Version 8. \u003cem\u003eInt. 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Association of Surgical Risk With Exogenous Hormone Use in Transgender Patients: A Systematic Review. \u003cem\u003eJAMA Surg.\u003c/em\u003e \u003cstrong\u003e154\u003c/strong\u003e, 109\u0026ndash;115 (2019).\u003c/li\u003e\n\u003cli\u003eMartinelli, I. \u003cem\u003eet al.\u003c/em\u003e Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use. \u003cem\u003eBlood\u003c/em\u003e \u003cstrong\u003e127\u003c/strong\u003e, 1417\u0026ndash;1425 (2016).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"gender incongruence, thrombosis, thrombophilia, anticoagulation, hormones","lastPublishedDoi":"10.21203/rs.3.rs-6573735/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6573735/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGender-affirming hormone therapy (GAHT), particularly estrogen-based regimens, is associated with an increased risk of venous thromboembolic events (VTE), which may be exacerbated in individuals with hereditary thrombophilia. Despite this risk, the prevalence and clinical implications of hereditary thrombophilia in transgender individuals remain underexplored.\u003c/p\u003e\n\u003cp\u003eWe screened 114 transgender individuals (54 AMAB, 60 AFAB) at the University Hospital of Padua (Italy) for hereditary thrombophilia, including factor V Leiden (FVL), prothrombin G20210A (PT20210A), antithrombin (AT), protein C (PC), and protein S (PS) deficiencies, as well as antiphospholipid antibodies.\u003c/p\u003e\n\u003cp\u003eHereditary thrombophilia was identified in 9.6% of participants, including two cases of severe thrombophilia. No participants tested positive for antiphospholipid antibodies. Individuals with thrombophilia had a higher prevalence of personal and family history of VTE. Three thrombotic events were recorded prior to GAHT: one transgender woman (heterozygous FVL) with unprovoked lower limb VTE, one transgender man (PC deficiency) with neonatal cerebral ischemia, and one transgender man (heterozygous FVL) with subclavian VTE during chemotherapy.\u003c/p\u003e\n\u003cp\u003eA multidisciplinary approach involving coagulation specialists and endocrinologists was implemented to optimize risk reduction strategies, including tailored GAHT regimens and anticoagulation when necessary. No VTE occurred during follow up. These findings highlight the importance of thrombophilia screening to enable individualized care and enhance the safety of GAHT protocols.\u003c/p\u003e","manuscriptTitle":"Risk and management of congenital thrombophilia in transgender individuals undergoing gender-affirming hormone therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-02 11:45:32","doi":"10.21203/rs.3.rs-6573735/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c86ad7a7-49a4-4e7c-b022-3178fe943b44","owner":[],"postedDate":"June 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":49194831,"name":"Health sciences/Cardiology"},{"id":49194832,"name":"Health sciences/Endocrinology"}],"tags":[],"updatedAt":"2025-06-13T09:24:04+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-02 11:45:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6573735","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6573735","identity":"rs-6573735","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}