CO15 | Longitudinal coagulation profiling of individuals undergoing gender-affirming hormone therapy: the hyper-gender study

A. Napolitano, E. Campello, A. Scala, C. Simion, C. Bulato, S. Gavasso, C. Samà, A. Benetti, S. Toffanin, G. Faggian, R. Scafa, A. Garolla, P. Simioni | First Chair of Internal Medicine, Department of Medicine, University Hospital of Padua; Unit of Andrology and Reproductive Medicine, Department of Medicine, University Hospital of Padua, Italy

Background and Aims: Transgender individuals appear to have an increased risk of thrombosis due to hypercoagulability associated with gender-affirming hormone therapy (GAHT). The aim of the study was to investigate the effects of GAHT on coagulation, metabolism, and erythropoiesis, and to explore the mechanisms underlying hypercoagulability in the transgender population. A better understanding of these mechanisms may help guide risk stratification and inform clinical monitoring strategies during hormone treatment.

Methods: We enrolled 112 adult transgender individuals initiating GAHT. Plasma samples were collected at baseline (prior to GAHT initiation) and at 3, 6, and 12 months thereafter. Parameters assessed included hereditary thrombophilia, procoagulant factors (factor VIII, fibrinogen), natural anticoagulants (protein C, protein S, antithrombin), thromboelastometry, whole blood aggregometry, thrombin generation with and without thrombomodulin, iron metabolism, and erythropoietin levels. Written informed consent was obtained from all participants.

Results: The cohort included 41 Assigned Male at Birth (AMAB) and 71 Assigned Female at Birth (AFAB) individuals; 7.1% had hereditary thrombophilia (7 mild, 2 severe). At baseline, AFAB participants exhibited higher levels of factor VIII and fibrinogen, lower protein C and protein S levels, shorter EXTEM clotting time, and greater maximum clot firmness (MCF) on thromboelastometry, as well as increased ASPI-induced platelet aggregation compared to AMAB individuals. AMAB participants received transdermal estrogen therapy with or without anti-androgens, while AFAB individuals were treated with testosterone. Over the 12-month follow-up, AMAB individuals showed increased platelet count, enhanced thrombin-driven aggregability, decreased hemoglobin, and elevated peak thrombin generation and endogenous thrombin potential ratio. In contrast, AFAB individuals exhibited significant increases in hemoglobin, hematocrit, and iron parameters. A significant reduction in MCF on thromboelastometry was observed, alongside a non-significant increase in thrombin-generation peak (Table 1). No thrombotic events occurred during the study period.

Conclusions: We found that 7% of transgender individuals initiating GAHT carry hereditary thrombophilia, including 2% with severe forms. Baseline sex-assigned differences in coagulation profiles were evident, with AFAB individuals displaying a more procoagulant phenotype. GAHT induced distinct biological effects: in AMAB individuals, it enhanced platelet reactivity and thrombin generation, while in AFAB individuals, the predominant changes were related to erythropoiesis and iron metabolism. These findings provide insight into sex-specific haemostatic responses to GAHT and underscore the importance of individualized thrombosis risk assessment in this population.