Vascular malformations are defects caused by the abnormal growth of the vasculature. Among them, venous malformation (VM) is an anomaly characterized by slow-flow vascular lesions with abnormally shaped veins, typically in sponge-like configuration. VMs can expand over years causing disfigurement, obstruction of vital structures, thrombosis, bleeding, and pain. Treatments have been very limited and primarily based on supportive care, compression garments, sclerotherapy, and/or surgical resection. Sirolimus treatment has recently shown efficacy in some patients with complicated vascular anomalies, including VMs. Activating somatic TIE2 gene mutations have been identified in up to 60% of VMs and PIK3CA mutations have been found in another 25%. Here, we report a xenograft model of VM that reflects the patients’ mutation heterogeneity. First, we established a protocol to isolate and expand in culture endothelial cells (VM–EC) from VM tissue or VM blood of nine patients. In these cells, we identified somatic mutations of TIE2, PIK3CA, or a combination of both. Both TIE2 and PIK3CA mutations induced constitutive AKT activation, while TIE2 mutations also showed high MAPK–ERK signaling. Finally, VM–EC implanted into immune-deficient mice generated lesions with ectatic blood-filled channels with scarce smooth muscle cell coverage, similar to patients’ VM. This VM xenograft model could be instrumental to test the therapeutic efficacy of Sirolimus in the presence of the different TIE2 or PIK3CA mutations or to test for efficacy of additional compounds in targeting the specific mutated protein(s), thus enabling development of personalized treatment options for VM patients.
BACKGROUND AND OBJECTIVES: Many transgender youth experience gender dysphoria, a risk factor for suicide. Gender-affirming hormone therapy (GAHT) ameliorates this risk but may increase the risk for thrombosis, as seen from studies in adults. The aim with this study was to examine thrombosis and thrombosis risk factors among an exclusively adolescent and young adult transgender population. METHODS: This retrospective chart review was conducted at a pediatric hospital-associated transgender health clinic. The primary outcome was incidence of arterial or venous thrombosis during GAHT. Secondary measures included the prevalence of thrombosis risk factors. RESULTS: Among 611 participants, 28.8% were transgender women and 68.1% were transgender men. Median age was 17 years at GAHT initiation. Median follow-up time was 554 and 577 days for estrogen and testosterone users, respectively. Individuals starting GAHT had estradiol and testosterone levels titrated to physiologic normal. Multiple thrombotic risk factors were noted among the cohort, including obesity, tobacco use, and personal and family history of thrombosis. Seventeen youth with risk factors for thrombosis were referred for hematologic evaluation. Five individuals were treated with anticoagulation during GAHT: 2 with a previous thrombosis and 3 for thromboprophylaxis. No participant developed thrombosis while on GAHT. CONCLUSIONS: In this study, we examined thrombosis and thrombosis risk factors in an exclusively adolescent and young adult population of transgender people receiving GAHT. These data suggest that GAHT in youth, titrated within physiologic range, does not carry a significant risk of thrombosis in the short-term, even with the presence of preexisting thrombosis risk factors.
An estimated 2-3% of US youth identify as transgender or gender non-conforming (hereafter transgender). Transgender youth may suffer from gender dysphoria, a condition associated with many health risks, including high risk of suicide. Transgender individuals have a 40% greater risk of attempting suicide than cis-gender individuals. Gender-affirming hormone therapy (GAHT) is associated with improvement of gender dysphoria and amelioration of the risk of suicide. GAHT consists of either estrogen [for transgender women (TGW)] or testosterone [for transgender men (TGM)]. However, GAHT may be associated with other risks, most notably thrombosis. Numerous studies documented increased thrombosis risk in cis-gender women using exogenous estrogen for contraception or hormone replacement therapy. Studies of GAHT suggest a risk of thrombosis with estrogen use; however, this data is not uniform. Studies of testosterone replacement in cis-gender show conflicting results with respect to thrombosis risk. All previous studies examining the risk of thrombosis with GAHT have included adults exclusively. Therefore we sought to determine the risk of thrombosis in a cohort of transgender youth receiving standardized GAHT regimens. Transgender youth have potential for a much longer exposure to GAHT, thus having different life-time risk of thrombosis than patients that start GAHT at an older age. Of all 1406 patients seen at the Cincinnati Children's Medical Center Transgender Health Clinic since its inception, 611 subjects started GAHT and were eligible for inclusion in the cohort. Of these, 176 (28.8%) identified as female, 416 (68.1%) as male, and 19 (3.1%) as non-binary. Thrombosis risks were common among the cohort: 34.5% had obesity, 15.4% used tobacco, 4.6% had migraine with aura, and 8.0% had a family history of thrombosis. Three subjects had a prior history of thrombosis: 2 with venous thromboembolism (VTE) and one with a stroke. 53.7% of the cohort had previously used hormones, most commonly for menstrual suppression. Of those with prior hormone use, the vast majority had used progesterone-only methods (5.7% previously used estrogen-containing contraceptives). All patients initiating GAHT were treated according to current guidelines with monitoring of estrogen and testosterone levels and titration of GAHT doses accordingly. Overall, 29.8% initiated estrogen therapy and 70.2% started testosterone therapy. Among the cohort, 17 individuals were referred to Hematology for evaluation for thrombosis risk prior to starting GAHT. The most common laboratory abnormality for these individuals was elevated factor VIII, elevated plasminogen-activator inhibitor 1 (PAI-1), and the PAI-1 polymorphism. Two TGW and one TGM started thromboprophylaxis prior to initiating GAHT due to thrombotic risk factors. Despite the presence of preexisting risk factors, no individual in the cohort developed a thrombosis (VTE or stroke) during GAHT. This is the first study to examine thrombosis risk of GAHT in an exclusively adolescent and young adult population. While there were no incidents of thrombosis in our cohort, we found individuals at risk for thrombosis. Careful history and counseling regarding risks are needed when discussing initiation of GAHT for transgender individuals. Additionally, further studies looking at long-term risk are needed. Disclosures Mullins: Takeda, Bayer: Other: Advisory Board.
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