Immunothrombotic endothelial reprogramming in endometriosis: GnRH agonist–driven vascular destabilization and the emergence of a pulmonary embolism–prone phenotype

Endometriosis affects ~ 10% of reproductive-age women yet its impact extends far beyond pelvic pain: accumulating epidemiologic and mechanistic data implicate endometriosis in systemic immunovascular dysfunction and elevated risk of arterial and venous thrombotic events. Current clinical paradigms treat reproductive disease, endocrine therapy, and thromboembolism as separate domains, overlooking how chronic lesion-level inflammation, iron-driven oxidative stress, and endothelial metabolic reprogramming interact with coagulation and immune effectors to determine embolic risk. Here we synthesize evidence that repetitive hemorrhage and iron overload prime endothelium and immune cells for a pro-coagulant state, that platelet–leukocyte crosstalk and neutrophil extracellular traps stabilize and protect thrombi from lysis, and that abrupt estrogen withdrawal (e.g., GnRH agonist therapy) may serve as a biologically meaningful second hit within a proposed mechanistic model, potentially promoting vascular destabilization in susceptible individuals. We propose the immunothrombotic continuum as a conceptual mechanistic framework, a systems-level framework in which inflammatory, redox, metabolic, and endocrine axes converge to produce emergent thrombotic vulnerability. This model prioritizes biomarker-guided phenotyping, dynamic surveillance during hormonal therapy, and mechanism-targeted prophylaxis, a translational roadmap for precision cardio-reproductive medicine aimed at preventing clinically meaningful embolic outcomes. Not applicable. Immunothrombotic continuum: Conceptualizes thrombotic risk as an emergent property of interacting inflammatory, redox, metabolic, and endocrine networks rather than isolated factors. Endothelial reprogramming as a therapeutic target: Highlights the endothelium as a dynamic integrator of chronic inflammation, iron-driven oxidative stress, and hormonal perturbation, enabling mechanism-guided interventions. Second-hit vulnerability framework: Frames abrupt estrogen withdrawal or endocrine therapy as a biologically significant “second hit” that unmasks pre-existing vascular priming, refining risk prediction. Personalized surveillance thresholds: Advocates adaptive biomarker trajectories, not single static values, to trigger therapy modification or prophylactic intervention. Cross-disease relevance: Positions lessons from endometriosis to inform thrombotic risk in autoimmune, chronic inflammatory, and reproductive-endocrine disorders with systemic vascular impact. Roadmap for precision cardio-reproductive medicine: Integrates mechanistic insights with biomarker-guided phenotyping and dynamic intervention strategies, defining a translational pipeline from molecular understanding to patient-tailored prophylaxis.