Endometriosis as a chronic endothelial disorder: thromboinflammation, vascular reprogramming, and systemic cardiovascular risk.

Abstract

Microvascular thromboinflammation is a pervasive yet under-recognized driver of multisystem morbidity that links focal endothelial injury to distal organ dysfunction through interacting cellular and plasmatic networks. Contemporary paradigms remain fragmented: clinicians often treat symptoms or isolated pathways, trials enroll biologically heterogenous populations, and candidate biomarkers lack harmonized standards-together impeding translation from mechanistic insight to durable patient benefit. In this review we synthesize the evidence into a cohesive, systems-level architecture in which endothelial activation, platelet hyperreactivity, innate immune effectors (including NETosis), and impaired fibrinolysis form predictable feed-forward circuits that generate organ-selective vulnerability. We propose an integrated diagnostic-translational toolkit that anchors spatially resolved imaging endophenotypes (molecular PET, quantitative perfusion MRI, advanced flow imaging) to fluid-phase molecular readouts (cfDNA topology, NET fragments, platelet transcriptomes, endothelial microparticles) and multi-omic modules. This framework enables reproducible endotype discovery and supports biomarker-guided, stage-specific interventions. Translational strategies prioritized here include targeted anti-NET approaches, precision layering of antiplatelet/anticoagulant therapy, endothelial-directed redox and metabolic reprogramming, selective epigenetic modulation, and lesion-directed nanoparticle delivery; each is linked to companion biomarker and imaging readouts and tailored safety considerations-especially for reproductive-age populations. To accelerate clinical impact we recommend a coordinated roadmap: (i) rigorous causal validation across human-relevant platforms and scaled animal models; (ii) consensus preanalytic and analytic standards with reference materials for key thromboinflammatory biomarkers; (iii) prospective cohorts embedding serial imaging and liquid-biopsy multi-omics to derive and validate endotypes; and (iv) adaptive, biomarker-enriched clinical trials with organ-relevant surrogate endpoints and long-term vascular surveillance. By aligning mechanistic clarity, diagnostic fidelity, and pragmatic trial design, this integrated approach aims to convert mechanistic knowledge into precision diagnostics and therapies-and to transform microvascular thromboinflammation from an intractable clinical problem into a tractable target for prevention and repair.