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

Background 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. Main body 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. Clinical trials Not applicable. Highlights • Immunothrombotic continuum: Conceptualizes thrombotic risk as an emergent property of interacting inflammatory, redox, metabolic, and endocrine networks rather than isolated factors. Page 2 of 17 Lesani et al. Beni-Suef University Journal of Basic and Applied Sciences (2026) 15:119 1 Introduction Endometriosis affects approximately 10% of reproduc - tive-age women worldwide and has traditionally been conceptualized as an estrogen-dependent gynecologic disorder defined by ectopic implantation of endometrial- like tissue and chronic pelvic pain [ 1, 2]. Yet mounting epidemiologic and mechanistic evidence indicates that its biological footprint extends well beyond the pelvis, encompassing systemic inflammation, endothelial dys - function, and increased long-term cardiovascular risk, thereby challenging its confinement to a localized repro - ductive pathology [ 3]. Large population-based cohort studies and meta-analyses demonstrate that women with endometriosis exhibit elevated risks of ischemic heart disease, cerebrovascular events, and other vascular out - comes, even after adjustment for traditional risk factors, suggesting a shared inflammatory-vascular substrate rather than coincidental comorbidity [4, 5]. Parallel advances in vascular biology have reframed thrombosis as an immunologically orchestrated process, “immunothrombosis” , in which innate immune activa - tion, neutrophil extracellular trap (NET) formation, platelet–leukocyte aggregates, and endothelial signaling converge to regulate thrombus initiation, propagation, and embolic potential [ 6]. NETs, in particular, provide a structural and biochemical scaffold that links inflamma - tion to coagulation by activating intrinsic and extrinsic pathways, amplifying thrombin generation, and impair - ing endogenous anticoagulant systems [ 7, 8]. Chronic inflammatory disorders such as systemic lupus ery - thematosus, inflammatory bowel disease, rheumatoid arthritis, and certain cancers exhibit an increased risk of thromboembolism through shared immunothrombotic mechanisms, suggesting that immune-vascular coupling represents a conserved pathogenic feature across diverse inflammatory diseases [9– 13]. Within this broader framework, endometriosis rep - resents a uniquely informative biological model: repeti - tive hemorrhage and iron deposition in ectopic lesions generate persistent oxidative stress and macrophage activation, conditions known to activate redox-sensitive transcriptional programs and promote endothelial dys - function [ 14– 16]. Iron-driven lipid peroxidation and reactive oxygen species production can perturb endo - thelial nitric oxide signaling and induce procoagulant phenotypic drift, thereby linking lesion-level iron over - load to systemic vascular vulnerability [ 17, 18]. Despite this mechanistic plausibility, the integration of chronic inflammatory priming, endothelial metabolic reprogram- ming, and thrombus biology in endometriosis has not been systematically synthesized within a unified immu - nothrombotic framework. An additional, underexplored dimension lies in the endocrine modulation of vascular homeostasis. Estrogen • 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.

Endometriosis, Immunothrombosis, Neutrophil extracellular traps, Endothelial dysfunction, Gonadotropin- releasing hormone agonists, Oxidative stress, Cardiovascular toxicity Graphical Abstract Page 3 of 17 Lesani et al. Beni-Suef University Journal of Basic and Applied Sciences (2026) 15:119 exerts potent vasoprotective effects through genomic and non-genomic signaling pathways that enhance endo - thelial nitric oxide synthase activity, suppress adhesion molecule expression, and modulate platelet reactivity and fibrinolysis [ 19, 20]. Abrupt estrogen withdrawal, whether physiologic (menopause) or therapeutic (e.g., GnRH agonist–induced hypoestrogenism), impairs endo - thelial function and shifts hemostatic balance toward procoagulant and pro-adhesive states [ 21, 22]. In cardio - vascular medicine, hypoestrogenic states are associated with endothelial dysfunction, altered vascular reactivity, and increased thrombotic susceptibility, reinforcing the concept that sex steroids are systemic vascular regulators rather than isolated reproductive hormones [23, 24]. Despite these converging lines of evidence, a critical conceptual gap persists: endometriosis, endocrine sup - pression therapy, and venous thromboembolism are typi- cally examined in isolation, as separate clinical domains, rather than as interconnected nodes within a dynamic immunothrombotic network. Current thromboembolic risk models emphasize static factors such as inherited thrombophilias, immobilization, or malignancy, but they insufficiently capture the contribution of chronic inflam - matory endothelial priming and hormone-mediated vas - cular modulation to embolic potential [ 25]. Moreover, while case reports and pharmacovigilance data describe thrombotic events in association with GnRH agonist therapy, mechanistic frameworks explaining how endo - crine perturbation interacts with pre-existing inflamma - tory vascular conditioning remain sparse [26]. Here, we propose a unifying systems-level model in which endometriosis establishes a chronically primed immunovascular state characterized by iron-driven oxi - dative stress, endothelial reprogramming, platelet–leu - kocyte crosstalk, and low-grade coagulation activation; subsequent endocrine perturbation, particularly abrupt estrogen withdrawal induced by GnRH agonists such as leuprorelin may function as a biologically significant sec - ond hit within this proposed mechanistic model, poten - tially destabilizing vascular homeostasis and lowering the threshold for immunothrombotic propagation and embolization. By synthesizing insights from reproductive immunology, redox biology, endothelial metabolism, and thrombus architecture, we delineate an immunothrom - botic continuum that bridges local lesion biology to sys - temic thromboembolic outcomes. Our central novelty lies not in identifying individual mechanisms, each well supported in isolation, but in integrating them into a coherent, multi-axis paradigm that reconceptualizes thromboembolic risk in endome - triosis as the emergent property of interacting inflamma - tory, metabolic, and endocrine networks. This framework has translational implications: it supports biomarker- guided vascular phenotyping, anticipatory surveillance during hormonal therapy, and targeted endothelial sta - bilization strategies that extend beyond conventional anticoagulation. More broadly, it situates endometriosis within a new class of chronic inflammatory diseases in which reproductive endocrine dynamics and immu - nothrombotic biology intersect, thereby advancing the foundation for precision cardio-reproductive medicine. 2 Reframing endometriosis as a systemic immunothrombotic disorder Endometriosis has increasingly been recognized not merely as a localized gynecological lesion but as a chronic systemic inflammatory condition with profound implications for vascular biology and homeostasis [ 27]. This reconceptualization is grounded in robust evidence that ectopic endometrial tissue exists in a milieu char - acterized by sustained immune activation, oxidative stress, and cytokine dysregulation, a milieu that extends beyond the pelvis and engages systemic endothelial and hemostatic networks [ 27]. To synthesize the key mecha - nistic themes underlying systemic vascular engagement in endometriosis, we summarize the pathways linking chronic inflammation, oxidative priming, and immu - nothrombosis in Table 1. Although the epidemiologic literature consistently demonstrates an association between endometriosis and adverse cardiovascular outcomes, these findings should be interpreted cautiously because most available studies are observational and therefore cannot establish causality [28]. Residual confounding may arise from several factors associated with endometriosis, including chronic pain, reduced physical activity, obesity, depression, smoking, surgical menopause, and exposure to hormonal thera - pies, all of which may independently influence cardiovas - cular risk. Furthermore, differences in diagnostic criteria, disease severity, treatment history, and adjustment for traditional cardiovascular risk factors contribute to het - erogeneity across studies [ 29]. Consequently, while epi - demiologic evidence supports a reproducible association between endometriosis and cardiovascular disease, it should be interpreted as complementary to, rather than definitive proof of, the mechanistic pathways discussed in this Review. Further prospective longitudinal studies incorporating comprehensive adjustment for clinical and therapeutic confounders will be required to clarify the extent to which endometriosis itself contributes causally to long-term cardiovascular risk. 2.1 Beyond ectopia: from pelvic inflammation to vascular biology Traditionally described by retrograde menstruation and ectopic implantation, endometriosis pathogenesis is now understood to involve persistent sterile inflamma - tion and immune maladaptation, wherein infiltrating Page 4 of 17 Lesani et al. Beni-Suef University Journal of Basic and Applied Sciences (2026) 15:119 defenses in ectopic stromal cells and macrophages, which in turn sustains oxidative stress and reinforces inflam - matory signaling, a state that simultaneously primes the endothelium toward dysfunction and promotes systemic vascular perturbation [ 33]. Evidence also indicates that iron-derived reactive oxygen species can activate redox- sensitive transcription factors (e.g., NF-κB), further amplifying cytokine production and endothelial activa - tion, thereby linking local iron-driven oxidative priming with global vascular vulnerability [34]. 2.3 Platelet–leukocyte crosstalk and the architecture of immunothrombosis The interplay between inflammation and coagulation is a hallmark of chronic inflammatory disorders, and in endometriosis, activated platelets accumulate in ecto - pic lesions, releasing pro-fibrotic and pro-inflammatory mediators that not only support lesion progression but also signify systemic activation of hemostatic pathways [35, 36]. Activated platelets interact with neutrophils and monocytes to induce neutrophil extracellular trap formation (NETosis), a process increasingly recognized as central to immunothrombosis, whereby neutrophil DNA webs decorated with proteases and tissue factor promote local thrombus nucleation and amplify coagu - lation cascades [ 37– 39]. This platelet–leukocyte cross - talk culminates in the release of extracellular vesicles and microparticles rich in procoagulant phospholipids and tissue factor, which can traffic systemically and interact with vascular endothelium at distant sites, effectively linking the chronic inflammatory state in endometrio - sis to a prothrombotic vascular phenotype [ 40]. Indeed, markers of coagulation activation, including soluble macrophages, lymphocytes, and other immune effec - tors generate a pro-inflammatory microenvironment that influences tissues far beyond the lesion site [ 30]. Chronic inflammation in endometriotic lesions drives tissue remodeling and angiogenic signaling, manifested by elevated levels of cytokines, chemokines, and growth factors such as TNF-α, IL-6, IL-8, and VEGF that not only sustain local lesion survival but also perturb endo - thelial function and vascular integrity systemically [ 31]. Reflecting this systemic engagement, epidemiological and mechanistic studies now link endometriosis with increased markers of endothelial dysfunction, altered vascular reactivity, and elevated risk of cardiovascular events, consistent with a broader inflammatory-vascular interface rather than a localized gynecological pathology [32]. 2.2 Iron-driven oxidative priming and endothelial vulnerability Repeated shedding, hemorrhage, and reflux of endome - trial tissue into the peritoneal cavity expose macrophages and local tissues to high levels of catalytic iron derived from erythrocyte breakdown, leading to an iron-over - loaded microenvironment [33]. This iron excess catalyzes Fenton chemistry, generating reactive oxygen species that induce sustained oxidative stress, lipid peroxidation, and redox imbalance, processes mechanistically implicated in ferroptosis and other regulated cell death programs but more importantly capable of compromising endothelial barrier integrity and enhancing procoagulant signal - ing [33]. The paradox in endometriotic tissue is its abil - ity to resist ferroptosis despite persistent iron overload, a resistance that is mirrored by upregulation of antioxidant Table 1 Mechanistic landscape of endometriosis as a systemic immunothrombotic disorder Pathway Key Mechanisms Molecular/Cellular Mediators Systemic Vascular Consequences 1. Chronic Sterile Inflammation Persistent immune activation from retrograde menstruation and ectopic implantation; immune maladaptation amplifies local and systemic inflammation Macrophages (M2 skewing); lympho- cytes; pro-inflammatory cytokines (TNF-α, IL-6, IL-8); chemokines; growth factors (VEGF) Sustained inflammatory milieu extends beyond pelvis → endothelial activation, vascular remodeling, and chronic systemic inflammation 2. Iron-Driven Oxi- dative Priming Peritoneal hemorrhage and erythrocyte break- down lead to iron accumulation; iron catalyzes ROS (Fenton chemistry) → redox imbalance and lipid peroxidation Free iron, ferrous/ferric iron pools; ROS (hydroxyl radicals); lipid peroxida- tion markers; redox-sensitive TFs (e.g., NF-κB) Oxidative stress damages endothe- lium, disrupts barrier integrity, primes vascular cells toward pro-inflammato- ry responses 3. Immune-Meta- bolic Dysregulation Chronic inflammation fosters metabolic rewir- ing and antioxidant depletion in local and systemic compartments Reduced antioxidant enzymes (SOD, GPx); increased oxidative damage (MDA, 8-HdG); metabolic stress signals Endothelial dysfunction, redox imbal- ance, and altered immune responses facilitate vascular priming 4. Platelet–Leuko- cyte Crosstalk & NETosis Activated platelets in lesions interact with neutrophils and monocytes → NET formation; procoagulant scaffold generation Platelets (activated); neutrophil extra- cellular traps (NETs); proteases; tissue factor; microparticles Pro-coagulant networks promote local thrombus nucleation and sys- temic hemostatic activation 5. Microparticle- Mediated Systemic Activation Release of extracellular vesicles enriched in tissue factor/phospholipids from activated immune cells Procoagulant microparticles; soluble clotting markers (P-selectin, D-dimer, prothrombin fragments) Hemostatic factors circulate and inter- act with distant vascular endothelium, increasing thrombotic vulnerability 6. Epidemiologic Evidence for Vascu- lar Involvement Observational studies link endometriosis with increased cardiovascular risk and endothelial dysfunction Epidemiologic risk ratios; endothelial dysfunction measures (e.g., AGEs, RHI) Higher incidence of cardiovascular disease, hypertension, and vascular events in endometriosis cohorts Page 5 of 17 Lesani et al. Beni-Suef University Journal of Basic and Applied Sciences (2026) 15:119 P-selectin, D-dimer, and prothrombin fragments, are elevated in patients with endometriosis, aligning with the concept that chronic inflammation, immune activation, and hemostatic dysregulation are integrated components of the disease’s systemic footprint [35]. Beyond NET formation, immunothrombosis in endo - metriosis is orchestrated through several interconnected hemostatic pathways. Activated platelets provide a cata - lytic phospholipid surface that accelerates thrombin generation while releasing P-selectin, CD40L, and pro- inflammatory mediators that amplify leukocyte recruit - ment and endothelial activation [ 41– 43]. Tissue factor expressed by activated monocytes, endothelial cells, and tissue factor-bearing extracellular vesicles initiates the extrinsic coagulation cascade, whereas thrombin fur - ther reinforces platelet activation and fibrin formation through positive feedback loops [ 44]. Concurrently, impairment of endogenous fibrinolysis, mediated by increased plasminogen activator inhibitor-1 (PAI-1) activity and stabilization of fibrin networks, may favor thrombus persistence [45]. Emerging evidence also impli- cates complement activation as an important amplifier of thromboinflammation through reciprocal interactions with platelets, neutrophils, endothelial cells, and coagula- tion pathways, further illustrating that thromboembolic risk arises from a coordinated immunovascular network rather than a single effector mechanism [46]. 3 Endothelial reprogramming as the central integrator Endothelial cells, long considered passive barriers to blood flow, are now recognized as highly plastic, immune-responsive effectors whose phenotype and func- tion can be durably reshaped by chronic inflammatory conditioning and metabolic stress [ 47]. Under sustained pathogenic cues, the vascular endothelium undergoes a dynamic shift from a quiescent, anticoagulant state toward a pro-inflammatory and pro-coagulant pheno - type, fundamentally altering its role in vascular homeo - stasis and disease susceptibility [ 48]. This adaptive yet maladaptive reprogramming orchestrates a systemic immunovascular response that integrates inflammatory, metabolic, and redox signals into a unified axis of throm - bogenic risk (see Fig. 1). 3.1 Chronic inflammatory conditioning and procoagulant drift Chronic exposure of endothelial cells to inflammatory cytokines such as TNF-α, IL-1β, and IFN-γ induces persistent transcriptional and epigenetic changes that encode a “memory-like” inflammatory imprint, predis - posing endothelium to exaggerated immune activation and leukocyte adhesion even after the initial stimulus wanes [ 49]. Such cytokine-driven memory responses in endothelial cells have been shown to alter expression of adhesion molecules (e.g., ICAM-1, VCAM-1) and immune signaling pathways, linking historical inflamma - tory exposures to future vascular dysfunction and disease risk [ 49]. Concomitantly, chronic inflammatory stimuli cause a progressive loss of the endothelium’s anticoagu - lant phenotype, typified by reduced nitric oxide (NO) bioavailability, diminished thrombomodulin expression, and disrupted regulation of anti-thrombin pathways, thereby facilitating a drift toward procoagulant signal - ing and enhancing susceptibility to thrombosis [ 50]. This shift is mechanistically tied to sustained NF-κB activation and inflammasome signaling within endothelial cells, which not only amplify pro-inflammatory transcriptional programs but also directly promote coagulation cascade engagement [51]. 3.2 Metabolic and redox rewiring of the endothelium Endothelial metabolic reprogramming is a central feature of dysfunctional endothelium under chronic stress, inte - grating altered glycolytic flux, mitochondrial perturba - tions, and redox imbalance into pathogenic phenotypes that favor inflammation and thrombosis [ 52]. Chronic oxidative stress, driven by excess reactive oxygen species (ROS) from inflammatory, metabolic, and iron-mediated pathways, disrupts cellular redox networks, impairing mitochondrial function and depleting antioxidant sys - tems such as glutathione peroxidase and superoxide dis - mutase [ 53]. This redox disturbance not only promotes endothelial cell activation but also increases susceptibility to regulated cell death pathways like ferroptosis, which is characterized by iron-dependent lipid peroxidation and further exacerbates endothelial injury and inflammatory signaling [ 54]. Mechanistically, the integration of oxida - tive stress with metabolic shifts skews endothelial behav - ior toward reduced barrier function, impaired nitric oxide signaling, and enhanced expression of pro-coagu - lant mediators, creating a milieu in which redox imbal - ance and metabolic rewiring synergistically promote an immunothrombotic endothelial phenotype [55]. 3.3 Microvascular instability and systemic spillover As endothelial reprogramming progresses, microvascu - lar networks lose their ability to maintain homeostatic vasodilatory, anti-inflammatory, and anticoagulant func - tions, transitioning instead to a state of heightened per - meability, leukocyte recruitment, and thrombogenic potential [ 56]. This microvascular instability facilitates systemic spillover of inflammatory and pro-coagulant signals, amplifying vascular priming beyond local pel - vic or organ-specific environments and predisposing distant vascular beds, including pulmonary and sys - temic circuits, to immune-driven thrombotic events [57]. Endotheliitis, basement membrane disruption, and Page 6 of 17 Lesani et al. Beni-Suef University Journal of Basic and Applied Sciences (2026) 15:119 widespread microthrombus deposition observed in set - tings of dysregulated endothelial activation reinforce the concept that local inflammatory and metabolic stress - ors can reshape the endothelium into a systemic driver of thromboinflammation [ 58]. Together, these processes underscore endothelial reprogramming as a central inte - grator of chronic inflammation, metabolic and redox imbalance, and thrombogenic signaling, thereby posi - tioning the endothelium as the mechanistic fulcrum linking local immune perturbations to systemic vascu - lar pathology and thrombotic risk in complex diseases. This primed endothelial state is not static but sensitive to systemic hormonal milieus, particularly the neuro - endocrine regulation of sex steroids, which profoundly modulate endothelial function and vascular homeostasis. Indeed, physiological estrogen signaling engages endo - thelial estrogen receptors to enhance nitric oxide produc- tion, vasodilation, and anti-inflammatory gene programs, while hypoestrogenic conditions, such as those induced by prolonged GnRH agonist therapy, can attenuate these protective pathways and alter endothelial responses at the genomic and non-genomic level. Fig. 1 Systemic Immunothrombotic Remodeling in Endometriosis. Schematic representation of the mechanistic pathways through which endometrio- sis transitions from a localized pelvic disorder to a systemic immunothrombotic condition Left panel (Local pelvic pathology): Retrograde menstrua- tion delivers endometrial fragments into the peritoneal cavity, where persistent sterile inflammation and immune maladaptation establish a chronic pro-inflammatory microenvironment with elevated cytokines (e.g., TNF-α, IL-6, IL-8, VEGF) and sustained macrophage and lymphocyte activation that extend beyond the lesion site. This local inflammatory niche is compounded by repeated hemorrhage and iron deposition from erythrocyte break - down, creating an iron-overloaded microenvironment that catalyzes Fenton chemistry and the generation of reactive oxygen species, driving oxidative stress, lipid peroxidation, and redox imbalance (panel annotations reflect elevated inflammatory and oxidative markers). These processes contribute to endothelial perturbation and angiogenic remodeling within and beyond pelvic tissues. Middle panel (Immunothrombotic conversion): Chronic inflammation recruits and activates platelets within endometriotic niches. Activated platelets interact with neutrophils and monocytes to induce neu - trophil extracellular trap (NET) formation (NETosis), which is a key effector of immunothrombosis and provides a scaffold of DNA, histones, and proteases that amplifies coagulation signaling and promotes localized thrombus formation. Platelet–leukocyte crosstalk also releases pro-coagulant extracellular vesicles and microparticles bearing tissue factor and phospholipids, which enter the circulation and propagate systemic coagulation activation. This interplay between innate immune cells and coagulation pathways evidences the integration of inflammation and thrombosis pathways characteristic of immunothrombosis. Right panel (Systemic vascular engagement and priming): Circulating pro-inflammatory and pro-coagulant signals from activated immune cells and platelets interact with vascular endothelium at distant sites. Primed endothelium undergoes functional reprogramming from an anticoagulant, vasodilatory phenotype toward a pro-inflammatory, pro-coagulant state, characterized by increased leukocyte adhesion, impaired barrier integrity, and heightened thrombogenic potential. These systemic vascular alterations predispose distant vascular beds, including pulmonary and systemic circulations, to immune-driven thrombotic events. The figure highlights this transition from local pelvic inflammation to systemic vascular priming, emphasizing the interconnected immunothrombotic architecture underlying endometriosis-associated vascular risk (designed using Power Point and Adobe Illustrator software) Page 7 of 17 Lesani et al. Beni-Suef University Journal of Basic and Applied Sciences (2026) 15:119 The mechanistic observations summarized above pro - vide a biologically plausible basis for considering endo - crine therapy as a potential modifier of thrombotic risk. However, mechanistic plausibility should not be inter - preted as proof of clinical causality. Although isolated case reports, observational studies, and pharmacovigi - lance analyses have raised concern regarding venous thromboembolic events during GnRH agonist therapy, direct clinical evidence remains heterogeneous and sub - stantially less robust than the underlying mechanistic literature. Moreover, interpretation of available studies is complicated by differences in underlying disease states, particularly between oncology populations, in whom cancer itself markedly increases thrombotic risk, and women receiving GnRH agonists for benign conditions such as endometriosis. Therefore, before presenting the proposed mechanistic framework, the current clinical evidence linking GnRH therapies with venous thrombo - embolism should be considered in its appropriate context [59]. 4 The endocrine-vascular axis: a proposed mechanistic framework Chronic inflammatory priming sensitizes vascular net - works to additional perturbations, among which systemic hormonal shifts, particularly those induced by gonado - tropin-releasing hormone (GnRH) agonist therapy, rep - resent a potent modifier of endothelial and hemostatic homeostasis [ 60, 61]. Continuous exposure to GnRH agonists such as leuprorelin desensitizes pituitary GnRH receptors, leading to profound suppression of lutein - izing hormone (LH) and follicle- stimulating hormone (FSH) secretion and consequent hypoestrogenism, a state functionally analogous to medical menopause [ 62]. This induced hypogonadotropic state disrupts the tightly regulated endocrine control of vascular function and exposes the primed endothelium to vulnerability, altering its vasoregulatory, anticoagulant, and barrier integrity mechanisms. 4.1 Estrogen withdrawal and loss of vascular homeostasis Endogenous estrogen is a fundamental regulator of vas - cular homeostasis, acting through both genomic and non-genomic mechanisms to enhance endothelial nitric oxide synthase (eNOS) activity and bioavailability of nitric oxide (NO), a critical mediator of vasodilation, anti-inflammatory signaling, and inhibition of plate - let adhesion [ 20, 63]. Estrogen receptors expressed on endothelial cells engage signaling pathways, including PI3K/Akt-mediated eNOS phosphorylation, to sus - tain NO production and maintain vasodilatory capacity [64]. The abrupt withdrawal of estrogen under GnRH agonist-induced hypoestrogenic conditions results in a marked reduction of NO bioavailability, thereby impairing endothelium-dependent vasodilation and diminishing the vasoprotective “anti-inflammatory” phe- notype of the vascular lining [ 65]. This diminishment is accompanied by upregulated expression of vasoconstric - tive and pro-adhesive factors such as endothelin-1 and adhesion molecules, which further destabilize endothelial barrier integrity and promote leukocyte tethering [ 22]. These alterations converge to produce an endothelial milieu characterized by reduced adaptability to hemody - namic stress, increased oxidative burden, and enhanced potential for thrombogenic adhesion events. 4.2 Leuprorelin-induced hemostatic rebalancing Beyond its effects on vasomotor tone, estrogen exerts modulatory influences on hemostatic balance by regu - lating both platelet reactivity and the fibrinolytic sys - tem [ 66]. Estrogen generally promotes a vasoprotective phenotype that suppresses platelet aggregation through enhanced NO and prostacyclin signaling, and modulates fibrinolytic activity by reducing plasminogen activator inhibitor-1 expression while enhancing tissue plasmino - gen activator activity, which collectively favor clot resolu- tion pathways [22, 67]. In contrast, estrogen deprivation induced by sus - tained GnRH agonist therapy can shift platelet reactivity toward a more activated state and attenuate fibrinolytic capacity, manifesting as increased expression of adhe - sion receptors and pro-coagulant profiles on platelets and endothelial surfaces [ 68]. This rebalancing accentu - ates coagulation amplification and platelet–endothelium interactions, particularly in a vascular system already primed by chronic inflammation and oxidative stress, thereby lowering the threshold for thrombus formation. Although direct human data for leuprorelin’s effects on coagulation profiles remain limited, analogous findings from estrogen withdrawal models demonstrate impaired anticoagulant and fibrinolytic mechanisms with reduced estrogenic support [69]. 4.3 Current clinical evidence linking GnRH agonists to venous thromboembolism Despite increasing mechanistic evidence suggesting that hypoestrogenism may promote endothelial dysfunction and immunothrombotic activation, clinical evidence directly linking GnRH agonist therapy to venous throm - boembolism (VTE) remains limited. Unlike the extensive literature describing cardiovascular effects of andro - gen-deprivation therapy in prostate cancer, prospective studies specifically evaluating VTE incidence in women receiving GnRH agonists for endometriosis are scarce, and thromboembolic events have generally not been primary outcomes in randomized trials [ 70– 72]. Con - sequently, current knowledge is derived predominantly from case reports, retrospective observational studies, Page 8 of 17 Lesani et al. Beni-Suef University Journal of Basic and Applied Sciences (2026) 15:119 pharmacovigilance databases, and indirect evidence from other disease settings. Notably, randomized controlled trials evaluating GnRH agonists for endometriosis have consistently been designed to assess treatment efficacy and general safety, with primary endpoints focused on pelvic pain, symptom improvement, quality of life, bone mineral density, and treatment-related adverse effects rather than vascular safety or venous thromboembolism. Accordingly, these studies were neither powered nor spe- cifically designed to detect uncommon thromboembolic events, precluding reliable estimation of the absolute incidence of VTE during therapy [73]. Pharmacovigilance databases provide an additional source of post-marketing safety surveillance and have identified sporadic reports of deep vein thrombosis and pulmonary embolism following GnRH agonist ther - apy [ 74]. However, spontaneous reporting systems are inherently subject to underreporting, reporting bias, incomplete clinical information, and the absence of denominator data, precluding reliable estimation of inci - dence or definitive assessment of causality. Consequently, pharmacovigilance findings should be interpreted pri - marily as hypothesis-generating safety signals that war - rant further pharmacoepidemiologic investigation rather than confirmation of a causal association. Interpretation of clinical evidence requires careful distinction between oncology and benign gynecologic populations. In prostate cancer, several large observa - tional studies have reported modest increases in VTE among patients receiving androgen-deprivation therapy with GnRH agonists [75, 76]. However, these findings are intrinsically confounded by advanced age, malignancy- associated hypercoagulability, concomitant chemother - apy or radiotherapy, reduced mobility, and competing cardiovascular comorbidities. Accordingly, the throm - botic risk observed in oncology populations cannot be directly extrapolated to younger women receiving GnRH agonists for endometriosis, whose baseline cardiovascu - lar risk profile differs substantially. Another unresolved question concerns whether differ - ent methods of pituitary suppression carry similar vas - cular consequences. Emerging pharmacovigilance and observational evidence suggests that GnRH antagonists may exhibit a more favorable cardiovascular safety pro - file than GnRH agonists, particularly in oncology popula- tions, although comparative data remain limited and are derived primarily from studies evaluating major cardio - vascular outcomes rather than VTE specifically. At pres - ent, comparable evidence in women with endometriosis is lacking, precluding definitive conclusions regarding differential thrombotic risk between these therapeutic classes [77]. Taken together, the available clinical evidence neither conclusively establishes nor excludes a causal association between GnRH agonist therapy and VTE. Rather, it sup - ports biological plausibility while highlighting substantial evidence gaps. These uncertainties provide the rationale for the proposed mechanistic framework presented in the following sections, which seeks to explain how chronic endothelial priming in endometriosis might interact with endocrine perturbation to increase thrombotic suscepti - bility in a subset of vulnerable patients. 4.4 Hormonal suppression as a second hit in a primed system Integrating these lines of evidence allows us to propose a “two-hit” mechanistic model in which chronic inflamma- tory and iron-driven endothelial priming constitutes the first hit, whereas endocrine withdrawal-mediated vascu - lar perturbation induced by leuprorelin may represent a biologically meaningful second hit. Although biologi - cally plausible and supported by converging mechanistic evidence, this model remains conceptual because direct prospective clinical evidence demonstrating this sequen - tial causal relationship is currently limited. In this frame - work, the first hit establishes a baseline state of low-grade endothelial dysfunction characterized by inflammatory memory responses, redox imbalance, and pro-coagulant drift [ 78]. The second hit, an abrupt systemic hormone withdrawal, exacerbates this vulnerability by suppress - ing vasoprotective signaling, perturbing hemostatic bal - ance, and amplifying platelet–endothelium interactions [68]. Table 2 captures the combined first- and second-hit effects in a clear mechanistic framework. Importantly, this framework should be regarded as a hypothesis-generating model intended to integrate exist - ing mechanistic evidence and guide future experimental and clinical investigation rather than as confirmation of an established causal pathway. The combination of these insults produces a compounded immunothrom - botic predisposition that extends beyond traditional risk frameworks, underscoring the critical interplay between endocrine and vascular systems in modulating throm - botic risk under therapeutic hormonal perturbation (see Fig. 2). 5 Toward a proposed pulmonary embolism-prone phenotype The transition from localized venous thrombosis to clinically significant pulmonary embolism (PE) reflects more than simple hemodynamic obstruction; it embod - ies a systemic immunothrombotic evolution in which pre-existing vascular priming from chronic inflammation and endothelial dysfunction synergizes with dynamic thrombus propagation processes to generate embolic potential [79]. Unlike isolated clot formation, which may remain confined within a venous segment, a PE- prone phenotype arises when thrombi acquire structural and Page 9 of 17 Lesani et al. Beni-Suef University Journal of Basic and Applied Sciences (2026) 15:119 biochemical features that favor stability, resistance to endogenous fibrinolysis, and dislodgement into the pul - monary circulation, a process underpinned by complex interactions among endothelial cells, neutrophils, plate - lets, and circulating biomolecular mediators. 5.1 From venous stasis to immunothrombotic propagation Venous thrombosis traditionally initiates at sites of blood flow stagnation, endothelial activation, and hemostatic imbalance, where turbulent or low -shear conditions facilitate deposition of fibrin and recruitment of plate - lets and leukocytes [ 80]. However, clot initiation (forma - tion) and clot propagation (growth and stabilization) are mediated by distinct mechanistic pathways, particularly in a vascular milieu primed by chronic inflammation and endothelial dysfunction [ 81]. Neutrophil extracellular traps (NETs) provide a scaffold that incorporates plate - lets, red blood cells, von Willebrand factor (vWF), and coagulation factors, effectively bridging innate immune responses and the coagulation cascade [ 82]. NETs not only enhance the local assembly of intrinsic coagulation factors such as FXII but also bind TF and fibrinogen, aug- menting both intrinsic and extrinsic pathways and fuel - ing further thrombin generation and fibrin deposition [82]. Collectively, this immunothrombotic propagation shifts venous clots from unstable, fibrin-rich formations toward more complex, stabilized structures with greater potential for embolization. 5.2 NET-driven thrombus stabilization and embolic potential NETs play a central structural role in thrombus architec - ture that directly influences embolic risk. Upon activa - tion, neutrophils release decondensed chromatin fibers decorated with histones, myeloperoxidase, and pro - teolytic enzymes that form an extracellular meshwork capable of capturing cellular and acellular blood ele - ments [82]. This NET scaffold, by binding platelets, vWF, and fibrin, increases thrombus mechanical integrity and resistance to fibrinolysis, rendering clots more stable and less susceptible to endogenous degradation. In vitro and in vivo models have shown that the presence of NETs within thrombi is associated with delayed clot resolution and increased structural resilience, effects that directly enhance the potential for larger portions of clot to detach and traverse the venous-to-pulmonary circulation [83]. Mechanistically, NET -associated histones and DNA interact with coagulation factors to amplify thrombin production and inhibit anticoagulant pathways, while proteases such as neutrophil elastase degrade endoge - nous anticoagulant proteins like TFPI and thrombomod - ulin, further fostering prothrombotic conditions and clot persistence [ 79]. The resultant thrombus is not merely a fibrin deposit but a biochemically fortified immu - nothrombotic entity with enhanced embolic potential. Table 2 Endocrine-vascular perturbations and the emergence of a pulmonary embolism–prone phenotype in endometriosis under GnRH agonist therapy Axis Mechanistic Feature / Perturbation Downstream Endothelial & Hemostatic Consequences PE-Prone Biomolecular / Cellular Signatures Translational Implications Endocrine Hit GnRH agonist therapy (e.g., leuprorelin) → pituitary desensitization → hypoestrogenism ↓ Endothelial NO bioavailability, impaired vasodilation, ↑ endothelin-1, ↑ adhesion molecule expression; shifts endothelium toward pro-adhesive, pro-thrombotic state Functional hypoestrogenic readouts (e.g., reduced eNOS activity, impaired flow-mediated dilation) Candidate for hormone add- back or therapy modification; endocrine status informs personalized thrombotic risk stratification Inflammatory Priming Chronic lesion-level in- flammation → cytokines (TNF-α, IL-6, IL-1β) Endothelial “memory” → persistent adhesion molecule expression, NF-κB activation, inflammasome engagement; enhanced leukocyte tethering Elevated CRP , IL-6, NLR; heightened leukocyte- endothelial interactions Identify high-risk vascular phe- notypes prior to therapy; guide intensity of surveillance Oxidative / Redox Stress Iron overload from ectopic hemorrhage → lipid peroxidation, ROS accumulation Endothelial metabolic rewiring → mitochondrial dysfunction, ferroptosis susceptibility; barrier disruption; impaired NO signaling Lipid peroxides, catalytic iron, glutathione depletion Targetable with antioxidants, NAC, or redox-modulating co-therapies Hemostatic Rebalancing Estrogen deprivation → platelet hyperreactivity; impaired fibrinolysis ↑ Platelet adhesion, ↑ PAI-1, ↓ tPA; proco- agulant endothelial shift Platelet–leukocyte aggre- gates, elevated P-selectin, vWF, TF exposure Mechanism-guided antiplatelet prophylaxis (low-dose aspirin) in biomarker-selected patients Immu- nothrombotic Propagation NET formation & stabili- zation of thrombi NET scaffolds recruit platelets, RBCs, and coagulation factors → amplify thrombin generation; resist fibrinolysis MPO-DNA complexes, citrullinated histone H3, stabilized thrombus architecture Predictive biomarker for early thromboembolic risk; candi- date for NET-targeted therapies Clinical Phenotype Emergence Cumulative two-hit insult: chronic endo- thelial priming + abrupt hypoestrogenism Formation of systemic PE-prone pheno- type with enhanced embolic potential Convergent biomarker pro- file: PNAs, EMPs, NET mark- ers, inflammatory indices, iron/lipid peroxidation Supports dynamic risk-adapted monitoring, therapy modifica- tion, and personalized prophy- lactic interventions Page 10 of 17 Lesani et al. Beni-Suef University Journal of Basic and Applied Sciences (2026) 15:119 5.3 Defining the PE-prone phenotype: biomolecular signature Emergence of a PE- prone phenotype can be concep - tualized as the convergence of multiple measurable biomarkers reflecting immune, endothelial, and hema - tologic contributions to thrombus evolution and sys - temic vulnerability [ 84]. Prominent among these are: Platelet–leukocyte aggregates (PNAs): Complexes of activated platelets and neutrophils or monocytes that signal heightened immunothrombotic engagement and predict propagation of thrombotic processes [ 85, 86]. PNAs facilitate NETosis and represent a mechanistic bridge between innate immunity and coagulation ampli - fication. Endothelial microparticles (EMPs): Vesicles shed from activated or apoptotic endothelial cells that carry pro-coagulant phospholipids, tissue factor, and adhesion molecules [ 87]. EMP levels correlate with endothelial dysfunction and have been linked to elevated risk of thrombotic events including deep vein thrombosis and PE. Inflammatory indices (NLR, CRP , IL-6): Systemic inflammatory markers such as neutrophil- to-lymphocyte ratio (NLR), C -reactive protein (CRP), and interleukin-6 (IL-6) reflect the systemic immune activation that pre - disposes to immunothrombotic propagation and have been associated with PE severity and prognosis [ 88, 89]. Iron/lipid peroxidation indices: Biomarkers of oxidative stress such as lipid peroxides and catalytic iron reflect redox imbalance that can drive endothelial injury, neu - trophil activation, and NET formation, all of which con - tribute to thrombus stability and resistance to fibrinolysis [90]. Together, these biomolecular signatures delineate a pathophysiologically distinct PE- prone phenotype, char - acterized by enhanced immunothrombotic activity, clot stabilization mechanisms, and systemic inflammatory Fig. 2 Endothelial reprogramming as the central integrator of immunothrombotic risk. Chronic inflammatory conditioning and iron-driven oxidative stress induce durable endothelial reprogramming that integrates immune, metabolic, and redox signals into a unified axis of thrombogenic suscep - tibility. Persistent exposure to cytokines (e.g., TNF-α, IL-1β, IFN-γ) establishes transcriptional and epigenetic “memory-like” imprints within endothelial cells, sustaining adhesion molecule expression (ICAM-1, VCAM-1) and sensitizing the vasculature to exaggerated inflammatory responses. Concomitant suppression of anticoagulant pathways—including reduced endothelial nitric oxide synthase activity, diminished nitric oxide bioavailability, and de - creased thrombomodulin expression—promotes procoagulant drift through sustained NF-κB and inflammasome signaling. Metabolic rewiring toward enhanced glycolytic flux and mitochondrial dysfunction, coupled with iron-mediated reactive oxygen species generation and lipid peroxidation, destabi- lizes endothelial redox homeostasis and increases susceptibility to ferroptotic injury. These integrated alterations compromise barrier integrity, enhance platelet–leukocyte adhesion, and facilitate microparticle and neutrophil extracellular trap (NET)–associated thrombus stabilization. The reprogrammed microvasculature thus transitions from a quiescent anticoagulant interface to a pro-inflammatory, pro-thrombotic effector, enabling systemic spillover of thromboinflammatory signals to distant vascular beds. Inset: Estrogen signaling maintains endothelial vasoprotective tone via PI3K/Akt-mediated eNOS activation and anti-inflammatory gene programs; hypoestrogenic states (e.g., GnRH agonist–induced suppression) attenuate these protective pathways, lowering the threshold for immunothrombotic propagation in a primed endothelium (designed using Power Point and Adobe Illustrator software) Page 11 of 17 Lesani et al. Beni-Suef University Journal of Basic and Applied Sciences (2026) 15:119 engagement that collectively extend traditional views of venous thromboembolism into a broader systemic dis - ease framework. Recognizing this phenotype’s complex molecular and cellular underpinnings not only refines risk stratification for thromboembolic events in women with endometriosis, a group already demonstrably at higher risk of broader cardiovascular pathology, but also highlights the pressing need for translation of these insights into personalized clinical strategies. Indeed, women with endometriosis exhibit elevated risks of adverse cardiovascular outcomes such as ischemic heart disease and cerebrovascular events, reflecting the inter - play between chronic inflammation, endothelial dysfunc - tion, and systemic vascular perturbation, which standard diagnostic paradigms alone fail to capture. This evolving understanding sets the stage for preci - sion cardio-reproductive medicine, an integrative clinical discipline that seeks to tailor risk assessment, prediction, prevention, and therapeutic approaches to the unique pathobiological profiles of individuals, bridging repro - ductive endocrinology with cardiovascular systems sci - ence to improve outcomes across health trajectories. The concept of precision medicine, which has already reshaped fields such as oncology and cardiology by lever - aging detailed molecular, imaging, and computational phenotyping to optimize individualized risk prediction and therapy, provides a compelling framework for this integration. Just as precision cardiology is moving from generalized treatment paradigms toward risk stratification based on genomic and multi-omic signatures and advanced analyt- ics, the integration of reproductive hormonal dynamics, immune–vascular phenotypes, and molecular biomark - ers offers an analogous opportunity in women’s cardio - vascular health. Together, these advances underscore the need to translate mechanistic insights from endometrio - sis-associated immunothrombosis into clinically action - able strategies, forming the basis for the next section on translational implications and precision cardio-reproduc- tive medicine. 6 Future research directions toward precision cardio-reproductive medicine Translating the mechanistic insights above requires a deliberate shift from population-level pharmacovigilance to individualized, mechanism-driven clinical care that integrates reproductive endocrinology with cardiovas - cular systems science, a precision cardio-reproductive medicine paradigm that combines biomarkers, multi- omic phenotyping, and dynamic surveillance to predict, prevent, and mitigate vascular complications of therapies such as GnRH agonists [91]. 6.1 Risk stratification before GnRH agonist initiation Although not part of current routine clinical practice, future precision cardio-reproductive medicine may incorporate pre-treatment vascular phenotyping to iden - tify women at increased thrombotic susceptibility. Such approaches require prospective validation before clini - cal implementation [ 92]. First-line stratification should include careful clinical cardiovascular risk appraisal (personal and family history of VTE/PE, prior arterial events, and traditional risk factors) combined with tar - geted laboratory screening for high-yield thrombophil - ias or hypercoagulable states when indicated by history; this combined strategy improves detection of patients at materially elevated thrombotic risk [ 93]. Baseline mea - surement of mechanistically relevant circulating bio - markers, for example, D-dimer and soluble P-selectin (coagulation/hemostatic activity), endothelial micropar - ticles (endothelial activation), and platelet–leukocyte aggregates (cellular immunothrombosis), provides a biologically anchored risk snapshot that augments clini - cal assessment [ 94]. Where available, integration of molecular phenotyping (e.g., targeted proteomics, tran - scriptomic endothelial signatures, or single-cell immune profiling) can further resolve subphenotypes of vascular vulnerability and identify patients for intensified surveil - lance or alternative therapies [95]. 6.2 Biomarker-guided surveillance during therapy Rather than applying binary contraindications, we advo - cate dynamic, biomarker-guided monitoring during GnRH agonist exposure to detect early signals of vascu - lar destabilization and enable timely intervention [ 96]. Future biomarker-guided surveillance strategies could incorporate serial assessment of coagulation, endothe - lial, platelet, and NET-related biomarkers to detect early vascular perturbation. However, none of these biomark - ers has yet been prospectively validated for routine moni- toring of women receiving GnRH agonists, and their clinical utility remains investigational [ 92]. Point-of-care technologies that quantify platelet–leukocyte aggregates or cell-aggregate signatures may permit near-real-time risk detection in outpatient settings and facilitate rapid decisions about therapy continuation, intensification of prophylaxis, or alternative strategies [ 97]. Crucially, surveillance must be adaptive: biomarker trends (trajec - tory, not single value) should trigger predefined clinical actions (e.g., intensified monitoring, short-term throm - boprophylaxis, endocrine therapy modification), thereby converting mechanistic signals into actionable clinical workflows. Page 12 of 17 Lesani et al. Beni-Suef University Journal of Basic and Applied Sciences (2026) 15:119 6.3 Preventive co-therapies and vascular stabilization strategies Mechanism-driven prevention focuses on stabilizing endothelium, reducing platelet hyperreactivity, and buff - ering redox stress, interventions selected to counter the specific axes identified during phenotyping [98]. 6.3.1 Endothelial protectants Statins, antiplatelet agents, antioxidant therapies, and individualized hormone-management strategies repre - sent biologically plausible approaches deserving future prospective evaluation rather than established preven - tive strategies for GnRH-associated thrombotic risk. Randomized clinical studies will be required before such interventions can be recommended in routine practice [98] 6.3.2 Antiplatelet modulation Low-dose aspirin and other antiplatelet agents reduce VTE risk in select high-risk settings and may be con - sidered where platelet-driven immunothrombosis pre - dominates, recognizing that the absolute benefit must be balanced against bleeding risk and that randomized data in the GnRH-treated endometriosis population are lack - ing [99] 6.3.3 Redox buffering and mitochondrial support Interventions such as N-acetylcysteine (NAC) and other antioxidant strategies can attenuate oxidative stress and have preliminary evidence for improving endothelial function in metabolic and inflammatory settings, sug - gesting potential adjunctive roles to reduce NETosis and ferroptotic vulnerability in iron-primed phenotypes [100] 6.3.4 Therapeutic hormone management: Where vasculoprotective estrogenic signaling is essen - tial (and reproductive goals allow), add-back estrogen or dose/schedule modifications may mitigate abrupt endothelial deconditioning during GnRH therapy and have been shown to restore endothelium-dependent relaxation in controlled studies [ 101] Finally, the choice between GnRH agonists versus antagonists may itself be an actionable decision point in patients with elevated cardiovascular vulnerability, since emerging compara - tive data suggest differential cardiovascular risk profiles across these drug classes and thus inform personalized therapeutic selection (Fig. 3). 6.4 Redefining safety: from adverse event to mechanistic predictability Looking ahead, future integration of longitudinal bio - markers, multi-omic profiling, and machine-learning models may enable individualized prediction of ther - apy-associated vascular complications. However, these approaches remain investigational and require analyti - cal validation, external validation, prospective clinical evaluation, and demonstration of clinical utility before implementation into routine care [ 102]. Achieving this requires harmonizing longitudinal biomarker data with deeper molecular and imaging phenotypes, and apply - ing machine-learning and multi-omic integration to generate predictive risk models and decision tools that are interpretable and clinically actionable [ 103]. Pilot implementation should follow an iterative translational pathway: [1] cohort discovery and multi-omic phenotyp - ing [2], prospective biomarker validation with predefined intervention thresholds [ 3], randomized evaluation of biomarker-guided risk-reduction strategies (e.g., statin/ antiplatelet/add-back approaches), and [ 4] deployment of validated clinical decision support into routine care, a pathway that parallels successful precision approaches in other cardiovascular domains [95]. Ultimately, embed- ding mechanistic assays and predictive models into the standard workflow will convert ad hoc safety signals into predictable, preventable events and will allow clinicians to tailor reproductive therapies to minimize vascular harm while preserving reproductive and symptomatic benefits. 7 Conceptual synthesis: the immunothrombotic continuum The mechanistic threads developed above, chronic pel - vic inflammation, iron-driven oxidative priming, plate - let–leukocyte crosstalk, endothelial reprogramming, and hormonal perturbation, are not discrete phenom - ena but elements of a continuous immunothrombotic spectrum in which immune activation and coagulation are reciprocally reinforcing and progressively remodel vascular biology toward thrombotic vulnerability. This immunothrombotic continuum reframes endometriosis from a localized gynecologic disorder into a systemic, multi-axis disease in which local lesion biology can prop - agate to distant vascular beds through defined cellular and molecular pathways. 7.1 Endometriosis as a model of reproductive immunovascular crosstalk Endometriosis offers a uniquely informative human model to study reproductive-immune-vascular interac - tions because it couples repetitive, hormone-driven tis - sue injury and repair with sustained local iron overload and chronic sterile inflammation, providing a natural experiment in how cyclical reproductive physiology can entrain persistent vascular perturbations [ 104]. At the cellular level, the lesion microenvironment, rich in acti - vated macrophages, cytokines, and oxidative products, conditions neighboring endothelium and releases cir - culating mediators (microparticles, NET remnants) that Page 13 of 17 Lesani et al. Beni-Suef University Journal of Basic and Applied Sciences (2026) 15:119 convey inflammatory and procoagulant signals systemi - cally, thereby mechanistically linking pelvic biology to remote vascular dysfunction [ 105]. Because endometrio - sis commonly affects women in their reproductive years and is managed with hormonal therapies that themselves modulate vascular biology, it serves as a tractable context for testing how reproductive endocrine shifts interact with immunothrombotic mechanisms to modulate short- and long-term vascular risk. 7.2 Hormonal therapies as systemic vascular modulators Sex steroids exert powerful, pleiotropic effects on vas - cular cells: estrogen promotes endothelial nitric oxide synthase activity, accelerates endothelial repair, and sup - presses pro-inflammatory gene programs, while estro - gen withdrawal impairs these protective pathways and unmasks endothelial vulnerability [ 106]. Therapeutic manipulations of the hypothalamic–pituitary–gonadal axis, for example, continuous GnRH agonists, therefore act as systemic biological perturbations that can tip a primed endothelium into overt dysfunction by abruptly removing vasoprotective signaling, altering platelet and fibrinolytic balance, and modifying metabolic state. Com- parative clinical and mechanistic data indicate that differ- ent classes of gonadotropin-suppressing agents (agonists vs. antagonists) and add-back strategies produce distinct cardiovascular and metabolic footprints, supporting the concept that endocrine therapies should be considered vascular modulators rather than organ-restricted treat - ments [107]. 7.3 A new paradigm for thromboembolic risk in chronic inflammatory disease Beyond endometriosis, a broader body of evidence shows that chronic inflammatory and autoimmune diseases reconfigure thrombotic risk through shared immunothrombotic mechanisms, NETosis, endothelial activation, procoagulant microparticles, and dysregulated anticoagulant pathways, arguing for a paradigm shift from risk estimation based on classical hemodynamic or Fig. 3 Translational pipeline for precision cardio-reproductive medicine in endometriosis. Legend: This figure illustrates a systems-level, translational framework for preventing immunothrombotic complications during GnRH agonist therapy in women with endometriosis. Panel A — Pre-treatment Phenotyping & Risk Stratification: Clinical history, conventional cardiovascular risk factors, and mechanistic biomarkers (e.g., D-dimer, platelet–neutro- phil aggregates [PNAs], endothelial microparticles [EMPs], iron/lipid-peroxidation indices, endothelial transcriptomic signatures) stratify patients into low-, intermediate-, and high-risk vascular phenotypes. Panel B — Adaptive Biomarker-Guided Surveillance : Serial, trajectory-based monitoring of coagu- lation, platelet activation, endothelial injury, NETosis, and redox markers informs real-time decision nodes. Upward trends trigger graded clinical actions, from intensified monitoring to prophylactic intervention, enabling dynamic management of immunothrombotic risk. Panel C — Mechanism-Targeted Interventions: Phenotype-driven preventive strategies include endothelial stabilizers (e.g., statins), antiplatelet agents (low-dose aspirin), redox/mito - chondrial support (N-acetylcysteine, antioxidants), anti-NET therapies, and tailored hormonal regimens (GnRH agonist vs antagonist, add-back estrogen). Iterative monitoring ensures therapy is adapted to evolving vascular states. Panel D — Predictive Modeling & Clinical Decision Support : Multi-omic and biomarker data integrate into predictive algorithms, validated through prospective trials and embedded in clinical decision support systems, en - abling mechanistic forecasting of thromboembolic events and personalized intervention (designed using Power Point and Adobe Illustrator software) Page 14 of 17 Lesani et al. Beni-Suef University Journal of Basic and Applied Sciences (2026) 15:119 thrombophilia models toward integrated immunovascu - lar phenotyping [ 108]. This new paradigm emphasizes (i) dynamic network-level drivers of thrombosis rather than single biomarkers, (ii) the importance of host-state (immune, metabolic, endocrine) in determining whether a clot will form, propagate, or embolize, and (iii) the ther- apeutic consequences, namely, that targeting immuno - logic and endothelial nodes (for example, NET inhibitors, endothelial stabilizers, redox modulators) may comple - ment anticoagulation to prevent clinically meaningful embolic events [109]. 7.4 Limitations of the proposed mechanistic model The framework presented in this Review is intended as a hypothesis-generating mechanistic model rather than an established causal sequence. While substantial experi - mental and epidemiologic evidence supports individual components of the model, including endothelial dysfunc- tion in endometriosis, the vascular effects of hypoestro - genism, and immunothrombotic mechanisms, direct prospective clinical evidence demonstrating that endo - metriosis-induced endothelial priming is sequentially followed by GnRH agonist-mediated vascular destabiliza- tion culminating in thromboembolism remains limited. Consequently, the proposed “two-hit” paradigm should be interpreted as a conceptual framework that integrates current knowledge, identifies testable biological hypoth - eses, and provides a foundation for future mechanistic studies and prospective clinical validation. Similarly, the precision cardio-reproductive medicine framework pro - posed in this Review, including biomarker-guided sur - veillance, NET and endothelial microparticle monitoring, and machine-learning-assisted risk prediction, should be regarded as future research priorities rather than com - ponents of current standard clinical care. These concepts are intended to stimulate prospective translational inves - tigation aimed at determining their analytical validity, clinical utility, cost-effectiveness, and impact on patient outcomes before routine implementation can be consid - ered [92]. 8 Conclusion We propose reframing endometriosis not as an isolated gynecologic lesion but as a systemic immunothrombotic disorder whose local biology (iron-rich hemorrhage, ster- ile inflammation, platelet–leukocyte crosstalk) durably primes the endothelium and hemostatic systems. This reframing dissolves the artificial barrier between repro - ductive pathology and vascular medicine: the lesion is the signal, and the vasculature is the transducer that con- verts cyclical reproductive injury into persistent throm - boinflammatory risk. Mechanistically, the evidence converges on an inte - grated cascade, iron-driven oxidative priming → immune amplification → endothelial reprogramming → immu - nothrombotic propagation, in which therapeutic endo - crine perturbations (for example, GnRH-agonist-induced hypoestrogenism) can act as a biologically meaningful second hit that unmasks embolic vulnerability. Thinking in these terms shifts emphasis away from isolated risk factors toward network states and dynamic transitions: it is less whether a patient “has” a risk factor and more which vascular state the patient occupies and how close that state is to a tipping point for thrombus propagation and embolization. The clinical implication is equally transformative. Pre - venting thromboembolic harm in reproductive-aged women requires prediction, prevention, and personal - ization rather than retrospective pharmacovigilance. We must [1] phenotype patients before therapy using clinical, cellular, and molecular assays that capture endothelial, immune, and redox axes; [ 2] monitor trajectories during therapy with mechanistically informative biomarkers and point-of-care tools; and [ 3] deploy targeted co-therapies (endothelial stabilizers, selective antiplatelet strategies, redox modulators, tailored endocrine regimens) tested in biomarker-selected cohorts. In short, safety becomes a function of mechanistic anticipation rather than event counting. Research priorities to realize this agenda are clear and urgent: validate compact, clinically deployable biomarker panels that predict an immunothrombotic phenotype; perform mechanistic human and transla - tional studies that link lesion biology to systemic vas - cular readouts; compare endocrine regimens for their vascular footprints; and ethically design randomized, biomarker-guided prevention trials of vascular stabiliz - ers in high-risk patients. Parallel efforts should develop interpretable predictive models that integrate multi- omic, imaging, and clinical time-series data and that can be prospectively validated in diverse populations. If realized, this program will accomplish more than prevent rare adverse events: it will generate a replicable template for how reproductive biology informs sys - temic vascular health, create a new subspecialty ethos, precision cardio-reproductive medicine, and provide mechanistically grounded interventions that preserve reproductive choices while minimizing vascular harm. The path forward is translational and collective: rigorous mechanistic inquiry, prospective phenotyping, and prag - matic trials conducted in concert between reproductive endocrinology and vascular medicine will convert the immunothrombotic insight from concept to clinical care.

None. Author contributions All authors reviewed the manuscript. Page 15 of 17 Lesani et al. Beni-Suef University Journal of Basic and Applied Sciences (2026) 15:119 Funding None. Data availability No datasets were generated or analysed during the current study. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Author details 1Department of Obstetrics and Gynecology, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran 2Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran 3Pulmonary Subspecialty, Lorestan University of Medical Sciences, Khorramabad, Islamic Republic of Iran 4Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Science, Tehran, Islamic Republic of Iran 5Department of Obstetrics and Gynecology, School of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Islamic Republic of Iran 6Department of Cardiology, School of Medicine, Hajar Hospital, Shahrekord University of Medical Sciences, Shahr-e Kord, Islamic Republic of Iran 7Reproductive Health Research Center, Department of Obstetrics & Gynecology, Alzahra Hospital, Guilan University of Medical Sciences, Rasht, Islamic Republic of Iran Received: 20 June 2026 / Accepted: 29 September 2026

1. As-Sanie S, Mackenzie SC, Morrison L, Schrepf A, Zondervan KT, Horne AW et al (2025) Endometriosis: Rev Jama 334(1):64–78 2. Hafizi L, Parsai N, Abolhasani Y, Zeinadini S, Shahryarpanah Z, Sameipoor F et al (2026) Laparoscopic management of endometriosis; new techniques and clinical outcomes. Immunopathol Persa 12(2):e44037–e 3. Smyk JM, Danielecka Z, Kotowska M, Zawadka M, Andruszkiewicz P , Grąt M et al (2024) Cardiovascular risks and endothelial dysfunction in reproductive- age women with endometriosis. Sci Rep 14(1):24127 4. Saad M, Ansari I, Ibrahim ZS, Batool RM, Ahsan SI, Arshad MS et al (2025) Increased risk of cardiovascular disease in women with endometriosis: A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 312:114081 5. Foroughi Abari K, Derakhshandeh A, Tayefi F, Hosseini SM, Salehi K, Hosseini SM et al (2026) Dual therapeutic role of dienogest and vitamin E in endome- triosis management and cardiovascular risk modulation; a narrative review study. J Prev Epidemiol 11(2):e39346–e 6. Aklilu A, Lai MS, Jiang Z, Yip SP , Huang C-L (2025) Immunothrombosis in Sep- sis: Cellular Crosstalk, Molecular Triggers, and Therapeutic Opportunities—A Review. Int J Mol Sci [Internet] 26(13):6114 7. Meyers S, Crescente M, Verhamme P , Martinod K (2022) Staphylococcus aureus and Neutrophil Extracellular Traps: The Master Manipulator Meets Its Match in Immunothrombosis. Arterioscler Thromb Vasc Biol 42(3):261–276 8. Naghinezhad J, Moradpanah S, Khodakarim N, Hamblin MR, Rezaeeyan H (2025) Nanodrug-based modulation of platelet–leukocyte interactions in ovarian cancer: a new frontier in targeted therapy. Cancer Nanotechnol 16(1):37 9. Zöller B, Li X, Sundquist J, Sundquist K (2012) Autoimmune diseases and venous thromboembolism: a review of the literature. Am J Cardiovasc Dis 2(3):171–183 10. Naghinezhad J, Zarifi N, Soleymani S, Kandovan MN, Chermehini NY, Hamblin MR et al (2025) Smart DNA hydrogels for post-surgical hemostasis and tumor recurrence prevention: bridging bioengineering and clinical translation. Cancer Nanotechnol 17(1):4 11. Heydari F, Feli M, Maleknia M, Habibi Z, Sohrabi A, Hamblin MR et al (2026) Beyond Remission: The Cardiotoxic and Thrombotic Shadow of AML Chemo- therapy. Cardiovasc Toxicol 26(3):31 12. Moradi A, Siyasari A, Abutalebi Nasrabad S, Ezazi Bojnordi T, Bazzazi S, Ras- souli S et al (2026) Investigating the relationship between vitamin B intake and endometriosis: a systematic review and meta-analysis. J Prev Epidemiol 11(1):e39282–e 13. Moradi G, Etehadi SS, Mousavi SH, Mohammadi R (2024) Evaluating the Cavi- tary Lung Lesions on CT Scan of COVID-19 Patients: A Retrospective Study. J Community Hosp Intern Med Perspect 14(6):23–29 14. Thézénas M-L, De Leo B, Laux-Biehlmann A, Bafligil C, Elger B, Tapmeier T et al (2020) Amine oxidase 3 is a novel pro-inflammatory marker of oxidative stress in peritoneal endometriosis lesions. Sci Rep 10(1):1495 15. Wyatt J, Fernando SM, Powell SG, Hill CJ, Arshad I, Probert C et al (2023) The role of iron in the pathogenesis of endometriosis: a systematic review. Hum Reprod Open 2023(3):hoad033 16. Wang X, Wu N, Xue Q (2025) Macrophages in endometriosis: key roles and emerging therapeutic opportunities—a narrative review. Reproductive Biol - ogy Endocrinol 23(1):134 17. Chen X, Li H, Wang Z, Zhou Q, Chen S, Yang B et al (2020) Quercetin protects the vascular endothelium against iron overload damages via ROS/ADMA/ DDAHⅡ/eNOS/NO pathway. Eur J Pharmacol 868:172885 18. He H, Qiao Y, Zhou Q, Wang Z, Chen X, Liu D et al (2019) Iron Overload Dam- ages the Endothelial Mitochondria via the ROS/ADMA/DDAHII/eNOS/NO Pathway. Oxid Med Cell Longev 2019:2340392 19. Cid MC, Schnaper HW, Kleinman HK (2002) Estrogens and the vascular endo- thelium. Ann N Y Acad Sci 966:143–157 20. Chambliss KL, Shaul PW (2002) Estrogen Modulation of Endothelial Nitric Oxide Synthase. Endocr Rev 23(5):665–686 21. Moreau KL, Hildreth KL, Klawitter J, Blatchford P , Kohrt WM (2020) Decline in endothelial function across the menopause transition in healthy women is related to decreased estradiol and increased oxidative stress. Geroscience 42(6):1699–1714 22. Cassavaugh J, Longhi MS, Robson SC (2025) Impact of estrogen on purinergic signaling in microvascular disease. Int J Mol Sci. 26(5) 23. Kampka Z, Balwierz-Podgórna M, Wybraniec MT (2026) Sex hormone supple- mentation and cardiovascular disease risk. Medicina. 62(1) 24. SenthilKumar G, Katunaric B, Bordas-Murphy H, Sarvaideo J, Freed JK (2023) Estrogen and the vascular endothelium: the unanswered questions. endocrinology.164(6) 25. Glazier CR, Baciewicz FA (2024) Jr. Epidemiology, Etiology, and Pathophysiol- ogy of Pulmonary Embolism. Int J Angiol 33(2):76–81 26. Cicione A, Nacchia A, Guercio A, Gravina C, Franco A, Grimaldi MC et al (2023) Cardiovascular adverse events-related to GnRH agonists and GnRH antagonists: analysis of real-life data from Eudra-Vigilance and Food and Drug Administration databases entries. Prostate Cancer Prostatic Dis 26(4):765–771 27. Zondervan KT, Becker CM, Koga K, Missmer SA, Taylor RN (2018) Viganò P . Endometriosis. Nat Reviews Disease Primers 4(1):9 28. Okoli U, Charoenngam N, Ponvilawan B, Jaroenlapnopparat A, Mettler S, Obiejesie O (2023) Endometriosis and Risk of Cardiovascular Disease: System- atic Review and Meta-Analysis. J Womens Health (Larchmt) 32(12):1328–1339 29. Cavadias I, Maitrot-Mantelet L, Perol S, Bourdon M, Santulli P , Marcellin L et al (2026) Risk of cardiovascular disease and mortality among women with endometriosis: A systematic review and meta-analysis. Acta Obstet Gynecol Scand 105(2):225–237 30. Wang Y, Nicholes K, Shih I-M (2020) The Origin and Pathogenesis of Endome- triosis. Annu Rev Pathol 15(15, 2020):71–95 31. Szpila G, Szczotka J, Suchodolski A, Szulik M (2025) Endometriosis and Car- diovascular Disease: Exploring Pathophysiological Interconnections and Risk Mechanisms. Diagnostics [Internet] 15(12):1458 p.] 32. Tulandi T, Vercellini P (2024) Growing evidence that endometriosis is a sys- temic disease. Reprod Biomed Online 49(3):104292 33. Ni C, Li D (2024) Ferroptosis and oxidative stress in endometriosis: A system- atic review of the literature. Med (Baltim) 103(11):e37421 34. Limam I, Abdelkarim M, Kacem-Berjeb K, Khrouf M, Feki A, Braham M et al (2025) Precision therapeutic and preventive molecular strategies for endometriosis-associated infertility. Int J Mol Sci. 26(16) Page 16 of 17 Lesani et al. Beni-Suef University Journal of Basic and Applied Sciences (2026) 15:119 35. Shifon S, Tyrinova T, Veretelnikova T, Pasman N, Chernykh E (2025) Endo- metriosis as an immune-mediated disease: pathogenetic mechanisms and therapeutic strategies. Front Immunol 16:1727183 36. Zahiri Z, Alborzi S, Hosseini SSM, Sharifian F, Farahani N, Goodarzi V et al (2026) Lesion-centric reprogramming: hydrogel-enabled photothermal reset of endometriosis pain. Int Immunopharmacol 183:116882 37. Mandel J, Casari M, Stepanyan M, Martyanov A, Deppermann C (2022) Beyond Hemostasis: Platelet Innate Immune Interactions and Throm- boinflammation. Int J Mol Sci [Internet] 23(7):3868 p.] 38. Amirlatifi S, Forouzin S, Sadati E, Moradpanah S, Fazeli R, Panahinia P et al (2025) Ovarian cancer, neutrophil hitchhiking, and NETs: unraveling their role in pathogenesis and management. Med Oncol 42(8):302 39. Moradpanah S, Aghaei ZH, Eslamnik P , Goldiani NK, Sargolzaei Z, Doosty F et al (2025) NETs in ovarian cancer progression: innovative nanoparticle-based therapeutic strategies. Eur J Med Res 30(1):1199 40. Casalechi M, Tripodi A, Reis FM, Carullo G, Mondini I, Di Stefano G et al (2023) The link between inflammation and hemostasis in endometriosis: a call for research. J Endometr Uterine Disorders 3:100040 41. Naghinezhad J, Mohajerian A, Ahadi S, Khodakarim N, Hamblin MR, Reza- eeyan H (2026) When GPVI Goes Rogue: Pathogenesis and Therapeutic Horizons in ITP . Expert Rev Mol Med 28:e20 42. Naghinezhad J, Kamali Yazdi E, Mohajerian A, Yousefi Chermehini N, Ghana- vati P , Motamedi H et al (2026) The tumor-platelet-immune interface: driving metastasis, pre-metastatic niche formation, and therapeutic vulnerabilities. Expert Rev Mol Med.1–34 43. Heydari F, Zendehdel H, Varkiani MM, Fahmi S, Derakhshani M, Anvari S et al (2026) Guided immunotherapy for residual solid tumor: integrating platelets and CAR T cells to reduce post-surgical recurrence. Biomark Res 44. Hisada Y, Sachetto ATA, Mackman N (2022) Circulating tissue factor-positive extracellular vesicles and their association with thrombosis in different diseases. Immunol Rev 312(1):61–75 45. Morrow GB, Mutch NJ (2023) Past, Present, and Future Perspectives of Plas- minogen Activator Inhibitor 1 (PAI-1). Semin Thromb Hemost 49(3):305–313 46. Noris M, Galbusera M (2023) The complement alternative pathway and hemostasis. Immunol Rev 313(1):139–161 47. de Queiroz DB, Parente JM, Pernomian L, Waigi EW, Alfaidi M, Tan W et al (2025) Endothelial Cell Phenotypic Plasticity in Cardiovascular Physiology and Disease: Mechanisms and Therapeutic Prospects. Am J Hypertens 38(7):411–421 48. Pilard M, Ollivier EL, Gourdou-Latyszenok V, Couturaud F, Lemarié CA (2022) Endothelial Cell Phenotype, a Major Determinant of Venous Thrombo-Inflam- mation. Front Cardiovasc Med 9:864735 49. Le KTT, Keur N, Middelkamp H, Linh Do T, van den Berg A, Orlova V et al (2025) Cytokine-induced memory-like responses in endothelial cells link chronic inflammation to vascular disease risk. Mol Omics 21(6):706–722 50. Colling ME, Tourdot BE, Kanthi Y (2021) Inflammation, Infection and Venous Thromboembolism. Circ Res 128(12):2017–2036 51. Penna C, Pagliaro P , Endothelial Dysfunction (2025) Redox imbalance, NLRP3 inflammasome, and inflammatory responses in cardiovascular diseases. Antioxidants(Basel). 14(3) 52. Dzobo KE, Hanford KML, Kroon J (2021) Vascular Metabolism as Driver of Atherosclerosis: Linking Endothelial Metabolism to Inflammation. Immuno- metabolism 3(3):e210020 53. Förstermann U (2008) Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies. Nat Clin Pract Cardiovasc Med 5(6):338–349 54. Li Pomi F, Di Leo G, Genovese S, Borgia F, Gangemi S (2025) Redox network dysfunction: integrating ferroptosis and cuproptosis across human diseases. Antioxidants (Basel). 15(1) 55. Joffre J, Hellman J (2021) Oxidative Stress and Endothelial Dysfunction in Sepsis and Acute Inflammation. Antioxid Redox Signal 35(15):1291–1307 56. Chen K, Wang D, Qian M, Weng M, Lu Z, Zhang K et al (2024) Endothelial cell dysfunction and targeted therapeutic drugs in sepsis. Heliyon 10(13):e33340 57. Loo J, Spittle DA, Newnham M (2021) COVID-19, immunothrombosis and venous thromboembolism: biological mechanisms. Thorax 76(4):412–420 58. Zhou K, Chen Y, Pang J, Zhang J, Lu J (2026) The endothelial-immunothrom- botic storm in viral sepsis: lessons from COVID-19. Front Immunol. 2025;16 59. Hong CS, Chen YC, Ho CH, Hsieh KL, Chen M, Shih JY et al (2022) Association of Gonadotropin-Releasing Hormone Therapies With Venous Thromboem- bolic Events in Patients With Prostate Cancer: A National Cohort Study. Front Cardiovasc Med 9:794310 60. Etezadi A, Marashi SM, Nazari L, Sina M, Samadi Nasab F, Amirlatifi S et al (2025) Effects of GnRH agonists and antagonists on cardiovascular and meta- bolic systems in adults: Mechanistic pathways and risk management. Biomed Pharmacother 193:118860 61. Miraj S, Forood AMK, Azimi S, Panahinia P , Ebadi E, Moradpanah S et al (2025) The Cardiovascular Burden of Gonadotropin-Releasing Hormone (GnRH) Therapy: Mechanisms, Risks, and Interventions. Cardiovasc Toxicol 25(9):1411–1428 62. Chwalisz K (2023) Clinical development of the GnRH agonist leuprolide acetate depot. F S Rep 4(2 Suppl):33–39 63. Mendelsohn ME (2002) Genomic and nongenomic effects of estrogen in the vasculature. Am J Cardiol 90(1a):3f–6f 64. Haynes MP , Sinha D, Russell KS, Collinge M, Fulton D, Morales-Ruiz M et al (2000) Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells. Circ Res 87(8):677–682 65. Ganz P (2002) Vasomotor and vascular effects of hormone replacement therapy. Am J Cardiol 90(1a):11f–6f 66. Abou-Ismail MY, Citla Sridhar D, Nayak L (2020) Estrogen and thrombosis: A bench to bedside review. Thromb Res 192:40–51 67. Gebara OC, Mittleman MA, Sutherland P , Lipinska I, Matheney T, Xu P et al (1995) Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring Study. Circulation 91(7):1952–1958 68. Hashemzadeh M, Haseefa F, Peyton L, Park S, Movahed MR (2022) The effects of estrogen and hormone replacement therapy on platelet activity: a review. Am J Blood Res 12(1):33–42 69. Gilabert J, Estellés A, Cano A, España F, Barrachina R, Grancha S et al (1995) The effect of estrogen replacement therapy with or without progestogen on the fibrinolytic system and coagulation inhibitors in postmenopausal status. Am J Obstet Gynecol 173(6):1849–1854 70. Brown J, Pan A, Hart RJ (2010) Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database Syst Rev 2010(12):Cd008475 71. Rodríguez-Tárrega E, Monzo AM, Quiroga R, Polo-Sánchez P , Fernández- Colom P , Monterde-Estrada M et al (2020) Effect of GnRH agonist before IVF on outcomes in infertile endometriosis patients: a randomized controlled trial. Reprod Biomed Online 41(4):653–662 72. Guzick DS, Huang LS, Broadman BA, Nealon M, Hornstein MD (2011) Ran- domized trial of leuprolide versus continuous oral contraceptives in the treat- ment of endometriosis-associated pelvic pain. Fertil Steril 95(5):1568–1573 73. Veth VB, van de Kar MM, Duffy JM, van Wely M, Mijatovic V, Maas JW (2023) Gonadotropin-releasing hormone analogues for endometriosis. Cochrane Database Syst Rev 6(6):Cd014788 74. Bai M, Shen S, Chen JY (2026) Comparative post-marketing reporting signals of elagolix and myfembree in endometriosis: a FAERS pharmacovigilance study. Front Pharmacol 17:1860816 75. Hu JC, Williams SB, O’Malley AJ, Smith MR, Nguyen PL, Keating NL (2012) Androgen-deprivation therapy for nonmetastatic prostate cancer is associ- ated with an increased risk of peripheral arterial disease and venous throm- boembolism. Eur Urol 61(6):1119–1128 76. Modabber N, Mahboub SS, Khoshravesh S, Karimpour F, Karimi A, Goodarzi VA-OX evaluation of long non-coding RNA (LncRNA) in the pathogenesis of chemotherapy resistance in cervical cancer: diagnostic and prognostic approach. (1559 – 0305 (Electronic)). 77. Davey P , Alexandrou K (2022) Assessment and Mitigation of Cardiovascular Risk for Prostate Cancer Patients: A Review of the Evidence. Int J Clin Pract 2022:2976811 78. Stark K, Massberg S (2021) Interplay between inflammation and thrombosis in cardiovascular pathology. Nat Reviews Cardiol 18(9):666–682 79. Imiela AM, Kucharska J, Kukliński F, Fernandez Moreno T, Dzik K, Pruszczyk P (2025) Advanced Research in the Pathophysiology of Venous Thromboembo- lism–Acute Pulmonary Embolism. Biomedicines [Internet] 13(4):906 80. Navarrete S, Solar C, Tapia R, Pereira J, Fuentes E, Palomo I (2023) Pathophysi- ology of deep vein thrombosis. Clin Exp Med 23(3):645–654 81. Kuijpers MJE, Heemskerk JWM, Jurk K (2022) Molecular Mechanisms of Hemostasis, Thrombosis and Thrombo-Inflammation. Int J Mol Sci [Internet] 23(10):5825 p.] 82. Li W, Wang Z, Cg S, Liao Z, Pei Y, Wang J et al (2023) The effect of neutrophil extracellular traps in venous thrombosis. Thromb J 21(1):67 Page 17 of 17 Lesani et al. Beni-Suef University Journal of Basic and Applied Sciences (2026) 15:119 83. Shi Y, Gauer JS, Baker SR, Philippou H, Connell SD, Ariëns RAS (2021) Neutro- phils can promote clotting via FXI and impact clot structure via neutrophil extracellular traps in a distinctive manner in vitro. Sci Rep 11(1):1718 84. Özdemir L, Özdemir B, Gegin S, Aksu EA, Pazarlı AC (2025) Can Systemic Inflammatory Markers Be Used in Pulmonary Embolism Risk Assessment in Patients with Acute Pulmonary Thromboembolism? J Inflamm Res 18:5969–5977 85. McGregor L, Martin J, McGregor JL (2006) Platelet-leukocyte aggregates and derived microparticles in inflammation, vascular remodelling and thrombo- sis. Front Biosci 11:830–837 86. Farhid F, Rezaeeyan H, Habibi R, Kamali Yazdi E, Hamblin MR, Naghinezhad J (2025) When the victim becomes the villain: Platelets as drivers of immune dysregulation in ITP . J Translational Autoimmun 11:100309 87. Han J, Bloxham CJ, Kirmes K, Viggiani G, Unkelbach LP , von Scheidt M et al (2025) Platelet–leukocyte aggregates in cardiovascular disease: prognostic significance and therapeutic potential. Cardiovascular Res 121(11):1679–1696 88. Donadini MP , Calcaterra F, Romualdi E, Ciceri R, Cancellara A, Lodigiani C et al (2025) The Link Between Venous and Arterial Thrombosis: Is There a Role for Endothelial Dysfunction? Cells [Internet] 14(2):144 89. Ding J, Yue X, Tian X, Liao Z, Meng R, Zou M (2023) Association between inflammatory biomarkers and venous thromboembolism: a systematic review and meta-analysis. Thromb J 21(1):82 90. Deng Y, Lin X, Wei J, Chen B, Yan H, Wang B et al (2025) Endothelial cell iron overload and ferroptosis mediate thrombosis and inflammation through the miR-32-5p/neurofibromin 2 pathway. Eur J Med Res 30(1):463 91. Giudice LC, Oskotsky TT, Falako S, Opoku-Anane J, Sirota M (2023) Endometri- osis in the era of precision medicine and impact on sexual and reproductive health across the lifespan and in diverse populations. Faseb j 37(9):e23130 92. Califf RM (2018) Biomarker definitions and their applications. Exp Biol Med (Maywood) 243(3):213–221 93. Miceli G, Ciaccio AM, Tuttolomondo A (2025) From circulating biomarkers to polymorphic variants: a narrative review of challenges in thrombophilia evaluation. J Clin Med.;14(10) 94. Joy S, Kaliyamurthi V, Binesh A (2025) Emerging perspectives on biomarker panels in deep vein thrombosis: the combined roles of D-Dimer, P-Selectin, and Microparticles. Ann Vasc Surg.;122 95. Osório TG, Pavesi E, El-Ardat KA, Qureshi N, Cassidy L, St John TL et al (2025) Single-cell multi-omics for precision cardiovascular and longevity medicine: from methods to clinical translation. Front Aging 6:1656727 96. Yang P , Li H, Zhang J, Xu X (2021) Research progress on biomarkers of pulmo- nary embolism. Clin Respir J 15(10):1046–1055 97. Klenk C, Erber J, Fresacher D, Röhrl S, Lengl M, Heim D et al (2023) Platelet aggregates detected using quantitative phase imaging associate with COVID-19 severity. Commun Med 3(1):161 98. Liu C, Shen M, Tan WLW, Chen IY, Liu Y, Yu X et al (2023) Statins improve endo- thelial function via suppression of epigenetic-driven EndMT. Nat Cardiovasc Res 2(5):467–485 99. Watson HG, Chee YL (2008) Aspirin and other antiplatelet drugs in the pre- vention of venous thromboembolism. Blood Rev 22(2):107–116 100. Li X, Zou J, Lin A, Chi J, Hao H, Chen H et al (2024) Oxidative Stress, Endothe- lial Dysfunction, and N-Acetylcysteine in Type 2 Diabetes Mellitus. Antioxid Redox Signal 40(16–18):968–989 101. Yim SF, Lau TK, Sahota DS, Chung TK, Chang AM, Haines CJ (1998) Prospec- tive randomized study of the effect of add-back hormone replacement on vascular function during treatment with gonadotropin-releasing hormone agonists. Circulation 98(16):1631–1635 102. Yost CD, Callas B, Halligan P , Palumbo P , Rawal S, Leyfman Y et al (2026) Evaluation frameworks for predictive and generative oncology ai: current standards, cancer-specific gaps, and a path toward clinical use. Cancers (Basel).;18(12) 103. Khera R, Oikonomou EK, Nadkarni GN, Morley JR, Wiens J, Butte AJ et al (2024) Transforming Cardiovascular Care With Artificial Intelligence: From Discovery to Practice: JACC State-of-the-Art Review. J Am Coll Cardiol 84(1):97–114 104. Parsa S, Noroozpoor R, Dehghanbanadaki H, Khateri S, Moradi Y (2025) Endometriosis and risk of cardiovascular disease: a systematic review and meta-analysis. BMC Public Health 25(1):245 105. De Nardi AC, Coy-Canguçu A, Saito A, Florio MF, Marti G, Degasperi GR et al (2024) Immunothrombosis and its underlying biological mechanisms. Hematol Transfus Cell Therapy 46(1):49–57 106. McNeill AM, Zhang C, Stanczyk FZ, Duckles SP , Krause DN (2002) Estrogen Increases Endothelial Nitric Oxide Synthase via Estrogen Receptors in Rat Cerebral Blood Vessels. Stroke 33(6):1685–1691 107. Nelson AJ, Lopes RD, Hong H, Hua K, Slovin S, Tan S et al (2023) Cardiovascu- lar Effects of GnRH Antagonists Compared With Agonists in Prostate Cancer: A Systematic Review. JACC CardioOncol 5(5):613–624 108. Menichelli D, Cormaci VM, Marucci S, Franchino G, Del Sole F, Capozza A et al (2023) Risk of venous thromboembolism in autoimmune diseases: A compre- hensive review. Autoimmun rev 22(11):103447 109. Marcos-Jubilar M, Lecumberri R, Páramo JA (2023) Immunothrombosis: molecular aspects and new therapeutic perspectives. J Clin Med.;12(4) Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.