Endothelial Cell‐Specific Molecule‐1 (ESM1): An Endogenous Anticoagulant and Protective Factor in Venous Thrombosis

ABSTRACT Deficiencies in endogenous anticoagulation pathways can lead to vascular occlusion and thrombosis. Endothelial cell‐specific molecule‐1 (ESM1), a proteoglycan secreted by endothelial cells, is elevated in patients with venous thromboembolism (VTE), yet its role in coagulation regulation remains undefined. Serum ESM1 concentrations are significantly higher in individuals with VTE (498.54 pg/mL) than in healthy controls (198.68 pg/mL), and the combination of ESM1 and D‐dimer increases diagnostic discrimination. The anticoagulant potential of ESM1 is assessed using time‐to‐occlusion (TTO) assays in zebrafish and mouse models, complemented by in vitro analyses of endogenous thrombin inhibitor activation. The anticoagulant effect of recombinant human ESM1 was further examined in mouse model. Loss of esm1 in zebrafish results in vascular occlusion in the cardinal vein, whereas esm1 overexpression dose‐dependently reduces venous thrombosis and prolongs TTO. Similarly, Esm1 knockout in mice leads to an alteration of coagulation function, which is rescued by human ESM1 protein. Mechanistically, ESM1's anticoagulant function is found to rely on its covalently linked glycosaminoglycans (GAGs), which activate the thrombin inhibitor heparin cofactor II (HCII). This study uncovers a novel function of ESM1 in anticoagulation through HCII activation, highlighting its potential as a therapeutic target for preventing venous thrombus formation.