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Endothelial cell\u2010specific molecule\u20101 (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\u2010dimer increases diagnostic discrimination. The anticoagulant potential of ESM1 is assessed using time\u2010to\u2010occlusion (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\n                    <jats:italic>esm1<\/jats:italic>\n                    in zebrafish results in vascular occlusion in the cardinal vein, whereas\n                    <jats:italic>esm1<\/jats:italic>\n                    overexpression dose\u2010dependently reduces venous thrombosis and prolongs TTO. Similarly,\n                    <jats:italic>Esm1<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1002\/advs.202515994","type":"journal-article","created":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T06:10:27Z","timestamp":1768025427000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Endothelial Cell\u2010Specific Molecule\u20101 (ESM1): An Endogenous Anticoagulant and Protective Factor in Venous Thrombosis"],"prefix":"10.1002","volume":"13","author":[{"given":"Changsheng","family":"Chen","sequence":"first","affiliation":[{"name":"School of Life Sciences, Co\u2010innovation Center of Neuroregeneration Nantong University  Nantong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojuan","family":"Ge","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Co\u2010innovation Center of Neuroregeneration Nantong University  Nantong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongxu","family":"Fu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Co\u2010innovation Center of Neuroregeneration Nantong University  Nantong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haijun","family":"Mei","sequence":"additional","affiliation":[{"name":"Department of Interventional and Vascular Surgery Affiliated Hospital of Nantong University  Nantong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Lv","sequence":"additional","affiliation":[{"name":"Nantong Science and Technology College  Nantong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Special Environmental Medicine Nantong University  Nantong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahao","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Co\u2010innovation Center of Neuroregeneration Nantong University  Nantong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhong","family":"Shen","sequence":"additional","affiliation":[{"name":"Medical College of Nantong University  Nantong China"},{"name":"State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center For Translational Medicine Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bowen","family":"Li","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Co\u2010innovation Center of Neuroregeneration Nantong University  Nantong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoning","family":"Wang","sequence":"additional","affiliation":[{"name":"Research Center of Clinical Medicine Affiliated Hospital of Nantong University  Nantong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2764-6544","authenticated-orcid":false,"given":"Dong","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Co\u2010innovation Center of Neuroregeneration Nantong University  Nantong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,9]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.26996"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature06797"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.853119"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.50.33566"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1877-1173(10)93015-9"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood\u20102007\u201012\u2010127928"},{"key":"e_1_2_9_8_1","first-page":"233","article-title":"Activation of Heparin Cofactor II by Heparin and Dermatan Sulfate","volume":"26","author":"Tollefsen D. 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