{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T17:31:42Z","timestamp":1786383102446,"version":"build-2736575974"},"reference-count":0,"publisher":"American Society of Hematology","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Heparin-induced thrombocytopenia (HIT) is a life-threatening prothrombotic disorder with substantial clinical mortality, characterized by pathologic antibody formation against platelet factor 4 (PF4)-heparin complexes. This study identified early pathologic mechanisms that initiate HIT immune complex formation and regulate thrombosis development. We found that repeated heparin administration over five days markedly enhanced platelet activation which implies an additional activating mechanism. Through plasma proteomic analysis, we observed that histidine-rich glycoprotein (HRG) levels were significantly reduced following successive heparin administration, and inversely related to platelet activation. Mechanistically, heparin and PF4 suppressed HRG expression via inhibiting the FGFR-ERK-Elk1 pathway whereby Elk1 directly binds to the HRG promoter region to regulate its liver expression. Physiological levels of HRG potently inhibited platelet activation, procoagulant activity, spreading, and aggregation, and significantly reduced thrombus formation under flow conditions. HRG bound to activated \u03b1IIb\u03b23 integrin in a zinc-dependent manner, thereby blocking its ligand-binding capacity. HRG also inhibited the formation of ultralarge PF4-heparin complexes (ULCs), disrupted the immune complexes (ULICs) comprising the HIT-like antibody KKO and ULCs, and blocked the binding of KKO to PF4\/heparin on platelets. Furthermore, HRG attenuated ULCs-triggered autoantibody generation, inhibited the ULICs-induced neutrophil extracellular traps and microvascular thrombosis formation both in vitro and in a mouse model of HIT. In conclusion, our work establishes HRG as a pivotal regulator of pathologic immune responses and thrombosis in HIT, providing mechanistic insights into disease pathogenesis.<\/jats:p>","DOI":"10.1182\/blood.2026033378","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T17:10:28Z","timestamp":1786381828000},"update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":0,"title":["The hepatic FGFR-ERK-HRG axis regulates heparin-induced thrombocytopenia with thrombosis"],"prefix":"10.1182","author":[{"given":"Shaoyun","family":"Zhou","sequence":"first","affiliation":[{"name":"Ocean University of China, Qingdao, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Ocean University of China, Qingdao, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel 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