{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:19:28Z","timestamp":1787019568679,"version":"build-2736575974"},"reference-count":50,"publisher":"American Society of Hematology","issue":"25","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,12,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Severe traumatic brain injury (TBI) often causes an acute systemic hypercoagulable state that rapidly develops into consumptive coagulopathy. We have recently demonstrated that TBI-induced coagulopathy (TBI-IC) is initiated and disseminated by brain-derived extracellular vesicles (BDEVs) and propagated by extracellular vesicles (EVs) from endothelial cells and platelets. Here, we present results from a study designed to test the hypothesis that anticoagulation targeting anionic phospholipid-expressing EVs prevents TBI-IC and improves the outcomes of mice subjected to severe TBI. We evaluated the effects of a fusion protein (ANV-6L15) for improving the outcomes of TBI in mouse models combined with in vitro experiments. ANV-6L15 combines the phosphatidylserine (PS)-binding annexin V (ANV) with a peptide anticoagulant modified to preferentially target extrinsic coagulation. We found that ANV-6L15 reduced intracranial hematoma by 70.2%, improved neurological function, and reduced death by 56.8% in mice subjected to fluid percussion injury at 1.9 atm. It protected the TBI mice by preventing vascular leakage, tissue edema, and the TBI-induced hypercoagulable state. We further showed that the extrinsic tenase complex was formed on the surfaces of circulating EVs, with the highest level found on BDEVs. The phospholipidomic analysis detected the highest levels of PS on BDEVs, as compared with EVs from endothelial cells and platelets (79.1, 15.2, and 3.5 nM\/mg of protein, respectively). These findings demonstrate that TBI-IC results from a trauma-induced hypercoagulable state and may be treated by anticoagulation targeting on the anionic phospholipid-expressing membrane of EVs from the brain and other cells.<\/jats:p>","DOI":"10.1182\/blood.2021011310","type":"journal-article","created":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T09:16:55Z","timestamp":1633684615000},"page":"2714-2726","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":30,"title":["Anticoagulation targeting membrane-bound anionic phospholipids improves outcomes of traumatic brain injury in mice"],"prefix":"10.1182","volume":"138","author":[{"given":"Xinlong","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China;"},{"name":"Bloodworks Research Institute, Seattle, WA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Pathology, School of Medical Sciences and Gansu Provincial Key Laboratory of Preclinical Study for New Drug Development, Lanzhou University, Lanzhou, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Shen","sequence":"additional","affiliation":[{"name":"Bloodworks Research Institute, Seattle, WA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Houck","sequence":"additional","affiliation":[{"name":"Bloodworks Research Institute, Seattle, WA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengchen","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zilong","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Wu","sequence":"additional","affiliation":[{"name":"Department\u00a0of Pathology, University of Washington School of Medicine, Seattle, WA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teri","family":"Blevins","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, Fred Hutch Cancer Center, Seattle, WA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda L.","family":"Koehne","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, Fred Hutch Cancer Center, Seattle, WA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5823-4166","authenticated-orcid":false,"given":"Tze-Chein","family":"Wun","sequence":"additional","affiliation":[{"name":"EVAS Therapeutics, LLC, Ballwin, MO; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyun","family":"Fu","sequence":"additional","affiliation":[{"name":"Bloodworks Research Institute, Seattle, WA;"},{"name":"Division of Hematology, Department of Medicine, University of Washington, School of Medicine, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Pathology, School of Medical Sciences and Gansu Provincial Key Laboratory of Preclinical Study for New Drug Development, Lanzhou University, Lanzhou, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianning","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6379-4133","authenticated-orcid":false,"given":"Jing-fei","family":"Dong","sequence":"additional","affiliation":[{"name":"Bloodworks Research Institute, Seattle, WA;"},{"name":"Division of Hematology, Department of Medicine, University of Washington, School of Medicine, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"6","key":"2021122316302692400_B1","first-page":"1459","article-title":"Increased mortality associated with the early coagulopathy of trauma in combat casualties","volume":"64","author":"Niles","year":"2008","journal-title":"J 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