Anticoagulation Targeting Membrane-Bound Anionic Phospholipids Improved Outcomes of Traumatic Brain Injury in Mice


Posted: 2021-10-05 19:00:00
. 2021 Oct 5;blood.2021011310. doi: 10.1182/blood.2021011310. Online ahead of print. Xinlong Dong 1 , Wei Liu 2 , Yu Shen 3 , Katie L Houck 4 , Mengchen Yang 1 , Yuan Zhou 5 , Zilong Zhao 6 , Xiaoping Wu 7 , Teri Blevins 8 , Amanda L Koehne 9 , Tze-Chein Wun 10 , Xiaoyun Fu 11 , Min Li 12 , Jianning Zhang 13 , Jing-Fei Dong 14 Affiliations Expand Affiliations 1 Bloodworks Research Institute, United States. 2 Institute of Pathology, School of Medical Sciences and Gansu Provincial Key Laboratory of Preclinical Study for New Drug Development, Lanzhou University, Lanzhou, China. 3 Bloodworks NW Research Institute, Seattle, Washington, United States. 4 Bloodworks Northwest Research Institute, Seattle, Washington, United States. 5 Tianjin Medical University General Hospital. 6 Tianjin Neurological Institute; Department of Neurosurgery, Tianjin General Hospital, Tianjin, China. 7 Department of Pathology, University of Washington School of Medicine, Seattle, Washington, United States. 8 Fred Hutchinson Cancer Research Center, Seattle, Washington, United States. 9 Department of Comparative Medicine, the Fred Hutch Cancer Center, Seattle, Washington, United States. 10 EVAS Therapeutics, Ballwin, Missouri, United States. 11 Division of Hematology, Department of Medicine, University of Washington, School of Medicine, United States. 12 Pathology, Lanzhou, China. 13 Tianjin Medical University General Hospital, Tianjin, China. 14 Division of Hematology, Department of Medicine, University of Washington, School of Medicine, Seattle, WA, United States. Item in Clipboard Xinlong Dong et al. Blood. 2021. Show details Display options Display options Format . 2021 Oct 5;blood.2021011310. doi: 10.1182/blood.2021011310. Online ahead of print. Authors Xinlong Dong 1 , Wei Liu 2 , Yu Shen 3 , Katie L Houck 4 , Mengchen Yang 1 , Yuan Zhou 5 , Zilong Zhao 6 , Xiaoping Wu 7 , Teri Blevins 8 , Amanda L Koehne 9 , Tze-Chein Wun 10 , Xiaoyun Fu 11 , Min Li 12 , Jianning Zhang 13 , Jing-Fei Dong 14 Affiliations 1 Bloodworks Research Institute, United States. 2 Institute of Pathology, School of Medical Sciences and Gansu Provincial Key Laboratory of Preclinical Study for New Drug Development, Lanzhou University, Lanzhou, China. 3 Bloodworks NW Research Institute, Seattle, Washington, United States. 4 Bloodworks Northwest Research Institute, Seattle, Washington, United States. 5 Tianjin Medical University General Hospital. 6 Tianjin Neurological Institute; Department of Neurosurgery, Tianjin General Hospital, Tianjin, China. 7 Department of Pathology, University of Washington School of Medicine, Seattle, Washington, United States. 8 Fred Hutchinson Cancer Research Center, Seattle, Washington, United States. 9 Department of Comparative Medicine, the Fred Hutch Cancer Center, Seattle, Washington, United States. 10 EVAS Therapeutics, Ballwin, Missouri, United States. 11 Division of Hematology, Department of Medicine, University of Washington, School of Medicine, United States. 12 Pathology, Lanzhou, China. 13 Tianjin Medical University General Hospital, Tianjin, China. 14 Division of Hematology, Department of Medicine, University of Washington, School of Medicine, Seattle, WA, United States. Item in Clipboard CiteDisplay options Display options Format Abstract 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. ANV-6L15 combines the phosphatidylserine (PS)-binding annexin V 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. Phospholipidomic analysis detected the highest levels of PS on BDEVs, as compared to 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. Copyright © 2021 American Society of Hematology. [x] Cite Copy Format: Send To [x]

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