title: Brain-derived microparticles induce systemic coagulation in a murine model of traumatic brain injury.
abstract: Traumatic brain injury (TBI) is associated with coagulopathy, although it often lacks 2 key risk factors: severe bleeding and significant fluid resuscitation associated with hemorrhagic shock. The pathogenesis of TBI-associated coagulopathy remains poorly understood. We tested the hypothesis that brain-derived microparticles (BDMPs) released from an injured brain induce a hypercoagulable state that rapidly turns into consumptive coagulopathy. Here, we report that mice subjected to fluid percussion injury (1.9 ± 0.1 atm) developed a BDMP-dependent hypercoagulable state, with peak levels of plasma glial cell and neuronal BDMPs reaching 17 496 ± 4833/μL and 18 388 ± 3657/μL 3 hours after TBI, respectively. Uninjured mice injected with BDMPs developed a dose-dependent hyper-turned hypocoagulable state measured by a progressively prolonged clotting time, fibrinogen depletion, and microvascular fibrin deposition in multiple organs. The BDMPs were 50 to 300 nm with intact membranes, expressing neuronal or glial cell markers and procoagulant phosphatidylserine and tissue factor. Their procoagulant activity was greater than platelet microparticles and was dose-dependently blocked by lactadherin. Microparticles were produced from injured hippocampal cells, transmigrated through the disrupted endothelial barrier in a platelet-dependent manner, and activated platelets. These data define a novel mechanism of TBI-associated coagulopathy in mice, identify early predictive markers, and provide alternative therapeutic targets.
authors: Tianjin Neurological Institute, Department of Neurosurgery, General Hospital, Tianjin Medical University, Tianjin, China; Puget Sound Blood Research Institute, Seattle, WA;
authors: Ye
authors: Y
authors: Tian
authors: Puget Sound Blood Research Institute, Seattle, WA;
authors: Breia
authors: B
authors: Salsbery
authors: Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China;
authors: Min
authors: M
authors: Wang
authors: Tianjin Neurological Institute, Department of Neurosurgery, General Hospital, Tianjin Medical University, Tianjin, China; Puget Sound Blood Research Institute, Seattle, WA;
authors: Hengjie
authors: H
authors: Yuan
authors: Puget Sound Blood Research Institute, Seattle, WA;
authors: Jing
authors: J
authors: Yang
authors: Tianjin Neurological Institute, Department of Neurosurgery, General Hospital, Tianjin Medical University, Tianjin, China;
authors: Zilong
authors: Z
authors: Zhao
authors: Puget Sound Blood Research Institute, Seattle, WA;
authors: Xiaoping
authors: X
authors: Wu
authors: Tianjin Neurological Institute, Department of Neurosurgery, General Hospital, Tianjin Medical University, Tianjin, China;
authors: Yanjun
authors: Y
authors: Zhang
authors: Puget Sound Blood Research Institute, Seattle, WA; Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, WA;
authors: Barbara A
authors: BA
authors: Konkle
authors: Departments of Pathology and Medicine, Baylor College of Medicine, Houston, TX; and Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey VA Medical Center, Houston, TX.
authors: Perumal
authors: P
authors: Thiagarajan
authors: Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China;
authors: Min
authors: M
authors: Li
authors: Tianjin Neurological Institute, Department of Neurosurgery, General Hospital, Tianjin Medical University, Tianjin, China;
authors: Jianning
authors: J
authors: Zhang
authors: Puget Sound Blood Research Institute, Seattle, WA; Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, WA;
authors: Jing-Fei
authors: JF
authors: Dong
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001777:Blood Coagulation; D001921:Brain / Q000473:pathology* / Q000648:ultrastructure; D001930:Brain Injuries / Q000097:blood* / Q000473:pathology*; D055252:Cell-Derived Microparticles / Q000473:pathology / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
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