title: Cardiolipin-mediated procoagulant activity of mitochondria contributes to traumatic brain injury-associated coagulopathy in mice.
abstract: Cardiolipin (CL) is an anionic phospholipid located exclusively in the mitochondrial inner membrane. Its presence in blood indicates mitochondrial damage and release from injured cells. Here, we report the detection of CL-exposed brain-derived mitochondrial microparticles (mtMPs) at 17 547 ± 2677/μL in the peripheral blood of mice subjected to fluid percussion injury to the brain. These mtMPs accounted for 55.2% ± 12.6% of all plasma annexin V-binding microparticles found in the acute phase of injury. They were also released from cultured neuronal and glial cells undergoing apoptosis. The mtMPs synergized with platelets to facilitate vascular leakage by disrupting the endothelial barrier. The disrupted endothelial barrier allowed the release of mtMPs into the systemic circulation to promote coagulation in both traumatically injured and mtMP- or CL-injected mice, leading to enhanced fibrinolysis, vascular fibrin deposition, and thrombosis. This mtMP-induced coagulation was mediated by CL transported from the inner to the outer mitochondrial membrane and was blocked by the scavenging molecule lactadherin. The mtMP-bound CL was ∼1600 times as active as purified CL in promoting coagulation. This study uncovered a novel procoagulant activity of CL and CL-exposed mitochondria that may contribute to traumatic brain injury-associated coagulopathy and identified potential pathways to block this activity.
authors.affiliation: Department of Neurosurgery, Tianjin Institute of Neurology, Tianjin Medical University General Hospital, Tianjin, China; BloodWorks Northwest Research Institute, Seattle, WA;
authors.forename: Zilong
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China;
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Tianjin Institute of Neurology, Tianjin Medical University General Hospital, Tianjin, China;
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: BloodWorks Northwest Research Institute, Seattle, WA;
authors.forename: Tristan
authors.initials: T
authors.lastname: Hilton
authors.affiliation: BloodWorks Northwest Research Institute, Seattle, WA;
authors.forename: Breia
authors.initials: B
authors.lastname: Salsbery
authors.affiliation: BloodWorks Northwest Research Institute, Seattle, WA;
authors.forename: Eric Z
authors.initials: EZ
authors.lastname: Zhou
authors.affiliation: BloodWorks Northwest Research Institute, Seattle, WA;
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pathology and Department of Medicine, Baylor College of Medicine, Houston, TX;
authors.forename: Perumal
authors.initials: P
authors.lastname: Thiagarajan
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Department of Infectious Diseases and Immunity, Université Laval and Faculté de Médecine de l'Université Laval, Quebec City, QC, Canada; and.
authors.forename: Eric
authors.initials: E
authors.lastname: Boilard
authors.affiliation: Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China;
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Tianjin Institute of Neurology, Tianjin Medical University General Hospital, Tianjin, China;
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhang
authors.affiliation: BloodWorks Northwest Research Institute, Seattle, WA; Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, WA.
authors.forename: Jing-Fei
authors.initials: JF
authors.lastname: Dong
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000097:blood; D000954:Antigens, Surface / Q000097:blood; D001778:Blood Coagulation Disorders / Q000097:blood*; D000070642:Brain Injuries, Traumatic / Q000097:blood* / Q000150:complications; D002308:Cardiolipins / Q000097:blood*; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D051379:Mice; D008894:Milk Proteins / Q000097:blood; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*
chemical_list: D017304:Annexin A5; D000954:Antigens, Surface; D002308:Cardiolipins; C490919:Mfge8 protein, mouse; D008894:Milk Proteins