Extracellular mitochondria released from traumatized brains induced platelet procoagulant activity
Zilong Zhao,
Yuan Zhou,
Tristan Hilton,
Fanjian Li,
Cha Han,
Li Liu,
Hengjie Yuan,
Ying Li,
Xin Xu,
Xiaoping Wu,
Fangyi Zhang,
Perumal Thiagarajan,
Andrew Cap,
Fu-Dong Shi,
Jianning Zhang,
Jing-fei Dong
Affiliations
Zilong Zhao
BloodWorks Research Institute, Seattle, WA, USA;Tianjin Institute of Neurology, Departments of Neurosurgery and Neurology, Tianjin Medical University General Hospital, Tianjin, China
Yuan Zhou
BloodWorks Research Institute, Seattle, WA, USA;Tianjin Institute of Neurology, Departments of Neurosurgery and Neurology, Tianjin Medical University General Hospital, Tianjin, China
Tristan Hilton
BloodWorks Research Institute, Seattle, WA, USA
Fanjian Li
Tianjin Institute of Neurology, Departments of Neurosurgery and Neurology, Tianjin Medical University General Hospital, Tianjin, China
Cha Han
BloodWorks Research Institute, Seattle, WA, USA
Li Liu
Tianjin Institute of Neurology, Departments of Neurosurgery and Neurology, Tianjin Medical University General Hospital, Tianjin, China
Hengjie Yuan
Tianjin Institute of Neurology, Departments of Neurosurgery and Neurology, Tianjin Medical University General Hospital, Tianjin, China
Ying Li
Tianjin Institute of Neurology, Departments of Neurosurgery and Neurology, Tianjin Medical University General Hospital, Tianjin, China
Xin Xu
BloodWorks Research Institute, Seattle, WA, USA
Xiaoping Wu
BloodWorks Research Institute, Seattle, WA, USA
Fangyi Zhang
Department of Neurosurgery, University of Washington School of Medicine, Seattle, WA, USA
Perumal Thiagarajan
Departments of Medicine and Pathology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA
Andrew Cap
US Army Institute of Surgical Research, San Antonio, TX, USA
Fu-Dong Shi
Tianjin Institute of Neurology, Departments of Neurosurgery and Neurology, Tianjin Medical University General Hospital, Tianjin, China;Department of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA
Jianning Zhang
Tianjin Institute of Neurology, Departments of Neurosurgery and Neurology, Tianjin Medical University General Hospital, Tianjin, China
Jing-fei Dong
BloodWorks Research Institute, Seattle, WA, USA;Division of Hematology, Department of Medicine, University of Washington, School of Medicine, Seattle, WA, USA
Coagulopathy often develops soon after acute traumatic brain injury and its cause remains poorly understood. We have shown that injured brains release cellular microvesicles that disrupt the endothelial barrier and induce consumptive coagulopathy. Morphologically intact extracellular mitochondria accounted for 55.2% of these microvesicles, leading to the hypothesis that these extracellular mitochondria are metabolically active and serve as a source of oxidative stress that activates platelets and renders them procoagulant. In testing this hypothesis experimentally, we found that the extracellular mitochondria purified from brain trauma mice and those released from brains subjected to freeze-thaw injury remained metabolically active and produced reactive oxygen species. These extracellular mitochondria bound platelets through the phospholipid-CD36 interaction and induced α-granule secretion, microvesiculation, and procoagulant activity in an oxidant-dependent manner, but failed to induce aggregation. These results define an extracellular mitochondria-induced and redox-dependent intermediate phenotype of platelets that contribute to the pathogenesis of traumatic brain injury-induced coagulopathy and inflammation.
