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Coagulation & its Disorders
Extracellular mitochondria released from traumatized brains induced platelet procoagulant activity
Ferrata Storti Foundation
Haematologica 2020 Volume 105(1):209-217
Zilong Zhao,1,2 Yuan Zhou,1,2 Tristan Hilton,1 Fanjian Li,2 Cha Han,1 Li Liu,2 Hengjie Yuan,2 Ying Li,2 Xin Xu,1 Xiaoping Wu,1 Fangyi Zhang,3
Perumal Thiagarajan,4 Andrew Cap,5 Fu-Dong Shi,2,6 Jianning Zhang2
and Jing-fei Dong1,7
1BloodWorks Research Institute, Seattle, WA, USA; 2Tianjin Institute of Neurology, Departments of Neurosurgery and Neurology, Tianjin Medical University General Hospital, Tianjin, China; 3Department of Neurosurgery, University of Washington School of Medicine, Seattle, WA, USA; 4Departments of Medicine and Pathology, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA; 5US Army Institute of Surgical Research, San Antonio, TX, USA; 6Department of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA and 7Division of Hematology, Department of Medicine, University of Washington, School of Medicine, Seattle, WA, USA
ABSTRACT
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 endothe- lial 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 metabol- ically 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 proco- agulant activity in an oxidant-dependent manner, but failed to induce aggre- gation. 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 inflam- mation.
Introduction
Traumatic brain injury (TBI) induces coagulopathy that promotes secondary bleeding and propagates cerebral injury,1 resulting in poor clinical outcomes of the patients.2-6 Laboratory findings suggest that coagulopathy results from a hypercoag- ulable state that rapidly develops into consumptive coagulopathy.1,7 This consump- tive coagulopathy has been recapitulated in animal models of TBI with thrombotic and hemorrhagic manifestations in the pulmonary and cerebral microvasculature.8,9 Despite strong clinical and laboratory evidence of its presence and association with poor clinical outcomes, the pathogenesis of TBI-associated coagulopathy remains poorly understood.
We have recently shown in mouse models that cellular microvesicles released from traumatically injured brains disrupt endothelial cell junctions through a syn- ergistic action with platelets.8 These brain-derived microvesicles are highly proco- agulant due to the abundant expression of surface-exposed anionic phospholipids and tissue factor. The sudden and substantial release of brain-derived microvesicles into the circulation results in a consumptive coagulopathy that is characterized by progressive fibrinogen depletion from plasma and fibrin deposition in the vascula- ture.8
Correspondence:
JING-FEI DONG
jfdong@bloodworksnw.org
JIANNING ZHANG
jianningzhang@hotmail.com
Received: December 18, 2018. Accepted: April 9, 2019. Pre-published: April 11, 2019.
doi:10.3324/haematol.2018.214932
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/1/207
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