Publication Date
1-1-2020
Journal
Haematologica
DOI
10.3324/haematol.2018.214932
PMID
30975909
PMCID
PMC6939511
PubMedCentral® Posted Date
4-11-2019
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, Blood Coagulation Disorders, Blood Platelets, Cell-Derived Microparticles, Mice, Mitochondria, Platelet Aggregation, Reactive Oxygen Species
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 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.