BloodWorks Research Institute, Seattle, WA, USA.
Tianjin Institute of Neurology, Departments of Neurosurgery and Neurology, Tianjin Medical University General Hospital, Tianjin, China.
Haematologica. 2020 Jan;105(1):209-217. doi: 10.3324/haematol.2018.214932. Epub 2019 Apr 11.
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.
创伤性脑损伤后常很快发生凝血病，但发病机制仍不清楚。我们发现损伤的大脑会释放细胞微泡，破坏血管内皮屏障并导致消耗性凝血病。这些微泡中形态完整的细胞外线粒体占 55.2%，这促使我们提出假设，即这些细胞外线粒体具有代谢活性，可作为氧化应激的来源，激活血小板使其促凝。在实验中验证这一假说时，我们发现从创伤性脑损伤小鼠中纯化的细胞外线粒体和经历冻融损伤的大脑中释放的细胞外线粒体仍然具有代谢活性，并产生活性氧。这些细胞外线粒体通过磷脂-CD36 相互作用与血小板结合，并以依赖氧化剂的方式诱导α-颗粒释放、微泡形成和促凝活性，但不能诱导聚集。这些结果定义了一种细胞外线粒体诱导的、依赖氧化还原的血小板中间表型，有助于创伤性脑损伤诱导的凝血病和炎症的发病机制。
