Extracellular Mitochondria in Traumatic Brain Injury Induced Coagulopathy

Abstract

Traumatic brain injury (TBI) induced coagulopathy remains a significant clinical challenge, with unmet needs for standardizing diagnosis and optimizing treatments. TBI-induced coagulopathy is closely associated with poor outcomes in affected patients. Recent studies have demonstrated that TBI induces coagulopathy, which is mechanistically distinct from the deficient and dilutional coagulopathy found in patients with injuries to the body/limbs and hemorrhagic shock. Multiple causal and disseminating factors have been identified to cause TBI-induced coagulopathy. Among these are extracellular mitochondria (exMTs) released from injured cerebral cells, endothelial cells, and platelets. These circulating exMTs not only express potent procoagulant activity but also promote inflammation, and could remain metabolically active to become a major source of oxidative stress. They activate platelets and endothelial cells to propagate TBI-induced coagulopathy and secondary tissue injury after primary traumatic impact. In this review, we discuss recent advances in our understanding of the role of exMTs in the development of TBI-induced coagulopathy.

Platelets fuel mesenchymal stem cells by providing live mitochondria

“…Finally, the results from this study add to a growing body of evidence that mitochondria can be released into the extracellular space and transferred between cells, 9,16–18 suggesting a common pathway of cell‐to‐cell communication through live mitochondria. This communication can regulate both the physiology and pathophysiology of cells, depending on the types of cells and the environment.…”

“…The latter is a passive process that occurs during tissue injury or after apoptosis. We have shown that traumatically injured brain cells release metabolically competent mitochondria into circulation, 9 likely through this passive process. Platelet activation has been considered by some as the process of apoptosis, 10,11 but it is less likely in this case because platelets release functional mitochondria, instead of condensed and damaged mitochondria found during apoptosis.…”

“…(3) Do the mitochondria released from activated platelets differ structurally from those inside platelets? The mitochondria released from injured brains maintain their metabolic activity, but also express the anionic phospholipid cardiolipin on their surface 9 . Cardiolipin is located exclusively in the inner membrane of intracellular mitochondria during homeostasis, 12 suggesting structural changes of the mitochondrial membrane.…”

Acrolein Induces Systemic Coagulopathy via Autophagy-dependent Secretion of von Willebrand Factor in Mice after Traumatic Brain Injury

“…Previous studies have shown that TBI-induced coagulopathy manifests as a hypercoagulable state induced by pro-coagulant molecules (such as tissue factors, phosphatidylserine, and Wenxing Cui, Xun Wu, and Dayun Feng contributed equally to this work. cardiolipin) released from injured brain tissue; this then develops into a late consumptive hypocoagulable state [5,[8][9][10]. However, the removal of these pro-coagulant molecules does not completely correct the coagulation dysfunction [11], which suggests that there may be other molecules involved in TBI-induced coagulopathy.…”

The Complexity of Trauma-Induced Coagulopathy

“…The changes in traumatic brain injury are reviewed by Maegele et al, 5 whereas Zhao et al discuss the role of mitochondria in brain injury. 6 There are also differences in organ-specific contributions to coagulopathy, requiring ongoing investigation to better understand the pathophysiology of TIC. Combining all trauma patients into one category of TIC will provide a limitation in understanding the complete picture of what drives coagulopathic bleeding and mortality in affected patients.…”