Extracellular mitochondria released from traumatized brains induced platelet procoagulant activity

Platelets and Fibrinogen: Emerging Complexity in Trauma-Induced Coagulopathy

“…There is evidence that free mitochondria and brain-derived microparticles released from injured brain tissue in traumatic brain injury (TBI) also directly activate platelets, causing them to degranulate and circulate in a procoagulant state. 39,40 This process is augmented by endothelial VWF release and is associated with vascular leakage, another sequela of major injury. 41…”

Extracellular Mitochondria in Traumatic Brain Injury Induced Coagulopathy

“…These findings add to a growing body of evidence that mitochondria can be released into the extracellular space and transferred between cells. [23][24][25] The question remains as to whether mitochondria are released exclusively from apoptotic or injured cells or from cells undergoing normal renewal as well. In a phospholipidomic study, high levels of the brain-specific mitochondrial anionic phospholipid cardiolipin (1,3-bis(sn-3′-phosphatidyl)-sn-glycerol) were detected in peripheral blood samples collected from neonatal rats subjected to TBI, in parallel with the reduction of cardiolipin in injured brain tissue.…”

“…38 In addition to promoting coagulation through cardiolipin, exMTs promote coagulation by binding and activating platelets and other cells to expose anionic phospholipids and release procoagulant EVs. 24,40 Platelet activation could also contribute to the cerebral infarction found in approximately 10% of TBI patients detected by neuroimaging 41 and histopathology. 4,42,43 The platelet-and fibrin-rich cerebral intravascular microthrombi have also been detected by histopathology in experimental animals subjected to severe TBI.…”

“…75,76 We have recently shown that exMTs circulating in mice subjected to severe TBI are metabolically active and produce adenosine triphosphate (ATP) and ROS. 24 These exMTs bind platelets through the phospholipid receptor CD36 (platelet glycoprotein [GP] 4) to locally release ROS, which induces an intermediate platelet phenotype characterized by α-granule secretion, microvesiculation, and procoagulant activity, but minimal aggregation. These results are consistent with previous reports that ROS activates platelets.…”

“…83 The peroxidation of membrane-bound cardiolipin has been implicated in autophagy, apoptosis, and inflammation. [84][85][86] ROS produced from circulating exMTs could become a major source of persistent and targeted oxidative stress in blood as compared with chemical oxidants because (1) ROS can be produced continuously from metabolically active exMTs, (2) ROS released from intracellular mitochondria is rapidly neutralized in the highly reducing environment of the cytoplasm, but blood is only mildly reducing, [87][88][89][90] allowing the prolonged presence of exMT-derived oxidants in circulation, and (3) exMTs can bind target cells such as platelets 24 to localize (concentrate) oxidative stress or evade blood-borne antioxidants. ExMTs therefore possess unique oxidative activity that differs from the intracellular mitochondrial dysfunction documented in TBI.…”