Gas-6 Scavenges Anionic Phospholipid-Expressing Microparticles and Mitigates TBI-Induced Endotheliopathy and Coagulopathy in Mice

BACKGROUND: Traumatic brain injury (TBI) results in the release of microparticles from injured brain cells into circulation. These microparticles induce a systemic hypercoagulable state that rapidly transitions into secondary coagulopathy and endotheliopathy. We hypothesize that removing these microparticles from circulation could mitigate the TBI-induced secondary pathologies and improve outcomes. In this study, we investigated the role of Gas-6 (growth arrest-specific 6) as a scavenging factor for microparticles. METHODS: We quantified plasma Gas-6 levels in a mouse model of TBI and administered exogenous Gas-6 either before or after TBI to evaluate its effects on endotheliopathy, coagulopathy, and outcomes. Mechanistic studies assessed Gas-6-mediated clearance of circulating microparticles in TBI mice and investigated the molecular interactions by which Gas-6 binds microparticles and macrophages to facilitate microparticle scavenging. RESULTS: We found that plasma levels of Gas-6 were significantly reduced in mice subjected to severe TBI. Exogenous Gas-6 given either preinjury or postinjury attenuated coagulopathy, protected the integrity of the cerebral and pulmonary endothelium, improved neurological recovery, and increased overall survival of TBI mice. Gas-6 increased the clearance of anionic phospholipid-expressing microparticles from circulation by coupling microparticles with macrophages and monocytes through the γ-carboxyglutamate and the LG1 (laminin G-like domain 1), respectively, to facilitate phagocytosis of microparticles in the liver. CONCLUSIONS: These findings demonstrate the therapeutic potential of Gas-6 for TBI and potentially for other acute pathologies, in which microparticles initiate and propagate coagulation dysfunction and endothelial injuries.