Trauma-induced innate immune activation and disseminated intravascular coagulation

Abstract

Dysregulated innate immunity participates in the pathomechanisms of disseminated intravascular coagulation (DIC) in trauma-induced coagulopathy. Accidental and regulated cell deaths and neutrophil extracellular traps release damage-associated molecular patterns (DAMPs), such as histones, nuclear and mitochondrial DNA, and high-mobility group box 1, into circulation immediately after trauma. DAMP-induced inflammation activation releases tissue factor-bearing procoagulant extracellular vesicles through gasdermin D-mediated pore formation and plasma membrane rupture by regulated cell death. DAMPs also evoke systemic inflammation, platelet, coagulation activation, and impaired fibrinolysis associated with endothelial injury, leading to the dysfunction of anticoagulation systems, which are the main pathophysiological mechanisms of DIC. All these processes induce systemic thrombin generation in vivo, not restricted to the injury sites immediately after trauma. Thrombin generation at the site of injury stops bleeding and maintains homeostasis. However, DIC associated with endothelial injury generates massive thrombin, enhancing protease-activated, receptor-mediated bidirectional interplays between inflammation and coagulation, aggravating the diverse actions of thrombin and disturbing homeostasis. Insufficiently regulated thrombin causes disseminated microvascular thrombosis, resulting in tissue hypoxia due to reduced oxygen delivery, and mitochondrial dysfunction due to DAMPs causes tissue dysoxia. In addition, DAMP-induced calcium influx and overload, as well as neutrophil activation, play a role in endothelial cell injury. Tissue hypoxia and cytotoxicity result in multiple organ dysfunction in DIC after trauma. Controls against dysregulated innate immunity evoking systemic inflammation, thrombin generation, and cytotoxicity are key issues in improving the prognosis of DIC in trauma-induced coagulopathy.