Department of Acute and Critical Care Medicine, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan; Division of Acute and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Hokkaido University Faculty of Medicine, Sapporo, Japan.
Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands; Department of Medicine, University College London Hospitals NHS Foundation Trust, and Cardio-Metabolic Program - NIHR UCLH/UCL BRC London, London, United Kingdom.
J Thromb Haemost. 2024 Feb;22(2):337-351. doi: 10.1016/j.jtha.2023.09.028. Epub 2023 Oct 8.
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.
失调的固有免疫参与创伤性凝血病中弥散性血管内凝血（DIC）的发病机制。意外和受调控的细胞死亡以及中性粒细胞胞外诱捕网释放损伤相关分子模式（DAMPs），如组蛋白、核和线粒体 DNA 以及高迁移率族蛋白 B1，在创伤后立即进入循环。DAMP 诱导的炎症激活通过 Gasdermin D 介导的孔形成和受调控的细胞死亡导致的质膜破裂，释放组织因子携带的促凝细胞外囊泡。DAMPs 还引发全身性炎症、血小板、凝血激活和纤溶受损，与内皮损伤相关，导致抗凝系统功能障碍，这是 DIC 的主要病理生理机制。所有这些过程在体内诱导全身性凝血酶生成，不仅限于创伤后立即发生的损伤部位。损伤部位的凝血酶生成停止出血并维持内环境稳定。然而，与内皮损伤相关的 DIC 会产生大量凝血酶，增强蛋白酶激活受体介导的炎症和凝血之间的双向相互作用，加重凝血酶的多种作用并扰乱内环境稳定。调节不当的凝血酶导致弥散性微血管血栓形成，由于氧输送减少导致组织缺氧，以及 DAMPs 引起的线粒体功能障碍导致组织缺氧。此外，DAMP 诱导的钙内流和超载以及中性粒细胞激活在内皮细胞损伤中起作用。组织缺氧和细胞毒性导致创伤后 DIC 中的多器官功能障碍。针对诱发全身性炎症、凝血酶生成和细胞毒性的失调固有免疫的控制是改善创伤性凝血病中 DIC 预后的关键问题。
