Liu Yi, Zhao Weili, Huang Qingqing, Wan Linjun, Ren Zongfang, Zhang Bangting, Han Chen, Yang Jin, Zhang Haoling, Zhang Jingjing
Department of Critical Care Medicine, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, People's Republic of China.
Laboratory Department, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, People's Republic of China.
J Inflamm Res. 2025 May 24;18:6719-6733. doi: 10.2147/JIR.S520726. eCollection 2025.
Sepsis, a lethal organ dysfunction syndrome driven by aberrant host responses to infection, intertwines excessive inflammatory responses and dysregulated coagulation processes in its pathophysiology. Emerging research reveals the complement terminal membrane attack complex C5b-9 orchestrates ultralarge von Willebrand factor (ULVWF) release from vascular endothelial cells (ECs) through multifaceted mechanisms: C5b-9 compromises EC membrane integrity, activates calcium influx cascades, and provokes NLRP3 inflammasome signaling, triggering massive exocytosis of ULVWF stored within Weibel-Palade bodies (WPBs). When ADAMTS13 activity falters, undegraded ULVWF complexes with platelets to spawn microthrombi, precipitating microvascular occlusion and multiorgan collapse. Strikingly, elevated plasma von Willebrand factor (vWF) antigen levels in sepsis patients correlate robustly with endothelial injury, thrombocytopenia, and mortality-underscoring C5b-9-driven vWF release as a linchpin of septic coagulopathy. Current therapeutic strategies targeting these pathways, including recombinant ADAMTS13 (rhADAMTS13), N-acetylcysteine (NAC), and complement inhibitors like eculizumab, face limitations in clinical translation, necessitating further validation of their efficacy. Additionally, investigating complement regulatory molecules such as CD59 may unlock novel therapeutic avenues. Deciphering the intricate interplay within the C5b-9-vWF axis and advancing precision therapies hold transformative potential for ameliorating sepsis outcomes.
脓毒症是一种由宿主对感染的异常反应驱动的致死性器官功能障碍综合征，其病理生理学涉及过度的炎症反应和凝血过程失调。新出现的研究表明，补体末端膜攻击复合物C5b-9通过多方面机制协调血管内皮细胞（ECs）释放超大血管性血友病因子（ULVWF）：C5b-9破坏EC膜完整性，激活钙内流级联反应，并引发NLRP3炎性小体信号传导，触发储存在魏尔-帕拉德小体（WPBs）内的ULVWF大量胞吐。当ADAMTS13活性减弱时，未降解的ULVWF与血小板结合形成微血栓，导致微血管阻塞和多器官衰竭。值得注意的是，脓毒症患者血浆血管性血友病因子（vWF）抗原水平升高与内皮损伤、血小板减少和死亡率密切相关，这突出了C5b-9驱动的vWF释放是脓毒症凝血病的关键因素。目前针对这些途径的治疗策略，包括重组ADAMTS13（rhADAMTS13）、N-乙酰半胱氨酸（NAC）和依库珠单抗等补体抑制剂，在临床转化中存在局限性，需要进一步验证其疗效。此外，研究CD59等补体调节分子可能会开辟新的治疗途径。解读C5b-9-vWF轴内的复杂相互作用并推进精准治疗，对于改善脓毒症预后具有变革性潜力。
