Wu Mike C L, Italiano Ethan, Jarvis-Child Rocko, Alwis Imala, Smythe Rhyll, Albornoz Eduardo A, Noonan Jonathan, Portelli Marie, Baptista Marissa, Maclean Jessica, Noori Pashtana, Yang Jinglu, Lee John D, McFadyen James D, Sharland Alexandra F, Woodruff Trent M, Samson Andre L, Rapkiewicz Amy, Barrett Tessa J, Pham Alan, Schoenwaelder Simone M, Yuan Yuping, Jackson Shaun P
The Heart Research Institute, Sydney, New South Wales, Australia.
Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia.
Nature. 2025 Jun 4. doi: 10.1038/s41586-025-09076-x.
Microangiopathy is a major complication of SARS-CoV-2 infection and contributes to the acute and chronic complications of the disease. Endotheliopathy and dysregulated blood coagulation are prominent in COVID-19 and are considered to be major causes of microvascular obstruction. Here we demonstrate extensive endothelial cell (EC) death in the microvasculature of COVID-19 organs. Notably, EC death was not associated with fibrin formation or platelet deposition, but was linked to microvascular red blood cell (RBC) haemolysis. Importantly, this RBC microangiopathy was associated with ischaemia-reperfusion injury, and was prominent in the microvasculature of humans with myocardial infarction, gut ischaemia, stroke, and septic and cardiogenic shock. Mechanistically, ischaemia induced MLKL-dependent EC necroptosis and complement-dependent RBC haemolysis. Deposition of haemolysed RBC membranes at sites of EC death resulted in the development of a previously unrecognized haemostatic mechanism preventing microvascular bleeding. Exaggeration of this haemolytic response promoted RBC aggregation and microvascular obstruction. Genetic deletion of Mlkl from ECs decreased RBC haemolysis, microvascular obstruction and reduced ischaemic organ injury. Our studies demonstrate the existence of a RBC haemostatic mechanism induced by dying ECs, functioning independently of platelets and fibrin. Therapeutic targeting of this haemolytic process may reduce microvascular obstruction in COVID-19, and other major human diseases associated with organ ischaemia.
微血管病变是新型冠状病毒2（SARS-CoV-2）感染的主要并发症，可导致该疾病的急慢性并发症。内皮病变和凝血功能失调在新型冠状病毒肺炎（COVID-19）中较为突出，被认为是微血管阻塞的主要原因。在此，我们证明了COVID-19患者器官微血管中存在广泛的内皮细胞（EC）死亡。值得注意的是，EC死亡与纤维蛋白形成或血小板沉积无关，而是与微血管红细胞（RBC）溶血有关。重要的是，这种RBC微血管病变与缺血再灌注损伤相关，在心肌梗死、肠道缺血、中风、脓毒性休克和心源性休克患者的微血管中较为突出。从机制上讲，缺血诱导了混合谱系激酶结构域样蛋白（MLKL）依赖性的EC坏死性凋亡和补体依赖性的RBC溶血。溶血的RBC膜在EC死亡部位的沉积导致了一种以前未被认识的止血机制的形成，从而防止微血管出血。这种溶血反应的过度增强促进了RBC聚集和微血管阻塞。内皮细胞中Mlkl基因的缺失减少了RBC溶血、微血管阻塞，并减轻了缺血性器官损伤。我们的研究证明了由濒死的EC诱导的RBC止血机制的存在，其独立于血小板和纤维蛋白发挥作用。针对这一溶血过程的治疗靶点可能会减少COVID-19以及其他与器官缺血相关的主要人类疾病中的微血管阻塞。
