Ischaemic endothelial necroptosis induces haemolysis and COVID-19 angiopathy

Wu, MCL; Italiano, E; Jarvis-Child, R; Alwis, I; Smythe, R; Albornoz, EA; Noonan, J; Portelli, M; Baptista, M; Maclean, J; Noori, P; Yang, J; Lee, JD; McFadyen, JD; Sharland, AF; Woodruff, TM; Samson, AL; Rapkiewicz, A; Barrett, TJ; Pham, A; Schoenwaelder, SM; Yuan, Y; Jackson, SP

Author(s): Wu, MCL; Italiano, E; Jarvis-Child, R; Alwis, I; Smythe, R; Albornoz, EA; Noonan, J; Portelli, M; Baptista, M; Maclean, J; Noori, P; Yang, J; Lee, JD; McFadyen, JD; Sharland, AF; Woodruff, TM; Samson, AL; Rapkiewicz, A; Barrett, TJ; Pham, A; Schoenwaelder, SM; Yuan, Y; Jackson, SP;
Details: Publication Year 2025-07,Volume 643,Issue #8070,Page 182-191
Journal Title: Nature
Abstract: Microangiopathy is a major complication of SARS-CoV-2 infection and contributes to the acute and chronic complications of the disease(1). Endotheliopathy and dysregulated blood coagulation are prominent in COVID-19 and are considered to be major causes of microvascular obstruction(1,2). 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.
Publisher: Springer Nature
Keywords: *COVID-19/pathology/complications/blood; Humans; *Necroptosis; *Hemolysis; Animals; Mice; Erythrocytes/pathology/metabolism/cytology; *Endothelial Cells/pathology/metabolism; Male; Protein Kinases/metabolism/genetics/deficiency; Female; Reperfusion Injury/pathology; Microvessels/pathology; *Ischemia/pathology/complications; SARS-CoV-2
Research Division(s): Inflammation
PubMed ID: 40468079
Publisher's Version: https://doi.org/10.1038/s41586-025-09076-x
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-07-28 08:47:52

Last Modified: 2025-07-28 08:48:02