Ischaemic endothelial necroptosis induces haemolysis and COVID-19 angiopathy

Mike C. L. Wu, Ethan Italiano, Rocko Jarvis-Child, Imala Alwis, Rhyll Smythe, Eduardo A. Albornoz, Jonathan Noonan, Marie Portelli, Marissa Baptista, Jessica Maclean, Pashtana Noori, Jinglu Yang, John D. Lee, James D. McFadyen, Alexandra F. Sharland, Trent M. Woodruff, Andre L. Samson, Amy Rapkiewicz, Tessa J. Barrett, Alan Pham, Simone M. Schoenwaelder, Yuping Yuan and Shaun P. Jackson ()
Additional contact information
Mike C. L. Wu: The Heart Research Institute
Ethan Italiano: The Heart Research Institute
Rocko Jarvis-Child: The Heart Research Institute
Imala Alwis: The Heart Research Institute
Rhyll Smythe: The Heart Research Institute
Eduardo A. Albornoz: University of Queensland
Jonathan Noonan: Baker Heart and Diabetes Institute
Marie Portelli: The Heart Research Institute
Marissa Baptista: The Heart Research Institute
Jessica Maclean: The Heart Research Institute
Pashtana Noori: The Heart Research Institute
Jinglu Yang: The Heart Research Institute
John D. Lee: University of Queensland
James D. McFadyen: Baker Heart and Diabetes Institute
Alexandra F. Sharland: University of Sydney
Trent M. Woodruff: University of Queensland
Andre L. Samson: Walter and Eliza Hall Research Institute (WEHI)
Amy Rapkiewicz: Long Island School of Medicine
Tessa J. Barrett: New York University
Alan Pham: The Alfred Hospital
Simone M. Schoenwaelder: The Heart Research Institute
Yuping Yuan: The Heart Research Institute
Shaun P. Jackson: The Heart Research Institute

Nature, 2025, vol. 643, issue 8070, 182-191

Abstract: Abstract Microangiopathy is a major complication of SARS-CoV-2 infection and contributes to the acute and chronic complications of the disease1. Endotheliopathy and dysregulated blood coagulation are prominent in COVID-19 and are considered to be major causes of microvascular obstruction1,2. 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.

Date: 2025
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DOI: 10.1038/s41586-025-09076-x

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