Article Impact Level: HIGH Data Quality: STRONG Summary of Nature. https://doi.org/10.1038/s41586-025-09076-x Dr. Mike C. L. Wu et al.
Points
- A newly identified pathological mechanism reveals that endothelial cell necroptosis, not classical thrombosis, is a primary driver of microvascular obstruction in severe COVID-19 and other ischemic diseases.
- Ischemia-induced death of endothelial cells initiates a localized, complement-dependent cascade that ruptures nearby red blood cells and deposits their membranes within the microvasculature.
- Analysis of over 1,000 human microvessels found red blood cell membrane deposits in up to 45 percent of vessels in ischemic organs, independent of fibrin or platelets.
- This red blood cell-based process serves a dual role: it acts as a hemostatic barrier to prevent bleeding but also, when exaggerated, promotes pathological aggregation and severe vascular obstruction.
- These findings explain the limited efficacy of anticoagulants and suggest that targeting necroptosis or complement pathways may offer novel therapeutic strategies for resolving microvascular blockages in patients.
Summary
A study investigating the mechanism of COVID-19 microangiopathy analyzed over 1,000 microvessels from autopsy tissues of the lungs, heart, kidneys, and liver. Researchers identified a pathological process distinct from classical fibrin- and platelet-based thrombosis. The findings demonstrate that ischemia-induced endothelial cell (EC) necroptosis triggers localized, complement-dependent red blood cell (RBC) hemolysis. Rather than coagulation, this process is presented as the primary driver of microvascular obstruction observed in severe COVID-19 and other major ischemic diseases.
Histological analysis of patient tissues revealed extensive EC death, with up to 50% of vessels showing signs of endothelial detachment in severely injured organs. An acellular material staining for the RBC membrane marker CD235, but not for fibrin or platelets, was deposited along vessel walls in 27–30% of microvessels in the heart, liver, and kidney. A similar pattern of EC death and RBC lysis was observed in non-COVID-19 tissues from patients with myocardial infarction and stroke, where hemolysis appeared in up to 45% of microvessels. Mechanistic studies in murine models confirmed that ischemia induces MLKL-dependent EC necroptosis, which subsequently initiates complement-mediated RBC lysis, a process suppressed in C9-deficient mice.
The study proposes that deposited RBC membranes serve a dual hemostatic and pathological function. In murine models, genetic deletion of Mlkl from ECs reduced RBC hemolysis and microvascular obstruction but concurrently increased localized bleeding. These findings suggest that RBC membrane deposition creates a physical barrier at sites of EC injury independent of platelets. When exaggerated, this response promotes obstructive aggregation. Therefore, targeting EC necroptosis or complement activation could represent a therapeutic strategy for microvascular obstruction in COVID-19 and other ischemic conditions, though this may come with an increased bleeding risk. This mechanism helps explain the limited efficacy of conventional anticoagulants in these patients.
Link to the article: https://www.nature.com/articles/s41586-025-09076-x
References Wu, M. C. L., Italiano, E., Jarvis-Child, R., Alwis, I., Smythe, R., Albornoz, E. A., Noonan, J., Portelli, M., Baptista, M., Maclean, J., Noori, P., Yang, J., Lee, J. D., McFadyen, J. D., Sharland, A. F., Woodruff, T. M., Samson, A. L., Rapkiewicz, A., Barrett, T. J., … Jackson, S. P. (2025). Ischaemic endothelial necroptosis induces haemolysis and COVID-19 angiopathy. Nature. https://doi.org/10.1038/s41586-025-09076-x
