A team led by the University of Sydney has identified red blood cell rupture at dying endothelial sites as a primary driver of microvascular obstruction in COVID-19, bypassing the expected role of fibrin and platelet clots.

Cases of severe injury to the body’s smallest blood vessels emerged during the COVID-19 pandemic, implicated in both sudden organ failure and persistent symptoms that span months. Tissue from affected patients reveals extensive endothelial damage across lung, heart, kidney and liver vasculature.

Standard models of thrombosis, microvascular clots formed by fibrin and platelets, have struggled to account for the extent of capillary dysfunction. Anticoagulant therapies have shown only modest benefit, raising the possibility that COVID-19 microangiopathy follows a different mechanism.

In the study, “Ischaemic endothelial necroptosis induces haemolysis and COVID-19 angiopathy,” published in Nature, researchers designed multimodal imaging and genetic models to determine whether red blood cell (RBC) hemolysis, rather than thrombosis, accounts for microvascular obstruction.

Autopsy tissue from COVID-19 patients was used to assess over 1,000 vessels from the lungs, heart, kidneys and liver. Samples showing post-mortem degradation were excluded.

Imaging revealed widespread loss of endothelial surface markers and cellular integrity. Cell death appeared most frequent in organs with severe tissue injury, particularly the heart, liver and kidneys. Up to 50% of vessels showed signs of endothelial detachment.

Histological and electron microscopy detected an acellular, protein-rich material deposited along vessel walls. This material stained strongly for CD235, an RBC membrane marker, but not for fibrin, platelets or DNA. Membranes from lysed RBCs accumulated around necrotic endothelium and wedged between intact RBCs.

In the lungs, this pattern was sparse. In the liver, kidney and heart, membrane deposition appeared in 27–30% of vessels. COVID-19 tissues showed more frequent RBC lysis than matched controls with non-COVID acute respiratory distress syndrome.

Autopsy samples from non-COVID patients with myocardial infarction, stroke and gut ischemia showed the same pattern of endothelial necrosis to the COVID cohort, RBC membrane deposition and microvascular obstruction.

RBC hemolysis appeared in up to 45% of microvessels in the kidneys, livers and hearts, with minimal involvement in the lungs. Correlative imaging and intensity mapping confirmed a spatial association between endothelial injury and membrane fragments from ruptured red cells.

In tissues from non-COVID-19 patients with myocardial infarction, stroke and gut ischemia, a similar pattern of endothelial death and RBC lysis was observed.

In mouse models, ischemia alone triggered endothelial necroptosis, marked by phosphorylated MLKL and RIPK3, along with complement-mediated RBC lysis.

SARS-CoV-2 infection produced minimal hemolysis in organs beyond the lung. Genetic deletion of Mlkl in endothelial cells reduced RBC fragmentation, microvascular obstruction and organ damage. In C9-deficient mice, red cell lysis was also suppressed, confirming a requirement for complement activation.

Real-time intravital microscopy revealed that hemolyzed red cell membranes adhered to necrotic endothelium, layering into physical obstructions that blocked perfusion. These endovascular deposits formed independently of platelets or fibrin.

In mice lacking MLKL or complement function, localized bleeding increased, implicating red cell membrane deposition as a structural hemostatic barrier. Aggregation of intact red cells was induced by lysed membranes and occurred exclusively under low shear conditions.

In vitro, RBC fragments alone were sufficient to trigger adhesion and aggregation in the absence of platelets, leukocytes or plasma. Perfusion was improved and tissue injury reduced in mice lacking endothelial MLKL, consistent with a role for necroptosis-driven hemolysis in promoting vascular blockage.

Researchers conclude that endothelial necroptosis initiates a cascade in which complement activation ruptures nearby red blood cells.

Fragments from these lysed cells form a physical seal across injured vessel walls, preventing interstitial bleeding under conditions where platelets and fibrin are impaired. Yet when this response is exaggerated, the same material accumulates into obstructive aggregates that block blood flow.

The findings suggest that necroptosis and complement together shape a red cell–based mechanism of microvascular control, one that operates independently of classical clotting pathways. Inhibition of MLKL or complement reduced vascular blockage and improved tissue perfusion, yet also increased bleeding risk, revealing a trade-off between protection and hemostasis.

By identifying a process outside of platelet-driven thrombosis, the study may explain why anticoagulants often fail to restore microvascular flow in COVID-19. Potential therapeutic approaches could include blocking necroptosis, inhibiting terminal complement, or scavenging free heme—though the authors note that disrupting this system may also impair its protective function.

“Our studies demonstrate the existence of an RBC hemostatic mechanism induced by dying ECs, functioning independently of platelets and fibrin,” the authors wrote.

“Therapeutic targeting of this hemolytic process may reduce microvascular obstruction in COVID-19, and other major human diseases associated with organ ischemia.”

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