Ischaemic endothelial necroptosis induces haemolysis and COVID-19 angiopathy, 2025, Wu et al.

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Ischaemic endothelial necroptosis induces haemolysis and COVID-19 angiopathy
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.

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.

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Australian researchers unlocking secrets of COVID-19 may have landed on new ways to reduce organ injury from heart attacks and stroke - InSight+

The SARS-CoV-2 virus has caused enormous global healthcare challenges and further led to longer-term health complications for millions of infected individuals. Much remains to be learned about the virus, but one thing is clear: the SARS-CoV-2 virus can unleash widespread, systemic effects...

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AI Summary:

New Discoveries in COVID-19 Research Offer Hope for Stroke and Heart Attack Treatment

COVID-19 and Microvascular Damage

Australian researchers studying the effects of COVID-19 have discovered a new mechanism by which the virus damages blood vessels, especially the microvasculature. The virus causes inflammation in the lining of blood vessels (endotheliitis), contributing to long-term complications such as Long COVID. By examining tissues from deceased COVID-19 patients, scientists observed a high rate of death in endothelial cells — a process not driven by clots or inflammation, but by a novel red blood cell (RBC) destruction process. These damaged RBCs stick together, clogging tiny vessels and worsening tissue oxygen deprivation.

A Broader Problem in Stroke and Heart Disease

This mechanism isn’t limited to COVID-19. The same red cell aggregation and microvascular obstruction were found in patients who died from heart attacks or strokes without having COVID-19. This may explain the ‘no-reflow’ phenomenon, where tissue continues to die even after large blood vessels are reopened during treatment. The findings suggest that real damage often occurs at the level of the smallest vessels, not just the large arteries.

Historical Clues Revisited

Interestingly, similar microvascular abnormalities were observed by scientists in the 1940s and 50s, but they lacked the tools to explain the cause. Now, using modern imaging and molecular techniques, researchers are finally able to confirm and understand what those early observations hinted at — that damaged blood vessel linings can cause red cells to clump and obstruct blood flow, even without traditional clots.

Towards a New Treatment: TBO-309

These insights have led to the development of a promising new antiplatelet therapy, TBO-309. Unlike older blood thinners, TBO-309 targets clotting mechanisms more precisely, reducing the risk of bleeding. It helps keep small blood vessels open by preventing both large and small clots. Early trials in animals and humans have shown strong results. Currently, two clinical trials — STARS and Co-STARS — are testing the drug in stroke patients, with results expected in the next year.

Looking Ahead

If proven effective, TBO-309 could become a game-changing therapy for stroke, heart attack, and other diseases involving microvascular blockage. Policymakers are urged to support clinical research and innovation to bring these findings into hospitals. For patients, the research offers both urgency and hope — a better understanding of why some recoveries fail, and new tools to improve outcomes.