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Updated: Sep 19, 2025
Monitoring Changes in Human Umbilical Vein Endothelial Cells upon Viral Infection Using Impedance-Based Real-Time Cell Analysis
Published on: May 5, 2023
Ischaemic endothelial necroptosis induces haemolysis and COVID-19 angiopathy
Mike C L Wu1,2, Ethan Italiano1,2, Rocko Jarvis-Child1,2,3
1The Heart Research Institute, Sydney, New South Wales, Australia.
Insights
SARS-CoV-2 infection causes microangiopathy via endothelial cell death and red blood cell (RBC) hemolysis. This study reveals a novel RBC hemostatic mechanism that, when exaggerated, causes microvascular obstruction in various ischemic conditions.
Area of Science:
- Pathology
- Vascular Biology
- Immunology
Background:
- Microangiopathy is a severe complication of SARS-CoV-2 infection, leading to acute and chronic issues.
- Endotheliopathy and coagulation disorders in COVID-19 contribute to microvascular obstruction.
- Existing research highlights the role of endothelial dysfunction and coagulation in COVID-19 complications.
Purpose of the Study:
- To investigate the mechanisms of microvascular obstruction in COVID-19.
- To identify the relationship between endothelial cell death, red blood cell (RBC) hemolysis, and microangiopathy.
- To explore a novel RBC hemostatic mechanism and its therapeutic potential.
Main Methods:
- Examined microvasculature of COVID-19 organs for endothelial cell death and associated factors.
- Investigated the role of MLKL-dependent necroptosis and complement-dependent hemolysis in ischemia.
- Utilized genetic deletion of MLKL in endothelial cells to assess its impact on microvascular injury.
Main Results:
- Extensive endothelial cell death was observed in COVID-19 microvasculature, linked to RBC hemolysis, not fibrin or platelets.
- Ischemia induced MLKL-dependent endothelial cell necroptosis and complement-dependent RBC hemolysis.
- A novel RBC hemostatic mechanism was identified, involving RBC membrane deposition at sites of endothelial cell death, which can promote microvascular obstruction when exaggerated.
Conclusions:
- Dying endothelial cells trigger a platelet- and fibrin-independent RBC hemostatic mechanism.
- This RBC hemostatic process, when dysregulated, contributes to microvascular obstruction in COVID-19 and other ischemic diseases.
- Targeting this RBC hemolytic pathway offers a potential therapeutic strategy for microvascular obstruction.
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.
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