New Insights into Vessel Blockage in COVID-19: Red Blood Cell Rupture Over Clots

Recent research has shed new light on the mechanisms behind blood vessel blockage in COVID-19, challenging traditional views centered on clot formation. A team from the University of Sydney has demonstrated that the rupture of red blood cells (RBCs), rather than the formation of fibrin and platelet clots, plays a primary role in causing microvascular obstructions in affected organs.

Severe microvascular injury has been a hallmark of COVID-19, contributing to sudden organ failures and persistent symptoms even months after infection. Autopsies of patients reveal extensive endothelial damage across various organs, including the lungs, heart, kidneys, and liver. Notably, the typical model of microthrombosis, driven by fibrin and platelets, does not fully explain the extent of capillary dysfunction observed, especially since anticoagulant therapies have provided limited benefits.

The study, published in Nature, used advanced imaging, genetic models, and tissue analysis from over 1,000 blood vessels in autopsied organs. Results indicated significant loss of endothelial integrity and widespread endothelial necroptosis, a form of programmed cell death, particularly in organs with severe tissue damage. Electron microscopy revealed the deposition of RBC membrane fragments along vessel walls—stained positively for RBC markers but not for fibrin or platelets—indicating extensive RBC lysis.

Interestingly, RBC breakdown was more prominent in the liver, kidneys, and heart than in the lungs, where it was less frequent. Similar patterns of endothelial damage and RBC membrane accumulation were also found in non-COVID patients with conditions like myocardial infarction, stroke, and gut ischemia. In mouse models, inducing ischemia led to endothelial necroptosis and subsequent RBC lysis, confirming the process’s role in vascular injury.

Further experiments demonstrated that blocking molecules involved in necroptosis (MLKL) or complement activation mitigated RBC fragmentation and vascular blockage, although this increased bleeding risks, indicating a delicate balance between protection and hemostasis. The rupture and deposition of RBC membranes create physical barriers, blocking blood flow independently of traditional clotting mechanisms. These findings reveal a red cell–based pathway for microvascular control that operates outside classic thrombosis pathways.

This discovery offers a potential explanation for why anticoagulant therapies often fail to improve microvascular flow in COVID-19. Targeting necroptosis or complement pathways could present new therapeutic options, although caution is needed to avoid impairing the body's natural protective responses. Ultimately, the study suggests a paradigm shift in understanding COVID-19 vascular pathology, highlighting the importance of RBC rupture and necroptosis in microvascular obstruction and organ damage.