Plasma microparticles of intubated COVID‐19 patients cause endothelial cell death, neutrophil adhesion and netosis, in a phosphatidylserine‐dependent manner

COVID-19 urges scientists to better describe its pathophysiology to find new therapeutic approaches. While risk factors such as ageing, obesity and diabetes mellitus suggest a central role of endothelial cells (ECs), autopsies revealed clots in the pulmonary microvasculature, which are rich in neutrophils and DNA traps produced by these cells and called NETs. Moreover, submicron extracellular vesicles called microparticles (MPs), are described in several diseases as involved in pro-inflammatory pathways. Therefore, we analyzed 3 patient groups: one for which intubation was not necessary, an intubated group, and the last one after extubating. In the most severe group, the intubated group, platelet-derived MPs and endothelial cell-derived MPs exhibited increased concentration and size, when compared to uninfected controls. MPs of intubated COVID-19 patients triggered ECs death and overexpression of two adhesion molecules: P-selectin and VCAM-1. Strikingly, neutrophils adhesion and NET production were increased following incubation with these ECs. Importantly, we also showed that preincubation of these COVID-19 MPs with the phosphatidylserine capping endogenous protein annexin A5, abolished cytotoxicity, P-selectin and VCAM-1 induction, all like increases in neutrophil adhesion and NET release. Altogether our results unveil that MPs are a key actor in COVID-19 pathophysiology and point towards a potential therapeutic: annexin A5.

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