Microvascular thrombosis can lead to multiorgan failure and mortality in coronavirus disease 2019 (COVID-19). Although thrombotic complications may be explained by the ability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to infect and replicate in endothelial cells, it has been scarcely investigated if, in the complexity of viral infection in the human host, specific viral elements independently can yield endothelial damage. 

A recent study detected circulating spike protein in the sera of severe COVID-19 patients and evaluated by enzyme-linked immunosorbent assay (ELISA). The investigators piloted in vitro research on human microvascular endothelial cells from the derma and lung exposed to SARS-CoV-2-derived spike protein 1 (S1). They studied the expression of adhesive molecules by immunofluorescence and assessed leukocyte adhesion and platelet aggregation under flow conditions. Investigation of angiotensin-converting enzyme 2 (ACE2) and AMPK expression was carried out by Western Blot analysis. Additionally, S1-treated endothelial cells were incubated with anti-ACE2 blocking antibody, AMPK agonist or complement inhibitors. 

The results were as follows:

• A significant level of spike protein in 30.4% of severe COVID-19 patients was found. 
• In vitro, the activation of endothelial cells with S1 protein, viaACE2, impaired AMPK signaling, causing robust leukocyte recruitment due to augmented adhesive molecule expression and thrombomodulin loss. 
• This S1-induced pro-inflammatory phenotype caused an increased C3 and C5b-9 sediment on endothelial cells, along with C3a and C5a generation that additionally intensified S1-induced complement activation. 
• Functional blockade of ACE2 or complement inhibition stopped S1-induced platelet aggregates by restricting von Willebrand factor and P-selectin exocytosis and expression on endothelial cells. 

Thus, it was inferred that SARS-CoV-2-derived S1 is self-sufficient to breed inflammatory and thrombogenic processes in the microvasculature, which is boosted by the complement system, recapitulating the thromboembolic complications of COVID-19.