Model of NET-mediated endothelial damage contributing to pulmonary vascular thrombosis in severe COVID-19.
Infection by SARS-CoV-2 in vulnerable population will lead to hyperinflammation either from underlying genetic mutations, specific epigenetic landscapes or external factors, that will result in the increase circulation of acute phase reactants such as CRP and pro-inflammatory cytokines associated with neutrophilia like IL-6, IL-17A/F and CXCL8 (IL-8). IL-17A activates the endothelium to induce neutrophil adhesion , where the increase in CRP can trigger the release of NETs, resulting in damage to the endothelium as well as aggregation and activation of platelets. Additionally, the presence of SARS-CoV-2 E protein in type II pneumocytes could disturb the surfactant cargo via its interaction with AP3B1, leading to impaired secretion of SP-D and greater NET formation by septal and intra-alveolar neutrophils increasing the risk of thrombosis in the pulmonary microvasculature. In some predisposed patients the combinations of these mechanisms will lead to severe COVID-19 complications. The identification of mediators of this pro-coagulation cascade is essential in achieving the two-fold task of identifying vulnerable populations and developing a personalized medicine approach.