The central role of neutrophil extracellular traps in SARS-CoV-2-induced thrombogenesis and vasculitis

ABSTRACT

Objective: Severe acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) seen in SARs-CoV-2 infection has been attributed to the disruption of the immune response in COVID-19 patients. Neutrophilia and marked lymphocyte reductions are associated with disease severity and seem predictive of disease outcome in moderate and severe COVID-19 patients. Herein, we aim to decipher possible mechanisms involved in extensive tissue injury observed in COVID-19 patients, accompanied by vasculopathy, coagulopathy, and a high incidence of thrombotic complications in severe patients. Method(s) We searched PubMED for keywords including COVID-19 pathogenesis, thrombosis, and vasculities. Result(s) Neutrophils can undergo a specialized form of apoptosis to yield thread-like extracellular structures termed neutrophil extracellular traps (NETs), termed NETosis, which form web-like scaffolds of DNA, histones, and toxic protein granules and enzymes, whose primary function is to trap and eliminate microbes. However, uncontrolled NET production can lead to ALI and ARDS, coagulopathy, multiple organ failure, and autoimmune disease. Dysregulation of NETs promotes production of anti-neutrophil cytoplasmic antibodies (ANCA) which affects small vessels through ANCA-associated vasculitis (AAV). Furthermore, NETs can also induce thrombosis via formation of scaffolds that trap platelets, RBCs, fibronectin, and other proteins, which can also induce coagulation. Conclusion(s) We suggest that NET production is central during SARS-CoV-2 infection and COVID-19 pathogenesis, associated with alveolar damage accumulation of edema, endothelial injury and coagulopathy, elevated platelet activation and thrombogenesis forming a NET production feed-forward loop, causing diffuse small vessel vasculitis in the lungs and other organs. Copyright © 2020 FSG Communications Ltd. All rights reserved.