The Emerging Role of Neutrophils in the Pathogenesis of Thrombosis in COVID-19

Abstract

Previous studies have shown that COVID-19 leads to thrombotic complications, which have been associated with high morbidity and mortality rates. Neutrophils are the largest population of white blood cells and play a pivotal role in innate immunity. During an infection, neutrophils migrate from circulation to the infection site, contributing to killing pathogens. This mechanism is regulated by chemokines such as IL-8. Moreover, it was shown that neutrophils play an important role in thromboinflammation. Through a diverse repertoire of mechanisms, neutrophils, apart from directly killing pathogens, are able to activate the formation of thrombi. In COVID-19 patients, neutrophil activation promotes neutrophil extracellular trap (NET) formation, platelet aggregation, and cell damage. Furthermore, neutrophils participate in the pathogenesis of endothelitis. Overall, this review summarizes recent progress in research on the pathogenesis of COVID-19, highlighting the role of the prothrombotic action of neutrophils in NET formation.

Keywords: COVID-19; NETs; SARS CoV-2; immunothrombosis.

Figure 1

Neutrophil and thromboinflammation in COVID-19. Host–virus interplay includes virus-related alveolar macrophage activation, which leads to a cascade of inflammatory stimuli, cell activation, and migration. Signals from different chemokines induce neutrophil–endothelium interactions, allowing neutrophil to crawl and arrest along the endothelium. Neutrophils accomplish their extravasation predominantly via endothelial cell–cell junctions. At the site of infection, neutrophils activate phagocytosis, degranulation, and NET formation, which can protect the host during its virus response. On the other hand, neutrophils can exacerbate lung hyperinflammation and cytokine storm in COVID-19 patients. Ultimately, NETs interact with the platelets and complements, thereby causing endothelial cell damage and triggering thrombi formation. Hyperinflammation and Inflammatory microvascular thrombi then lead to system inflammation, which affects kidney, gut, liver, and heart function. Abbreviations: SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; PAMP: pathogen-associated molecular pattern; DAMP: danger-associated molecular pattern; NETs: neutrophil extracellular traps.