Role of neutrophils, platelets, and extracellular vesicles and their interactions in COVID-19-associated thrombopathy

Abstract

The COVID-19 pandemic extended all around the world causing millions of deaths. In addition to acute respiratory distress syndrome, many patients with severe COVID-19 develop thromboembolic complications associated to multiorgan failure and death. Here, we review evidence for the contribution of neutrophils, platelets, and extracellular vesicles (EVs) to the thromboinflammatory process in COVID-19. We discuss how the immune system, influenced by pro-inflammatory molecules, EVs, and neutrophil extracellular traps (NETs), can be caught out in patients with severe outcomes. We highlight how the deficient regulation of the innate immune system favors platelet activation and induces a vicious cycle amplifying an immunothrombogenic environment associated with platelet/NET interactions. In light of these considerations, we discuss potential therapeutic strategies underlining the modulation of purinergic signaling as an interesting target.

Keywords: COVID-19; extracellular vesicles; neutrophils; platelets; therapeutic strategy; thrombosis.

FIGURE 1

Schematic representation of thromboinflammation that results from the interaction between platelets and neutrophils. On one hand, systemic inflammation induced by SARS‐CoV‐2 infection is associated with the release of pro‐inflammatory cytokines and endothelial dysfunction. On the other hand, increase of innate immune activation without effective adaptive immune system response leads to neutrophil accumulation, which participates in neutrophil extracellular trap (NET) formation and pro‐thrombotic mediators’ production. Together with platelet activation, extracellular vesicle (EV) release and NET emission neutrophils and platelets aggregate, driving strong and sustained thrombosis. Therapeutic approaches targeting inflammation, NET formation, and platelet aggregation aiming at limiting thromboinflammation are represented in green