Novel mechanisms of thrombo-inflammation during infection: spotlight on neutrophil extracellular trap-mediated platelet activation

A state-of-the-art lecture titled "novel mechanisms of thrombo-inflammation during infection" was presented at the ISTH Congress in 2022. Platelet, neutrophil, and endothelial cell activation coordinate the development, progression, and resolution of thrombo-inflammatory events during infection. Activated platelets and neutrophil extracellular traps (NETs) are frequently observed in patients with sepsis and COVID-19, and high levels of NET-derived damage-associated molecular patterns (DAMPs) correlate with thrombotic complications. NET-associated DAMPs induce direct and indirect platelet activation, which in return potentiates neutrophil activation and NET formation. These coordinated interactions involve multiple receptors and signaling pathways contributing to vascular and organ damage exacerbating disease severity. This state-of-the-art review describes the main mechanisms by which platelets support NETosis and the key mechanisms by which NET-derived DAMPs trigger platelet activation and the formation of procoagulant platelets leading to thrombosis. We report how these DAMPs act through multiple receptors and signaling pathways differentially regulating cell activation and disease outcome, focusing on histones and S100A8/A9 and their contribution to the pathogenesis of sepsis and COVID-19. We further discuss the complexity of platelet activation during NETosis and the potential benefit of targeting selective or multiple NET-associated DAMPs to limit thrombo-inflammation during infection. Finally, we summarize relevant new data on this topic presented during the 2022 ISTH Congress.