Platelets amplify endotheliopathy in COVID-19

Barrett, Tessa J.; Cornwell, MacIntosh; Myndzar, Khrystyna; Rolling, Christina C.; Xia, Yuhe; Drenkova, Kamelia; Biebuyck, Antoine; Fields, Alexander T.; Tawil, Michael; Luttrell-Williams, Elliot; Yuriditsky, Eugene; Smith, Grace; Cotzia, Paolo; Neal, Matthew D.; Kornblith, Lucy Z.; Pittaluga, Stefania; Rapkiewicz, Amy V.; Burgess, Hannah M.; Mohr, Ian; Stapleford, Kenneth A.; Voora, Deepak; Ruggles, Kelly; Hochman, Judith; Berger, Jeffrey S.

Given the evidence for a hyperactive platelet phenotype in COVID-19, we investigated effector cell properties of COVID-19 platelets on endothelial cells (ECs). Integration of EC and platelet RNA sequencing revealed that platelet-released factors in COVID-19 promote an inflammatory hypercoagulable endotheliopathy. We identified S100A8 and S100A9 as transcripts enriched in COVID-19 platelets and were induced by megakaryocyte infection with SARS-CoV-2. Consistent with increased gene expression, the heterodimer protein product of S100A8/A9, myeloid-related protein (MRP) 8/14, was released to a greater extent by platelets from COVID-19 patients relative to controls. We demonstrate that platelet-derived MRP8/14 activates ECs, promotes an inflammatory hypercoagulable phenotype, and is a significant contributor to poor clinical outcomes in COVID-19 patients. Last, we present evidence that targeting platelet P2Y(12) represents a promising candidate to reduce proinflammatory platelet-endothelial interactions. Together, these findings demonstrate a previously unappreciated role for platelets and their activation-induced endotheliopathy in COVID-19.