Abstract 109: Platelets Amplify Endotheliopathy In Covid-19

In addition to their pivotal role in thrombosis and hemostasis, platelets participate in inflammatory responses and endothelial cell activation - hallmarks in the pathogenesis of coronavirus disease 2019 (COVID-19). Given the evidence for a hyperactive platelet phenotype in COVID-19, we investigated effector cell properties of COVID-19 platelets on endothelial cells (ECs). To explore this interaction, ECs were treated with platelet releasate from patients with and without COVID-19, and EC mRNA sequencing performed. We demonstrate that platelet released factors in COVID-19 promote an inflammatory hypercoagulable endotheliopathy. Investigation of the COVID-19 platelet transcriptome identified pathways related to organelle/granule release, metabolism, and immune effector function in addition to upregulation of S100A8 and S100A9 mRNA. Incubation of primary megakaryocytes with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) also induced upregulation of S100A8 and S100A9 mRNA. 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 microvascular endothelial cells, promotes an inflammatory hypercoagulable phenotype, and is a significant contributor to thromboinflammation and poor clinical outcomes in COVID-19 patients. Finally, we present evidence that therapeutic targeting of platelet P2Y 12 represents a promising candidate to reduce proinflammatory and prothrombotic platelet-endothelial interactions. Altogether, these findings demonstrate a previously unappreciated role for platelets and their activation-induced endotheliopathy in COVID-19.