RT Journal Article SR Electronic T1 Signaling through FcγRIIA and the C5a-C5aR pathway mediates platelet hyperactivation in COVID-19 JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.05.01.442279 DO 10.1101/2021.05.01.442279 A1 Sokratis A. Apostolidis A1 Amrita Sarkar A1 Heather M. Giannini A1 Rishi R. Goel A1 Divij Mathew A1 Aae Suzuki A1 Amy E. Baxter A1 Allison R. Greenplate A1 Cécile Alanio A1 Mohamed Abdel-Hakeem A1 Derek A. Oldridge A1 Josephine Giles A1 Jennifer E. Wu A1 Zeyu Chen A1 Yinghui Jane Huang A1 Ajinkya Pattekar A1 Sasikanth Manne A1 Oliva Kuthuru A1 Jeanette Dougherty A1 Brittany Weiderhold A1 Ariel R. Weisman A1 Caroline A. G. Ittner A1 Sigrid Gouma A1 Debora Dunbar A1 Ian Frank A1 Alexander C. Huang A1 Laura A. Vella A1 The UPenn COVID Processing Unit A1 John P. Reilly A1 Scott E. Hensley A1 Lubica Rauova A1 Liang Zhao A1 Nuala J. Meyer A1 Mortimer Poncz A1 Charles S. Abrams A1 E. John Wherry YR 2021 UL http://biorxiv.org/content/early/2021/05/03/2021.05.01.442279.abstract AB Patients with COVID-19 present with a wide variety of clinical manifestations. Thromboembolic events constitute a significant cause of morbidity and mortality in patients infected with SARS-CoV-2. Severe COVID-19 has been associated with hyperinflammation and pre-existing cardiovascular disease. Platelets are important mediators and sensors of inflammation and are directly affected by cardiovascular stressors. In this report, we found that platelets from severely ill, hospitalized COVID-19 patients exhibit higher basal levels of activation measured by P-selectin surface expression, and have a poor functional reserve upon in vitro stimulation. Correlating clinical features to the ability of plasma from COVID-19 patients to stimulate control platelets identified ferritin as a pivotal clinical marker associated with platelet hyperactivation. The COVID-19 plasma-mediated effect on control platelets was highest for patients that subsequently developed inpatient thrombotic events. Proteomic analysis of plasma from COVID-19 patients identified key mediators of inflammation and cardiovascular disease that positively correlated with in vitro platelet activation. Mechanistically, blocking the signaling of the FcγRIIa-Syk and C5a-C5aR pathways on platelets, using antibody-mediated neutralization, IgG depletion or the Syk inhibitor fostamatinib, reversed this hyperactivity driven by COVID-19 plasma and prevented platelet aggregation in endothelial microfluidic chamber conditions, thus identifying these potentially actionable pathways as central for platelet activation and/or vascular complications in COVID-19 patients. In conclusion, we reveal a key role of platelet-mediated immunothrombosis in COVID-19 and identify distinct, clinically relevant, targetable signaling pathways that mediate this effect. These studies have implications for the role of platelet hyperactivation in complications associated with SARS-CoV-2 infection.One-sentence summary The FcγRIIA and C5a-C5aR pathways mediate platelet hyperactivation in COVID-19Competing Interest StatementScEH has received consultancy fees from Sanofi Pasteur, Lumen, Novavax, and Merck for work unrelated to this report. ACH is a consultant for Immunai. EJW is consulting or is an advisor for Merck, Elstar, Janssen, Related Sciences, Synthekine and Surface Oncology. EJW is a founder of Surface Oncology and Arsenal Biosciences. EJW is an inventor on a patent (US Patent number 10,370,446) submitted by Emory University that covers the use of PD-1 blockade to treat infections and cancer.