PT - JOURNAL ARTICLE AU - Sokratis A. Apostolidis AU - Amrita Sarkar AU - Heather M. Giannini AU - Rishi R. Goel AU - Divij Mathew AU - Aae Suzuki AU - Amy E. Baxter AU - Allison R. Greenplate AU - Cécile Alanio AU - Mohamed Abdel-Hakeem AU - Derek A. Oldridge AU - Josephine Giles AU - Jennifer E. Wu AU - Zeyu Chen AU - Yinghui Jane Huang AU - Ajinkya Pattekar AU - Sasikanth Manne AU - Oliva Kuthuru AU - Jeanette Dougherty AU - Brittany Weiderhold AU - Ariel R. Weisman AU - Caroline A. G. Ittner AU - Sigrid Gouma AU - Debora Dunbar AU - Ian Frank AU - Alexander C. Huang AU - Laura A. Vella AU - The UPenn COVID Processing Unit AU - John P. Reilly AU - Scott E. Hensley AU - Lubica Rauova AU - Liang Zhao AU - Nuala J. Meyer AU - Mortimer Poncz AU - Charles S. Abrams AU - E. John Wherry TI - Signaling through FcγRIIA and the C5a-C5aR pathway mediates platelet hyperactivation in COVID-19 AID - 10.1101/2021.05.01.442279 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.05.01.442279 4099 - http://biorxiv.org/content/early/2021/05/03/2021.05.01.442279.short 4100 - http://biorxiv.org/content/early/2021/05/03/2021.05.01.442279.full 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.