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