Related Experiment Video
Updated: Nov 6, 2025
Comprehensive Analysis of Procoagulant Platelets Exhibiting Features of Necrosis, Apoptosis and Platelet Activation
Published on: May 23, 2025
Signaling through FcγRIIA and the C5a-C5aR pathway mediates platelet hyperactivation in COVID-19
Sokratis A Apostolidis1,2, Amrita Sarkar3, Heather M Giannini4
1Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Insights
Platelets in severe COVID-19 patients show heightened activation and impaired function. Targeting FcγRIIa-Syk and C5a-C5aR pathways may prevent immunothrombosis and vascular complications in SARS-CoV-2 infection.
Area of Science:
- Immunology
- Hematology
- Infectious Diseases
Background:
- Severe COVID-19 is linked to hyperinflammation and cardiovascular issues.
- Platelets are key in inflammation and are affected by cardiovascular stress.
- Thromboembolic events are a major cause of mortality in SARS-CoV-2 patients.
Approach:
- Assessed platelet activation (P-selectin expression) in hospitalized COVID-19 patients.
- Correlated clinical markers with plasma-induced platelet hyperactivation.
- Investigated the role of FcγRIIa-Syk and C5a-C5aR signaling pathways.
Key Points:
- COVID-19 platelets exhibit elevated basal activation and reduced functional reserve.
- Ferritin levels correlated with platelet hyperactivation, especially in patients with thrombotic events.
- Blocking FcγRIIa-Syk and C5a-C5aR pathways reversed platelet hyperactivity and aggregation.
Conclusions:
- Platelet-mediated immunothrombosis plays a critical role in COVID-19 pathogenesis.
- Identified FcγRIIa-Syk and C5a-C5aR as targetable pathways for COVID-19 complications.
- Findings suggest therapeutic strategies to mitigate platelet hyperactivation in SARS-CoV-2 infection.
Abstract:
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-19.
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