Complement and tissue factor–enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis
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Abstract
Emerging data indicate that complement and neutrophils contribute to the maladaptive immune response that fuels hyperinflammation and thrombotic microangiopathy, thereby increasing coronavirus 2019 (COVID-19) mortality. Here, we investigated how complement interacts with the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 specimens, cell-based inhibition studies, and NET/human aortic endothelial cell (HAEC) cocultures. Increased plasma levels of NETs, tissue factor (TF) activity, and sC5b-9 were detected in patients. Neutrophils of patients yielded high TF expression and released NETs carrying active TF. Treatment of control neutrophils with COVID-19 platelet-rich plasma generated TF-bearing NETs that induced thrombotic activity of HAECs. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. COVID-19 serum induced complement activation in vitro, consistent with high complement activity in clinical samples. Complement C3 inhibition with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis for a pivotal role of complement and NETs in COVID-19 immunothrombosis. This study supports strategies against severe acute respiratory syndrome coronavirus 2 that exploit complement or NETosis inhibition.
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NETs promote tissue factor activation and fibrin deposition.
“NETs have been shown to promote tissue factor activation and fibrin deposition, consistent with our observations, suggesting a role for NETs in intra-alveolar thrombosis and the formation or organization of platelet-rich clots (43, 45).”
From Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19 (2021) · cites this paper as [45]
Findings from this study and others indicate that inflammatory responses serve as a primary driver of the progressive and persistent pathophysiologic features of severe COVID-19.
“Findings from this study and others indicate that inflammatory responses serve as a primary driver of the progressive and persistent pathophysiologic features of severe COVID-19 (43–46).”
From Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19 (2021) · cites this paper as [45]
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- Authors
- Skendros, P., Mitsios, A., Chrysanthopoulou, A., Mastellos, D. C., Metallidis, S., Rafailidis, P., Ntinopoulou, M., Sertaridou, E., Tsironidou, V., Tsigalou, C., Tektonidou, M., Konstantinidis, T., Papagoras, C., Mitroulis, I., Germanidis, G., Lambris, J. D., & Ritis, K.
- Affiliations
- Democritus University of Thrace (GR)
- National Centre of Scientific Research "Demokritos" (GR)
- University Hospital of Alexandroupolis (GR)
- National and Kapodistrian University of Athens (GR)
- Aristotle University of Thessaloniki (GR)
- University of Pennsylvania (US)
- Corresponding author
- Ritis, Konstantinos
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2020-10-19
- Volume
- 130
- Issue
- 11
- Pages
- 6151-6157
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC7598040
- OpenAlex
- W3048259608
- Cited by
- 786
- References
- 35
- Citations by year
- 2026: 49 · 2025: 58 · 2024: 96 · 2023: 126 · 2022: 200 · 2021: 206 · 2020: 48 · 2018: 1 · 2012: 1
- FWCI
- 50.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- medRxiv (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- GSRT (<03A4>1<0395>DK-00617)
- State Scholarships Foundation (MIS-5000432)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- COVID-19 pandemic, immunothrombosis, neutrophil extracellular traps, tissue factor, complement activation, C5aR1, thrombin, NETosis, thrombotic microangiopathy, hyperinflammation, platelet-rich plasma, SARS-CoV-2
- MeSH terms
- Betacoronavirus, COVID-19, SARS-CoV-2, Aged, Complement Activation, Female, Humans, Male, Middle Aged, Neutrophils, Peptides, Cyclic, Pneumonia, Viral, Respiratory Distress Syndrome, Thrombin, Thromboplastin, Thrombosis, Complement Membrane Attack Complex, Coronavirus Infections, Receptor, Anaphylatoxin C5a, Pandemics, Extracellular Traps
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