Complement and tissue factor–enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis

2020/08/06 by Panagiotis Skendros, Alexandros Mitsios, Akrivi Chrysanthopoulou +14 · 7 citations
Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · Medicine · #COVID-19 Clinical Research Studies #Inflammasome and immune disorders #Neutrophil, Myeloperoxidase and Oxidative Mechanisms

paper · pdf · doi:10.1172/jci141374

openalex publication_date 2020/08/06 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30

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.

Citations

• Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China
• Targeting potential drivers of COVID-19: Neutrophil extracellular traps
• Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19
• Endothelial cell infection and endotheliitis in COVID-19
• Neutrophil extracellular traps in COVID-19
• Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19
• La certeza de lo impredecible: Cultura Educación y Sociedad en tiempos de COVID19

Cited by

• Visualizing a lung neutrophil-platelet immunothrombosis cascade during sepsis in mice
• COVID-19 disease and autoimmune disorders: A mutual pathway
• VIP plasma levels associate with survival in severe COVID-19 patients, correlating with protective effects in SARS-CoV-2-infected cells
• Neutrophil extracellular traps in rheumatoid arthritis: biomarkers, drivers, and emerging therapeutic targets
• The concept of immunothrombosis in pancreas transplantation
• 2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults: Myocarditis and Other Myocardial Involvement, Post-Acute Sequelae of SARS-CoV-2 Infection, and Return to Play
• Post-acute COVID-19 syndrome

Related

• Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome
• Targeting potential drivers of COVID-19: Neutrophil extracellular traps
• The coming of age of neutrophil extracellular traps in thrombosis: Where are we now and where are we headed?
• Neutrophil extracellular traps in COVID-19
• Linking Complement Activation, Coagulation, and Neutrophils in Transplant-Associated Thrombotic Microangiopathy