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

J Clin Invest. 2020 Nov 2;130(11):6151-6157. doi: 10.1172/JCI141374.


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.

Keywords: COVID-19; Complement; Immunology; Neutrophils; Thrombosis.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Betacoronavirus* / immunology
  • Betacoronavirus* / metabolism
  • COVID-19
  • Complement Activation / drug effects
  • Complement Membrane Attack Complex* / immunology
  • Complement Membrane Attack Complex* / metabolism
  • Coronavirus Infections* / blood
  • Coronavirus Infections* / immunology
  • Extracellular Traps* / immunology
  • Extracellular Traps* / metabolism
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neutrophils* / immunology
  • Neutrophils* / metabolism
  • Pandemics*
  • Peptides, Cyclic / pharmacology
  • Pneumonia, Viral* / blood
  • Pneumonia, Viral* / immunology
  • Receptor, Anaphylatoxin C5a / antagonists & inhibitors
  • Receptor, Anaphylatoxin C5a / blood
  • Receptor, Anaphylatoxin C5a / immunology
  • Respiratory Distress Syndrome / blood
  • Respiratory Distress Syndrome / immunology
  • Respiratory Distress Syndrome / virology
  • SARS-CoV-2
  • Thrombin / immunology
  • Thrombin / metabolism
  • Thromboplastin* / immunology
  • Thromboplastin* / metabolism
  • Thrombosis* / blood
  • Thrombosis* / immunology
  • Thrombosis* / virology


  • C5AR1 protein, human
  • Complement Membrane Attack Complex
  • Peptides, Cyclic
  • Receptor, Anaphylatoxin C5a
  • compstatin
  • Thromboplastin
  • Thrombin