Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome

Elizabeth A. Middleton, Xue Yan He, Frederik Denorme, Robert A. Campbell, David Ng, Steven P. Salvatore, Maria Mostyka, Amelia Baxter-Stoltzfus, Alain C. Borczuk, Massimo Loda, Mark J. Cody, Bhanu Kanth Manne, Irina Portier, Estelle S. Harris, Aaron C. Petrey, Ellen J. Beswick, Aleah F. Caulin, Anthony Iovino, Lisa M. Abegglen, Andrew S. WeyrichMatthew T. Rondina, Mikala Egeblad, Joshua D. Schiffman, Christian Con Yost

Research output: Contribution to journalArticlepeer-review

976 Scopus citations

Abstract

COVID-19 affects millions of patients worldwide, with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support. Neutrophil extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens, and they can trigger immunothrombosis. We studied the connection between NETs and COVID-19 severity and progression. We conducted a prospective cohort study of COVID-19 patients (n 5 33) and age- and sex-matched controls (n 5 17). We measured plasma myeloperoxidase (MPO)-DNA complexes (NETs), platelet factor 4, RANTES, and selected cytokines. Three COVID-19 lung autopsies were examined for NETs and platelet involvement. We assessed NET formation ex vivo in COVID-19 neutrophils and in healthy neutrophils incubated with COVID-19 plasma. We also tested the ability of neonatal NET-inhibitory factor (nNIF) to block NET formation induced by COVID-19 plasma. Plasma MPO-DNA complexes increased in COVID-19, with intubation (P < .0001) and death (P < .0005) as outcome. Illness severity correlated directly with plasma MPO-DNA complexes (P 5 .0360), whereas PaO2/fraction of inspired oxygen correlated inversely (P 5 .0340). Soluble and cellular factors triggering NETs were significantly increased in COVID-19, and pulmonary autopsies confirmed NET-containing microthrombi with neutrophil-platelet infiltration. Finally, COVID-19 neutrophils ex vivo displayed excessive NETs at baseline, and COVID-19 plasma triggered NET formation, which was blocked by nNIF. Thus, NETs triggering immunothrombosis may, in part, explain the prothrombotic clinical presentations in COVID-19, and NETs may represent targets for therapeutic intervention.

Original languageEnglish
Pages (from-to)1169-1179
Number of pages11
JournalBlood
Volume136
Issue number10
DOIs
StatePublished - Sep 3 2020

Bibliographical note

Publisher Copyright:
© 2020 American Society of Hematology. All rights reserved.

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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