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

  • Blood. 2020 Sep 3;136(10):1169-1179. doi: 10.1182/blood.2020007008.
Elizabeth A Middleton  1  2 ,  Xue-Yan He  3 ,  Frederik Denorme  1 ,  Robert A Campbell  1  2 ,  David Ng  3 ,  Steven P Salvatore  4  5 ,  Maria Mostyka  4 ,  Amelia Baxter-Stoltzfus  4 ,  Alain C Borczuk  4  5 ,  Massimo Loda  4  5 ,  Mark J Cody  1  6 ,  Bhanu Kanth Manne  1 ,  Irina Portier  1 ,  Estelle S Harris  2 ,  Aaron C Petrey  1  7 ,  Ellen J Beswick  2 ,  Aleah F Caulin  8 ,  Anthony Iovino  6  8 ,  Lisa M Abegglen  6  8 ,  Andrew S Weyrich  1  2 ,  Matthew T Rondina  1  2  9  10 ,  Mikala Egeblad  3 ,  Joshua D Schiffman  1  6  8 ,  Christian Con Yost  1  6
Affiliations
  • 1. Molecular Medicine Program and.
  • 2. Department of Internal Medicine, University of Utah, Salt Lake City, UT.
  • 3. Cold Spring Harbor Laboratory, Cancer Center, Cold Spring Harbor, NY.
  • 4. Department of Pathology and Laboratory Medicine, New York Presbyterian Hospital, New York, NY.
  • 5. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY.
  • 6. Department of Pediatrics and.
  • 7. Department of Pathology, University of Utah, Salt Lake City, UT.
  • 8. PEEL Therapeutics, Inc, Salt Lake City, UT; and.
  • 9. Department of Internal Medicine and.
  • 10. Geriatric Research, Education, and Clinical Center (GRECC), George E. Wahlen Veterans Affairs (VA) Medical Center, Salt Lake City, UT.
PMID: 32597954 DOI: 10.1182/blood.2020007008
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 = 33) and age- and sex-matched controls (n = 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 = .0360), whereas Pao2/fraction of inspired oxygen correlated inversely (P = .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.

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