NETosis induction reflects COVID-19 severity and long COVID: insights from a 2-center patient cohort study in Israel

Nitzan Krinsky, Sofia Sizikov, Sivan Nissim, Adi Dror, Anna Sas, Hodaya Prinz, Ester Pri-Or, Shay Perek, Ayelet Raz-Pasteur, Izabella Lejbkowicz, Sivan Ida Cohen-Matsliah, Ronit Almog, Nikanor Chen, Ramzi Kurd, Amir Jarjou'i, Ariel Rokach, Eli Ben-Chetrit, Avi Schroeder, Aleah F. Caulin, Christian Con YostJoshua D. Schiffman, Mor Goldfeder, Kimberly Martinod

Research output: Contribution to journalArticlepeer-review


Background: COVID-19 severity and its late complications continue to be poorly understood. Neutrophil extracellular traps (NETs) form in acute COVID-19, likely contributing to morbidity and mortality. Objectives: This study evaluated immunothrombosis markers in a comprehensive cohort of acute and recovered COVID-19 patients, including the association of NETs with long COVID. Methods: One-hundred-seventy-seven patients were recruited from clinical cohorts at 2 Israeli centers: acute COVID-19 (mild/moderate, severe/critical), convalescent COVID-19 (recovered and long COVID), along with 54 non-COVID controls. Plasma was examined for markers of platelet activation, coagulation, and NETs. Ex vivo NETosis induction capability was evaluated after neutrophil incubation with patient plasma. Results: Soluble P-selectin, factor VIII, von Willebrand factor, and platelet factor 4 were significantly elevated in patients with COVID-19 versus controls. Myeloperoxidase (MPO)-DNA complex levels were increased only in severe COVID-19 and did not differentiate between COVID-19 severities or correlate with thrombotic markers. NETosis induction levels strongly correlated with illness severity/duration, platelet activation markers, and coagulation factors, and were significantly reduced upon dexamethasone treatment and recovery. Patients with long COVID maintained higher NETosis induction, but not NET fragments, compared to recovered convalescent patients. Conclusions: Increased NETosis induction can be detected in patients with long COVID. NETosis induction appears to be a more sensitive NET measurement than MPO-DNA levels in COVID-19, differentiating between disease severity and patients with long COVID. Ongoing NETosis induction capability in long COVID may provide insights into pathogenesis and serve as a surrogate marker for persistent pathology. This study emphasizes the need to explore neutrophil-targeted therapies in acute and chronic COVID-19.

Original languageEnglish
Pages (from-to)2569-2584
Number of pages16
JournalJournal of Thrombosis and Haemostasis
Issue number9
Early online date11 Apr 2023
StatePublished - Sep 2023
Externally publishedYes

Bibliographical note

Funding Information:
Funding information This work was sponsored by Peel Therapeutics , Inc., and supported in part by the US NIH (R01HD093826 to C.C.Y. - NICHD; Peel Therapeutics, Inc. (Sponsored Research Agreement to C.C.Y.), and the University of Utah Department of Pediatrics, Division of Neonatology.

Publisher Copyright:
© 2023 The Authors


  • COVID-19
  • extracellular traps
  • immunothrombosis
  • neutrophil
  • post-acute COVID-19 syndrome

ASJC Scopus subject areas

  • Hematology


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