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. 2025 Feb;58(2):199-209.
doi: 10.1007/s11239-024-03057-z. Epub 2024 Nov 15.

Impact of antiplatelets, anticoagulants and cyclic nucleotide stimulators on neutrophil extracellular traps (NETs) and inflammatory markers during COVID-19

José D Oliveira  1   2 , Gislaine Vieira-Damiani  3 , Letícia Q da Silva  1   4 , Guilherme R Leonardi  5 , Camila O Vaz  1   2 , Bruna C Jacintho-Robison  1   2 , Bruna M Mazetto  1   4 , Erich V de Paula  1   4 , Fabíola Z Monica  5 , Fernanda A Orsi  6   7   8
Affiliations

Impact of antiplatelets, anticoagulants and cyclic nucleotide stimulators on neutrophil extracellular traps (NETs) and inflammatory markers during COVID-19

José D Oliveira et al. J Thromb Thrombolysis. 2025 Feb.

Abstract

While the association between coronavirus disease-19 (COVID-19) and neutrophils extracellular traps (NETs) is recognized, uncertainties remain regarding its precise onset, timing of resolution and target therapy. To assess changes in inflammatory and NET markers during the first week of COVID-19 hospitalization, and the association with disease severity. "In vitro" experiments investigated the effect of antiplatelets, anticoagulants, and cyclic nucleotide stimulators on NETs release. Prospective cohort study, changes in interleukin (IL)-6, IL-8, IL-17, TNF-α, RANTES, PF4, and citrullinated-H3 (citH3) levels within each outcome group was evaluated using ANOVA. Differences between moderately ill, critically ill, and non-survivors were determined using Kruskal-Wallis and logistic regression. Healthy neutrophils were stimulated with phorbol-12-myristate-13-acetate (PMA) or COVID-19 sera and treated with unfractionated heparin (UFH), low molecular weight heparin (LMWH), aspirin (ASA), ticagrelor, cinaciguat, sildenafil, and milrinone. The proportion of NETosis was assessed using IncuCyte Cell Imager. Of the 125 patients, 40.8% had moderate COVID-19, 40.8% had critical COVID-19 but recovered, and 18.4% died. From admission to hospitalization day 8, IL-6 levels decreased in moderately and critically ill, but not in non-survivors, while citH3 levels increased in critically ill and non-survivors. IL-6, IL-8, and TNF-α levels were associated with critical and fatal COVID-19. The release of NETs by neutrophils stimulated with PMA or COVID-19 sera was decreased in the presence of ASA, UFH, LMWH and cyclic nucleotide stimulators in a dose-dependent manner. In the first week of hospitalization, NET markers rose later than inflammatory markers in severe COVID-19 cases. Cyclic nucleotide stimulators, ASA and heparin may emerge as treatment approaches as they may modulate NETosis.

Keywords: Anticoagulants; Antiplatelet agents; COVID-19; Cyclic nucleotides; Neutrophil extracellular traps.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare no conflict of interest. Generative AI and AI-assisted technologies in the writing process: During the preparation of this work the author(s) used https://www.deepl.com/ in order to correct grammatical errors in the text. After using this tool, the authors reviewed and edited the content as needed and took full responsibility for the content of the publication. Informed consent: The study was conducted in compliance with the Helsinki Declaration. A waiver of the Informed Consent was granted based on the emergence of the pandemic, the observational nature of the study, the utilization of data obtained from medical records, and the use of residual samples. The study ensured the deidentification of patient records. In addition, patients diagnosed with COVID-19 were isolated, and access to the patients and their relatives was restricted to healthcare personnel.

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