Neutrophil Extracellular Traps May Prompt Lethal Blood Clots, Inflammation in Patients with COVID-19

Research recently published in Blood suggested that neutrophil extracellular traps may prompt the lethal blood clots and inflammation that occur in some patients with coronavirus disease 2019 (COVID-19).¹

"It will be important to investigate (neutrophil extracellular traps’) role in clot formation (thrombosis) not only in light of the COVID-19 pandemic, but also to understand their broader role in disease," Mikala Egeblad, PhD, associate professor in the Cold Spring Harbor Laboratory, said in a press release.²

With neutrophil extracellular traps having the ability to trigger immunothrombosis, researchers decided to study the connection between neutrophil extracellular traps and COVID-19 severity and progression. In this prospective cohort study, 33 patients with COVID-19 were evaluated with 17 age- and sex-matched controls. In addition, 3 COVID-19 lung autopsies were examined for neutrophil extracellular traps and platelet involvement.

Ultimately, plasma myeloperoxidase-DNA complexes increased in those with COVID-19 related intubation (P < 0.0001) and death as an outcome (P < 0.005). Severity of a patient’s illness also directly correlated with plasma myeloperoxidase-DNA complexes (P = 0.0360), though PaO₂/FiO₂ correlated inversely (P=0.0340).

Moreover, soluble and cellular factors triggering neutrophil extracellular traps were significantly increased in patients with COVID-19 and pulmonary autopsies confirmed neutrophil extracellular traps-containing microthrombi with neutrophil-platelet infiltration. COVID-19 neutrophils ex vivo also displayed excessive neutrophil extracellular traps at baseline and COVID-19 plasma triggered neutrophil extracellular traps formation.

Given the overall study findings, investigators believe that neutrophil extracellular traps triggering immunothrombosis may be partially to blame for prothrombotic clinical presentations in patients with severe COVID-19. Additionally, researchers suggested that neutrophil extracellular traps may represent targets for therapeutic intervention moving forward.

"Excess (neutrophil extracellular traps) are formed in other viral diseases," Egeblad explained. "We also know that clotting is a major cause of death in people with end-stage cancer, so what we are learning in COVID-19 may help us understand basic properties in cancer and other diseases."

Importantly, the investigators were able to halt neutrophil extracellular traps production by exposing cells to neonatal neutrophil extracellular trap-Inhibitory Factor (nNIF), which is an anti-inflammatory peptide derived from umbilical cord blood. Furthermore, several nNIF and related neutrophil extracellular trap-inhibitory peptides are currently being evaluated in the preclinical setting for their therapeutic potential in COVID-19 and other disease associated with immunothrombosis. These include the nNIF peptide, which is in pre-clinical development by PEEL Therapeutics.

"Although further studies will be required, the (neutrophil extracellular trap)-inhibitory protein may block exaggerated (neutrophil extracellular traps) formation in COVID-19 patients," Christian Con Yost, MD, whose laboratory at the University of Utah Health discovered nNIF in 2016, said in a press release.

Though a limited number of patients with COVID-19 with lacking long-term follow-up for ischemic events were enrolled, this study represents the first prospective cohort thus far to assess the effects of neutrophil extracellular trapsosis in COVID-19. However, future studies will be necessary in larger COVID-19 patient cohorts to validate the current findings.

References:

1. Middleton E, He X, Denorme F, et al. Neutrophil Extracellular Traps (NETs) Contribute to Immunothrombosis in COVID-19 Acute Respiratory Distress Syndrome. Blood. doi: 10.1182/blood.2020007008.

2. New evidence for how blood clots may form in very ill COVID-19 patients [news release]. Cold Spring Harbor, NY. Published June 29, 2020. prnmedia.prnewswire.com/news-releases/new-evidence-for-how-blood-clots-may-form-in-very-ill-covid-19-patients-301085133.html. Accessed July 2, 2020.