# Defective NET clearance contributes to sustained FXII activation in COVID-19-associated pulmonary thrombo-inflammation

## TL;DR

This study shows that defective removal of NETs in the lungs of COVID-19 patients leads to increased FXII activation, contributing to dangerous blood clotting and inflammation.

## Contribution

The study identifies a novel mechanism linking NETs and FXII activation in the progression of thrombo-inflammation in COVID-19.

## Key findings

- FXII expression and activity were elevated in lung tissues from COVID-19 patients.
- NETs accumulation correlates with FXIIa activation in the lungs of these patients.
- DNase substitution reduced NETs and FXII activation in vitro, suggesting a potential therapeutic approach.

## Abstract

Coagulopathy and inflammation are hallmarks of Coronavirus disease 2019 (COVID-19) and are associated with increased mortality. Clinical and experimental data have revealed a role for neutrophil extracellular traps (NETs) in COVID-19 disease. The mechanisms that drive thrombo-inflammation in COVID-19 are poorly understood.

We performed proteomic analysis and immunostaining of postmortem lung tissues from COVID-19 patients and patients with other lung pathologies. We further compared coagulation factor XII (FXII) and DNase activities in plasma samples from COVID-19 patients and healthy control donors and determined NET-induced FXII activation using a chromogenic substrate assay.

FXII expression and activity were increased in the lung parenchyma, within the pulmonary vasculature and in fibrin-rich alveolar spaces of postmortem lung tissues from COVID-19 patients. In agreement with this, plasmaaac acafajföeFXII activation (FXIIa) was increased in samples from COVID-19 patients. Furthermore, FXIIa colocalized with NETs in COVID-19 lung tissue indicating that NETs accumulation leads to FXII contact activation in COVID-19. We further showed that an accumulation of NETs is partially due to impaired NET clearance by extracellular DNases as DNase substitution improved NET dissolution and reduced FXII activation in vitro.

Collectively, our study supports that the NET/FXII axis contributes to the pathogenic chain of procoagulant and proinflammatory responses in COVID-19. Targeting both NETs and FXIIa may offer a potential novel therapeutic strategy.

This study was supported by the European Union (840189), the Werner Otto Medical Foundation Hamburg (8/95) and the German Research Foundation (FR4239/1-1, A11/SFB877, B08/SFB841 and P06/KFO306).