Defective NETs Clearance contributes to sustained FXII Activation in COVID-19-associated Pulmonary Thrombo-Inflammation

Coagulopathy and inflammation are hallmarks of Coronavirus disease 2019 (COVID-19) and are associated with increased mortality. The mechanisms that drive thrombo-inflammation in COVID-19 are poorly understood. Here, we report a role of the NETs/ Factor XII (FXII) axis for initiating procoagulant and proinflammatory reactions in COVID-19. Proteomic analysis revealed enrichment of FXII in postmortem lung tissue from COVID-19 patients. Immunofluorescence analysis of COVID-19 lung tissue showed that FXII is activated in the lung parenchyma, within the pulmonary vessel walls and in fibrin-rich alveolar spaces. In particular, activated FXII (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 caused by impaired NETs clearance via extracellular DNases. In contrast, addition of DNase I improved NETs clearance and reduced FXII activation in vitro. We propose that targeting both, FXIIa and the FXII activator NETs, is therapeutically effective in mitigating thrombo-inflammation in COVID-19.