Abstract
Background 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.
Methods 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 Factor XIII (FXII) activation using a chromogenic substrate assay.
Findings 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, plasma FXII 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.
Interpretation Collectively, our study supports that the NETs/FXII axis contributes to the pathogenic chain of procoagulant and proinflammatory responses in COVID-19. Targeting both, NETs and FXIIa, could provide a strategy to mitigate COVID-19-induced thrombo-inflammation.
Funding 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).
Competing Interest Statement
H.E. has a patent WO 2019/036719A2, licensed to Neutrolis Therapeutics, outside the submitted work. C.R. has a patent EP3570667A1, licensed to Neutrolis Therapeutics, outside the submitted work. K.Pa. is an employee and shareholder of CSL Limited and has patents 9.856.326, 9.856.325 and 9.518.127 issued, outside the submitted work. C.M. is part-time employee of TargED Biopharmaceuticals and has a patent WO2019185723A1 pending, both outside the submitted work. T.R. and the University of Hamburg have a patent (EU and U.S. reference numbers EP18736859.2 and US16/622064) licensed, outside of the submitted work.