Defective NET clearance contributes to sustained FXII activation in COVID-19-associated pulmonary
Hanna Englert1, Chandini Rangaswamy1, Carsten Deppermann1
1Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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 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, 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.
Interpretation:
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.
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).
Related Concept Videos
Clot Retraction and Fibrinolysis
Anticoagulant Drugs: Low-Molecular-Weight Heparins
Extrinsic and Intrinsic Pathways of Hemostasis
The Extrinsic Pathway
The extrinsic pathway of coagulation is typically initiated by tissue damage that exposes blood to tissue factor (TF), a protein released by the damaged tissue cells outside the blood vessels—this interaction with TF triggers biochemical reactions involving specific clotting factors. The key player here is Factor VII, which...
Chronic Obstructive Pulmonary Disease-II: Pathophysiology
Chronic Inflammation
Pulmonary Embolism II: Diagnostic Studies and Interprofessional Care
Formation of the Platelet Plug
As the injured blood vessel contracts, endothelial cells undergo contraction, revealing collagen fibers in the basement membrane and underlying connective tissue. Furthermore, the plasma membrane of endothelial cells becomes adhesive, preparing the site for platelet adhesion. Platelets...


