Neutrophil extracellular trap-associated responses are associated with tissue factor expression and coagulation...

Anaphylaxis is a severe, fast-onset hypersensitivity reaction. Studies have shown that neutrophils play an important role in the acute phase of anaphylaxis. Activated neutrophils can release neutrophil extracellular traps (NETs); however, the potential involvement of NET-associated responses in anaphylaxis and their relationship with coagulation abnormalities remain unclear.

The aim of this study was to investigate the potential involvement of NET-associated responses in anaphylaxis and their association with tissue factor (TF) expression and coagulation abnormalities.

NET-associated markers, inflammatory mediators, coagulation-related parameters, and indices of anaphylactic responses were assessed in patients with anaphylaxis, passive systemic anaphylaxis (PSA) and passive cutaneous anaphylaxis (PCA) mouse models, and IgE-stimulated primary neutrophils. DNase I was used to degrade extracellular DNA structures, and tissue factor pathway inhibitor (TFPI) was used to modulate TF-related coagulation signaling. Heparin sodium and dexamethasone (DXM) were administered to evaluate whether anticoagulant or anti-inflammatory treatment was accompanied by changes in NET-associated and coagulation-related markers.

Bioinformatics analysis identified NET-associated genes and related biological pathways in anaphylaxis. Increased NET-associated markers were detected in patients with anaphylaxis, PSA mice, and IgE-treated primary neutrophils. DNase I treatment reduced NET-associated markers, inflammatory cytokine levels, and the experimental anaphylactic responses. Mast-cell degranulation and NET-associated extracellular DNA signals were increased in PCA mice. Elevated TF levels were detected in patients with anaphylaxis, and increased TF expression was observed in neutrophils from PSA mice. TFPI treatment was associated with reduced TF expression, inflammatory cytokine expression, and NET-associated markers in experimental models. Among 323 patients, higher D-dimer and fibrin degradation product levels were associated with greater anaphylaxis severity, and D-dimer levels were positively correlated with neutrophil counts. DNase I and TFPI treatment reduced D-dimer and fibrin degradation product levels in PSA mice. Heparin sodium and DXM attenuated experimental anaphylactic responses and were accompanied by reductions in NET-associated, TF-related, and coagulation markers.

NET-associated markers were increased in anaphylaxis and were associated with TF expression, coagulation abnormalities, and disease severity. Extracellular DNA degradation and TF pathway modulation were associated with attenuation of experimental anaphylactic responses. These findings support a potential association among NET-associated responses, TF expression and coagulation abnormalities, and anaphylaxis, although further mechanistic studies are required to establish direct causality.