Procoagulant role of neutrophil extracellular traps in patients with gastric cancer.

Abstract

BACKGROUND: Patients with gastric cancer (GC) commonly exhibit a hypercoagulable state that results in significant morbidity and mortality. Recent studies have shown that neutrophil extracellular traps (NETs) trigger coagulation through an intrinsic pathway and contribute to thrombus initiation and progression. In this study, we aimed to determine the procoagulant activity (PCA) of NETs in patients with GC. METHODS: NET formation and their PCAs were assessed in 48 patients with GC and 36 healthy controls using immunofluorescence microscopy of neutrophil markers and extracellular DNA as well as a modified capture ELISA technique, and thrombin-antithrombin complex and clot (fibrin) spectroscopic detection, respectively. RESULTS: Here we showed that neutrophils isolated from patients with GC displayed significantly enhanced NET formation compared with those from healthy controls; furthermore, plasma or platelets obtained from patients with GC induced control neutrophils to release NETs. In addition, NETs released by GC neutrophils significantly increased the potency of control plasma to generate thrombin and fibrin. Notably, these procoagulant effects were dramatically attenuated by application of DNase I. We further found that spontaneous NET formation in patients with GC was significantly higher than that in controls, increased with tumor- node-metastasis stage elevation, and positively correlated with thrombin-antithrombin complex levels and D-dimers. Additionally, the effect of DNase I on cell-free plasma generation of fibrin was dependent on the concentration of NET formation. CONCLUSION: These results suggest that GC creates a systemic environment that primes neutrophils to release procoagulant NETs. Thus, targeting NETs might improve the coagulopathy of patients with GC.