Effects of Neutrophil Extracellular Traps in Patients With Septic Coagulopathy and Their Interaction With Autophagy.

Jia-Yu Mao,Jian-Wei Chen,Wei Cheng,Jia-Hui Zhang,Na Cui

doi:10.3389/fimmu.2021.757041

Abstract

IntroductionNeutrophil extracellular traps (NETs) act as a critical trigger of inflammation and coagulation. We hypothesized that NETs are associated with septic hypercoagulability.Materials and MethodsIn total, 82 patients admitted with sepsis in the Department of Critical Care Medicine of Peking Union Medical College Hospital were enrolled between February 2017 and April 2018. Clinical and hematological parameters and thrombotic or hemorrhagic events were recorded. Blood samples were obtained to assess biomarkers of NET formation, including neutrophil elastase 2 (ELA2) and citrullinated histone H3, and endothelial-derived biomarker syndecan-1. Autophagy levels and their regulation pathway were also examined to explore their interaction with NETs.ResultSepsis patients with disseminated intravascular coagulation (DIC) showed significantly higher levels of NET formation [ELA2, 1,247 (86–625) vs. 2,039 (1,544–2,534), p < 0.0001; H3, 140 (47–233) vs. 307 (199–415), p < 0.0001]. NET formation was independently associated with DIC risk [ELA2, OR 1.0028, 95% CI, 1.0010–1.0045; H3, OR 1.0104, 95% CI, 1.0032–1.0176] and mortality [ELA2, HR 1.0014, 95% CI, 1.0004–1.0024; H3, HR 1.0056, 95% CI, 1.0008–1.0115]. The area under the curve value for ELA2 in predicting DIC occurrence was 0.902 (95% CI, 0.816–0.957), and that of H3 was 0.870 (95% CI, 0.778–0.934). Furthermore, biomarkers of NET formation, endothelial cells, and autophagy exhibited a significant correlation [ELA2 and Syn (r = 0.5985, p < 0.0001), LC3B (r = −0.4224, p < 0.0001); H3 and Syn (r = 0.6383, p < 0.0001), LC3B (r = −0.3005, p = 0.0061)].ConclusionIncreased NET formation is significantly associated with sepsis-induced DIC incidence and mortality in sepsis patients, revealing a significant relationship with the autophagy pathway.Clinical Trial Registrationchictr.org.cn, identifier ChiCTR-ROC-17010750.

Highlights

Neutrophil extracellular traps (NETs) act as a critical trigger of inflammation and coagulation
NET formation was independently associated with disseminated intravascular coagulation (DIC) risk [elastase 2 (ELA2), odds ratio (OR) 1.0028, 95% CI, 1.0010–1.0045; citrullinated histone H3 (H3), OR 1.0104, 95% CI, 1.0032–1.0176] and mortality [ELA2, hazard ratio (HR) 1.0014, 95% CI, 1.0004– 1.0024; H3, HR 1.0056, 95% CI, 1.0008–1.0115]
Sepsis is characterized by a broad inflammatory response and coagulation activation that both contribute to bacterial containment and lead to microangiopathy through uncontrolled thrombin and fibrin generation, potentially evolving toward disseminated intravascular coagulation (DIC) [1, 2]

Summary

Introduction

Neutrophil extracellular traps (NETs) act as a critical trigger of inflammation and coagulation. DIC exacerbates multiple organ dysfunction and increases the risk of death; blood coagulation processes are a therapeutic target of interest [3]. Neutrophil extracellular traps (NETs) produced by activated neutrophils have recently been shown to provide a novel link between inflammation and thrombosis [4]. In accompany with red blood cells (RBCs), platelets, and fibrin, NET components promote formation of thrombi, especially in microvessels [6, 7]. Cytokines released by neutrophils contribute to alteration of the membrane of vascular, especially endothelial cells (ECs), and participate in sepsis-induced endothelial dysfunction and coagulation activation [8, 9]

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Conclusion