Neutrophil extracellular traps enhance procoagulant activity and thrombotic tendency in patients with obstructive jaundice

• Published in: Liver international 2021-02, Vol.41 (2), p.333-347
• Main Authors: Zhang, Jinming, Yu, Muxin, Liu, Biou, Zhou, Peng, Zuo, Nan, Wang, Yufeng, Feng, Yiming, Zhang, Yue, Wang, Jiaojiao, He, Yujing, Wu, Yinsong, Dong, Zengxiang, Hong, Luojia, Shi, Jialan
• Format: Article
• Language: English
• Subjects: Accumulation; Bilirubin; Cell junctions; Coagulation; Complications; Confocal microscopy; Deoxyribonuclease; Endothelial cells; Fibrin; Fluorescence; Jaundice; Leukocytes (neutrophilic); Mitochondria; neutrophil extracellular traps; Neutrophils; obstructive jaundice; Phenotypes; Phosphatidylserine; procoagulant activity; Reactive oxygen species; Thromboembolism; Thrombosis; Umbilical vein; unconjugated bilirubin
• ISSN: 1478-3223; 1478-3231
• DOI: 10.1111/liv.14725

Background & Aims Patients with obstructive jaundice (OJ) are considered to be prothrombotic with increased risk of thromboembolism complications. The role of neutrophil extracellular traps (NETs) in procoagulant activity (PCA) and thrombosis risk in patients with OJ is unclear. In this study, we investigated NETs formation in OJ patients and the role of elevated unconjugated bilirubin (UCB) in inducing NETs, resulting in enhanced PCA and endothelial injury. Methods NETs of OJ patients and healthy controls were measured. NETs PCA was assessed via coagulation time (CT), fibrin formation and purified coagulation complex production assays. Visualization of NETs and mitochondrial reactive oxygen species (MitoROS) were performed with a fluorescence microscope. We further used confocal microscopy to quantify the exposure of phosphatidylserine (PS), fibrin strands and FVa/Xa on Human umbilical vein endothelial cells (HUVECs). Results Assessment of NETs components levels revealed greater NETs production in OJ patients than in healthy controls. Importantly, OJ‐NETs were responsible for enhanced PCA. UCB induced NETs formation via MitoROS accumulation and mitochondrial mobilization. HUVECs cocultured with OJ NETs lost their cell–cell junctions and consequently converted to a procoagulant phenotype. The PCA was attenuated by using DNase I alone or in combination with lactadherin. Conclusions Our results suggest that UCB‐induced NETs play a prominent role in promoting the hypercoagulable and prothrombotic state in OJ patients. The increased MitoROS accumulation in neutrophils initiated NETosis. NETs are promising targets for indicating or improving coagulation disorders in OJ patients.