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

Abstract

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.

The Emerging Role of Neutrophil Extracellular Traps in Arterial, Venous and Cancer-Associated Thrombosis

“…Based on accumulating evidence, neutrophils play a key role in the process of thrombosis (5)(6)(7)(8). The depletion of neutrophils has been shown to reverse experimental thrombosis (9,10). Another study reported that neutrophils produce tissue factor (TF) and contribute to the formation of thrombosis in vivo and in vitro (11).…”

Pathophysiological consequences and treatment strategy of obstructive jaundice

“…Research into procoagulant activity, specifically by measuring coagulation time, fibrin formation, and purified coagulation complexes, has revealed that the presence of neutrophil extracellular traps (NETs) in patients with OJ is significantly higher than in healthy individuals. This suggests that targeting NET values could be a promising approach to improving coagulation disorders in OJ patients[ 50 ]. Cakir et al [ 51 ] conducted a study that observed hypercoagulability in more than half of patients with OJ.…”

Neutrophil extracellular traps induce intrahepatic thrombotic tendency and liver damage in cholestatic liver disease

“…Elevated levels of NETs have been correlated with poor prognosis in liver diseases, such as NASH 19 and HCC 20 . Our previous study indicated increased NET levels in the circulation of patients with CLD due to heightened bilirubin, with these NETs amplifying circulation coagulation activity in patients with CLD 21 . In CLD, accumulating large bilirubin in the liver prompts activated KCs to release chemotactic factors, recruiting neutrophils.…”

“…[20] Our previous study indicated increased NET levels in the circulation of patients with CLD due to heightened bilirubin, with these NETs amplifying circulation coagulation activity in patients with CLD. [21] In CLD, accumulating large bilirubin in the liver prompts activated KCs to release chemotactic factors, recruiting neutrophils. However, the presence of NETs in the liver in CLD and their role in promoting liver coagulation activity remain undetermined.…”