Generation of neutrophil extracellular traps in patients with acute liver failure is associated with poor outcome

Abstract

Background and Aims: Acute liver failure (ALF) is characterized by significant changes in the hemostatic system and by systemic inflammation. The formation of neutrophil extracellular traps (NETs), in which an activated neutrophil expels its DNA, histones, and granular enzymes, such as myeloperoxidase (MPO), has been associated with immune-mediated and thrombotic diseases. We hypothesized that formation of NETs in patients with ALF contributes to progression of disease. Approach and Results:A total of 676 patients with ALF (international normalized ratio [INR], ≥1.5) or severe acute liver injury (ALI; INR, ≥2.0) were recruited from the U.S. ALF Study Group Registry between 2011 and 2018, of whom 308 patients (45.6%) had acetaminophen-induced ALF. Up to 21 days after admission, 483 patients (71.5%) survived without liver transplantation (LT). Levels of cell-free DNA (cfDNA) and the specific NET marker MPO-DNA complexes were measured in plasma samples obtained on admission and compared to levels in healthy controls. In addition, liver tissue obtained at transplantation of 20 ALF patients was stained for NETs. Levels of cfDNA were 7.1-fold, and MPO-DNA complexes 2.5-fold, higher in patients with ALF compared to healthy controls. cfDNA levels were not associated with 21-day transplant-free survival, but were higher in those patients with more-severe disease on admission, as reflected by various laboratory and clinical parameters. MPO-DNA levels were 30% higher in patients with ALF who died or required urgent LT. Liver tissue of ALF patients stained positive for NETs in 12 of 18 evaluable patients.

A NET gain in our understanding of acute liver failure

“…This study by von Meijenfeldt et al provides the first description of the generation of neutrophil extracellular traps (NETs) in 676 patients with ALF and associates NETs with poor outcomes. [ 1 ]…”

A Novel Animal Model of Primary Blast Lung Injury and Its Pathological Changes in Mice

“…Compared with the control group, the level of NETs in the lung tissue increased signi cantly in the model group, and reached the peak at 6-12 h (Figure 4b). MPO is a component of NETs, and its protein expression is highly correlated with the level of NETs [10] . The level of MPO in the lung tissues of mice in the model group was signi cantly increased at 2-12 h after injury, and peaked at 6 h, but there was no signi cant difference between the model group and the control group at 24 h (Figure 4c).…”

The association between prothrombin time-international normalized ratio and long-term mortality in patients with coronary artery disease: a large cohort retrospective study with 44,662 patients

“…PT-INR is regulated by multiple coagulation factors synthesized in the liver and is widely used to monitor anticoagulation, to assess hepatic function, and to evaluate coagulation abnormalities. Previous studies revealed that PT-INR level was closely related to status of inflammation among serious of diseases [ 8 , 9 ]. Similarly, some studies showed a higher PT-INR level was significantly associated mortality in patients undergoing endarterectomy [ 10 ], or with acute heart failure [ 11 ].…”