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 MPODNA 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.
Conclusions: Here, we provide evidence for NET formation in patients with
ALF. Elevated plasma levels of MPO-DNA complexes in patients with ALF