Neutrophil Extracellular Traps Are Not Linked to Decompensation, ACLF, or Death in Clinically Stable Patients With ACLD

Background and Aims Neutrophil extracellular traps (NETs) are part of the body's innate immune response. In animal models, NETs aggravated liver injury and promoted disease progression/portal hypertension by the formation of (micro)thrombi leading to parenchymal extinction. This study aimed to investigate NETosis in patients with clinically stable advanced chronic liver disease (ACLD). Methods We evaluated stable ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement in whom an extensive panel of laboratory tests related to coagulation and NET biomarkers was assessed in plasma. Hepatic decompensation/liver‐related death (LRD) as well as the development of ACLF/LRD were the outcomes of interest. Results 194 patients (70 compensated/124 decompensated; mean Child‐Turcotte‐Pugh score (CTP): 7 ± 2 points; mean HVPG: 17 ± 6 mmHg) were included. Compared to healthy controls ( n = 29), levels of cell‐free DNA (cf‐DNA) were higher (0.88 [IQR 0.84–0.93] vs. 0.94 [IQR 0.88–1.03] μg/mL; p = 0.001) in ACLD, whereas myeloperoxidase‐DNA (MPO‐DNA) values were similar (0.32 [IQR 0.17–0.54] vs. 0.39 [IQR 0.18–0.76] AU; p = 0.400). Factor XIII activity levels, soluble P‐selectin, and cf‐DNA but not MPO‐DNA levels were linked to HD/LRD and/or ACLF/LRD in univariable analysis. However, none of these tests were associated with the aforementioned outcomes after adjusting for established prognostic indicators. Conclusion Patients with stable ACLD showed increased cf‐DNA levels (i.e., NETosis, but also apoptosis/necrosis). However, MPO‐DNA as a NETosis‐specific marker was comparable to healthy controls. NETosis does not appear to drive disease progression in clinically stable ACLD as it was not linked to endpoints, thereby questioning whether findings obtained in animal models are translatable to humans.