Elevated Plasma Levels of Cell-Free DNA During Liver Transplantation Are Associated With Activation of Coagulation

BACKGROUND & AIMS: Patients undergoing liver transplantation have complex changes in their hemostatic system, and the net effect of these changes appears a 'rebalanced' hemostatic profile. Recently, a process called NETosis, in which a neutrophil expels DNA and proteins that form a web-like structure, has been described as a mechanism of pathogen entrapment. Increasing evidence suggests a pivotal role for neutrophil extracellular traps (NETs), and their main component cell-free DNA in activation of coagulation. As liver transplantation is associated with substantial (hepatocyte) cell death and intrahepatic neutrophil accumulation, NETs might play an important role in the hemostatic balance during liver transplantation. Here, we determined markers for NETs in plasma of patients undergoing a liver transplantation and examined their association with activation of coagulation.

METHODS: Markers for NETs and markers for activation of coagulation were determined in serial plasma samples taken from patients undergoing a liver transplantation (n=21) and compared with plasma levels in healthy controls.

RESULTS: We found perioperative increases of markers for NETs with levels of cell-free DNA and nucleosomes that peaked after reperfusion, and myeloperoxidase-DNA complexes that peaked during the anhepatic phase. Cell-free DNA and nucleosome levels, but not MPO-DNA levels correlated with prothrombin fragment 1+2 and thrombin-antithrombin complex levels, which are established markers for activation of coagulation. Neutrophils undergoing NETosis were observed by immunostainings in post-reperfusion biopsies.

CONCLUSIONS: Although NETosis occurs during liver transplantation, the majority of circulating DNA appears to be derived from cell death within the graft. The perioperative increases in cell-free DNA and nucleosomes might contribute to the complex hemostatic rebalance during liver transplantation. This article is protected by copyright. All rights reserved.