Imbalance of von Willebrand factor and its cleaving protease ADAMTS13 during systemic inflammation superimposed on advanced cirrhosis.

Abstract

Systemic inflammation in advanced cirrhosis represents a spectrum ranging from subclinical pathological bacterial translocation and immune activation to overt bacterial infection and sepsis. We hypothesized that systemic inflammation in cirrhosis is accompanied by a failure of ADAMTS13 to control the prothrombotic function of von Willebrand factor (VWF), which is increased in portal hypertension and hepatic fibrosis. Patients with Child A cirrhosis (n = 25), Child B/C cirrhosis without clinical features of systemic inflammation (n = 31), and Child B/C cirrhosis with overt bacterial infections or systemic inflammatory response syndrome (n = 24) were analysed for ADAMTS13 and associated parameters and were followed to determine transplant-free survival. Plasma concentration and activity of ADAMTS13 were decreased in patients with systemic inflammation. Furthermore, ADAMTS13 inversely correlated with the extent of bacterial translocation and the severity of acute-phase reaction. As a function of reduced ADAMTS13 activity and increased VWF antigen, plasma from patients with superimposed inflammation strongly aggregated the platelet receptor glycoprotein Ib in presence of ristocetin. VWF:RCo correlated with higher concentrations of leucocytes and lipopolysaccharide-binding protein, organ dysfunction, augmented turnover of cross-linked intravascular fibrin, and the occurrence of acute kidney injury during follow-up. VWF:RCo of 390% or more predicted transplant-free survival in univariate analysis [HR = 8.24 (3.30-20.54)] and after adjustment for MELD [HR = 3.58 (1.30-9.88)]. However, adverse outcome was not associated with the accumulation of high-molecular weight VWF multimers. Systemic inflammation complicating advanced cirrhosis is accompanied by reduced activity of ADAMTS13 promoting a prothrombotic function of VWF, which can be employed to predict clinical outcome.