Plasma from Patients Undergoing Liver Transplantation Is Resistant to Anticoagulant Activity of Soluble Thrombomodulin (ART-123)

BACKGROUND: Recombinant soluble human thrombomodulin (ART-123) is an anticoagulant and anti-inflammatory agent clinically used for treatment of disseminated intravascular coagulation. Preclinical studies have shown that ART-123 reduces hepatic ischemia/reperfusion. Although ART-123 may therefore have clinical benefit in orthotopic liver transplantation the substantial alterations in the hemostatic system may complicate its use in this setting. OBJECTIVE: Here we studied the in vitro effect of ART-123 on coagulation of patients with end-stage liver disease undergoing liver transplantation. PATIENTS/METHODS: Ten patients with end-stage liver disease undergoing liver transplantation were included in this study. Plasma samples of 10 healthy individuals were included to establish reference values. Different concentrations of ART-123 were added to plasma samples and peak thrombin generation and clot lysis times were determined. RESULTS: In patient samples, plasma was profoundly resistant to the anticoagulant action of ART-123, as reflected by significantly higher IC50 values of peak thrombin generation compared to controls. This might be partially explained by low levels of protein C, protein S and elevated levels of factor VIII during transplantation. Intraoperative levels of thrombin activatable fibrinolysis inhibitor (TAFI) were significantly lower, compared to controls. However, ART-123-dependent prolongation of clot lysis times was not significantly different from healthy controls. CONCLUSION: This study suggests that ART-123 is unlikely to provoke bleeding in patients undergoing liver transplantation as proposed clinical dosages have a virtually absent anticoagulant effect in these patients. Clinical studies are required to confirm safety of ART-123 and efficacy on alleviating I/R injury during liver transplantation. This article is protected by copyright. All rights reserved