Administration

The Fontan surgery is a palliative approach to treating functional single ventricle congenital heart disease. As a result thereof, an impairment of the hepatic blood supply and drainage may cumulate in Fontan-associated liver disease (FALD). Although intrahepatic coagulation has been shown to foster fibrosis via thrombin generation and intraparenchymal fibrin deposition, the etiology of FALD remains unresolved. As Fontan patients are disposed to exhibiting mild cholestasis, it was hypothesized that an accumulation of intraparenchymal bile acids (BA) is the elicitor of intrahepatic coagulation.

The aim of this study was to investigate the correlation between BA levels and intrahepatic coagulation in Fontan patients. Additionally, endothelial damage was examined as a potential catalyst for hepatic fibrosis through the induction of tissue factor (TF) activity.

The BA profiles of 34 Fontan patients were assessed through reverse-phase LCMS/MS. Aside from TF activity, the thrombin generation was analyzed via calibrated automated thrombography, prothrombin fragment 1+2 and the thrombin-antithrombin complex. In addition to the immunoturbidimetric assessment of the von Willebrand factor, endothelial damage was analyzed through the ELISA testing of thrombomodulin, tissuetype plasminogen activator and plasminogen activator inhibitor-1.

Cholestasis was determined in 6 out of 34 Fontan patients (total BA > 10 μM). However, the statistical analysis revealed no significant correlation between BA parameters and TF activity (p ≥ 0.05). Furthermore, no significant difference was found between the thrombin generation of cholestatic and non-cholestatic Fontan patients receiving PhC (p ≥0.05). Also, no significant difference was determined, regarding the analyzed endothelial markers (p ≥ 0.05).

The low incidence rate of cholestasis within the Fontan cohort is a novel finding, demanding further investigation. Although no significant correlation between BA and TF activity was uncovered, the limited number of cholestatic Fontan patients within the sampled cohort gives cause for further investigation into the role of TF activity in FALD. Furthermore, cholestasis did not seem to significantly impact the examined endothelial damage parameters. Nonetheless, elevated VWF antigen levels within the Fontan cohort argue for endothelial perturbation, which is not reflected in the VWF activity hinting to acquired von Willebrand disease.