Mild Acquired von Willebrand Syndrome and Cholestasis in Pediatric and Adult Patients with Fontan Circulation

Abstract

Background: Hemodynamic alterations in Fontan patients (FP) are associated with hemostatic dysbalance and Fontan-associated liver disease. Studies of other hepatopathologies indicate an interplay between cholestasis, tissue factor (TF), and von Willebrand factor (VWF). Hence, we hypothesized a relationship between the accumulation of bile acids (BA) and these hemostatic factors in FP. Methods: We included 34 FP (Phenprocoumon n = 15, acetylsalicylic acid (ASA) n = 16). BA were assessed by mass spectrometry. TF activity and VWF antigen (VWF:Ag) were determined by chromogenic assays. VWF collagen-binding activity (VWF:CB) was assessed via ELISA. Results: Cholestasis was observed in 6/34 FP (total BA ≥ 10 µM). BA levels and TF activity did not correlate (p = 0.724). Cholestatic FP had lower platelet counts (p = 0.013) from which 5/6 FP were not treated with ASA. VWF:Ag levels were increased in 9/34 FP and significantly lower in FP receiving ASA (p = 0.044). Acquired von Willebrand syndrome (AVWS) was observed in 10/34-FP, with a higher incidence in cholestatic FP (4/6) (p = 0.048). Conclusions: Cholestasis is unexpectedly infrequent in FP and seems to be less frequent under ASA therapy. Therefore, ASA may reduce the risk of advanced liver fibrosis. FP should be screened for AVWS to avoid bleeding events, especially in cholestatic states.

Keywords: Fontan circulation; Fontan-associated liver disease; acquired von Willebrand syndrome; bile acids; cholestasis; hemostasis; thromboprophylaxis.

Figure 1

Comparison of the distribution of total bile acid (tBA) concentrations between Fontan patients <18 and ≥18 years of age. Cholestatic patients are highlighted by the red dots (A). BA profiles of cholestatic and non-cholestatic Fontan patients (B). * p $\le$ 0.05. Abbreviations: See Supplementary Table S1.

Figure 2

VWF:Ag and VWF:CB (A) values in cholestatic (red dots) and non-cholestatic Fontan patients. Comparison of VWF:Ag levels between Fontan patients with and without acetylsalicylic acid (ASA) treatment. Cholestatic patients are highlighted by the red dots (B). * p $\le$ 0.05. Abbreviations: VWF, von Willebrand factor; VWF:Ag, VWF antigen; VWF:CB, VWF collagen binding activity.

Figure 3

VWF:CB/VWF:Ag ratio in cholestatic (red dots) and non-cholestatic Fontan patients. Abbreviations: VWF:Ag, von Willebrand factor antigen; VWF:CB, von Willebrand factor collagen binding activity.