Abstract
In surgical settings, managing von Willebrand disease (VWD) often requires von Willebrand factor (VWF) concentrate administration, and close monitoring of factor VIII (FVIII) and VWF to balance bleeding control with the risk of excessive factor elevation. This management is further complicated by VWD-related variability and the pharmacokinetic (PK) impact of VWF products, containing or not exogenous FVIII. We hypothesized that building a PK model based on high-purity VWF concentrates may clarify the VWF-FVIII relationship by eliminating exogenous FVIII interference. Our aim was to characterize the PK/pharmacodynamic (PD) relationship and variability of a high-purity VWF concentrate in patients with VWD undergoing surgery. A retrospective analysis was conducted on patients treated perioperatively with a high-purity plasma-derived VWF concentrate (Wilfactin, Laboratoire Français du Fractionnement et des Biotechnologies, France), nearly devoid of FVIII, from January 2016 to December 2018. Data were analyzed using a population PK/PD modeling approach. VWF antigen (VWF:Ag) was prioritized as it better reflects VWF-FVIII binding capacity rather than VWF activity, which measures platelet interaction. Covariates influencing VWF:Ag and FVIII:C PK/PD were analyzed. Seventy-four patients undergoing 99 surgeries were included. The model revealed substantial variability in VWF:Ag and FVIII:C volume of distribution, clearance, and baseline levels. Covariates such as age, bodyweight, VWD type, blood group, and VWF propeptide significantly affected PK/PD parameters. Interindividual variability in PK parameters (eg, clearance, volume), ranged from 25.3% to 73.8%. High interindividual PK/PD variability was observed with high-purity VWF concentrate. This highlights the need to develop a robust dose-adjustment model to optimize factor concentrate utilization, avoid unnecessary waste, and reduce the frequency of laboratory monitoring.