Correlation between endogenous VWF:Ag and PK parameters and bleeding frequency in severe haemophilia A subjects during three‐times‐weekly prophylaxis with rFVIII‐FS

Abstract

Patients with severe haemophilia A experience frequent and spontaneous bleeding, causing debilitating damage to joints and decreasing quality of life. Prophylaxis with factor VIII (FVIII) reduces joint damage if initiated early. Circulating FVIII levels may be influenced by endogenous von Willebrand factor (VWF), a chaperone protein that binds and stabilizes FVIII. The aim of this study was to determine whether endogenous VWF antigen (VWF:Ag) levels are correlated with FVIII pharmacokinetic (PK) parameters and clinical outcomes in patients with severe haemophilia A. Previously treated, non-inhibitor patients in a multinational, randomized, double-blind, Ph II study received prophylaxis with once-weekly BAY 79-4980 (35 IU kg−1) or thrice-weekly recombinant sucrose-formulated FVIII (rFVIII-FS; 25 IU kg−1). PK parameters were evaluated at weeks 1 and 26. The number of bleeds per patient during the study was captured as part of the core efficacy endpoint. Spearman rank correlations assessed relationships of VWF:Ag levels with patient age, PK and annualized bleeding rate. Of 131 study patients (aged 13−64 years; BAY 79-4980, n = 63; rFVIII-FS, n = 68), 27 (21%; n = 15 and 12 respectively) were evaluable for PK assessment. Baseline VWF:Ag levels correlated with patient age (P < 0.0001). There was no significant difference in PK results between treatments; thus, PK parameters and VWF levels of all patients were analysed together. AUCnorm and T1/2 significantly increased with increased VWF:Ag (P < 0.001); clearance significantly decreased with increased VWF:Ag (P = 0.002). Annualized bleeding rate in patients treated with 3× per week rFVIII-FS significantly correlated with VWF:Ag and age (P = 0.038 and 0.021 respectively). PK parameters as well as the clinical outcome significantly correlated with endogenous VWF:Ag. The improved clinical outcome in subjects with high VWF:Ag levels may be explained by VWF:Ag influence on FVIII PK.

Low‐dose factor VIII infusion in Chinese adult haemophilia A patients: pharmacokinetics evidence that daily infusion results in higher trough level than with every‐other‐day infusion with similar factor VIII consumption

“…This prolongation was likely related in part to the use of pdFVIII containing a relatively higher amount of vWF. We also observed the increased levels of vWF after infusion (Table ), confirming that increased VWF:Ag level is associated with a significant increase in FVIII T1/2 and decrease in clearance . We have not explored why the in vivo recovery was high, but to the best of our knowledge, there is no established relationship between FVIII in vivo recovery and VWF level.…”

Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A

“…17 Such a positive correlation between T 1/2 of rFVIII and VWF levels has been previously reported. 18,19 This finding suggests that the clinical management of prophylaxis in subjects with low VWF:Ag levels be monitored more closely, as these subjects might benefit from a personalized dosing regimen. 20 Subjects in the prophylaxis group had a significantly reduced (90%) ABR compared with those in the on-demand group.…”

A systematic review of definitions and reporting of bleeding outcome measures in haemophilia

“… using [(number of bleeds)/(study duration in days)] × 365, Lalezari et al . using [(number of bleeds)/(study duration in days)] × 365.25, Oldenburg et al . using [(number of bleeds)/(study duration in days)] × 365.24 and Fischer et al .…”

“…The sites of bleeding reported are varied – joint , muscle , all sites of bleeding . The number of bleeding events are defined differently – annualized bleeding , mean joint bleed per month , bleeds per month , mean annual joint bleed , and the central tendency of the outcome are reported as either mean with SD or median with inter quartile range (IQR) . More importantly, the observation time is varied from several months to many years.…”