Heterogeneity in the half-life of factor VIII concentrate in patients with hemophilia A is due to variability in the clearance of endogenous von Willebrand factor
Background: Previous studies have reported marked interindividual variation in factor VIII (FVIII) clearance in patients with hemophilia (PWH) and proposed a number of factors that influence this heterogeneity.
Objectives: To investigate the importance of the clearance rates of endogenous von Willebrand factor (VWF) compared with those of other FVIII half-life modifiers in adult PWH.
Methods: The half-life of recombinant FVIII was determined in a cohort of 61 adult PWH. A range of reported modifiers of FVIII clearance was assessed (including plasma VWF:antigen and VWF propeptide levels; VWF-FVIII binding capacity; ABO blood group; and nonneutralizing anti-FVIII antibodies). The FVIII-binding region of the VWF gene was sequenced. Finally, the effects of variation in FVIII half-life on clinical phenotype were investigated.
Results: We demonstrated that heterogeneity in the clearance of endogenous plasma VWF is a key determinant of variable FVIII half-life in PWH. Both ABO blood group and age significantly impact FVIII clearance. The effect of ABO blood group on FVIII half-life in PWH is modulated entirely through its effect on the clearance rates of endogenous VWF. In contrast, the age-related effect on FVIII clearance is, at least in part, VWF independent. In contrast to previous studies, no major effects of variation in VWF-FVIII binding affinity on FVIII clearance were observed. Although high-titer immunoglobulin G antibodies (≥1:80) were observed in 26% of PWH, these did not impact FVIII half-life. Importantly, the annual FVIII usage (IU/kg/y) was significantly (p = .0035) increased in patients with an FVIII half-life of <12 hours.
Conclusion: Our data demonstrate that heterogeneity in the half-life of FVIII concentrates in patients with hemophilia A is primarily attributable to variability in the clearance of endogenous VWF.
Funding
Science Foundation (SFI) under the SFI Strategic Partnership Programme Grant number 16/SPP3303
Shire US Inc., a member of the Takeda group of companies, Lexington, Massachusetts.
National Institutes of Health for the Zimmerman Program (HL081588)
Science Foundation Ireland Frontiers for the Future (FFP) Award (20/FFP-A/8952)
History
Comments
The original article is available at https://www.sciencedirect.com/Published Citation
Elsheikh E, et al. Heterogeneity in the half-life of factor VIII concentrate in patients with hemophilia A is due to variability in the clearance of endogenous von Willebrand factor. J Thromb Haemost. 2023;21(5):1123-1134.Publication Date
20 January 2023External DOI
PubMed ID
36775768Department/Unit
- Irish Centre for Vascular Biology
- School of Pharmacy and Biomolecular Sciences
Publisher
Elsevier B.V.Version
- Published Version (Version of Record)