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

• Published in: Journal of thrombosis and haemostasis 2023-05, Vol.21 (5), p.1123-1134
• Main Authors: Elsheikh, Einas, Lavin, Michelle, Heck, Lilian Antunes, Larkin, Niamh, Mullaney, Brendan, Doherty, Dearbhla, Kennedy, Megan, Keenan, Catriona, Guest, Thomas, O'Mahony, Brian, Fazavana, Judicael, Fallon, Padraic G., Preston, Roger J.S., Gormley, John, Ryan, Kevin, O'Connell, Niamh M., Singleton, Evelyn, Byrne, Mary, McGowan, Mark, Roche, Sheila, Doyle, Mairead, Crowley, Maeve P., O'Shea, Susan I., Reipert, Birgit M., Johnsen, Jill M., Pipe, Steven W., Di Paola, Jorge, Turecek, Peter L., O'Donnell, James S.
• Format: Article
• Language: English
• Subjects: ABO blood group; ABO Blood-Group System; factor VIII; Factor VIII - metabolism; Factor VIII - therapeutic use; FVIII pharmacokinetics; Half-Life; Hemophilia A - diagnosis; Hemophilia A - drug therapy; Hemostatics; Humans; von Willebrand Diseases; von Willebrand factor; von Willebrand Factor - metabolism
• ISSN: 1538-7836; 1538-7836
• DOI: 10.1016/j.jtha.2023.01.013

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. 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. 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. 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