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. 2023 May;21(5):1123-1134.
doi: 10.1016/j.jtha.2023.01.013. Epub 2023 Jan 20.

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

Einas Elsheikh  1 , Michelle Lavin  1 , Lilian Antunes Heck  2 , Niamh Larkin  3 , Brendan Mullaney  4 , Dearbhla Doherty  5 , Megan Kennedy  6 , Catriona Keenan  4 , Thomas Guest  5 , Brian O'Mahony  7 , Judicael Fazavana  5 , Padraic G Fallon  8 , Roger J S Preston  5 , John Gormley  6 , Kevin Ryan  3 , Niamh M O'Connell  3 , Evelyn Singleton  3 , Mary Byrne  3 , Mark McGowan  3 , Sheila Roche  3 , Mairead Doyle  3 , Maeve P Crowley  9 , Susan I O'Shea  9 , Birgit M Reipert  10 , Jill M Johnsen  11 , Steven W Pipe  12 , Jorge Di Paola  2 , Peter L Turecek  13 , James S O'Donnell  14 ; iPATH study group
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Free article

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

Einas Elsheikh et al. J Thromb Haemost. 2023 May.
Free article

Abstract

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.

Keywords: ABO blood group; FVIII pharmacokinetics; factor VIII; von Willebrand factor.

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Conflict of interest statement

Declaration of competing interests M.L. has served as a consultant for SOBI, CSL Behring, and Band Therapeutics and received indirect funding for the development of educational content from Takeda and speaker’s fees from CSL Behring and Pfizer. N.M.O’C. has acted as a principal investigator on clinical trials sponsored by Baxalta (now Takeda), Freeline, Pfizer, SOBI, and Sanofi; has received research support from SOBI and Takeda; and has received speaker’s fees and/or served on advisory boards for Freeline, Novo Nordisk, Pfizer, Roche, SOBI, Takeda, and uniQure. B.M.R. has served as a consultant for Takeda, Boehringer Ingelheim, and Novo Nordisk. P.L.T. is a full-time employee of Baxalta Innovations GmbH, a member of the Takeda group companies, and a shareholder in Takeda Pharmaceutical Company Limited. J.S.O’D has served on the speaker’s bureau for Baxter, Bayer, Novo Nordisk, SOBI, Boehringer Ingelheim, Leo Pharma, Takeda, and Octapharma; served on the advisory boards of Baxter, SOBI, Bayer, Octapharma, CSL Behring, Daiichi Sankyo, Boehringer Ingelheim, Takeda, and Pfizer; and received research grant funding awards from 3M, Baxter, Bayer, Pfizer, Shire, Takeda, 3M, and Novo Nordisk. The remaining authors declare no conflicts of interest.

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