Genetic determinants of VWF clearance and FVIII-binding modify FVIII pharmacokinetics in pediatric hemophilia A patients

Laura L. Swystun, Kenichi Ogiwara, Orla Rawley, Christine Brown, Ilinca Georgescu, Wilma Hopman, Veerle Labarque, Christoph Male, Katharina Thom, Victor S. Blanchette, Manuel Carcao and David Lillicrap

Key Points

  • VWF gene variants that modify FVIII binding influence FVIII PK

  • Variants in clearance receptors for VWF-FVIII influence FVIII PK


Factor VIII (FVIII) pharmacokinetic properties show high inter-patient variability in hemophilia A patients. While previous studies have determined that age, body mass index, von Willebrand factor (VWF) antigen levels, and ABO blood group status can influence FVIII pharmacokinetics, they do not account for all observed variability. In this study, we aim to describe the genetic determinants that modify the FVIII pharmacokinetic profile in a population of 43 pediatric hemophilia A patients. We observed that VWF:Ag and VWFpp/VWF:Ag, but not VWFpp, associated with FVIII half-life. VWFpp/VWF:Ag negatively correlated with FVIII half-life in patients with non-O blood type, but no correlation was observed for type O patients, suggesting that VWF half-life as modified by ABO blood group is a strong regulator of FVIII pharmacokinetics. The FVIII-binding activity of VWF positively correlated with FVIII half-life and the rare or low frequency, non-synonymous VWF variants p.(Arg826Lys) and p.(Arg852Glu) were identified in patients with reduced VWF:FVIIIB but not VWF:Ag. Common variants at the VWF, CLEC4M, and STAB2 loci, which have been previously associated with plasma levels of VWF and FVIII, associated with the FVIII pharmacokinetic profile. Together, these studies characterize the mechanistic basis by which VWF clearance and ABO glycosylation modify FVIII pharmacokinetics in a pediatric population. Moreover, this study is the first to identify non­-VWF and ABO variants that modify FVIII pharmacokinetics in pediatric hemophilia A patients.

  • Submitted February 15, 2019.
  • Revision received July 25, 2019.
  • Accepted July 17, 2019.