Factor VIII pharmacokinetics associates with genetic modifiers of VWF and FVIII clearance in an adult hemophilia A population.

ABSTRACT

BACKGROUND: Factor VIII (FVIII) pharmacokinetics (PK) in adult hemophilia A populations are highly variable and have been previously determined to be influenced by von Willebrand factorantigen (VWFAg), ABO blood group, and age. However, additional genetic determinants of FVIII PK are largely unknown. OBJECTIVES: The contribution of VWF clearance, VWF-FVIII-binding activity, and genetic variants in VWF clearance receptors to FVIII PK in adult patients were assessed. METHODS: FVIII PK assessment was performed in 44 adult subjects (age 18-61 years) with moderate or severe hemophilia A. VWFAg, VWF propeptide (VWFpp), VWFpp/VWFAg, and VWFFVIII binding activity were measured. The VWF modifying loci CLEC4M, SCARA5, STAB2, and ABO, and the D'D3 FVIII-binding region of the VWF gene were genotyped. RESULTS: VWFAg, VWFpp, and VWFFVIIIB positively correlated with FVIII half-life and negatively correlated with FVIII clearance. VWFpp/VWFAg negatively correlated with FVIII half-life and positively correlated with FVIII clearance. The correlation between VWFpp/VWFAg and FVIII half-life was stronger for type non-O patients than for type O patients, suggesting that slower VWF clearance increases FVIII half-life. Patients heterozygous for the CLEC4M rs868875 variant had increased FVIII clearance when compared with individuals homozygous for the reference allele. The CLEC4M variable number of tandem repeat (VNTR) alleles were also associated with the rate of FVIII clearance. When compared with the quartile of patients with the fastest FVIII clearance, the quartile of patients with the slowest FVIII clearance had a decreased frequency of the CLEC4M 5-VNTR. CONCLUSIONS: VWF-FVIII binding activity and genetic determinants of VWF clearance are important contributors to FVIII pharmacokinetics in adult patients.