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

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 factor:antigen (VWF:Ag), 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. VWF:Ag, VWF propeptide (VWFpp), VWFpp/VWF:Ag, and VWF:FVIII 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: VWF:Ag, VWFpp, and VWF:FVIIIB positively correlated with FVIII half-life and negatively correlated with FVIII clearance. VWFpp/VWF:Ag negatively correlated with FVIII half-life and positively correlated with FVIII clearance. The correlation between VWFpp/VWF:Ag 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.

The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity.

Quantitative abnormalities of the von Willebrand factor-factor VIII (VWF-FVIII) complex associate with inherited bleeding or thrombotic disorders. Receptor-mediated interactions between plasma VWF-FVIII and phagocytic or immune cells can influence their hemostatic and immunogenic activities. Genetic association studies have demonstrated that variants in the STAB2 gene, which encodes the scavenger receptor stabilin-2, associate with plasma levels of VWF-FVIII. However, the mechanistic basis and pathophysiological consequences of this association are unknown. We have demonstrated that stabilin-2-expressing cells bind and internalize human VWF and FVIII in a VWF-dependent manner, and stabilin-2-deficient mice displayed prolonged human VWF-FVIII half-life compared with controls. The stabilin-2 variant p.E2377K significantly decreased stabilin-2 expression and impaired VWF endocytosis in a heterologous expression system, and common STAB2 variants associated with plasma VWF levels in type 1 von Willebrand disease patients. STAB2-deficient mice displayed a decreased immunogenic response to human VWF-FVIII complex, while coinfusion of human VWF-FVIII with the stabilin-2 ligand hyaluronic acid attenuated the immune response to exogenous FVIII. Collectively, these data suggest that stabilin-2 functions as both a clearance and an immunoregulatory receptor for VWF-FVIII, making stabilin-2 a novel molecular target for modification of the half-life of VWF-FVIII and the immune response to VWF-FVIII concentrates.