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Factor VIII pharmacokinetics associates with genetic modifiers of VWF and FVIII clearance in an adult hemophilia A population
Author(s) -
Ogiwara Kenichi,
Swystun Laura L.,
Paine A. Simonne,
Kepa Sylvia,
Choi Seon Jai,
Rejtö Judit,
Hopman Wilma,
Pabinger Ingrid,
Lillicrap David
Publication year - 2021
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.15183
Subject(s) - von willebrand factor , medicine , clearance rate , abo blood group system , endocrinology , von willebrand disease , coagulation , population , immunology , platelet , environmental health
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.