Factor VIII pharmacokinetics associates with genetic modifiers of VWF and FVIII clearance in an adult hemophilia A population
Factor VIII pharmacokinetics associates with genetic modifiers of VWF and FVIII clearance in an adult hemophilia A population
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DOI：
10.1111/jth.15183
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发表时间：
2020-12-31
影响因子：
10.4
通讯作者：
Lillicrap, David
中科院分区：
文献类型：
--
作者：
Ogiwara, Kenichi;Swystun, Laura L.;Lillicrap, David
背景：成人血友病A人群中凝血因子VIII（FVIII）的药代动力学（PK）高度可变，先前已确定受血管性血友病因子：抗原（VWF：Ag）、ABO血型和年龄的影响。然而，其他的基因决定因子的FVIII PK在很大程度上是unknown. ObjectiveThe贡献的VWF清除，VWF-FVIII结合活性，和遗传变异的VWF清除受体的FVIII PK在成人patients.Methods FVIII PK评估进行了44例成人受试者（年龄18-61岁），中度或重度血友病A。测定VWF：Ag、VWF前肽（VWFpp）、VWFpp/VWF：Ag和VWF：FVIII结合活性。结果VWF：Ag、VWFpp和VWF：FVIIIB与FVIII半衰期呈正相关，与FVIII清除率呈负相关。VWFpp/VWF：Ag与FVIII半衰期呈负相关，与FVIII清除率呈正相关。非O型患者的VWFpp/VWF：Ag与FVIII半衰期之间的相关性强于O型患者，表明VWF清除较慢会增加FVIII半衰期。CLEC 4 M rs 868875变异杂合子患者与参考等位基因纯合子个体相比，FVIII清除率增加。CLEC 4 M可变串联重复序列（VNTR）等位基因也与FVIII清除率相关。与FVIII清除最快的四分位数患者相比，FVIII清除最慢的四分位数患者的CLEC 4 M 5-VNTR.Conclusions VWF-FVIII结合活性和VWF清除的遗传决定因素是成年患者FVIII药代动力学的重要贡献者。
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.