Swystun Laura L, Lillicrap David
Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
Pharmgenomics Pers Med. 2023 Mar 24;16:239-252. doi: 10.2147/PGPM.S383221. eCollection 2023.
The inherited bleeding disorder hemophilia A involves the quantitative deficiency of the coagulation cofactor factor VIII (FVIII). Prophylactic treatment of severe hemophilia A patients with FVIII concentrates aims to reduce the frequency of spontaneous joint bleeding and requires personalized tailoring of dosing regimens to account for the substantial inter-individual variability of FVIII pharmacokinetics. The strong reproducibility of FVIII pharmacokinetic (PK) metrics between repeat analyses in the same individual suggests this trait is genetically regulated. While the influence of plasma von Willebrand factor antigen (VWF:Ag) levels, ABO blood group, and patient age on FVIII PK is well established, estimates suggest these factors account for less than 35% of the overall variability in FVIII PK. More recent studies have identified genetic determinants that modify FVIII clearance or half-life including gene variants that impair VWF-FVIII binding resulting in the accelerated clearance of VWF-free FVIII. Additionally, variants in receptors that regulate the clearance of FVIII or the VWF-FVIII complex have been associated with FVIII PK. The characterization of genetic modifiers of FVIII PK will provide mechanistic insight into a subject of clinical significance and support the development of personalized treatment plans for patients with hemophilia A.
遗传性出血性疾病甲型血友病涉及凝血辅助因子凝血因子VIII（FVIII）的定量缺乏。用FVIII浓缩物对重度甲型血友病患者进行预防性治疗旨在减少自发性关节出血的频率，并且需要根据FVIII药代动力学的个体间显著差异对给药方案进行个性化调整。同一个体重复分析之间FVIII药代动力学（PK）指标的高度可重复性表明该特征受基因调控。虽然血浆血管性血友病因子抗原（VWF:Ag）水平、ABO血型和患者年龄对FVIII PK的影响已得到充分证实，但据估计这些因素仅占FVIII PK总体变异性的不到35%。最近的研究已经确定了影响FVIII清除率或半衰期的遗传决定因素，包括损害VWF-FVIII结合从而导致游离FVIII清除加速的基因变异。此外，调节FVIII或VWF-FVIII复合物清除的受体变异也与FVIII PK相关。FVIII PK遗传修饰因子的特征将为具有临床意义的主题提供机制性见解，并支持为甲型血友病患者制定个性化治疗方案。
