National Hemophilia Center, Chaim Sheba Medical Center, Tel Hashomer, Israel.
Haemophilia. 2014 Jan;20(1):e15-22. doi: 10.1111/hae.12294. Epub 2013 Nov 20.
Patients with severe haemophilia A experience frequent and spontaneous bleeding, causing debilitating damage to joints and decreasing quality of life. Prophylaxis with factor VIII (FVIII) reduces joint damage if initiated early. Circulating FVIII levels may be influenced by endogenous von Willebrand factor (VWF), a chaperone protein that binds and stabilizes FVIII. The aim of this study was to determine whether endogenous VWF antigen (VWF:Ag) levels are correlated with FVIII pharmacokinetic (PK) parameters and clinical outcomes in patients with severe haemophilia A. Previously treated, non-inhibitor patients in a multinational, randomized, double-blind, Ph II study received prophylaxis with once-weekly BAY 79-4980 (35 IU kg(-1)) or thrice-weekly recombinant sucrose-formulated FVIII (rFVIII-FS; 25 IU kg(-1)). PK parameters were evaluated at weeks 1 and 26. The number of bleeds per patient during the study was captured as part of the core efficacy endpoint. Spearman rank correlations assessed relationships of VWF:Ag levels with patient age, PK and annualized bleeding rate. Of 131 study patients (aged 13-64 years; BAY 79-4980, n = 63; rFVIII-FS, n = 68), 27 (21%; n = 15 and 12 respectively) were evaluable for PK assessment. Baseline VWF:Ag levels correlated with patient age (P < 0.0001). There was no significant difference in PK results between treatments; thus, PK parameters and VWF levels of all patients were analysed together. AUC(norm) and T1/2 significantly increased with increased VWF:Ag (P < 0.001); clearance significantly decreased with increased VWF:Ag (P = 0.002). Annualized bleeding rate in patients treated with 3× per week rFVIII-FS significantly correlated with VWF:Ag and age (P = 0.038 and 0.021 respectively). PK parameters as well as the clinical outcome significantly correlated with endogenous VWF:Ag. The improved clinical outcome in subjects with high VWF:Ag levels may be explained by VWF:Ag influence on FVIII PK.
患有严重血友病 A 的患者会频繁地自发出血，导致关节受损，生活质量下降。如果早期开始使用凝血因子 VIII（FVIII）进行预防治疗，可以减少关节损伤。循环中的 FVIII 水平可能受到内源性血管性血友病因子（VWF）的影响，VWF 是一种伴侣蛋白，可结合并稳定 FVIII。本研究旨在确定严重血友病 A 患者的内源性 VWF 抗原（VWF：Ag）水平是否与 FVIII 药代动力学（PK）参数和临床结局相关。在一项多中心、随机、双盲、二期研究中，先前接受过治疗且无抑制剂的患者每周一次接受 BAY 79-4980（35IUkg(-1)）或每周三次接受重组蔗糖制剂 FVIII（rFVIII-FS；25IUkg(-1)）预防治疗。在第 1 周和第 26 周评估 PK 参数。研究期间每位患者的出血次数作为核心疗效终点的一部分进行记录。Spearman 秩相关分析评估了 VWF：Ag 水平与患者年龄、PK 和年化出血率的关系。在 131 例研究患者（年龄 13-64 岁；BAY 79-4980，n=63；rFVIII-FS，n=68）中，有 27 例（21%；n=15 和 12 分别）可进行 PK 评估。基线 VWF：Ag 水平与患者年龄相关（P<0.0001）。两种治疗方法的 PK 结果无显著差异；因此，对所有患者的 PK 参数和 VWF 水平进行了综合分析。AUC(norm)和 T1/2 随 VWF：Ag 增加而显著增加（P<0.001）；清除率随 VWF：Ag 增加而显著降低（P=0.002）。每周三次接受 rFVIII-FS 治疗的患者年化出血率与 VWF：Ag 和年龄显著相关（P=0.038 和 0.021）。PK 参数和临床结局与内源性 VWF：Ag 显著相关。VWF：Ag 对 FVIII PK 的影响可能解释了高 VWF：Ag 水平患者的临床结局改善。
