Department of Pediatric Hematology, Emma Children's Hospital, Amsterdam, the Netherlands.
Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
J Thromb Haemost. 2017 Feb;15(2):246-254. doi: 10.1111/jth.13581. Epub 2017 Feb 3.
Essentials Factor VIII levels vary in mild and moderate hemophilia A (MHA) patients with the same mutation. We aimed to estimate the variation and determinants of factor VIII levels among MHA patients. Age and genotype explain 59% of the observed inter-individual variation in factor VIII levels. Intra-individual variation accounted for 45% of the variation in the three largest mutation groups.
Background The bleeding phenotype in patients with mild/moderate hemophilia A (MHA) is inversely associated with the residual plasma concentration of factor VIII (FVIII:C). Within a group of patients with the same F8 missense mutation, baseline FVIII:C may vary, because, in healthy individuals, von Willebrand factor (VWF) levels, ABO blood group and age are also known to influence baseline FVIII:C. Our understanding of the pathophysiologic process of the causative genetic event leading to reduced baseline FVIII:C in MHA patients is still limited. Objectives To estimate the variation and determinants of baseline FVIII:C among MHA patients with the same F8 missense mutation. Methods Three hundred and forty-six patients carrying mutations that were present in at least 10 patients in the cohort were selected from the INSIGHT and the RISE studies, which are cohort studies including data of 3534 MHA patients from Europe, Canada, and Australia. Baseline FVIII:C was measured with a one-stage clotting assay. We used Levene's test, univariate and multivariate linear regression, and mixed-model analyses. Results For 59% of patients, the observed variation in baseline FVIII:C was explained by age and genotype. Compared to FVIII:C in patients with Arg612Cys, FVIII:C was significantly different in patients with eight other F8 missense mutations. Intra-individual variation explained 45% of the observed variance in baseline FVIII:C among patients with the same mutation. Conclusion Our results indicate that baseline FVIII:C levels are not exclusively determined by F8 genotype in MHA patients. Insights into other factors may provide potential novel targets for the treatment of MHA.
在具有相同突变的轻度和中度血友病 A (MHA) 患者中，Essentials 因子 VIII 水平存在差异。我们旨在估计 MHA 患者因子 VIII 水平的变化和决定因素。年龄和基因型解释了因子 VIII 水平个体间差异的 59%。在三个最大突变组中，个体内变异占变异的 45%。
在轻度/中度血友病 A (MHA) 患者中，出血表型与因子 VIII (FVIII:C) 的残留血浆浓度呈反比。在具有相同 F8 错义突变的一组患者中，基础 FVIII:C 可能会有所不同，因为在健康个体中，von Willebrand 因子 (VWF) 水平、ABO 血型和年龄也已知会影响基础 FVIII:C。我们对导致 MHA 患者基础 FVIII:C 降低的致病基因突变的病理生理过程的理解仍然有限。
估计具有相同 F8 错义突变的 MHA 患者基础 FVIII:C 的变化和决定因素。
从包括来自欧洲、加拿大和澳大利亚的 3534 名 MHA 患者数据的 INSIGHT 和 RISE 研究中，选择了 346 名携带突变的患者，这些突变在队列中至少存在于 10 名患者中。使用一期凝血测定法测量基础 FVIII:C。我们使用了 Levene 检验、单变量和多变量线性回归以及混合模型分析。
对于 59%的患者，基础 FVIII:C 的观察到的变化由年龄和基因型解释。与 Arg612Cys 的 FVIII:C 相比，其他 8 种 F8 错义突变的患者的 FVIII:C 明显不同。同一突变患者的基础 FVIII:C 个体内变异解释了观察到的方差的 45%。
我们的结果表明，基础 FVIII:C 水平在 MHA 患者中不仅仅由 F8 基因型决定。对其他因素的了解可能为 MHA 的治疗提供新的潜在靶点。
