Boekhorst J, Lari G R, D'Oiron R, Costa J M, Nováková I R O, Ala F A, Lavergne J M, VAN Heerde W L
Department of Haematology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Haemophilia. 2008 Jul;14(4):729-35. doi: 10.1111/j.1365-2516.2008.01694.x. Epub 2008 May 12.
The appearance of inhibitory antibodies against factor VIII (FVIII) is the most severe and costly complication of replacement therapy in patients with haemophilia A (HA). To determine the relationship between FVIII genotype and inhibitor development, baseline FVIII activity, genotype and inhibitor development were reviewed in 1104 patients with HA. In patients with severe HA, splicing errors present the highest frequency of inhibitors, ahead of inversion of intron 1 and of intron 22, nonsense mutations and large deletions. The lowest inhibitor frequency in severe HA is found in patients with missense mutations and small deletions/insertions. Subanalyses indicate that nonsense mutations and small deletions/insertions leading to a frameshift in the light chain are associated with a significant higher risk of inhibitor formation than similar mutations occurring in the heavy chain (27% vs. 14%). These mutation types also have a higher frequency of inhibitors when occurring in exons 23-26, where a second FVIII transcript originates, compared with similar mutations in exons 1-22 (28% vs. 17%). These results suggest that complete absence of FVIII because of null mutations, including splice site mutations, or the absence of a second transcript result in an increased risk of inhibitor development.
针对凝血因子VIII（FVIII）的抑制性抗体的出现是甲型血友病（HA）患者替代治疗中最严重且成本最高的并发症。为了确定FVIII基因型与抑制剂产生之间的关系，我们回顾了1104例HA患者的基线FVIII活性、基因型和抑制剂产生情况。在重度HA患者中，剪接错误导致抑制剂产生的频率最高，高于内含子1和内含子22的倒位、无义突变和大片段缺失。重度HA患者中抑制剂频率最低的是错义突变以及小缺失/插入患者。亚分析表明，导致轻链移码的无义突变和小缺失/插入与抑制剂形成风险显著高于重链中发生的类似突变（27%对14%）。与外显子1 - 22中的类似突变相比，这些突变类型在外显子23 - 26（第二个FVIII转录本产生的位置）中出现时，抑制剂频率也更高（28%对17%）。这些结果表明，由于无效突变（包括剪接位点突变）导致FVIII完全缺失或缺乏第二个转录本会增加抑制剂产生的风险。
