血友病治疗最新进展

Advances in the Treatment of Hemophilia

摘要: 血友病(PWH)治疗的创新始于19世纪50年代对血浆分离的描述，人们在冰冻血浆的冷沉淀物中发现首个浓缩物因子VIII (FVIII)，使得替代疗法初步进入临床。但是，缺乏病毒病原体筛查导致了血友病患者接受被甲型/丙型肝炎病毒或人类免疫缺陷病毒污染的浓缩物。后期，病毒筛选方法和适当的病毒灭活技术被开发，使浓缩物变得安全。外源性浓缩物的免疫原性问题尚未完全解决，大约25%~35%的PWH产生针对FVIII的同种抗体是替代疗法最严重的不良反应。血友病治疗领域的重大进展是FVIII基因被克隆，为通过重组DNA技术获得重组人凝血因子VIII (r FVIII)奠定了基础。r FVIII在血友病A患者的血浆中具有相对较短的半衰期，约为12~14小时，将r FVIII和IgG/白蛋白的Fc段或者聚乙二醇结合，可延长r FVIII血浆半衰期和延长注射间隔，从而使得r FVIII的半衰期增加。遗憾的是，血友病A的基因治疗结果并不显著，其持久性仍需证明。本文对目前血友病治疗及药物的相关进展进行综述。

Abstract: Progress in hemophilia therapy has been innovative with the description the fractionation of plasma in 1950s. The first concentrates were purified followed the discovery of FVIII in the cryoprecipitate of frozen plasma, which led to replacement therapy in the clinical treatment. Unfortunately, the lack of screening for viral pathogens resulted in hemophilia (PWH) patients receiving concentrates contaminated by hepatitis A virus, hepatitis C virus, and human immunodeficiency virus. Later, viral screening and proper virucidal techniques were developed that made concentrates safe. However, the development of all oantibodies against FVIII in about 25%~35% of PWH is the most serious adverse effect of replacement therapy which has not yet resolved completely. The next major advance was the cloning of the F8 gene, which paved the way to produce concentrates of factors obtained by the recombinant DNA technology. The FVIII had a relatively short half-life in the plasma in hemophilia A patients, approximately 12~14 hours. The ability to prolong the plasma half-life and extend the interval of injections was obtained according to conjugate the factor molecule with the fragment crystallizable of IgG1 or albumin or by adding polyethylene glycol, which has led to an increase in the half-life of concentrates. Unfortunately, the results with gene therapy for hemophilia A have not been as remarkable and the durability must still be demonstrated. This article reviews the current progress in the treatment of hemophilia.