Klinge Jens, Ananyeva Natalya M, Hauser Charlotte A E, Saenko Evgueni L
Hospital for Children and Adolescents, University of Erlangen, Erlangen, Germany.
Semin Thromb Hemost. 2002 Jun;28(3):309-22. doi: 10.1055/s-2002-32667.
This article summarizes achievements of basic research and their implementation in clinical treatment of one of the most common inherited bleeding disorders hemophilia A, which is caused by genetic deficiency of coagulation factor VIII (FVIII). We discuss the structure of FVIII, its major interactions in the intrinsic pathway of blood coagulation, and the catabolism of FVIII. We also discuss achievements in the contemporary clinical practice of treatment of hemophilia A. Replacement therapy has substantially improved by development of purification and virus inactivation procedures, allowing preparation of safe and effective therapeutic plasma-derived FVIII concentrates. We give special attention to the principles used in the development of contemporary recombinant FVIII products, which do not inherit a potential risk for viral or prion transmission. Development of FVIII inhibitory antibodies is the major complication of FVIII replacement therapy. We summarize the accumulated knowledge regarding epitopes of FVIII inhibitors and mechanisms by which they inactivate FVIII and discuss approaches to overcome the effects of inhibitors and to prevent their formation by induction of immunotolerance. We also analyze the main concepts and scientific priorities in the gene-therapeutic approach for treatment of hemophilia A.
本文总结了基础研究的成果及其在临床治疗最常见的遗传性出血性疾病之一甲型血友病中的应用，该病由凝血因子VIII（FVIII）的基因缺陷引起。我们讨论了FVIII的结构、其在凝血内源性途径中的主要相互作用以及FVIII的分解代谢。我们还讨论了当代甲型血友病临床治疗的成果。通过纯化和病毒灭活程序的发展，替代疗法有了显著改善，使得制备安全有效的治疗性血浆源性FVIII浓缩物成为可能。我们特别关注当代重组FVIII产品开发所采用的原则，这些产品不存在病毒或朊病毒传播的潜在风险。FVIII抑制性抗体的产生是FVIII替代疗法的主要并发症。我们总结了关于FVIII抑制剂表位的积累知识及其灭活FVIII的机制，并讨论了克服抑制剂作用以及通过诱导免疫耐受来预防其形成的方法。我们还分析了甲型血友病基因治疗方法的主要概念和科学重点。
