Institute of Experimental Haematology and Blood Transfusion, University of Bonn, Bonn, Germany.
Blood Center of Wisconsin & Medical College of Wisconsin, Milwaukee, WI, USA.
Haemophilia. 2018 Apr;24 Suppl 3:3-14. doi: 10.1111/hae.13445.
Development of inhibitory antibodies to infused factor VIII (FVIII) concentrates continues to be the most serious complication of haemophilia A management. Induction of immune tolerance by administering high doses of FVIII concentrate (antigen) and prothrombin complex concentrates to control bleeding was originated in the 1970s in Bonn, Germany, by Dr Hans-Hermann Brackmann, and became known as the Bonn protocol. ITI transformed the life of the index patient, who was 19 years of age when he began treatment, and dramatically improved the medical landscape for all patients with haemophilia and inhibitors. Over the past 40 years, variations to the Bonn protocol have been proposed. All protocols are effective although some are better suited than others for use in certain situations. The specific molecular defect in FVIII and the human leucocyte antigen (HLA) type of an individual with haemophilia are major codependent determinants to inhibitor development. Given the range of potential molecular defects and the staggering number of potential HLA types, it is likely that treatment arms of randomized studies in haemophilia represent highly diverse populations, which reduces the power of a study to demonstrate differences between treatments. Although available clinical guidelines and consensus recommendations for ITI therapy are not always in complete agreement, collectively the guidelines provide a reasonable level of guidance for administering ITI therapy under different clinical scenarios. Several studies of ITI therapy are ongoing with the aim of clarifying unresolved issues in haemophilia management including the role of von Willebrand factor in inhibitor eradication.
抑制性抗体的产生是血友病 A 管理中最严重的并发症。德国波恩的 Hans-Hermann Brackmann 博士于 20 世纪 70 年代开创了通过给予高剂量 FVIII 浓缩物（抗原）和凝血酶原复合物浓缩物来控制出血以诱导免疫耐受的方法，该方法被称为波恩方案。免疫耐受诱导（ITI）改变了接受治疗时 19 岁的这位首发患者的生活，并极大地改善了所有血友病伴抑制物患者的医疗状况。在过去的 40 年中，已经提出了对波恩方案的各种修改。所有方案均有效，尽管某些方案在某些情况下比其他方案更适用。FVIII 的特定分子缺陷和血友病患者的人类白细胞抗原（HLA）类型是抑制物产生的主要相互依存决定因素。鉴于潜在的分子缺陷范围和令人震惊的潜在 HLA 类型数量，接受随机研究治疗的血友病患者手臂可能代表着高度多样化的人群，这降低了研究证明治疗之间差异的能力。尽管 ITI 治疗的现有临床指南和共识建议并不总是完全一致，但这些指南共同为不同临床情况下实施 ITI 治疗提供了合理的指导水平。目前正在进行几项 ITI 治疗研究，旨在阐明血友病管理中未解决的问题，包括 von Willebrand 因子在抑制物消除中的作用。
