Division of Haematology/Oncology, Department of Paediatrics and Child Health Evaluative Sciences, Research Institute, Hospital for Sick Children, University of Toronto, Toronto, Canada.
Department of Laboratory Medicine, Tokyo Medical University, Tokyo, Japan.
Semin Thromb Hemost. 2017 Feb;43(1):59-68. doi: 10.1055/s-0036-1585076. Epub 2016 Aug 24.
Congenital factor XIII (FXIII) deficiency is a rare, autosomal recessive bleeding disorder with potentially life-threatening consequences. FXIII is composed of two subunits (A and B), and a deficiency or dysfunction of either can result in FXIII deficiency. Traditionally, FXIII deficiency has been managed by infusing plasma-derived products containing FXIII (fresh frozen plasma, cryoprecipitate, and plasma-derived FXIII concentrates), all of which contain both subunits. Despite the increased safety of plasma-derived products, concern remains regarding potential viral safety issues. This review describes the development, from concept to clinical use, of a recombinant FXIII molecule (containing subunit A only; rFXIII-A) for congenital FXIII-A subunit deficiency. Unmet needs and ongoing challenges in congenital FXIII deficiency are also discussed. Despite the challenges in developing a product for a very rare bleeding disorder, the information gathered on efficacy, safety, and pharmacokinetics of FXIII replacement therapy represents the largest dataset on congenital FXIII-A subunit deficiency in the world. It also provides evidence for the safety and efficacy of monthly prophylaxis with 35 IU/kg of rFXIII-A in patients with FXIII-A subunit deficiency. The issues encountered and overcome, along with lessons learned, may be applied to and encourage the development of new recombinant products for other rare bleeding disorders.
先天性因子 XIII (FXIII) 缺乏症是一种罕见的常染色体隐性遗传性出血性疾病，可能有生命危险。FXIII 由两个亚基（A 和 B）组成，任何一个亚基的缺乏或功能障碍都可能导致 FXIII 缺乏症。传统上，FXIII 缺乏症通过输注含有 FXIII 的血浆衍生产品（新鲜冷冻血浆、冷沉淀和血浆衍生的 FXIII 浓缩物）来治疗，这些产品都含有两个亚基。尽管血浆衍生产品的安全性有所提高，但人们仍然担心潜在的病毒安全问题。本文综述了仅含有亚基 A 的重组 FXIII 分子（rFXIII-A）在先天性 FXIII-A 亚基缺乏症中的开发历程，从概念到临床应用。还讨论了先天性 FXIII 缺乏症的未满足需求和正在面临的挑战。尽管在开发用于治疗非常罕见的出血性疾病的产品方面存在挑战，但关于 FXIII 替代治疗的疗效、安全性和药代动力学的信息代表了世界上关于先天性 FXIII-A 亚基缺乏症的最大数据集。它还为 FXIII-A 亚基缺乏症患者每月接受 35IU/kg rFXIII-A 的预防性治疗的安全性和有效性提供了证据。所遇到的问题及其克服方法，以及吸取的经验教训，可能适用于并鼓励开发其他罕见出血性疾病的新型重组产品。
