Department of Pathology and Molecular Medicine, Richardson Laboratory, Queen's University, Kingston, ON, Canada.
Haemophilia. 2014 May;20 Suppl 4:87-93. doi: 10.1111/hae.12412.
It is known that a large number of both genetic and environmental factors contribute to the risk of inhibitor development, but underlying pathogenetic mechanisms are still under investigation. The clinical research on inhibitors towards factor VIII (FVIII) is challenged by the fact that this is an infrequent event occurring in a rare disease. Therefore, it is widely accepted that complementary studies involving animal models can provide important insights into the pathogenesis and treatment of this complication. In this respect, mouse models have been studied for clues to FVIII immunogenicity, natural history of immunity and for different approaches to primary and secondary tolerance induction. In the clinical setting, the type of FVIII product used and the occurrence of product switching are considered important factors which may have an influence on inhibitor development. The evaluation of data currently available in the literature does not prove unequivocally that a difference in the immunogenicity exists between particular FVIII products (e.g. recombinant vs. plasma-derived, full length vs. B-domainless). In addition, national products switches have occurred and, in this context, switching was not associated with an enhanced inhibitor risk. In contrast with severe haemophilia A, patients with moderate and mild haemophilia A receive FVIII treatment infrequently for bleeds or surgery. In this condition the inhibitor risk is low but remains present lifelong, requiring continuous vigilance, particularly after intensive FVIII exposure.
已知大量遗传和环境因素都会增加抑制剂产生的风险，但潜在的发病机制仍在研究中。针对因子 VIII（FVIII）抑制剂的临床研究面临的挑战是，这种情况在罕见疾病中很少发生。因此，人们普遍认为，涉及动物模型的补充研究可以为这种并发症的发病机制和治疗提供重要的见解。在这方面，已经研究了小鼠模型，以寻找 FVIII 免疫原性、免疫自然史以及原发性和继发性耐受诱导的不同方法的线索。在临床环境中，所使用的 FVIII 产品类型和产品转换的发生被认为是可能影响抑制剂产生的重要因素。目前对文献中现有数据的评估并不能明确证明特定 FVIII 产品（例如重组与血浆衍生、全长与无 B 结构域）之间存在免疫原性差异。此外，已经发生了国家产品转换，在这种情况下，转换并没有增加抑制剂的风险。与重度甲型血友病不同，中重度甲型血友病患者因出血或手术接受 FVIII 治疗的频率较低。在这种情况下，抑制剂的风险较低，但终生存在，需要持续警惕，尤其是在密集 FVIII 暴露后。
