Regional Reference Centre for Coagulation Disorders, Department of Clinical and Experimental Medicine, Federico II University, Via S. Pansini, 5 -80131 Naples, Italy.
Haemophilia. 2010 Jan;16 Suppl 1:13-9. doi: 10.1111/j.1365-2516.2009.02175.x.
Inhibitor development, because of its impact on patients' morbidity and quality of life, is presently the most serious complication of haemophilia A treatment. The identification of several genetic and non-genetic risk factors may be used for the stratification of inhibitor risk and the definition of prevention strategies, particularly for patients with a high-risk genetic profile. The most extensively studied genetic factor is the type of F8 mutation, i.e. large deletions, nonsense mutations and inversions, which are associated with a higher risk of inhibitor development. This is the basis for the increased risk in patients with inhibitor family history; however, concordance family studies showed that factors other than F8 mutations are involved. An emerging role is investigated for polymorphisms of immune-regulatory genes that may increase (IL-10 and TNF-alpha) or reduce (CTLA-4) inhibitor risk and whose heterogeneous ethnic distribution may correlate to the higher inhibitor risk in non-caucasian patients. A role for FVIII haplotypes, particularly in black haemophiliacs, has been recently proposed. Recent studies report an increased inhibitor risk for initial intensive treatments (surgery or severe bleeds requiring high-dose and/or prolonged treatment, presence of danger signals), whereas regular prophylaxis (absence of danger signals) exerts a protective effect. A clinical score including the type of F8 mutation, family history of inhibitors and intensive treatment has been recently validated for predicting inhibitor risk. Because of the lack of useful data regarding the role of different types of FVIII concentrates, the stratification of risk in patients starting replacement treatment together with the careful evaluation of indications, doses and duration of treatment at first exposures and further efforts for overcoming barriers to early implementation of prophylaxis are encouraged, particularly for patients with a predictable high inhibitor risk.
抑制剂的发展是目前影响血友病 A 患者发病率和生活质量的最严重并发症。确定几种遗传和非遗传风险因素可用于抑制剂风险分层和预防策略的定义，特别是对于具有高遗传风险特征的患者。研究最多的遗传因素是 F8 突变类型，即大片段缺失、无义突变和倒位，这些与更高的抑制剂发展风险相关。这是具有抑制剂家族史患者风险增加的基础；然而，一致性家族研究表明，除了 F8 突变之外，还有其他因素参与其中。免疫调节基因的多态性正在被研究，这些多态性可能增加（IL-10 和 TNF-α）或降低（CTLA-4）抑制剂的风险，其异质性的种族分布可能与非白种人群中更高的抑制剂风险相关。FVIII 单倍型的作用最近也被提出，特别是在黑人血友病患者中。最近的研究报告表明，初始强化治疗（手术或需要大剂量和/或长时间治疗的严重出血，存在危险信号）会增加抑制剂的风险，而常规预防（无危险信号）会产生保护作用。最近验证了一种包括 F8 突变类型、抑制剂家族史和强化治疗的临床评分，用于预测抑制剂的风险。由于缺乏关于不同类型 FVIII 浓缩物作用的有用数据，因此鼓励在开始替代治疗时对患者进行风险分层，并仔细评估首次暴露时的治疗指征、剂量和持续时间，进一步努力克服早期实施预防的障碍，特别是对于具有可预测的高抑制剂风险的患者。
