a Van Creveldkliniek , University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.
b Department of Pediatrics , Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University , Utrecht , The Netherlands.
Expert Rev Hematol. 2019 May;12(5):335-344. doi: 10.1080/17474086.2019.1604213. Epub 2019 Apr 25.
Nowadays, one of the most serious treatment complications in hemophilia A is the formation of neutralizing antibodies against coagulation factor VIII (FVIII). These so-called inhibitors develop in about 30% of all patients with severe hemophilia A. Once formed, inhibitors reduce FVIII efficacy in blood coagulation, which has a negative impact on patients' health and quality of life and significantly increases hemophilia A treatment costs. The pathophysiology of inhibitor development is a complex and multi-causal process, in which both genetic factors as well as environmental factors participate. So-called 'danger signals' are considered contributors to inhibitor formation, and can be triggered by surgery, joint bleeds or infections. A pro-inflammatory tissue micro-environment is thereby established, which is characterized by the upregulation of costimulatory molecules on antigen-presenting cells (APCs), that can facilitate the alloimmunization to FVIII and thereby inhibitor formation. Here, the authors will discuss evidence from (pre)clinical studies about this theory in hemophilia A. Areas covered: In this review, the current knowledge regarding the 'danger theory' with regard to inhibitor development in hemophilia A is summarized. Expert opinion: Danger signals might contribute to inhibitor development; however, the evidence is scarce and not conclusive. Future studies, like multinational registries, are warranted but challenging.
如今，A型血友病治疗中最严重的并发症之一是凝血因子 VIII（FVIII）中和抗体的形成。在所有严重的 A 型血友病患者中，约有 30%会出现这种所谓的抑制剂。一旦形成，抑制剂会降低血液凝固中 FVIII 的疗效，对患者的健康和生活质量产生负面影响，并显著增加 A 型血友病的治疗成本。抑制剂形成的病理生理学是一个复杂的多因素过程，其中遗传因素和环境因素都参与其中。所谓的“危险信号”被认为是抑制剂形成的促成因素，可由手术、关节出血或感染引发。由此建立起促炎的组织微环境，其特征是抗原呈递细胞（APC）上共刺激分子的上调，这可以促进对 FVIII 的同种免疫反应，从而导致抑制剂的形成。作者将在此讨论来自（前）临床试验的证据，以了解 A 型血友病中这一理论。涵盖领域：本文综述了目前关于 A 型血友病抑制剂形成的“危险理论”的相关临床前研究证据。专家意见：危险信号可能有助于抑制剂的形成；然而，证据稀缺且不具结论性。未来的研究，如多国登记处，是必要的，但具有挑战性。
