van Stam Lilianne Esmée, Lacroix-Desmazes Sébastien, Fijnvandraat Karin, Gouw Samantha Claudia
Department of Pediatric Hematology, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands.
Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, CNRS, Sorbonne Université, Université Paris Cité, Paris, France.
J Thromb Haemost. 2025 Apr;23(4):1169-1184. doi: 10.1016/j.jtha.2024.12.039. Epub 2025 Jan 10.
Persons with hemophilia A lack clotting factor (F)VIII (FVIII) due to a genetic mutation in the F8 gene. The administration of FVIII concentrate leads to the development of neutralizing anti-FVIII antibodies (inhibitors) in about 30% of children with severe hemophilia A. The other 70% of children do not mount a detectable antibody response, suggesting that they may have developed tolerance toward FVIII. Our knowledge on the underlying immunologic mechanisms that determine formation of inhibitors or apparent tolerance to FVIII is limited. Up to recently, FVIII concentrates were regularly used as prophylaxis. In the last years, nonfactor therapy for prophylaxis is increasingly used, in which case FVIII concentrate administration is limited to treatment for bleeding or perioperative hemostasis. As nonfactor therapy is very effective in the prevention of bleeds, patients may not be exposed to the deficient FVIII protein for periods up to a year or longer. Thus, while in the past persons with severe hemophilia were frequently exposed to the deficient antigen, exposure is now reduced to incidental treatment moments. It is currently not known how this will affect the tolerance for FVIII. In this review, we will discuss tolerance to FVIII from a clinical, immunologic, and epidemiologic perspective. We aimed to provide an outlook on the effect of reduced FVIII exposure on tolerance for FVIII in persons with hemophilia A.
A型血友病患者由于F8基因的基因突变而缺乏凝血因子（F）VIII。给予FVIII浓缩物会导致约30%的重度A型血友病儿童产生中和性抗FVIII抗体（抑制剂）。另外70%的儿童没有可检测到的抗体反应，这表明他们可能已对FVIII产生耐受。我们对决定抑制剂形成或对FVIII明显耐受的潜在免疫机制的了解有限。直到最近，FVIII浓缩物仍经常用于预防治疗。在过去几年中，越来越多地使用非因子预防疗法，在这种情况下，FVIII浓缩物的给药仅限于出血治疗或围手术期止血。由于非因子疗法在预防出血方面非常有效，患者可能长达一年或更长时间不会接触到缺乏的FVIII蛋白。因此，虽然过去重度血友病患者经常接触缺乏的抗原，但现在接触已减少到偶尔的治疗时刻。目前尚不清楚这将如何影响对FVIII的耐受性。在本综述中，我们将从临床、免疫和流行病学角度讨论对FVIII 的耐受性。我们旨在展望减少FVIII暴露对A型血友病患者对FVIII耐受性的影响。
