Department of Internal Medicine, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
School of Medicine, Universidad San Sebastian, Santiago, Chile.
J Thromb Haemost. 2024 Sep;22(9):2629-2652. doi: 10.1016/j.jtha.2024.05.026. Epub 2024 Jun 20.
Hemophilia is a rare congenital bleeding disorder that results from complete or partial deficiency of blood coagulation factor (F)VIII (hemophilia A) or FIX (hemophilia B) due to pathogenic variants in their coding genes. Hemophilia requires complex management. To date, there is no evidence-based clinical practice guideline on hemophilia treatment based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.
This evidence-based clinical practice guideline from the International Society on Thrombosis and Haemostasis aims to provide an overview of evidence and support patients, caregivers, hematologists, pediatricians, other clinicians, researchers, and stakeholders in treatment decisions about congenital hemophilia A and B.
The International Society on Thrombosis and Haemostasis formed a multidisciplinary guideline panel of physicians and patients with global representation, balanced to minimize potential bias from conflicts of interest. The panel prioritized a set of clinical questions and outcomes according to their importance for clinicians and patients. A methodological team supported the guideline development process, including searching for evidence and performing systematic reviews. The GRADE approach was used, including GRADE Evidence to Decision frameworks. The recommendations were subject to public comment.
The panel selected 13 questions, of which 11 addressed the treatment of hemophilia A and 2 the treatment of hemophilia B. Specifically, the panel addressed questions on prophylactic and episodic treatment with FVIII concentrates, bypassing agents, and nonfactor therapy (emicizumab) for hemophilia A (with and without inhibitors) as well as immune tolerance induction for hemophilia A. For hemophilia B, the panel addressed questions on prophylactic and episodic treatment of bleeding events with FIX concentrates. Agreement was reached for all 13 recommendations, of which 7 (54%) were based on evidence from randomized clinical trials, 3 (23%) on observational studies, and 3 (23%) on indirect comparisons.
Strong recommendations were issued for prophylactic over episodic treatment for severe and moderately severe hemophilia A and B. Only conditional recommendations were issued for the remaining questions. Future research should focus on direct treatment comparisons and the treatment of hemophilia B with and without inhibitors. Future updates of this guideline will provide an updated evidence synthesis on the current questions and focus on new FVIII and FIX concentrates, novel nonfactor therapies, and gene therapy for severe and nonsevere hemophilia A and B.
血友病是一种罕见的先天性出血性疾病，由于编码基因中的致病变异，导致凝血因子 VIII（血友病 A）或 FIX（血友病 B）完全或部分缺乏。血友病需要复杂的管理。迄今为止，尚无基于循证医学实践指南制定方法（GRADE）的血友病治疗循证医学实践指南。
本国际血栓止血学会循证医学实践指南旨在为血友病 A 和 B 的患者、护理人员、血液科医生、儿科医生、其他临床医生、研究人员和利益相关者提供有关先天性血友病 A 和 B 治疗的证据概述，并为其提供支持。
国际血栓止血学会成立了一个由具有全球代表性的医生和患者组成的多学科指南小组，该小组平衡了利益冲突，以尽量减少潜在的偏见。该小组根据对临床医生和患者的重要性，优先考虑了一组临床问题和结局。一个方法学团队支持指南的制定过程，包括搜索证据和进行系统评价。使用了 GRADE 方法，包括 GRADE 证据决策框架。建议接受公开评议。
小组选择了 13 个问题，其中 11 个涉及 FVIII 浓缩物的预防性和间歇性治疗、旁路制剂和非因子治疗（emicizumab）用于血友病 A（有无抑制剂）以及血友病 A 的免疫耐受诱导，2 个涉及 FIX 浓缩物的预防性和间歇性治疗用于血友病 B。小组就血友病 A（有无抑制剂）的严重和中度严重血友病 A 和 B 的预防性治疗优于间歇性治疗、FIX 浓缩物的预防性和间歇性治疗用于血友病 B 达成了一致意见。所有 13 项建议均达成一致，其中 7 项（54%）基于随机临床试验的证据，3 项（23%）基于观察性研究，3 项（23%）基于间接比较。
强烈建议对严重和中度严重血友病 A 和 B 进行预防性治疗而非间歇性治疗。对于其余问题，仅发布了有条件的建议。未来的研究应侧重于直接治疗比较以及有无抑制剂的血友病 B 的治疗。本指南的未来更新将提供当前问题的最新证据综合，并重点关注新型 FVIII 和 FIX 浓缩物、新型非因子治疗以及严重和非严重血友病 A 和 B 的基因治疗。
