International Society on Thrombosis and Haemostasis clinical practice guideline for treatmen to fcongenital hemophilia A and B based on the Grading of Recommendations Assessment, Development, and Evaluation methodology
Suely M. Rezende 1), Ignacio Neumann 2), Pantep Angchaisuksiri 3), Omolade Awodu 4), Ana Boban 5) 6), Adam Cuker 7), Julie A. Curtin 8), Karin Fijnvandraat 9) 10), Samantha C. Gouw 9) 10), Roberta Gualtierotti 11) 12), Michael Makris 13), Paula Nahuelhual 14) 15), Niamh O’Connell 16) 17), Renu Saxena 18), Midori Shima 19), Runhui Wu 20), Frits R. Rosendaal 21)
1-Department of Internal Medicine, Faculty of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
2-School of Medicine, Universidad San Sebastian, Santiago, Chile
3-Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
4-Department of Hematology, School of Medicine, University of Benin, Benin City, Nigeria
5-School of Medicine, University of Zagreb, Zagreb, Croatia
6-Department of Hematology, University Hospital Center Zagreb, Zagreb, Croatia
7-Department of Medicine and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
8-Department of Haematology, The Children’s Hospital at Westmead, Westmead, New South Wales, Australia
9-Department of Pediatric Hematology, Emma Children’s Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
10-Department of Molecular Cellular Hemostasis, Sanquin Research and Landsteiner Laboratory, Amsterdam, the Netherlands
11-Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
12-Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
13-Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom
14-Departamento de Evaluación de Tecnologías Sanitarias y Salud Basada en Evidencia, Ministerio de Salud, Santiago, Chile
15-Facultad de Medicina, Clínica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile
16-Department of Haematology, National Coagulation Centre, St. James’s Hospital Dublin, Dublin, Ireland
17-Department of Haematology, School of Medicine, Trinity College, Dublin, Ireland
18-Department of Hematopathology, Medanta Hospital, Gurugram, India
19-Thrombosis and Hemostasis Research Center, Nara Medical University, Nara, Japan
20-Department of Hematology, National Center for Children’s Health, Beijing Children’s Hospital, Capital Medical University, Beijing, China
21-Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
Abstract
Background
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.
Objectives
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.
Methods
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.
Results
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.
Conclusion
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.