International Society on Thrombosis and Haemostasis Clinical Practice Guideline for Treatment of Congenital Haemophilia-A Critical Appraisal

Manuela Albisetti¹, Jesús Ardila², Jan Astermark^{3

4}, Jan Blatny⁵, Manuel Carcao⁶, Pratima Chowdary⁷, Nathan T Connell⁸, Miguel Crato⁹, Yesim Dargaud^{10

11}, Roseline d'Oiron¹², Amy L Dunn¹³, Miguel A Escobar¹⁴, Carmen Escuriola Ettingshausen¹⁵, Kathelijn Fischer¹⁶, Emna Gouider¹⁷, Annie Harroche¹⁸, Cedric Hermans¹⁹, Victor Jimenez-Yuste²⁰, Radoslaw Kaczmarek²¹, Gili Kenet²², Liane Khoo²³, Robert Klamroth²⁴, Florian Langer²⁵, David Lillicrap²⁶, Johnny Mahlangu²⁷, Christoph Male²⁸, Maria Elisa Mancuso²⁹, Tadashi Matsushita³⁰, Sandrine Meunier³¹, Wolfgang Miesbach³², Beatrice Nolan³³, Johannes Oldenburg³⁴, Brian O'Mahony³⁵, Margareth Ozelo³⁶, Glenn F Pierce³⁷, Gloria Ramos³⁸, Michael Recht^{39

40}, Olivia Romero-Lux⁹, Dawn Rotellini⁴⁰, Rita C Santoro⁴¹, Tammuella C Singleton⁴², Mark W Skinner^{43

44}, Alok Srivastava⁴⁵, Sophie Susen⁴⁶, Kate Talks⁴⁷, Huyen Tran⁴⁸, Leonard A Valentino⁴⁹, Jerzy Windyga⁵⁰, Renchi Yang⁵¹; also on behalf of AICE, AHAD‐AP, AHCDC, ATHN, CLAHT, EHC, French CRH & MHEMO, GTH, HTCCNC, NBDF, PEDNET, UKHCDO, WFH

Affiliations

¹ University Children's Hospital, Zurich, Switzerland.
² Clínica Imbanaco Quirón Salud Hemophilia Center, IPS Especializada Coagulopathies Program, Universidad del Valle School of Public Health, Cali, Colombia.
³ Department of Translational Medicine, Lund University, Lund, Sweden.
⁴ Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Malmö, Sweden.
⁵ Department of Paediatric Haematology and Biochemistry, University Hospital Brno and Masaryk University, Brno, Czech Republic and Hospital Bory, Bratislava, Slovakia.
⁶ Division of Haematology/Oncology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
⁷ Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London, UK.
⁸ Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁹ European Haemopilia Consortium, Brussels, Belgium.
¹⁰ French Reference Center for Hemophilia, Clinical Haemostasis Unit, Louis Pradel Hospital, Hospices Civils de Lyon, Lyon, France.
¹¹ Universite Claude Bernard Lyon 1 (UCLB), Lyon, France.
¹² Centre de Référence de l'Hémophilie et des Maladies Hémorragiques Rares, Hôpital Bicêtre APHP, and HITh, UMR_S1176, INSERM, Université Paris-Saclay, Le Kremlin-Bicêtre, Paris, France.
¹³ Nationwide Children's Hospital Division of Hematology, Oncology and Bone Marrow Transplant, Columbus, Ohio, USA.
¹⁴ University of Texas Health Science Center at Houston, Houston, Texas, USA.
¹⁵ HZRM-Haemophilie Zentrum Rhein-Main, Frankfurt, Germany.
¹⁶ Center for Benign Haematology, Thrombosis and Haemostasis Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁷ Service d'hématologie biologique Hemophilia Center Aziza Othmana, University Tunis El Manar, Tunis, Tunisia.
¹⁸ Service d'Hématologie Clinique Centre de Traitement de l'Hémophilie, Hôpital Necker Enfants Malades, AP-HP, Paris, France.
¹⁹ Division of Adult Haematology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCLouvain), Brussels, Belgium.
²⁰ Hematology Department, Hospital Universitario La Paz-IdiPaz, Autonoma University, Madrid, Spain.
²¹ Indiana University School of Medicine, Indianapolis, Indiana, USA.
²² The Israeli National Hemophilia Center and Thrombosis Research Institute, Sheba Medical Center, Tel Hashomer & Tel Aviv University, Ramat Gan, Israel.
²³ Haematology Department, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
²⁴ Department for Internal Medicine and Vascular Medicine, Haemophilia Treatment Center, Vivantes Hospital im Friedrichshain, Berlin, Germany.
²⁵ Department of Hematology and Oncology, University Medical Center Eppendorf, Hamburg, Germany.
²⁶ Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
²⁷ Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, Gauteng, South Africa.
²⁸ Department of Paediatrics, Medical University of Vienna, Vienna, Austria.
²⁹ Center for Thrombosis and Hemorrhagic Diseases, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
³⁰ Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan.
³¹ Hospices Civils de Lyon- French Reference Center for Hemophilia, Clinical Haemostasis Unit Lyon, Louis Pradel Hospital, Bron, France.
³² Medical Clinic 2, University Hospital Frankfurt, Frankfurt, Germany.
³³ Children's Health Ireland at Crumlin, Dublin, Ireland.
³⁴ Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Bonn, Germany.
³⁵ Irish Haemophilia Society, Dublin, Ireland.
³⁶ Department of Internal Medicine, School of Medical Sciences, Hemocentro UNICAMP, University of Campinas, Campinas, SP, Brazil.
³⁷ World Federation of Hemophilia, Montreal, Quebec, Canada.
³⁸ Reference Laboratory in Haemostasis and Hematology, National University, Bogotà, Colombia.
³⁹ Yale University, New Haven, Connecticut, USA.
⁴⁰ National Bleeding Disorders Foundation, New York, New York, USA.
⁴¹ Centre for Hemorrhagic and Thrombotic Disorders, Azienda Ospedaliera-Universitaria Renato Dulbecco, Catanzaro, Italy.
⁴² OchsnerClinic Foundation, Pediatric Hematology and Bone Marrow Transplant, New Orleans, Louisiana, USA.
⁴³ Institute for Policy Development Ltd, Washington, District of Columbia, USA.
⁴⁴ McMaster University, Hamilton, Ontario, Canada.
⁴⁵ Haematology Research Unit, St. Johns Research Institute and Department of Clinical Haematology, St. John's Medical College Hospital, Bengaluru, India.
⁴⁶ Hemostasis and Transfusion Department, University of Lille, Lille University Hospital, Lille, France.
⁴⁷ Newcastle Haemophilia Centre, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.
⁴⁸ The Alfred Hospital, Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia.
⁴⁹ Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago, Illinois, USA.
⁵⁰ Department of Haemostasis Disorders and Internal Medicine, Laboratory of Haemostasis and Metabolic Diseases, Institute of Haematology and Transfusion Medicine, Warsaw, Poland.
⁵¹ Thrombosis and Hemostasis Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.

PMID: 39642092
DOI: 10.1111/hae.15135

International Society on Thrombosis and Haemostasis Clinical Practice Guideline for Treatment of Congenital Haemophilia-A Critical Appraisal

Manuela Albisetti et al. Haemophilia. 2024.

. 2024 Dec 6.

doi: 10.1111/hae.15135. Online ahead of print.

Authors

Affiliations

¹ University Children's Hospital, Zurich, Switzerland.
² Clínica Imbanaco Quirón Salud Hemophilia Center, IPS Especializada Coagulopathies Program, Universidad del Valle School of Public Health, Cali, Colombia.
³ Department of Translational Medicine, Lund University, Lund, Sweden.
⁴ Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Malmö, Sweden.
⁵ Department of Paediatric Haematology and Biochemistry, University Hospital Brno and Masaryk University, Brno, Czech Republic and Hospital Bory, Bratislava, Slovakia.
⁶ Division of Haematology/Oncology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
⁷ Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London, UK.
⁸ Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁹ European Haemopilia Consortium, Brussels, Belgium.
¹⁰ French Reference Center for Hemophilia, Clinical Haemostasis Unit, Louis Pradel Hospital, Hospices Civils de Lyon, Lyon, France.
¹¹ Universite Claude Bernard Lyon 1 (UCLB), Lyon, France.
¹² Centre de Référence de l'Hémophilie et des Maladies Hémorragiques Rares, Hôpital Bicêtre APHP, and HITh, UMR_S1176, INSERM, Université Paris-Saclay, Le Kremlin-Bicêtre, Paris, France.
¹³ Nationwide Children's Hospital Division of Hematology, Oncology and Bone Marrow Transplant, Columbus, Ohio, USA.
¹⁴ University of Texas Health Science Center at Houston, Houston, Texas, USA.
¹⁵ HZRM-Haemophilie Zentrum Rhein-Main, Frankfurt, Germany.
¹⁶ Center for Benign Haematology, Thrombosis and Haemostasis Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁷ Service d'hématologie biologique Hemophilia Center Aziza Othmana, University Tunis El Manar, Tunis, Tunisia.
¹⁸ Service d'Hématologie Clinique Centre de Traitement de l'Hémophilie, Hôpital Necker Enfants Malades, AP-HP, Paris, France.
¹⁹ Division of Adult Haematology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCLouvain), Brussels, Belgium.
²⁰ Hematology Department, Hospital Universitario La Paz-IdiPaz, Autonoma University, Madrid, Spain.
²¹ Indiana University School of Medicine, Indianapolis, Indiana, USA.
²² The Israeli National Hemophilia Center and Thrombosis Research Institute, Sheba Medical Center, Tel Hashomer & Tel Aviv University, Ramat Gan, Israel.
²³ Haematology Department, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
²⁴ Department for Internal Medicine and Vascular Medicine, Haemophilia Treatment Center, Vivantes Hospital im Friedrichshain, Berlin, Germany.
²⁵ Department of Hematology and Oncology, University Medical Center Eppendorf, Hamburg, Germany.
²⁶ Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
²⁷ Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, Gauteng, South Africa.
²⁸ Department of Paediatrics, Medical University of Vienna, Vienna, Austria.
²⁹ Center for Thrombosis and Hemorrhagic Diseases, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
³⁰ Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan.
³¹ Hospices Civils de Lyon- French Reference Center for Hemophilia, Clinical Haemostasis Unit Lyon, Louis Pradel Hospital, Bron, France.
³² Medical Clinic 2, University Hospital Frankfurt, Frankfurt, Germany.
³³ Children's Health Ireland at Crumlin, Dublin, Ireland.
³⁴ Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Bonn, Germany.
³⁵ Irish Haemophilia Society, Dublin, Ireland.
³⁶ Department of Internal Medicine, School of Medical Sciences, Hemocentro UNICAMP, University of Campinas, Campinas, SP, Brazil.
³⁷ World Federation of Hemophilia, Montreal, Quebec, Canada.
³⁸ Reference Laboratory in Haemostasis and Hematology, National University, Bogotà, Colombia.
³⁹ Yale University, New Haven, Connecticut, USA.
⁴⁰ National Bleeding Disorders Foundation, New York, New York, USA.
⁴¹ Centre for Hemorrhagic and Thrombotic Disorders, Azienda Ospedaliera-Universitaria Renato Dulbecco, Catanzaro, Italy.
⁴² OchsnerClinic Foundation, Pediatric Hematology and Bone Marrow Transplant, New Orleans, Louisiana, USA.
⁴³ Institute for Policy Development Ltd, Washington, District of Columbia, USA.
⁴⁴ McMaster University, Hamilton, Ontario, Canada.
⁴⁵ Haematology Research Unit, St. Johns Research Institute and Department of Clinical Haematology, St. John's Medical College Hospital, Bengaluru, India.
⁴⁶ Hemostasis and Transfusion Department, University of Lille, Lille University Hospital, Lille, France.
⁴⁷ Newcastle Haemophilia Centre, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.
⁴⁸ The Alfred Hospital, Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia.
⁴⁹ Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago, Illinois, USA.
⁵⁰ Department of Haemostasis Disorders and Internal Medicine, Laboratory of Haemostasis and Metabolic Diseases, Institute of Haematology and Transfusion Medicine, Warsaw, Poland.
⁵¹ Thrombosis and Hemostasis Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.

PMID: 39642092
DOI: 10.1111/hae.15135

Abstract

Introduction: Evidence-based clinical practice guidelines drive optimal patient care and facilitate access to high-quality treatment. Creating guidelines for rare diseases such as haemophilia, where evidence does not often come from randomized controlled trials but from non-randomized and well-designed observational studies and real-world data, is challenging. The methodology used for assessing available evidence should consider this critical fact. In formulating guidelines, it is essential to include treatment goals and patient preference.

Aim: This paper comprehensively critiques, against this background, the recommendations of the ISTH clinical practice guidelines for the treatment of haemophilia.

Methods: Each recommendation was critically reviewed against available evidence as well as existing guidelines and commented upon for its scientific validity, impact on clinical practice and access to care globally. The validity of the way in which the GRADE methodology was applied to existing evidence was also assessed.

Results: The critique provided shows that these recommendations have major limitations: they did not state treatment goals and contradict existing guidelines; opportunities for providing access to innovation were missed when the therapeutic benefits of the products approved in the last decades were not included. A major reason for this is the inappropriate adoption of the GRADE methodology without adaptations and without considering treatment goals and patient-relevant outcomes.

Conclusion: These recommendations may mislead healthcare professionals, payers and governments and therefore cannot serve the patient community well. They setback the advances made in haemophilia care because they overlook important available evidence and do not guide clinical practice to contemporary standards.

Keywords: GRADE; ISTH; WFH; evidence‐based medicine; guideline; haemophilia.

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References

1. A. Srivastava, A. K. Brewer, E. P. Mauser‐Bunschoten, et al., “Guidelines for the Management of Hemophilia,” Haemophilia 19, no. 1 (2013): e1–47.
1. A. Srivastava, E. Santagostino, A. Dougall, et al., “WFH Guidelines for the Management of Hemophilia, 3rd Edition,” Supplement, Haemophilia 26, no. S6 (2020): 1–158.
1. E. Krumb and C. Hermans, “Living With a ‘Hemophilia‐Free Mind’—The New Ambition of Hemophilia Care?,” Research and Practice in Thrombosis Haemostasis 5, no. 5 (2021): e12567.
1. L. A. Valentino, J. R. Baker, R. Butler, et al., “Integrated Hemophilia Patient Care Via a National Network of Care Centers in the United States: A Model for Rare Coagulation Disorders,” Journal of Blood Medicie 12 (2021): 897–911.
1. M. Makris, G. Calizzani, K. Fischer, et al., “EUHASS: The European Haemophilia Safety Surveillance System,” Supplement, Thrombosis Research 127, no. S2 (2011): S22–S25.

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International Society on Thrombosis and Haemostasis Clinical Practice Guideline for Treatment of Congenital Haemophilia-A Critical Appraisal

Affiliations

International Society on Thrombosis and Haemostasis Clinical Practice Guideline for Treatment of Congenital Haemophilia-A Critical Appraisal

Authors

Affiliations

Abstract

References

LinkOut - more resources

Full Text Sources