Radiosynovectomy (RS), which uses beta particle-emitting radiocolloids, has proven highly effective in significantly reducing the occurrence of haemarthroses and breaking the cycle of bleeding and synovitis. This study now presents the long-term outcomes of repeated RS in individuals with haemophilia.
Materials and Methods
Repeated RS was administered to 48 joints in 37 people with haemophilia (PwHs) diagnosed with chronic haemophilic synovitis. The frequency of bleeding episodes was meticulously recorded during the 6-month periods preceding and following each of the initial and subsequent RS procedures. Treatment failure was designated by the necessity for additional RS injections.
Results
The results for 48 joints were analysed. The mean bleeding frequency of the joints was 12.5 ± 7.29 (median 10) within the last 6 months in the pre-treatment evaluation and after the treatment, the mean bleeding frequency of the joints decreased to 2.25 ± 3.82 (median 0.5) for the first 6 months (p < 0.001) after the first RS. The mean survival of the first intervention was 40.52 ± 33.79 months (range, 1–124 months). In the second RS, the mean bleeding frequency of the joints was 10.29 ± 7.66 (median 8) within the last 6 months in the pre-treatment evaluation and after the treatment, and the mean bleeding frequency of the joints decreased to 0.93 ± 1.69 (median 0) for the first 6 months (p < 0.001). The survival rate of the second RS was 94% at 12 months, and 87% at 36 months.
Conclusion
Repeated RS was proven to be an effective and safe treatment for Pwh with recurrent bleeding episodes during long-term follow up. Thirty-six months survival rate was 87% (42 of 48 joints).
{"title":"Repeated Radiosynovectomy in Haemophilia: Revealing Long-Term Effectiveness and Safety","authors":"Basak Koc, Cuneyt Turkmen, Gokhan Polat, Bulent Zulfikar","doi":"10.1111/hae.15142","DOIUrl":"10.1111/hae.15142","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Radiosynovectomy (RS), which uses beta particle-emitting radiocolloids, has proven highly effective in significantly reducing the occurrence of haemarthroses and breaking the cycle of bleeding and synovitis. This study now presents the long-term outcomes of repeated RS in individuals with haemophilia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials and Methods</h3>\u0000 \u0000 <p>Repeated RS was administered to 48 joints in 37 people with haemophilia (PwHs) diagnosed with chronic haemophilic synovitis. The frequency of bleeding episodes was meticulously recorded during the 6-month periods preceding and following each of the initial and subsequent RS procedures. Treatment failure was designated by the necessity for additional RS injections.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results for 48 joints were analysed. The mean bleeding frequency of the joints was 12.5 ± 7.29 (median 10) within the last 6 months in the pre-treatment evaluation and after the treatment, the mean bleeding frequency of the joints decreased to 2.25 ± 3.82 (median 0.5) for the first 6 months (<i>p</i> < 0.001) after the first RS. The mean survival of the first intervention was 40.52 ± 33.79 months (range, 1–124 months). In the second RS, the mean bleeding frequency of the joints was 10.29 ± 7.66 (median 8) within the last 6 months in the pre-treatment evaluation and after the treatment, and the mean bleeding frequency of the joints decreased to 0.93 ± 1.69 (median 0) for the first 6 months (<i>p</i> < 0.001). The survival rate of the second RS was 94% at 12 months, and 87% at 36 months.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Repeated RS was proven to be an effective and safe treatment for Pwh with recurrent bleeding episodes during long-term follow up. Thirty-six months survival rate was 87% (42 of 48 joints).</p>\u0000 </section>\u0000 </div>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"156-161"},"PeriodicalIF":3.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acquired haemophilia A (AHA) is characterized by the development of autoantibodies against factor VIII, reducing its activity and potentially resulting in bleeding.
Aim
To assess the characteristics of people with AHA undergoing rehabilitation and/or with low activities of daily living (ADL) scores, thereby characterizing unmet needs in the management of AHA and informing treatment optimization.
Methods
ORIHIME II, the largest epidemiological and treatment survey of AHA in Japan, is a descriptive, retrospective, observational study conducted using health claims data from April 2008 to October 2021. The primary outcome measures were rehabilitation practice and ADL scores on hospital admission and discharge; use of haemostatic agents and immunosuppressive therapy were also assessed.
Results
Overall, 427 patients in Japan were eligible for the study. Median (Q1–Q3) age was 78.0 (70.0–84.0) years; 264 patients (61.8%) were male. Median (Q1–Q3) time to start rehabilitation was 9 (4–21) and 14 (6–31) days for those with an admission ADL score of <85 and ≥85, respectively. Of the 427 patients, 249 underwent rehabilitation. The most common rehabilitation type was for disuse syndrome; haemostatic agents were more commonly used in patients undergoing earlier rehabilitation.
Conclusion
The physical condition of the patient at hospitalization was associated with rehabilitation practice and the ability of the patient to perform day-to-day activities independently. Treatment strategies should be optimized to allow initiation of rehabilitation as early as possible in the course of AHA.
导言：目的：评估正在接受康复治疗和/或日常生活活动（ADL）评分较低的 AHA 患者的特征，从而了解 AHA 管理中尚未满足的需求，为优化治疗提供依据：ORIHIME II 是日本最大规模的 AHA 流行病学和治疗调查，是一项描述性、回顾性、观察性研究，使用的是 2008 年 4 月至 2021 年 10 月期间的健康索赔数据。主要结果指标是入院和出院时的康复实践和ADL评分；还评估了止血剂和免疫抑制剂的使用情况：日本共有 427 名患者符合研究条件。中位（Q1-Q3）年龄为 78.0（70.0-84.0）岁；264 名患者（61.8%）为男性。开始康复治疗的中位时间（Q1-Q3）为 9 天（4-21 天），入院时 ADL 评分为结论的患者为 14 天（6-31 天）：患者住院时的身体状况与康复训练和患者独立完成日常活动的能力有关。应优化治疗策略，以便在急性心肌梗死病程中尽早开始康复治疗。
{"title":"Real-World Data on Patients With Acquired Haemophilia A in Japan Undergoing Rehabilitation or With Low Activities of Daily Living Scores: The ORIHIME II Study","authors":"Yoshiyuki Ogawa, Kagehiro Amano, Yoshimasa Sugao, Daisuke Nosaka, Yoichi Murakami, Hiroki Adachi, Keiji Nogami","doi":"10.1111/hae.15132","DOIUrl":"10.1111/hae.15132","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Acquired haemophilia A (AHA) is characterized by the development of autoantibodies against factor VIII, reducing its activity and potentially resulting in bleeding.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To assess the characteristics of people with AHA undergoing rehabilitation and/or with low activities of daily living (ADL) scores, thereby characterizing unmet needs in the management of AHA and informing treatment optimization.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>ORIHIME II, the largest epidemiological and treatment survey of AHA in Japan, is a descriptive, retrospective, observational study conducted using health claims data from April 2008 to October 2021. The primary outcome measures were rehabilitation practice and ADL scores on hospital admission and discharge; use of haemostatic agents and immunosuppressive therapy were also assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Overall, 427 patients in Japan were eligible for the study. Median (Q1–Q3) age was 78.0 (70.0–84.0) years; 264 patients (61.8%) were male. Median (Q1–Q3) time to start rehabilitation was 9 (4–21) and 14 (6–31) days for those with an admission ADL score of <85 and ≥85, respectively. Of the 427 patients, 249 underwent rehabilitation. The most common rehabilitation type was for disuse syndrome; haemostatic agents were more commonly used in patients undergoing earlier rehabilitation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The physical condition of the patient at hospitalization was associated with rehabilitation practice and the ability of the patient to perform day-to-day activities independently. Treatment strategies should be optimized to allow initiation of rehabilitation as early as possible in the course of AHA.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"99-107"},"PeriodicalIF":3.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amy Dunn, Yesim Dargaud, Yasmina Abajas, Manuel Carcao, Giancarlo Castaman, Adam Giermasz, Cédric Hermans, Victor Jiménez-Yuste, Magdalena Lewandowska, Johnny Mahlangu, Shannon Meeks, Wolfgang Miesbach, Michael Recht, Vanessa Salinas, Tammuella Chrisentery-Singleton, Daniel Bonzo, Ian S. Mitchell, Thomas A. Wilkinson, Guy Young
Introduction
Eptacog beta is a novel human recombinant FVIIa approved for use in the United States, European Union, United Kingdom and Mexico for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors (≥12 years). It is also indicated for perioperative care in the same patient population in Europe and the United Kingdom.
Aim
To assess the incidence of rebleeding and review treatment outcomes in subjects with haemophilia with inhibitors enrolled in the phase 3 PERSEPT 1 clinical trial.
Methods
To treat mild/moderate bleeding episodes (BEs), subjects administered an initial 75 or 225µg/kg dose of eptacog beta, followed (if necessary) by additional 75µg/kg doses at predefined intervals until bleed control. This analysis used subject-reported rebleeding to determine a rebleeding incidence for the first 24 h. Rebleeding through later timepoints was an exploratory, intention-to-treat analysis of bleed treatment data.
Results
Four hundred and sixty-five BEs were analysed. Through 24 h, the proportion of rebleeds was 0% (initial 75µg/kg dose) and 0.5% (initial 225µg/kg dose). Through 48 h, the proportion of rebleeds was 3.2% (75µg/kg initial dose) and 5.6% (225µg/kg initial dose); the difference between initial dose strategies was not statistically significant. The majority of rebleeds were controlled with a single dose of eptacog beta and no subject who treated a rebleed required hospitalization.
Conclusion
Subjects with haemophilia with inhibitors who used eptacog beta to treat mild/moderate BEs experienced a low incidence of rebleeding. Rebleeds that did occur were effectively controlled with eptacog beta (median, one dose) without the need for hospitalization.
{"title":"Bleed treatment with eptacog beta (rFVIIa) results in a low incidence of rebleeding in adult and adolescent patients with haemophilia A or B with inhibitors","authors":"Amy Dunn, Yesim Dargaud, Yasmina Abajas, Manuel Carcao, Giancarlo Castaman, Adam Giermasz, Cédric Hermans, Victor Jiménez-Yuste, Magdalena Lewandowska, Johnny Mahlangu, Shannon Meeks, Wolfgang Miesbach, Michael Recht, Vanessa Salinas, Tammuella Chrisentery-Singleton, Daniel Bonzo, Ian S. Mitchell, Thomas A. Wilkinson, Guy Young","doi":"10.1111/hae.15109","DOIUrl":"10.1111/hae.15109","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Eptacog beta is a novel human recombinant FVIIa approved for use in the United States, European Union, United Kingdom and Mexico for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors (≥12 years). It is also indicated for perioperative care in the same patient population in Europe and the United Kingdom.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To assess the incidence of rebleeding and review treatment outcomes in subjects with haemophilia with inhibitors enrolled in the phase 3 PERSEPT 1 clinical trial.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To treat mild/moderate bleeding episodes (BEs), subjects administered an initial 75 or 225µg/kg dose of eptacog beta, followed (if necessary) by additional 75µg/kg doses at predefined intervals until bleed control. This analysis used subject-reported rebleeding to determine a rebleeding incidence for the first 24 h. Rebleeding through later timepoints was an exploratory, intention-to-treat analysis of bleed treatment data.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Four hundred and sixty-five BEs were analysed. Through 24 h, the proportion of rebleeds was 0% (initial 75µg/kg dose) and 0.5% (initial 225µg/kg dose). Through 48 h, the proportion of rebleeds was 3.2% (75µg/kg initial dose) and 5.6% (225µg/kg initial dose); the difference between initial dose strategies was not statistically significant. The majority of rebleeds were controlled with a single dose of eptacog beta and no subject who treated a rebleed required hospitalization.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Subjects with haemophilia with inhibitors who used eptacog beta to treat mild/moderate BEs experienced a low incidence of rebleeding. Rebleeds that did occur were effectively controlled with eptacog beta (median, one dose) without the need for hospitalization.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"78-86"},"PeriodicalIF":3.0,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mark W Skinner, Manuela Albisetti, Jesús Ardila, Jan Astermark, Jan Blatny, Manuel Carcao, Pratima Chowdary, Nathan T Connell, Miguel Crato, Yesim Dargaud, Roseline d'Oiron, Amy L Dunn, Miguel A Escobar, Carmen Escuriola-Ettingshausen, Emna Gouider, Annie Harroche, Cedric Hermans, Victor Jimenez-Yuste, Radoslaw Kaczmarek, Gili Kenet, Liane Khoo, Robert Klamroth, Florian Langer, David Lillicrap, Johnny Mahlangu, Christoph Male, Tadashi Matsushita, Sandrine Meunier, Wolfgang Miesbach, Beatrice Nolan, Johannes Oldenburg, Brian O'Mahony, Margareth Ozelo, Glenn F Pierce, Gloria Ramos, Michael Recht, Olivia Romero-Lux, Dawn Rotellini, Rita C Santoro, Tammuella C Singleton, Alok Srivastava, Sophie Susen, Kate Talks, Huyen Tran, Leonard A Valentino, Jerzy Windyga, Renchi Yang, Maria Elisa Mancuso
Introduction: The 2024 ISTH clinical practice guideline (CPG) for treatment of congenital haemophilia, the NBDF-McMaster Guideline on Care Models for Haemophilia Management, and ASH ISTH NBDF WFH guidelines on the diagnosis and management of VWD all utilised GRADE methodology.
Aim: Discuss missed opportunities and the methodological approach of the ISTH Guideline in contrast to how GRADE was previously applied in rare diseases.
Methods: Critically analyse the methodology of each guideline along with best practices in the use of GRADE. Where applicable, the WFH Guidelines for the Management of Haemophilia were analysed.
Results: Important differentiating features in applying GRADE were identified. Where a strong evidence base is lacking, data other than those from randomized controlled trials, which may not always be justified, need to be considered, including incorporation of outcomes important to people living with the disease. Justification and stakeholder input to prioritize questions requiring a new guideline, panel composition with necessary patient participation and content expertise were also found to be significant differentiating features.
Conclusion: The puristic approach taken in the ISTH Guideline development process, without consideration of accepted adaptations to GRADE implementation, created a missed opportunity for progressing haemophilia care, leading to guideline recommendations that have been widely deemed invalid and obsolete by expert healthcare professionals and by those living with the condition, the very people who are expected to implement or bear the impact of the recommendations. Lessons learnt from this comparative analysis should guide future guideline development and encourage collaboration to further advance haemophilia.
{"title":"Contrasting Approaches in the Implementation of GRADE Methodology in Guidelines for Haemophilia and Von Willebrand Disease.","authors":"Mark W Skinner, Manuela Albisetti, Jesús Ardila, Jan Astermark, Jan Blatny, Manuel Carcao, Pratima Chowdary, Nathan T Connell, Miguel Crato, Yesim Dargaud, Roseline d'Oiron, Amy L Dunn, Miguel A Escobar, Carmen Escuriola-Ettingshausen, Emna Gouider, Annie Harroche, Cedric Hermans, Victor Jimenez-Yuste, Radoslaw Kaczmarek, Gili Kenet, Liane Khoo, Robert Klamroth, Florian Langer, David Lillicrap, Johnny Mahlangu, Christoph Male, Tadashi Matsushita, Sandrine Meunier, Wolfgang Miesbach, Beatrice Nolan, Johannes Oldenburg, Brian O'Mahony, Margareth Ozelo, Glenn F Pierce, Gloria Ramos, Michael Recht, Olivia Romero-Lux, Dawn Rotellini, Rita C Santoro, Tammuella C Singleton, Alok Srivastava, Sophie Susen, Kate Talks, Huyen Tran, Leonard A Valentino, Jerzy Windyga, Renchi Yang, Maria Elisa Mancuso","doi":"10.1111/hae.15136","DOIUrl":"https://doi.org/10.1111/hae.15136","url":null,"abstract":"<p><strong>Introduction: </strong>The 2024 ISTH clinical practice guideline (CPG) for treatment of congenital haemophilia, the NBDF-McMaster Guideline on Care Models for Haemophilia Management, and ASH ISTH NBDF WFH guidelines on the diagnosis and management of VWD all utilised GRADE methodology.</p><p><strong>Aim: </strong>Discuss missed opportunities and the methodological approach of the ISTH Guideline in contrast to how GRADE was previously applied in rare diseases.</p><p><strong>Methods: </strong>Critically analyse the methodology of each guideline along with best practices in the use of GRADE. Where applicable, the WFH Guidelines for the Management of Haemophilia were analysed.</p><p><strong>Results: </strong>Important differentiating features in applying GRADE were identified. Where a strong evidence base is lacking, data other than those from randomized controlled trials, which may not always be justified, need to be considered, including incorporation of outcomes important to people living with the disease. Justification and stakeholder input to prioritize questions requiring a new guideline, panel composition with necessary patient participation and content expertise were also found to be significant differentiating features.</p><p><strong>Conclusion: </strong>The puristic approach taken in the ISTH Guideline development process, without consideration of accepted adaptations to GRADE implementation, created a missed opportunity for progressing haemophilia care, leading to guideline recommendations that have been widely deemed invalid and obsolete by expert healthcare professionals and by those living with the condition, the very people who are expected to implement or bear the impact of the recommendations. Lessons learnt from this comparative analysis should guide future guideline development and encourage collaboration to further advance haemophilia.</p>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Manuela Albisetti, Jesús Ardila, Jan Astermark, Jan Blatny, Manuel Carcao, Pratima Chowdary, Nathan T Connell, Miguel Crato, Yesim Dargaud, Roseline d'Oiron, Amy L Dunn, Miguel A Escobar, Carmen Escuriola Ettingshausen, Kathelijn Fischer, Emna Gouider, Annie Harroche, Cedric Hermans, Victor Jimenez-Yuste, Radoslaw Kaczmarek, Gili Kenet, Liane Khoo, Robert Klamroth, Florian Langer, David Lillicrap, Johnny Mahlangu, Christoph Male, Maria Elisa Mancuso, Tadashi Matsushita, Sandrine Meunier, Wolfgang Miesbach, Beatrice Nolan, Johannes Oldenburg, Brian O'Mahony, Margareth Ozelo, Glenn F Pierce, Gloria Ramos, Michael Recht, Olivia Romero-Lux, Dawn Rotellini, Rita C Santoro, Tammuella C Singleton, Mark W Skinner, Alok Srivastava, Sophie Susen, Kate Talks, Huyen Tran, Leonard A Valentino, Jerzy Windyga, Renchi Yang
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.
{"title":"International Society on Thrombosis and Haemostasis Clinical Practice Guideline for Treatment of Congenital Haemophilia-A Critical Appraisal.","authors":"Manuela Albisetti, Jesús Ardila, Jan Astermark, Jan Blatny, Manuel Carcao, Pratima Chowdary, Nathan T Connell, Miguel Crato, Yesim Dargaud, Roseline d'Oiron, Amy L Dunn, Miguel A Escobar, Carmen Escuriola Ettingshausen, Kathelijn Fischer, Emna Gouider, Annie Harroche, Cedric Hermans, Victor Jimenez-Yuste, Radoslaw Kaczmarek, Gili Kenet, Liane Khoo, Robert Klamroth, Florian Langer, David Lillicrap, Johnny Mahlangu, Christoph Male, Maria Elisa Mancuso, Tadashi Matsushita, Sandrine Meunier, Wolfgang Miesbach, Beatrice Nolan, Johannes Oldenburg, Brian O'Mahony, Margareth Ozelo, Glenn F Pierce, Gloria Ramos, Michael Recht, Olivia Romero-Lux, Dawn Rotellini, Rita C Santoro, Tammuella C Singleton, Mark W Skinner, Alok Srivastava, Sophie Susen, Kate Talks, Huyen Tran, Leonard A Valentino, Jerzy Windyga, Renchi Yang","doi":"10.1111/hae.15135","DOIUrl":"https://doi.org/10.1111/hae.15135","url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Aim: </strong>This paper comprehensively critiques, against this background, the recommendations of the ISTH clinical practice guidelines for the treatment of haemophilia.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pratima Chowdary, Maria Teresa Álvarez-Román, Fariba Baghaei, Robert Klamroth, Wolfgang Miesbach, Jan Blatny
{"title":"EAHAD statement on the ISTH clinical practice guideline for treatment of congenital haemophilia A and B.","authors":"Pratima Chowdary, Maria Teresa Álvarez-Román, Fariba Baghaei, Robert Klamroth, Wolfgang Miesbach, Jan Blatny","doi":"10.1111/hae.15119","DOIUrl":"https://doi.org/10.1111/hae.15119","url":null,"abstract":"","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The shared decision-making (SDM) tool developed by the World Federation of Hemophilia (WFH) provides a clear and concise overview of the process by which people with haemophilia (PwH) can collaborate with their healthcare professionals (HCPs) to engage and arrive at a therapeutic decision. This tool will be useful for all people with all bleeding disorders, not just PwH.
{"title":"Giving Choice a Voice: Commentary on Development of the World Federation of Hemophilia Shared Decision-Making Tool","authors":"Leonard A. Valentino, Kate Khair","doi":"10.1111/hae.15133","DOIUrl":"10.1111/hae.15133","url":null,"abstract":"<p>The shared decision-making (SDM) tool developed by the World Federation of Hemophilia (WFH) provides a clear and concise overview of the process by which people with haemophilia (PwH) can collaborate with their healthcare professionals (HCPs) to engage and arrive at a therapeutic decision. This tool will be useful for all people with all bleeding disorders, not just PwH.</p>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"5-6"},"PeriodicalIF":3.0,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/hae.15133","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shimin Yuan, Liang Hu, Juanfang Zhong, Xiao Hu, Xiaomeng Zhao, Zhenxing Wan, Sicong Zeng, Wen-Bin He, Feng Gu, Sheng-Peng Wang, Guangxiu Lu, Ge Lin, Juan Du
Background
Haemophilia A (HA) is a rare bleeding disorder caused by variants in F8. Although traditional mutational analyses have identified numerous pathogenic variants, the aetiology of HA in certain patients remains unclear. Furthermore, female patients with severe HA are rare.
Aim
To investigate the molecular defects underlying severe HA in two patients and provide personalised reproductive interventions for their families.
Methods
Two patients diagnosed with severe HA without other clinical phenotypes were enrolled in the study. A combination of whole-exome sequencing, real-time quantitative polymerase chain reaction and long-read sequencing (LR-sequencing) was performed to reveal the molecular defects of them, followed by the application of different reproductive intervention strategies.
Results
Proband 1, a 29-year-old man with FVIII activity of 0.8%, did not exhibit common F8 variants, including Inv1 or Inv22, in the coding region. However, he carried a rare maternal novel inversion on ChrX:154148973_154170321, spanning approximately 21.345 Kbp, with breakpoints in introns 13 and 14 of F8. Finally, the couple of Proband 1 opted for assisted reproductive technology using preimplantation genetic testing and successfully conceived. Proband 2, a 20-year-old female with severe HA and FVIII activity of 0.6%, carried inv22 of F8. Further investigation combining whole exome sequencing (WES) and pedigree analysis revealed that she carried a maternal cross-deletion encompassing exons 1–22 of F8, FUNDC2, BRCC3 and CLIC2, along with a de novo missense variant c.5852T>C (p.Leu1951Ser) on her paternal X-chromosome. Chromosome X-inactivation (XCI) analysis demonstrated a highly skewed inactivation of the maternal X chromosome, with a ratio of 98:2. Subsequently, prenatal diagnosis confirmed that the third child in this family did not carry any of the F8 variants present in Proband 2.
Conclusion
Our findings provide novel insights into the genetic aetiology of HA and emphasise the importance of a definitive diagnosis in guiding genetic counselling and personalised reproductive interventions for affected individuals and their families.
{"title":"Genetic Analysis and Reproductive Interventions for Two Rare Families Affected by Severe Haemophilia A","authors":"Shimin Yuan, Liang Hu, Juanfang Zhong, Xiao Hu, Xiaomeng Zhao, Zhenxing Wan, Sicong Zeng, Wen-Bin He, Feng Gu, Sheng-Peng Wang, Guangxiu Lu, Ge Lin, Juan Du","doi":"10.1111/hae.15140","DOIUrl":"10.1111/hae.15140","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Haemophilia A (HA) is a rare bleeding disorder caused by variants in F8. Although traditional mutational analyses have identified numerous pathogenic variants, the aetiology of HA in certain patients remains unclear. Furthermore, female patients with severe HA are rare.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To investigate the molecular defects underlying severe HA in two patients and provide personalised reproductive interventions for their families.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Two patients diagnosed with severe HA without other clinical phenotypes were enrolled in the study. A combination of whole-exome sequencing, real-time quantitative polymerase chain reaction and long-read sequencing (LR-sequencing) was performed to reveal the molecular defects of them, followed by the application of different reproductive intervention strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Proband 1, a 29-year-old man with FVIII activity of 0.8%, did not exhibit common F8 variants, including Inv1 or Inv22, in the coding region. However, he carried a rare maternal novel inversion on ChrX:154148973_154170321, spanning approximately 21.345 Kbp, with breakpoints in introns 13 and 14 of F8. Finally, the couple of Proband 1 opted for assisted reproductive technology using preimplantation genetic testing and successfully conceived. Proband 2, a 20-year-old female with severe HA and FVIII activity of 0.6%, carried inv22 of F8. Further investigation combining whole exome sequencing (WES) and pedigree analysis revealed that she carried a maternal cross-deletion encompassing exons 1–22 of F8, FUNDC2, BRCC3 and CLIC2, along with a de novo missense variant c.5852T>C (p.Leu1951Ser) on her paternal X-chromosome. Chromosome X-inactivation (XCI) analysis demonstrated a highly skewed inactivation of the maternal X chromosome, with a ratio of 98:2. Subsequently, prenatal diagnosis confirmed that the third child in this family did not carry any of the F8 variants present in Proband 2.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings provide novel insights into the genetic aetiology of HA and emphasise the importance of a definitive diagnosis in guiding genetic counselling and personalised reproductive interventions for affected individuals and their families.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"148-155"},"PeriodicalIF":3.0,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kitti Sipos, Ildikó Márton, Marianna Móré, Attila Csaba Nagy, Csongor Kiss
<div> <section> <h3> Introduction</h3> <p>Patients with haemophilia (PWH) often have difficulty accessing dental services.</p> </section> <section> <h3> Aim</h3> <p>To determine the accessibility of dental care for PWH and to examine their perceptions of how coronavirus type-2 (CoV-2) disease (COVID-19) has affected their ability to access dental treatments following the pandemic.</p> </section> <section> <h3> Methods</h3> <p>The questionnaire survey was conducted between July 2022 and December 2022 at haemophilia treatment centres in Hungary. Variables with statistical significance (Pearson's Chi-squared test; <i>p</i> < .05) were included in logistic regression analyses. Least absolute shrinkage and selection operator (LASSO) regression was used as a machine learning technique to identify the most predictive variables.</p> </section> <section> <h3> Results</h3> <p>Twenty-one percent of the sixty-eight participants reported that they had been refused dental treatment, mainly in primary care (86%). Dental refusal was influenced by infectious disease (OR: 4.48, CI: 1.14–17.69) and previous dental bleeding complications (OR: 4.23, CI: 1.10–16.27). There was correlation between dental visits and having a permanent dentist or receiving oral hygiene advice (OR: 9.95, CI: 2.86–34.62 and OR: 3.84, CI: 1.09–13.58). Participation in an oral hygiene consultation increased patients’ satisfaction with their dental care (OR: 6.28, 95% CI: .71–55.88). Twenty-eight percent of patients had experienced difficulties since the start of the COVID-19, but 84% had visited their dentist at least once between 2021 and 2022 (<i>p</i> = .002). Nevertheless, 16% of respondents went for only the most necessary treatments due to pandemic.</p> </section> <section> <h3> Conclusion</h3> <p>Refusal of dental care was high among participants, especially in primary care. The COVID-19 pandemic has exaggerated the difficulties of PWH in accessing dental treatment.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Patients with haemophilia (PWH) have difficulty accessing dental care, and the coronavirus type 2 (CoV-2) disease pandemic (COVID-19) has created a new barrier.</li> <li>The study revealed a high prevalence of dental care refusal (21%), particularly in primary
{"title":"Assessing the factors affecting the accessibility of primary dental care for people with haemophilia","authors":"Kitti Sipos, Ildikó Márton, Marianna Móré, Attila Csaba Nagy, Csongor Kiss","doi":"10.1111/hae.15124","DOIUrl":"10.1111/hae.15124","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Patients with haemophilia (PWH) often have difficulty accessing dental services.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To determine the accessibility of dental care for PWH and to examine their perceptions of how coronavirus type-2 (CoV-2) disease (COVID-19) has affected their ability to access dental treatments following the pandemic.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The questionnaire survey was conducted between July 2022 and December 2022 at haemophilia treatment centres in Hungary. Variables with statistical significance (Pearson's Chi-squared test; <i>p</i> < .05) were included in logistic regression analyses. Least absolute shrinkage and selection operator (LASSO) regression was used as a machine learning technique to identify the most predictive variables.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Twenty-one percent of the sixty-eight participants reported that they had been refused dental treatment, mainly in primary care (86%). Dental refusal was influenced by infectious disease (OR: 4.48, CI: 1.14–17.69) and previous dental bleeding complications (OR: 4.23, CI: 1.10–16.27). There was correlation between dental visits and having a permanent dentist or receiving oral hygiene advice (OR: 9.95, CI: 2.86–34.62 and OR: 3.84, CI: 1.09–13.58). Participation in an oral hygiene consultation increased patients’ satisfaction with their dental care (OR: 6.28, 95% CI: .71–55.88). Twenty-eight percent of patients had experienced difficulties since the start of the COVID-19, but 84% had visited their dentist at least once between 2021 and 2022 (<i>p</i> = .002). Nevertheless, 16% of respondents went for only the most necessary treatments due to pandemic.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Refusal of dental care was high among participants, especially in primary care. The COVID-19 pandemic has exaggerated the difficulties of PWH in accessing dental treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Patients with haemophilia (PWH) have difficulty accessing dental care, and the coronavirus type 2 (CoV-2) disease pandemic (COVID-19) has created a new barrier.</li>\u0000 \u0000 <li>The study revealed a high prevalence of dental care refusal (21%), particularly in primary","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"69-77"},"PeriodicalIF":3.0,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Paul Saultier, Michel Grino, Céline Falaise, Sophie Voisin, Cécile Lavenu-Bombled, Manal Ibrahim-Kosta, Audrey Petit, Hélène Boutroux, Dominique Desprez, Mathieu Fiore, Roseline d'Oiron, Marie-Christine Alessi
Background
Platelet transfusion is considered the standard treatment for preventing or controlling severe haemorrhage in Glanzmann thrombasthenia (GT). However, platelet transfusion can have detrimental effects, including the production of anti-GPIIb/IIIa isoantibodies or anti-HLA antibodies (Ab) and platelet transfusion refractoriness. Recombinant activated factor VII (rFVIIa) has been proposed as an alternative treatment to platelet transfusion.
Methods
We analyzed data from 77 case reports including 100 subjects to investigate the effectiveness and safety of rFVIIa in combination with platelets or antifibrinolytics for preventing or treating non-surgical bleeds, as well as surgical and obstetrical procedures in GT.
Results
The dosage of rFVIIa was consistent with previous recommendations (90 µg/kg per infusion). In subjects without Ab/refractoriness (n = 56), rFVIIa was effective in managing 93% of non-surgical bleeds (n = 42), 91% of minor (n = 11) and 92% of major (n = 26) surgical procedures and 89% of obstetrical procedures (n = 9). In subjects with Ab/refractoriness (n = 44), rFVIIa was effective in managing 90% of non-surgical bleeds (n = 39), and 75% of minor (n = 12) and 100% of major (n = 17) surgical procedures. The use of rFVIIa was safe, with 4 (2.7%) serious adverse events associated with rFVIIa.
Conclusion
Although the use of rFVIIa is currently restricted to subjects with Ab/refractoriness or when platelets are not available, our findings suggest expanding the indications for rFVIIa to encompass GT without Ab/refractoriness. Frontline use of rFVIIa may be proposed when clinically possible to mitigate the risks associated with platelet transfusion.
{"title":"Efficacy and safety of recombinant activated factor VII in Glanzmann thrombasthenia: A systematic literature review","authors":"Paul Saultier, Michel Grino, Céline Falaise, Sophie Voisin, Cécile Lavenu-Bombled, Manal Ibrahim-Kosta, Audrey Petit, Hélène Boutroux, Dominique Desprez, Mathieu Fiore, Roseline d'Oiron, Marie-Christine Alessi","doi":"10.1111/hae.15130","DOIUrl":"10.1111/hae.15130","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Platelet transfusion is considered the standard treatment for preventing or controlling severe haemorrhage in Glanzmann thrombasthenia (GT). However, platelet transfusion can have detrimental effects, including the production of anti-GPIIb/IIIa isoantibodies or anti-HLA antibodies (Ab) and platelet transfusion refractoriness. Recombinant activated factor VII (rFVIIa) has been proposed as an alternative treatment to platelet transfusion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed data from 77 case reports including 100 subjects to investigate the effectiveness and safety of rFVIIa in combination with platelets or antifibrinolytics for preventing or treating non-surgical bleeds, as well as surgical and obstetrical procedures in GT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The dosage of rFVIIa was consistent with previous recommendations (90 µg/kg per infusion). In subjects without Ab/refractoriness (<i>n</i> = 56), rFVIIa was effective in managing 93% of non-surgical bleeds (<i>n</i> = 42), 91% of minor (<i>n</i> = 11) and 92% of major (<i>n</i> = 26) surgical procedures and 89% of obstetrical procedures (<i>n</i> = 9). In subjects with Ab/refractoriness (<i>n</i> = 44), rFVIIa was effective in managing 90% of non-surgical bleeds (<i>n</i> = 39), and 75% of minor (<i>n</i> = 12) and 100% of major (<i>n</i> = 17) surgical procedures. The use of rFVIIa was safe, with 4 (2.7%) serious adverse events associated with rFVIIa.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Although the use of rFVIIa is currently restricted to subjects with Ab/refractoriness or when platelets are not available, our findings suggest expanding the indications for rFVIIa to encompass GT without Ab/refractoriness. Frontline use of rFVIIa may be proposed when clinically possible to mitigate the risks associated with platelet transfusion.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"7-15"},"PeriodicalIF":3.0,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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