{"title":"Deceased Donor With Hemophilia A: To Consider or Not for Liver Donation.","authors":"Jagadeesh Menon, Prithviraj Nabi, Naresh Shanmugam, Ashwin Rammohan, Rajesh Rajalingam, Mohamed Rela","doi":"10.1111/hae.15154","DOIUrl":"https://doi.org/10.1111/hae.15154","url":null,"abstract":"","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046413","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}
Kirollos Kamel, Sofia Sardo Infirri, Anne Riddell, Pratima Chowdary, Paul Batty
Background: Acquired haemophilia A (AHA) is an acquired bleeding disorder resulting from autoantibodies against Factor VIII (FVIII). Previous studies have reported differences in FVIII inhibitor kinetics (type I or type II) in AHA compared to severe haemophilia A.
Aim: To characterise inhibitor kinetics in AHA and evaluate the proportions displaying type I, II or indeterminate kinetics.
Methods: Single-centre retrospective study of inhibitor kinetics in adults with AHA. Type I kinetics were defined as linear FVIII inhibition with ≥ 97% FVIII inactivation. Type II kinetics were defined as non-linear kinetics and inability to completely neutralise FVIII. Inhibitor titres were calculated using two methods outlined by the International Council for Standardisation in Haematology.
Results: Baseline samples from 34 patients were included. Fifteen samples (44.1%) exhibited type I kinetics, 16 samples (47.1%) exhibited type II kinetics and 3 (8.8%) were indeterminate. Plateau mean residual FVIII:C was higher for inhibitors displaying type II compared to type I kinetics (18.6 vs. 2.9 IU/dL, p < 0.0001). Non-linear regression using a dose-response curve without categorisation for kinetics type yielded a poor fit (R2 = 38%), which improved with refitting using categories of type I or II kinetics that explained 87% and 85% of the variability. The median difference in inhibitor titre between the two reporting methods was 5% and 15% in the type I and II kinetics groups, respectively.
Conclusion: FVIII autoantibodies demonstrate either type I or type II kinetics. Greater discrepancy in reported inhibitor titres depending on the method used is seen for inhibitors with type II kinetics.
背景：获得性血友病A （AHA）是一种由抗因子VIII （FVIII）自身抗体引起的获得性出血性疾病。先前的研究报道了与严重血友病a相比，AHA中FVIII抑制剂动力学（I型或II型）的差异。目的：表征AHA中抑制剂动力学并评估显示I型，II型或不确定动力学的比例。方法：单中心回顾性研究成人AHA患者抑制剂动力学。I型动力学定义为线性FVIII抑制，FVIII失活≥97%。II型动力学被定义为非线性动力学和无法完全中和FVIII。使用国际血液学标准化理事会概述的两种方法计算抑制剂滴度。结果：纳入了34例患者的基线样本。15个样品（44.1%）表现为I型动力学，16个样品（47.1%）表现为II型动力学，3个样品（8.8%）不确定。II型抑制剂的平台平均残余FVIII:C比I型抑制剂高（18.6 vs 2.9 IU/dL, p < 0.0001）。使用没有对动力学类型进行分类的剂量-反应曲线的非线性回归产生了较差的拟合（R2 = 38%），使用I型或II型动力学类别进行改装，可以解释87%和85%的变异性，从而改善了拟合效果。在I型和II型动力学组中，两种报告方法之间抑制剂滴度的中位数差异分别为5%和15%。结论：FVIII自身抗体表现为I型或II型动力学。对于II型动力学抑制剂，根据所使用的方法，报告的抑制剂滴度差异更大。
{"title":"Factor VIII Antibodies Demonstrate Type I or Type II Kinetics in Acquired Haemophilia A.","authors":"Kirollos Kamel, Sofia Sardo Infirri, Anne Riddell, Pratima Chowdary, Paul Batty","doi":"10.1111/hae.15144","DOIUrl":"https://doi.org/10.1111/hae.15144","url":null,"abstract":"<p><strong>Background: </strong>Acquired haemophilia A (AHA) is an acquired bleeding disorder resulting from autoantibodies against Factor VIII (FVIII). Previous studies have reported differences in FVIII inhibitor kinetics (type I or type II) in AHA compared to severe haemophilia A.</p><p><strong>Aim: </strong>To characterise inhibitor kinetics in AHA and evaluate the proportions displaying type I, II or indeterminate kinetics.</p><p><strong>Methods: </strong>Single-centre retrospective study of inhibitor kinetics in adults with AHA. Type I kinetics were defined as linear FVIII inhibition with ≥ 97% FVIII inactivation. Type II kinetics were defined as non-linear kinetics and inability to completely neutralise FVIII. Inhibitor titres were calculated using two methods outlined by the International Council for Standardisation in Haematology.</p><p><strong>Results: </strong>Baseline samples from 34 patients were included. Fifteen samples (44.1%) exhibited type I kinetics, 16 samples (47.1%) exhibited type II kinetics and 3 (8.8%) were indeterminate. Plateau mean residual FVIII:C was higher for inhibitors displaying type II compared to type I kinetics (18.6 vs. 2.9 IU/dL, p < 0.0001). Non-linear regression using a dose-response curve without categorisation for kinetics type yielded a poor fit (R<sup>2</sup> = 38%), which improved with refitting using categories of type I or II kinetics that explained 87% and 85% of the variability. The median difference in inhibitor titre between the two reporting methods was 5% and 15% in the type I and II kinetics groups, respectively.</p><p><strong>Conclusion: </strong>FVIII autoantibodies demonstrate either type I or type II kinetics. Greater discrepancy in reported inhibitor titres depending on the method used is seen for inhibitors with type II kinetics.</p>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983208","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}
Subcutaneous emicizumab, a factor VIII (FVIII)-mimicking bispecific monoclonal antibody, can effectively prevent bleeds in haemophilia A (HA) patients with/without inhibitors; however, its standard-dose regimens are financially burdensome. Low-dose emicizumab prophylaxis may alternatively be applied to noninhibitor HA patients in resource-limited settings.
Methods
During 2023, Thai patients with noninhibitor severe HA or moderate HA with severe bleeding phenotype (historical annualized bleeding rate [ABR] >5 bleeds/year before regular FVIII prophylaxis) who received low-/intermediate-dose FVIII secondary prophylaxis ≥8 months were enrolled. After the 4-day washout period, low-dose emicizumab prophylaxis (2.0–2.5 mg/kg every fortnight for two loading doses, then every 4 weeks) was implemented for 8 months. Pre-/post-emicizumab ABR, annualized joint bleeding rates (AJBR), haemophilia joint health scores (HJHS) and haemophilia-specific quality-of-life (QoL) scores were analysed. Emicizumab plasma levels on modified one-stage FVIII assays were also monitored.
Results
In 15 subjects, ABR (median of differences, −2 bleeds/year; interquartile range, −3 to 0; p = 0.002), but not AJBR (p = 0.07), were reduced after switching to low-dose emicizumab prophylaxis, although the pre-dose emicizumab plasma levels at the steady state, achieved since week 12, were modest (median monthly level, 8.4 µg/mL; interquartile range, 4.3–10.4). Concurrently, HJHS (p = 0.008) and QoL score (p < 0.001) were decreased, and 46.7% had zero bleeds while receiving low-dose emicizumab.
Conclusions
Low-dose emicizumab, compared to low-/intermediate-dose FVIII secondary prophylaxis, meaningfully improves bleeding prevention, joint health and QoL in patients with noninhibitor severe HA or moderate HA with severe bleeding phenotype. This regimen potentially helps address previously unmet needs in HA care among low-to-middle-income countries.
{"title":"Low-Dose Emicizumab Versus Low-/Intermediate-Dose Factor VIII Secondary Prophylaxis for Noninhibitor Haemophilia A Patients With Severe Bleeding Phenotype","authors":"Nuchanun Kessakorn, Itsaraet Gosriwatana, Nuttarak Sasipong, Chonlatis Srichumpuang, Chatphatai Moonla, Darintr Sosothikul","doi":"10.1111/hae.15146","DOIUrl":"10.1111/hae.15146","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Subcutaneous emicizumab, a factor VIII (FVIII)-mimicking bispecific monoclonal antibody, can effectively prevent bleeds in haemophilia A (HA) patients with/without inhibitors; however, its standard-dose regimens are financially burdensome. Low-dose emicizumab prophylaxis may alternatively be applied to noninhibitor HA patients in resource-limited settings.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>During 2023, Thai patients with noninhibitor severe HA or moderate HA with severe bleeding phenotype (historical annualized bleeding rate [ABR] >5 bleeds/year before regular FVIII prophylaxis) who received low-/intermediate-dose FVIII secondary prophylaxis ≥8 months were enrolled. After the 4-day washout period, low-dose emicizumab prophylaxis (2.0–2.5 mg/kg every fortnight for two loading doses, then every 4 weeks) was implemented for 8 months. Pre-/post-emicizumab ABR, annualized joint bleeding rates (AJBR), haemophilia joint health scores (HJHS) and haemophilia-specific quality-of-life (QoL) scores were analysed. Emicizumab plasma levels on modified one-stage FVIII assays were also monitored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In 15 subjects, ABR (median of differences, −2 bleeds/year; interquartile range, −3 to 0; <i>p</i> = 0.002), but not AJBR (<i>p</i> = 0.07), were reduced after switching to low-dose emicizumab prophylaxis, although the pre-dose emicizumab plasma levels at the steady state, achieved since week 12, were modest (median monthly level, 8.4 µg/mL; interquartile range, 4.3–10.4). Concurrently, HJHS (<i>p</i> = 0.008) and QoL score (<i>p </i>< 0.001) were decreased, and 46.7% had zero bleeds while receiving low-dose emicizumab.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Low-dose emicizumab, compared to low-/intermediate-dose FVIII secondary prophylaxis, meaningfully improves bleeding prevention, joint health and QoL in patients with noninhibitor severe HA or moderate HA with severe bleeding phenotype. This regimen potentially helps address previously unmet needs in HA care among low-to-middle-income countries.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registration</h3>\u0000 \u0000 <p>ClinicalTrials.gov identifier NCT06155955.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"122-131"},"PeriodicalIF":3.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907093","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}
{"title":"Successful Orthopaedic Surgeries With World Federation of Haemophilia Humanitarian Aid Program in Resource-Limited Settings","authors":"Rema Ganapathi, Neeraj Sidharthan, Jecko Thachil","doi":"10.1111/hae.15141","DOIUrl":"10.1111/hae.15141","url":null,"abstract":"","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"162-165"},"PeriodicalIF":3.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907102","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}
Shrimati Shetty, Cecil Ross, M. Joseph John, Shrinath Kshirsagar, Nimish Kulkarni, D. S. Pavitra, Diksha Sarwan, P. K. Misha, Antony Paul, Apurva More, Nazish Kaunchale, Magdalene D'silva, Shrushti Masurkar, Shruti Kharat, Kranti Patil, Shalaka Patel, Priti Mehendale, Prachi Sarvaiya, Savita Rangarajan
Introduction
Mortality and morbidity in persons with haemophilia (PWH) have decreased due to improved diagnosis and treatment along with comprehensive population outreach efforts, but the impact is not uniform in different countries.
Aim
The study aims to assess all-cause and intracranial haemorrhage (ICH)-specific mortality of PWH in India.
Methods
This is a retrospective, observational, multi-centric cohort study of 1020 haemophilia patients from three centres in India. The mortality data in the family was collected from personal interviews, and subsequently confirmed with the corresponding haemophilia treatment centres (HTCs). The demographic and clinical data, along with other comorbidities, were collected from the medical records.
Results
Among 170 reported deaths, 73 (42.9%) were caused by ICH, and 44 (25.9%) resulted from accidents or trauma. Gastrointestinal (GI) bleeding was the third most common cause of death, accounting for 27 cases (15.9%). The average and median ages at death were 27.7 and 26 years, respectively. None of the deceased cases were receiving any prophylactic or immune tolerance induction (ITI) therapy, and all had severe haemophilia. In addition, the prevalence of inhibitors and hypertension was significantly higher in deceased cases compared to that in the general haemophilia population (p < 0.05).
Conclusion
Severity of haemophilia, episodic treatment, hypertension and inhibitors showed significant association with mortality. ICH continues to be the leading cause of death among haemophilia patients in the country. This underscores the challenges in managing haemophilia and the need for improved treatment strategies to increase the life expectancy of PWH.
{"title":"Mortality in Haemophilia Patients in India: A National Cohort Study","authors":"Shrimati Shetty, Cecil Ross, M. Joseph John, Shrinath Kshirsagar, Nimish Kulkarni, D. S. Pavitra, Diksha Sarwan, P. K. Misha, Antony Paul, Apurva More, Nazish Kaunchale, Magdalene D'silva, Shrushti Masurkar, Shruti Kharat, Kranti Patil, Shalaka Patel, Priti Mehendale, Prachi Sarvaiya, Savita Rangarajan","doi":"10.1111/hae.15143","DOIUrl":"10.1111/hae.15143","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Mortality and morbidity in persons with haemophilia (PWH) have decreased due to improved diagnosis and treatment along with comprehensive population outreach efforts, but the impact is not uniform in different countries.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The study aims to assess all-cause and intracranial haemorrhage (ICH)-specific mortality of PWH in India.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This is a retrospective, observational, multi-centric cohort study of 1020 haemophilia patients from three centres in India. The mortality data in the family was collected from personal interviews, and subsequently confirmed with the corresponding haemophilia treatment centres (HTCs). The demographic and clinical data, along with other comorbidities, were collected from the medical records.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among 170 reported deaths, 73 (42.9%) were caused by ICH, and 44 (25.9%) resulted from accidents or trauma. Gastrointestinal (GI) bleeding was the third most common cause of death, accounting for 27 cases (15.9%). The average and median ages at death were 27.7 and 26 years, respectively. None of the deceased cases were receiving any prophylactic or immune tolerance induction (ITI) therapy, and all had severe haemophilia. In addition, the prevalence of inhibitors and hypertension was significantly higher in deceased cases compared to that in the general haemophilia population (<i>p</i> < 0.05).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Severity of haemophilia, episodic treatment, hypertension and inhibitors showed significant association with mortality. ICH continues to be the leading cause of death among haemophilia patients in the country. This underscores the challenges in managing haemophilia and the need for improved treatment strategies to increase the life expectancy of PWH.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"132-139"},"PeriodicalIF":3.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907099","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}
Chelsea Howie, Hannah Cameron, Mandy Bouchard, Victoria Price, Nancy L. Young, Meghan Pike
Aim
Heavy menstrual bleeding (HMB) affects up to 37% of adolescents. Given the paucity of available tools to assess health-related quality of life (HRQoL) in adolescents with HMB, we developed the adolescent menstrual bleeding questionnaire (aMBQ), a valid and reliable measure of bleeding-related quality of life. The aim of this study was cross-cultural translation and adaptation of the English aMBQ into French to ensure accessibility for more Canadian adolescents who menstruate.
Methods
A five-step process was followed: (1) forward translation from English to Canadian French; (2) backward translation from French to English; (3) review of source and translated aMBQ to create a reconciled version; (4) cognitive debriefing to ensure linguistic and clinical equivalence and (5) review of cognitive debriefings to produce the final version of the French aMBQ. Results of cognitive debriefings were reviewed after every three participants; items were revised if presented as an issue by ≥2 participants. These changes were implemented and tested in cognitive debriefings until saturation was reached.
Results
Linguistic changes were made to nine (33%) of the questions and one (3.7%) answer options. Major changes were made to four of the 27 questions (15%), and minor changes were made to five of the 27 questions (19%).
Conclusion
Professional translators, clinical experts and patient input through cognitive debriefing are pivotal to successful cross-cultural translation. Results of cognitive debriefing interviews suggest the French aMBQ is easily understood and confirms its face validity.
{"title":"Cross-Cultural Translation of the Adolescent Menstrual Bleeding Questionnaire (AMBQ)","authors":"Chelsea Howie, Hannah Cameron, Mandy Bouchard, Victoria Price, Nancy L. Young, Meghan Pike","doi":"10.1111/hae.15145","DOIUrl":"10.1111/hae.15145","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Heavy menstrual bleeding (HMB) affects up to 37% of adolescents. Given the paucity of available tools to assess health-related quality of life (HRQoL) in adolescents with HMB, we developed the adolescent menstrual bleeding questionnaire (aMBQ), a valid and reliable measure of bleeding-related quality of life. The aim of this study was cross-cultural translation and adaptation of the English aMBQ into French to ensure accessibility for more Canadian adolescents who menstruate.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A five-step process was followed: (1) forward translation from English to Canadian French; (2) backward translation from French to English; (3) review of source and translated aMBQ to create a reconciled version; (4) cognitive debriefing to ensure linguistic and clinical equivalence and (5) review of cognitive debriefings to produce the final version of the French aMBQ. Results of cognitive debriefings were reviewed after every three participants; items were revised if presented as an issue by ≥2 participants. These changes were implemented and tested in cognitive debriefings until saturation was reached.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Linguistic changes were made to nine (33%) of the questions and one (3.7%) answer options. Major changes were made to four of the 27 questions (15%), and minor changes were made to five of the 27 questions (19%).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Professional translators, clinical experts and patient input through cognitive debriefing are pivotal to successful cross-cultural translation. Results of cognitive debriefing interviews suggest the French aMBQ is easily understood and confirms its face validity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"118-121"},"PeriodicalIF":3.0,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881884","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}
Callie Berkowitz, Kristy Lee, Kristi Kirkland, Brenda Nielsen, Patrick Ellsworth, Alice Ma, Nigel S. Key
{"title":"Research Letter: Patient Attitudes Towards Haemophilia Gene Therapy at a US Haemophilia Treatment Center","authors":"Callie Berkowitz, Kristy Lee, Kristi Kirkland, Brenda Nielsen, Patrick Ellsworth, Alice Ma, Nigel S. Key","doi":"10.1111/hae.15139","DOIUrl":"10.1111/hae.15139","url":null,"abstract":"","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"166-168"},"PeriodicalIF":3.0,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881927","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}
John Chapin, Maria Teresa Álvarez Román, Mila Ayash-Rashkovsky, Dorothee Diogo, Jon Kenniston, Francisco-Jose Lopez-Jaime, Caterina Maggiore, María-Eva Mingot-Castellano, Kavitha Rajavel, Antoine Rauch, Sophie Susen, Marcin von Grotthuss, Matt Wagoner, Qin Wang
Introduction
Haemophilia A is an X-linked bleeding disorder resulting from a deficiency of factor VIII (FVIII). To date, multiple gene therapies have entered clinical trials with the goal of providing durable haemostatic protection from a single dose. TAK 754 (BAX 888) is an investigational AAV8-based gene therapy containing a FVIII transgene. Reduction in CpG motifs was performed to reduce immunogenicity based on prior observations. Here, we describe the results of the first two cohorts treated with TAK 754.
Aim
To report clinical and translational results of the TAK-754 phase 1/2 AAV gene therapy study for the treatment of haemophilia A.
Methods
A phase 1/2 single arm open-label dose escalation study of TAK-754 was performed in participants with severe haemophilia A (NCT03370172). Participants were monitored for safety events, endogenous FVIII activity and bleeding rates. Glucocorticoids were implemented to preserve transgene expression. A transcriptomics analysis was performed to evaluate immunogenicity along with additional post-hoc analyses.
Results
Four participants were dosed in two cohorts. Infusion of TAK 754 was well-tolerated. All participants developed mild transient transaminase elevation and subsequent loss of FVIII expression within the first 12 months of treatment despite use of glucocorticoids. Transcriptomic analysis did not demonstrate significant changes in immunogenicity signals in peripheral blood. One serious adverse event of hypophosphatemia occurred in the second cohort without obvious risk factors.
Conclusions
Sustained FVIII expression remains a challenge in haemophilia A AAV gene therapy trials. Mechanisms of transgene expression loss require further study as clinical studies enter long term follow-up periods.
{"title":"A phase 1/2 safety and efficacy study of TAK-754 gene therapy: The challenge of achieving durable factor VIII expression in haemophilia A clinical trials","authors":"John Chapin, Maria Teresa Álvarez Román, Mila Ayash-Rashkovsky, Dorothee Diogo, Jon Kenniston, Francisco-Jose Lopez-Jaime, Caterina Maggiore, María-Eva Mingot-Castellano, Kavitha Rajavel, Antoine Rauch, Sophie Susen, Marcin von Grotthuss, Matt Wagoner, Qin Wang","doi":"10.1111/hae.15121","DOIUrl":"10.1111/hae.15121","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Haemophilia A is an X-linked bleeding disorder resulting from a deficiency of factor VIII (FVIII). To date, multiple gene therapies have entered clinical trials with the goal of providing durable haemostatic protection from a single dose. TAK 754 (BAX 888) is an investigational AAV8-based gene therapy containing a FVIII transgene. Reduction in CpG motifs was performed to reduce immunogenicity based on prior observations. Here, we describe the results of the first two cohorts treated with TAK 754.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To report clinical and translational results of the TAK-754 phase 1/2 AAV gene therapy study for the treatment of haemophilia A.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A phase 1/2 single arm open-label dose escalation study of TAK-754 was performed in participants with severe haemophilia A (NCT03370172). Participants were monitored for safety events, endogenous FVIII activity and bleeding rates. Glucocorticoids were implemented to preserve transgene expression. A transcriptomics analysis was performed to evaluate immunogenicity along with additional post-hoc analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Four participants were dosed in two cohorts. Infusion of TAK 754 was well-tolerated. All participants developed mild transient transaminase elevation and subsequent loss of FVIII expression within the first 12 months of treatment despite use of glucocorticoids. Transcriptomic analysis did not demonstrate significant changes in immunogenicity signals in peripheral blood. One serious adverse event of hypophosphatemia occurred in the second cohort without obvious risk factors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Sustained FVIII expression remains a challenge in haemophilia A AAV gene therapy trials. Mechanisms of transgene expression loss require further study as clinical studies enter long term follow-up periods.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"108-117"},"PeriodicalIF":3.0,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881880","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}
Physical therapy benefits patients with haemophilia (PWH), but its impact on the health-related quality of life (HRQOL) remains unclear.
Aim
This systematic review and meta-analysis investigated the association of physical therapy, including therapeutic exercise, manual therapy, and physical agent modality, with HRQOL improvement in PWH.
Methods
Databases PubMed, Embase, MEDLINE, and Scopus were searched from inception until April 2024. This review included randomised controlled trials (RCTs) that compare the HRQOL between the physical therapy and control groups. Relevant data and outcome values of included study were collected. Cochrane collaboration's tool and the grading of recommendations, assessment, development, and evaluation approach were used for risk of bias (ROB) and evidence-level assessment, individually.
Results
The systematic review included eight RCTs that involved 298 male PWH. The meta-analysis for HRQOL improvement revealed a significant difference in favour of physical therapy (standardised mean difference [SMD] = .92; 95% confidence interval [CI]:.50–1.33; p < .001). Therapeutic exercise exhibited more benefits in HRQOL improvement than the control groups (SMD = 1.02; 95% CI:.49–1.55; p < .001). Physical therapy effectively improved HRQOL in PWH with better joint status (SMD = 1.74; 95% CI:.97–2.51; p < .001). Of the eight RCTs, six were rated as high ROB. The comparisons revealed a moderate certainty of evidence.
Conclusions
Physical therapy, especially therapeutic exercise, effectively improved the HRQOL of PWH. Maintaining better joint status and timely physical therapy intervention is crucial for HRQOL improvements in PWH. Cautious interpretation is required due to evidence limitations.
{"title":"Effects of physical therapy on health-related quality of life in patients with haemophilia: A systematic review and meta-analysis","authors":"Chien-Min Chen, Shang-Lin Liu, Mu-Ching Shie","doi":"10.1111/hae.15120","DOIUrl":"10.1111/hae.15120","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Physical therapy benefits patients with haemophilia (PWH), but its impact on the health-related quality of life (HRQOL) remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>This systematic review and meta-analysis investigated the association of physical therapy, including therapeutic exercise, manual therapy, and physical agent modality, with HRQOL improvement in PWH.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Databases PubMed, Embase, MEDLINE, and Scopus were searched from inception until April 2024. This review included randomised controlled trials (RCTs) that compare the HRQOL between the physical therapy and control groups. Relevant data and outcome values of included study were collected. Cochrane collaboration's tool and the grading of recommendations, assessment, development, and evaluation approach were used for risk of bias (ROB) and evidence-level assessment, individually.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The systematic review included eight RCTs that involved 298 male PWH. The meta-analysis for HRQOL improvement revealed a significant difference in favour of physical therapy (standardised mean difference [SMD] = .92; 95% confidence interval [CI]:.50–1.33; <i>p</i> < .001). Therapeutic exercise exhibited more benefits in HRQOL improvement than the control groups (SMD = 1.02; 95% CI:.49–1.55; <i>p</i> < .001). Physical therapy effectively improved HRQOL in PWH with better joint status (SMD = 1.74; 95% CI:.97–2.51; <i>p</i> < .001). Of the eight RCTs, six were rated as high ROB. The comparisons revealed a moderate certainty of evidence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Physical therapy, especially therapeutic exercise, effectively improved the HRQOL of PWH. Maintaining better joint status and timely physical therapy intervention is crucial for HRQOL improvements in PWH. Cautious interpretation is required due to evidence limitations.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"16-25"},"PeriodicalIF":3.0,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881855","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}
Behnaz Pezeshkpoor, Ronald Fischer, Barbara Preisler, Katrin Hartlieb, Heiko Rühl, Jens Müller, Silvia Horneff, Natascha Marquardt, Anna Pavlova, Johannes Oldenburg
Introduction
Maintaining the balance between procoagulant and anticoagulant factors is essential for effective haemostasis. Emerging evidence suggests a modulation of bleeding tendency by factors in the anticoagulant and fibrinolytic systems.
Aim
This study investigates the clinical and laboratory characteristics of a family with combined von Willebrand disease (VWD) and antithrombin (AT) deficiency.
Methods
The study focused on a 38-year-old female index patient (IP) with severe type 3 VWD and a history of bleeding disorders. Coagulation assays included VWF antigen, platelet-dependent VWF activity, factor VIII activity, thrombin generation assay (TGA) and AT activity. Molecular genetic analyses were conducted by a targeted DNA custom next generation sequencing (NGS) panel.
Results
The IP and one of her sisters suffered type 3 VWD. While the IP presents with a classical severe bleeding phenotype, the sister (II-2) exhibited less severe bleeding symptoms. Extended family members showed type 1 VWD with mild presentations. NGS revealed a homozygous deletion of exon 6 in the VWF gene in the IP and her sister (II-2). All other family members carry this genetic variant in a heterozygous state. Additionally, II-2 has a heterozygous variant in the SERPINC1 gene (c.133C>T, p.Arg45Trp). Both IP and II-2 carry a homozygous prothrombin G20210A variant. TGA results indicated reduced thrombin generation in severe VWD patients, with a pronounced thrombin burst in those with the AT and prothrombin G20210A variant.
Conclusions
AT deficiency appears to modulate bleeding symptoms in severe VWD. This study emphasizes the importance of comprehensive genetic and phenotypic evaluation in managing complex coagulation disorders.
{"title":"Modulation of Haemostatic Balance in Combined von Willebrand Disease and Antithrombin Deficiency: A Comprehensive Family Study","authors":"Behnaz Pezeshkpoor, Ronald Fischer, Barbara Preisler, Katrin Hartlieb, Heiko Rühl, Jens Müller, Silvia Horneff, Natascha Marquardt, Anna Pavlova, Johannes Oldenburg","doi":"10.1111/hae.15147","DOIUrl":"10.1111/hae.15147","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Maintaining the balance between procoagulant and anticoagulant factors is essential for effective haemostasis. Emerging evidence suggests a modulation of bleeding tendency by factors in the anticoagulant and fibrinolytic systems.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>This study investigates the clinical and laboratory characteristics of a family with combined von Willebrand disease (VWD) and antithrombin (AT) deficiency.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The study focused on a 38-year-old female index patient (IP) with severe type 3 VWD and a history of bleeding disorders. Coagulation assays included VWF antigen, platelet-dependent VWF activity, factor VIII activity, thrombin generation assay (TGA) and AT activity. Molecular genetic analyses were conducted by a targeted DNA custom next generation sequencing (NGS) panel.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The IP and one of her sisters suffered type 3 VWD. While the IP presents with a classical severe bleeding phenotype, the sister (II-2) exhibited less severe bleeding symptoms. Extended family members showed type 1 VWD with mild presentations. NGS revealed a homozygous deletion of exon 6 in the <i>VWF</i> gene in the IP and her sister (II-2). All other family members carry this genetic variant in a heterozygous state. Additionally, II-2 has a heterozygous variant in the <i>SERPINC1</i> gene (c.133C>T, p.Arg45Trp). Both IP and II-2 carry a homozygous prothrombin G20210A variant. TGA results indicated reduced thrombin generation in severe VWD patients, with a pronounced thrombin burst in those with the AT and prothrombin G20210A variant.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>AT deficiency appears to modulate bleeding symptoms in severe VWD. This study emphasizes the importance of comprehensive genetic and phenotypic evaluation in managing complex coagulation disorders.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12819,"journal":{"name":"Haemophilia","volume":"31 1","pages":"140-147"},"PeriodicalIF":3.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853630","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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