Haemophilia Outcomes Research Articles

Outcomes In Adult Hemophilia and Von Willebrand Disease Patients Undergoing Surgical and Invasive Procedures

IntroductionAdults with hemophilia and von Willebrand disease (VWD) frequently require surgical and invasive procedures. There is variability in current practice of peri-operative management in major surgery and in the management of invasive procedures. The purpose of this study was to evaluate outcomes and management strategies in patients with hemophilia and VWD undergoing surgical and invasive procedures in a comprehensive hemophilia center at a tertiary care hospital. MethodsA retrospective review of electronic medical records was carried out from patients with hemophilia and VWD seen at the Weill Cornell Hemophilia Treatment Center undergoing surgery or an invasive procedure from January 2006 to December 2012. Information on demographics, diagnosis, severity, and presence of inhibitors was also collected.Procedures and treatment strategies were reviewed including the type of procedure, use of factor bolus/DDAVP, continuous infusion(CI), and antifibrinolytics. Outcomes from these cases were reviewed for acute bleeding (<48 hours after procedure), delayed bleeding (>48 hours after procedure), transfusion of blood products, inhibitor development, and post-procedure thrombosis. Data were compared using Fischer's exact test. ResultsOur study population consisted of 59 patients (mean age=58, range 21-77). Our hemophilia group included 41 with hemophilia A and 7 with hemophilia B. Our hemophilia patients were severe (n=24), mild-mod (n=12), and 12 had inhibitors. We also identified 5 female carriers of hemophilia A.We identified 6 VWD patients including Type 1 (n=3), 2A (n=1), 3 (n=2). We reviewed 34 major surgeries (26 orthopedic, 8 non-orthopedic) and 91 invasive procedures. We covered all patients an initial dose of either factor VIII/IX or DDAVP. In addition, 55.9% of major procedures were covered by continuous factor infusion (CI), whereas only 9.9% of minor procedures were covered by CI. Conversely, antifibrinolytics were used in 14.7% of major surgeries and 34.1% of minor procedures. Antifibrinolytics were used in all types of minor procedures except those involving the genitourinary tract.Hematologic outcomes are shown in Table 1. We identified 4 cases of acute bleeding and 10 cases of delayed bleeding. We also identified 5 cases of inhibitor development. We identified one thrombotic episode in an orthopedic surgery case. We further examined several classes of procedures including dental, GI endoscopies, GU procedures, biopsies, and GYN procedures in carriers. One transfusion was needed in the case of a liver biopsy; acute bleeding was noted in 2 biopsies and 1 endoscopy. Delayed bleeding accompanied 28.6% of GU procedures and 16.1% of dental procedures. Inhibitor development was noted after 1 GU procedure and 2 dental procedures.MAJORMINORSurgical OutcomeOrthopedic SurgeryNon-orthopedic SurgeryDentalGI EndoGU ProcBxGYNN268311714245Transfusion1000010Acute bleeding1001020Delayed bleeding0050410Inhibitor development2020100Thrombosis1000000Treatment UseBolus268291313226Continuous infusion16325011Antifibrinolytics41243021Surgical OutcomeAll Major SurgeriesAll minor proceduresP-ValueN3491Transfusion11P=0.47Acute bleeding13P=0.99Delayed bleeding010P=0.06Inhibitor development23P=0.62Thrombosis10P=0.27 ConclusionsOur adult hemophilia and VWD population undergoing minor procedures showed similar rates of adverse hematologic outcomes compared to major surgery. This finding highlights the significant risk of even minor procedures in adults with bleeding disorders. Appropriate treatment standards should be designed to take into account patient responses, procedure type, and anticipated outcomes. Disclosures:No relevant conflicts of interest to declare.

Treatment for life for severe Haemophilia A: a cost-utility model

Introduction. Prophylaxis has been established as the treatment of choice in children with haemophilia and its continuation into the adult years has been shown to decrease morbidity throughout life. The cost of factor therapy has made the option questionable in costeffectiveness studies. Aim. The role of prophylaxis in pharmacokinetic dosage and tolerisation against inhibitor formation were used to model the cost-utility of prophylaxis versus on-demand (OD) therapy over a lifetime horizon in severe haemophilia A. Methods. Commercial software (TreeAgeTM) was used to construct a Markov model with 80 cycles of one year each. The model was populated with variables for costs and effectiveness for haemophilia outcomes including joint and soft tissue bleeds, inhibitors and dosage. Key inputs into the model which differed from previous exercises included the use of pharmacokinetic dosage and effect of prophylaxis on the probability of developing inhibitors.The model was applied to a single provider national health system exemplified by the United Kingdom’s National Health Service and a third party provider in the United States. The incremental cost effectiveness ratio was (ICER) was estimated and compared to threshold values used by payer agencies to guide reimbursement decisions. A cost per quality adjusted life year (QALY) was also estimated for Sweden. Results. Applying a bidiurnal dosage regimen and using the early tolerisation protocol of Kurnik et al (Haemophilia. 2010;16(2):256–62),prophylaxis was shown to be more effective and less costly (dominant) relative to OD treatment in the UK. In the USA, the model resulted in an ICER $68,000, which is within the range of treatments reimbursed by third party payers in that country.In Sweden, a cost/QALY of SEK 1.1 million was also within the range of reimbursed treatments in that country, and prophylaxis was dominant over OD treatment when daily dosage was applied. Sensitivity analysis showed that dosage and treatment-induced inhibitor incidence were the most important variables in the model. Conclusion. Subject to continuing clinical evidence of the effectiveness of pharmacokinetic dosage and the role of prophylaxis in decreasing inhibitor incidence, treatment for life with prophylaxis is a cost-effective therapy, using current criteria for the reimbursement of health care technologies in a number of countries.

Process and experience of cross-cultural adaptation of a quality of life measure (CHO-KLAT) for boys with haemophilia in Brazil

Health-related quality of life (HRQoL) is an important outcome from the perspective of boys with haemophilia and their parents. Few studies have captured the HRQoL of boys with haemophilia in developing countries. This article reports on the cross-cultural adaptation of the Canadian Haemophilia Outcomes - Kids Life Assessment Tool (CHO-KLAT) for use in São Paulo, Brazil. The CHO-KLAT(2.0) was translated into Portuguese, and then translated back into English. The original English and back-translation versions were compared by a group of three clinicians, whose first language was Portuguese. The resulting Portuguese version was assessed through a series of cognitive debriefing interviews with children and their parents. This process identified concepts that were not clear and revised items to ensure appropriate understanding through an iterative process. The initial back-translation was not discrepant from the original English version. We made changes to 66% of the CHO-KLAT(2.0) items based on clinical expert review and 26% of the items based on cognitive debriefings. In addition, two new items were added to the final Portuguese version to reflect the local cultural context. The final result had good face validity. This process was found to be extremely valuable in ensuring the items were accurately interpreted by the boys/parents in São Paulo Brazil. The results suggest that professional translators, clinical experts and cognitive debriefing are all required to achieve a culturally appropriate instrument. The Portuguese CHO-KLAT(2.0) is well understood by Sao Paulo boys/parents. The next step will be to test its validity and reliability locally.

Updating the Canadian Hemophilia Outcomes–Kids Life Assessment Tool (CHO-KLAT Version2.0)

ObjectivesHemophilia is an X-chromosome–linked disorder associated with recurrent bleeding into muscles and joints, leading to pain and limitations in physical function that may diminish quality of life. The Canadian Hemophilia Outcomes–Kids Life Assessment Tool (CHO-KLAT) is a disease-specific measure of quality of life that was recently revised to facilitate cross-cultural adaptation. This study assessed the validity and reliability of version 2.0 of the CHO-KLAT (CHO-KLAT2.0). MethodsContent validity was assessed via detailed cognitive debriefing to confirm that Canadian boys understood the CHO-KLAT2.0. The measurement properties of the CHO-KLAT2.0 were assessed in comparison to those of the PedsQL, the Haemo-QoL, and two global ratings. Most children completed the CHO-KLAT2.0 a second time to assess test-retest reliability. ResultsCognitive debriefing was completed with 12 boys (age 8.6–17.8 years) and 9 of their parents and resulted in no substantive changes. Sixty boys (mean age 11.8 years) participated in the validation phase, which showed a mean CHO-KLAT2.0 score of 75.4±12.0, strong correlations with the PedsQL (r = 0.62, P<0.001) and Haemo-QoL (r = 0.64, P<0.001), and moderate correlations with global ratings of hemophilia bother (ρ =−0.39, P = 0.002) and health (ρ =−0.47, P = 0.0002). Test-retest concordance was better among parents (0.79) than among boys (0.63). ConclusionsThis study establishes the measurement properties of the CHO-KLAT2.0. The summary scores are very similar to those from the original development study, and thus, these have not been affected by the revisions. These results provide reference standards for comparing data from other countries to the Canadian experience and to estimate sample sizes for future clinical trials.

Outcome in moderate haemophilia: back to the past? Remarks on haemophilia A classification and treatment.

Prophylaxis in haemophilia is now considered the standard treatment in developed countries for children with severe haemophilia (factor deficiency <1 IU/dL) and Uijl et al.1 in this issue of Blood Transfusion highlight the possibility that such an approach might also be applied to a subgroup of patients with moderate factor deficiency (factor level 1–5 IU/dL), but with an apparent more severe clinical phenotype. Two randomised controlled trials have been independently published in the last few years, demonstrating the advantages of prophylaxis compared to on demand treatment in patients with severe factor deficiency2,3. Furthermore the World Federation of Haemophilia has recommended prophylaxis as the best treatment for children with haemophilia and has invited national authorities and experts to endorse this treatment in care programmes for people with haemophilia4. Despite several advantages in terms of improved quality of life, reduction of bleeding episodes into the joints and consequently low risk for long-term disabling haemophilic arthropathy, there are some concerns about this strategy, related mainly to the high costs and the difficulty in managing very young children with poor venous access, often making invasive procedures necessary (indwelling central venous catheter, artero-venous fistula) with their inherent associated risks. The study by Uijl et al.1 shows that even patients with moderate disease may bleed frequently and clearly benefit from prophylaxis. However the analysis of these patients raises some concerns. Patients with a factor level of 2 IU/dL (group 2 in the study) had more frequent bleeds, received prophylaxis slightly more frequently, and had greater factor consumption (U/kg/year) than patients belonging to the group with a factor level of 1 IU/dL, who also used less factor VIII than the group with a factor level of 3 IU/dL, which is quite surprising and difficult to explain unless it is related to their older age. Given these results, the target factor level to achieve in patients with moderate deficiency would differ from that of patients with severe deficiency. However the major issue that this paper raises is whether a haemophilia classification based exclusively on plasma FVIII level, as stated by the Scientific and Standardization Committee in 20015, is still useful. Medicine is moving rapidly towards a personalised picture of signs, symptoms and laboratory results to reach a more precise diagnosis and tailored treatment. Haemophilia does not represent an exception and there are already examples of patients with severe factor deficiency, but with few bleeding episodes, often not affecting joints (so-called “mild-severe” patients)6. Thus, it should not be surprising to observe the reverse, i.e. patients with moderate deficiency and a severe clinical picture. The process of coagulation is complex involving mechanisms not completely understood. Other characteristics of the patient (pro-thrombotic polymorphisms, additional mild pro-haemorrhagic deficiencies, etc.) could significantly modify the patients’ bleeding tendency. Furthermore, the recent report of a higher frequency of major surgery in patients with haemophilia B than in those with haemophilia A7 has confirmed a possible difference between two inherited disorders, to date considered to share the same clinical and laboratory features. The more frequent prevalence of missense mutations in haemophilia B, which may produce consistent traces of plasma factor IX, could play a role in fostering better in loco coagulation inside joints than that in patients with severe haemophilia A who largely carry “null” mutations and do not produce any factor at all. To sum up, a more comprehensive definition of severity should probably take into account both phenotype and genotype. The combination of both might help a new classification of haemophilia A severity. Further considerations should be taken into account: in the world nearly 80% of patients with haemophilia do not receive any treatment at all and also in Europe there are relevant differences between per capita factor VIII consumption between western countries (the Netherlands, France, Germany, Italy, etc.) and eastern ones (Poland, Hungary, Czech Republic, etc.). Hence, also in Europe increasing usage of prophylaxis in patients with moderate deficiencies raises ethical issues when a large proportion of patients with severe deficiency does not yet receive the standard, on demand amount of factor for replacement therapy. Finally, a puzzle: in the past, many people dealing with haemophilia in clinical practice considered patients with a factor deficiency <2 IU/dL to have a severe deficiency. Is the “new approach” actually a return to the past?

Incidence, mortality rates and causes of deaths in haemophilia patients in Sweden

Sweden has been a pioneer in the treatment of haemophilia, with the first concentrate available in the 1950s. Treatment has improved over the years to its current state-of-the art. The aim of the current study was to evaluate the long-term outcome of haemophilia in terms of incidence, morbidity and mortality. Patients diagnosed with haemophilia A or B registered at the national haemophilia centres and/or the Patient Registry and born before 2009 and alive in 1968 were enrolled and linked to the Cause of Death-, Migration- and Medical Birth registries. Five age- and sex-matched controls were selected for each patient. A total of 1431 patients with haemophilia A or B were compared with 7150 controls. The 3-year moving average incidence rate per 100,000 population varied between 21 and 36. The hazard ratio for all-cause mortality compared with controls was 2.2, 95% CI: [1.8; 2.7], P < 0.001 for the entire group of patients and 1.7, 95% CI: [1.3; 2.2], P < 0.001 when patients with HIV and/or viral hepatitis were excluded. The corresponding figures for the severe haemophilia subgroup were 6.6, 95% CI: [4.5; 10.0], P < 0.001 and 8.2, 95% CI [3.2; 20.8], P < 0.001 respectively. The most common causes of death were related to malignancies and the haemostatic defect. People with haemophilia were 57% less likely to die from ischaemic heart disease than controls. People with haemophilia in Sweden demonstrate higher mortality over time, independent of HIV and viral hepatitis, despite relatively advantageous access to clotting factor concentrates.

Optimizing joint function: new knowledge and novel tools and treatments

Progressive joint destruction resulting from intra-articular bleeding is the major morbidity affecting patients with haemophilia (PWH), particularly those with inhibitors. Advances in understanding the detrimental processes set in motion by the exposure of joints to bleeding have shaped current management methods. However, to achieve optimal joint health in PWH, in addition to achieving haemostasis at the bleeding vessel, it may be appropriate to explore experimentally other conceptual frameworks. These include the possibilities that markers might help to identify individuals at the risk of more rapid joint deterioration, that clotting factors may have additional local action within tissues, and that outcomes might be improved with therapies that directly address wound healing and inflammation. Joint assessment tools are important. Conventional radiography is frequently used, but given the possibility of subclinical joint bleeds, accurate non-invasive imaging tools are required to detect soft tissue and cartilage changes. Magnetic resonance imaging and ultrasonography can prove valuable here. New imaging techniques should help to increase understanding of the biological basis of early events in haemophilic arthropathy. The optimal way to measure outcomes in haemophilia is to use several methods - in addition to imaging methods, a 360° approach will use physical, functional and quality-of-life instruments. In PWH, inhibitor development complicates treatment of joint bleeds and increases the risk of developing arthropathy. A new therapeutic approach for joint bleeds in inhibitor patients divides treatment into two phases: bleed control, with bypassing agent therapy until bleeding has definitely ceased, followed by regular dosing to prevent rebleeds until synovial recovery is complete.

Determinants of participation in patients with severe haemophilia

The multifactorial nature of disability makes it difficult to point out a specific cause for limitations in participation. The conceptual framework of the WHO-ICF (International Classification of Function, Disability and Health) was used to study the determinants participation in patients with severe haemophilia. Outcome was assessed in a single-centre cohort of 124 patients with severe haemophilia. Joint mobility and muscle strength of the elbows, knees and ankles, in combination with recent X-ray findings (N = 39 only) and the MPQ-DLV pain questionnaire were used to assess Body Functions and Structures. Four performance-based functional tasks and the HAL questionnaire were used to assess Activities. The IPA questionnaire was used to assess Participation. Stepwise and hierarchical regression analysis adjusted for age and psychological health (Dutch-AIMS 2) was used to associate the various domains of the ICF. Irrespective of age, joint mobility was an important factor in explaining self-reported and performance-based activities. Muscle strength had no significant association with participation. Self-reported activities showed a stronger association with participation than performance-based activities. Adjusted for age and psychological health, joint mobility and pain explained none of the variation in participation. Self-reported activities, however, significantly contributed in explaining participation (25%), whereas performance-based activities (3%) did not. This study adds to the knowledge of determinants of participation in haemophilia. As the currently used instruments on joint status and activities only partially explain differences in participation, this aspect of clinical outcome should be included to fully assess outcome in haemophilia.

Tribute: The American Society of Pediatric Hematology/Oncology (ASPHO) 2012 distinguished career award goes to Dr. Victor Blanchette

Tribute: The American Society of Pediatric Hematology/Oncology (ASPHO) 2012 distinguished career award goes to Dr. Victor Blanchette

Cross‐cultural validation of the CHO‐KLAT and HAEMO‐QoL‐A in Canadian French

Multi-site studies are necessary in the field of haemophilia to ensure adequate sample sizes. Quality of life (QoL) instruments need to be harmonized across languages and cultures to facilitate their inclusion. The purpose of this study was to adapt the Canadian Haemophilia Outcomes - Kids Life Assessment Tool (CHO-KLAT(©)) and HAEMO-QoL-A(©) to French for Canada. The CHO-KLAT and the HAEMO-QoL-A are haemophilia-specific measures of QoL for boys and men respectively. Both measures originated in English, were translated into Canadian French by clinicians with expertise in haemophilia care, back-translated by expert translators and harmonized by a multi-disciplinary team. The harmonized versions were evaluated through a cognitive debriefing process with 6 boys with haemophilia, their parents and 10 men with haemophilia. The final versions were validated in a sample of 19 boys with haemophilia, 19 parents, and 22 men with haemophilia along with a generic QoL scale: the PedsQL for children; and the SF-36 for adults. The translation and cognitive debriefing processes resulted in a preliminary version that maintained the intent of the original questions. The validation study estimated the mean score for the child-reported CHO-KLAT at 71.9 (SD 10.4), and the adult-reported HAEMO-QoL-A at 79.1 (SD 21.3). The CHO-KLAT correlated 0.64 with the PedsQL and the HAEMO-QoL-A correlated 0.78 with the SF-36 physical component summary score. The French-Canadian version of the CHO-KLAT and HAEMO-QoL-A are valid. These measures are available for use in multi-site haemophilia trials and clinical practices to capture QoL data from French Canadians.

Joint health and functional ability in children with haemophilia who receive intensive replacement therapy

Joint physical examination is an important outcome in haemophilia; however its relationship with functional ability is not well established in children with intensive replacement therapy. Boys aged 4-16 years were recruited from two European and three North American treatment centres. Joint physical structure and function was measured with the Haemophilia Joint Health Score (HJHS) while functional ability was measured with the revised Childhood Health Assessment Questionnaire (CHAQ₃₈. Two haemophilia-specific domains were created by selecting items of the CHAQ₃₈ that cover haemophilia-specific problems. Associations between CHAQ, HJHS, cumulative number of haemarthroses and age were assessed. A total of 226 subjects - mean 10.8 years old (SD 3.8) - participated; the majority (68%) had severe haemophilia. Most severe patients (91%) were on prophylactic treatment. Lifetime number of haemarthroses [median=5; interquartile range (IQR)=1-12] and total HJHS (median = 5; IQR=1-12) correlated strongly (ρ = 0.51). Total HJHS did not correlate with age and only weakly (ρ=-0.19) with functional ability scores (median=0; IQR=-0.06-0). Overall, haemarthroses were reported most frequently in the ankles. Detailed analysis of ankle joint health scores revealed moderate associations (ρ=0.3-0.5) of strength, gait and atrophy with lower extremity tasks (e.g. stair climbing). In this population, HJHS summating six joints did not perform as well as individual joint scores, however, certain elements of ankle impairment, specifically muscle strength, atrophy and gait associated significantly with functional loss in lower extremity activities. Mild abnormalities in ankle assessment by HJHS may lead to functional loss. Therefore, ankle joints may warrant special attention in the follow up of these children.

Characterization of factor VIII pharmaceutical preparations by means of MudPIT proteomic approach

For a good clinical outcome of Haemophilia A substitutive therapy a detailed characterization of factor VIII (FVIII) concentrates is required, in order to disclose the eventual relations between differently composed concentrates and their biological effects. This preliminary work could be a first step towards a deep structural characterization of FVIII concentrates, using the fast and simply manageable MudPIT technology, which enables the identification and characterization of protein mixtures taking advantage of both the high separation capacity of two-dimensional chromatography and the powerful peptide characterization ability of tandem mass spectrometry. The aim of this study was to evaluate the suitability of for the characterization of FVIII molecule in complex mixtures such its commercial concentrates, both plasma-derived and recombinant, and for the determination of the protein composition of different FVIII preparations. By means of Multidimensional Protein Identification Technology (MudPIT) it was possible to assess the presence of factor VIII in its preparations and to identify most of the contaminant proteins without gel separation. In particular, 125 and 42 proteins were identified in plasma-derived and recombinant concentrates, respectively. Concerning investigation of FVIII, 24 different peptides were identified in plasma-derived corresponding to 7, 29, 27, 19 and 67 of percentage coverage for A1, A2, A3, C1 and C2 domains, respectively. About its multimeric carrier von Willebrand factor (VWF), we have sequenced 42% of domain interacting with A3 and C2 domains of FVIII. Finally, it has been observed that normalized parameters, such as total peptide hits obtained by SEQUEST may be used for evaluation of the relative abundance of FVIII in different preparations.

AHEAD

The clinical picture of haemophilia A patients is often characterised by recurrent bleedings, in particular joint bleeds. Thus far, long-term data on the outcome of haemophilia A patients are scarce as regards the development of target joints, joint replacement, lost days from school or work due to bleedings, and the quality of life, as most previous studies were limited to the aspects of safety and efficacy. The Baxter-initiated AHEAD (Advate in HaEmophilia A outcome Database) study is a multi-centre, prospective, non-interventional observational study of haemophilia A patients. All patients with a residual FVIII activity of £5% who are being treated with ADVATE are eligible. There are no limitations in terms of patient age or treatment regimen. AHEAD is scientifically supported by a renowned interdisciplinary steering board and is intended to yield data on 500 patients in up to 30 haemophilia centres, collected during a period of four years. The large patient population has been chosen in order to ensure a valid database. The objective of the study is to record haemophilia-related arthropathies, which will be defined based on imaging techniques (e. g. MRI, X-ray, ultrasound) and the judgment of the attending physician. In addition, extensive data will be collected on joint replacement surgeries, pseudotumour development, bleeding-related pain, quality of life (age-related questionnaires: Haem-A-QoL, Haemo-QoL, SF10, SF12v2), risk factors (diabetes mellitus, arterial hypertension, nicotine abuse), blood group, gene mutation, physical activity, and on the efficacy and safety of Advate. The patient data will be entered into an electronic CRF system at the centres. Plausibility checks during data entry, regular monitoring visits, and the option of auditing all serve to ensure a high data quality for AHEAD. The first patient was enrolled in the study in early June 2010; recruitment is planned to continue until the end of 2011. The Ethics Committee of the University of Bonn has given its favorable opinion.

Errata

HaemophiliaVolume 15, Issue 2 p. 637-637 Free Access Errata This article corrects the following: Clinical outcome of moderate haemophilia compared with severe and mild haemophilia I. E. M. DEN UIJL, K. FISCHER, J. G. VAN DER BOM, D. E. GROBBEE, F. R. ROSENDAAL, I. PLUG, Volume 15Issue 1Haemophilia pages: 83-90 First Published online: August 17, 2008 First published: 23 March 2009 https://doi.org/10.1111/j.1365-2516.2009.02014_3.xAboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat In Iorio et al. [3], one of the co-authors was omitted from Appendix A. The additional co-author is ‘Roma – Istituto Superiore di Sanità (Jane Hassan)’. References 1 Den Uijl IEM, Fischer K, Van Der Bom JG, Grobbee DE, Rosendaal FR, Plug I. Clinical outcome of moderate haemophilia compared with severe and mild haemophilia. Haemophilia 2009; 15: 83– 90. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 2 Oldenberg J, ZupančićŠalek S. Introduction. Haemophilia 2009; 15(Suppl. 1): 1. Wiley Online LibraryPubMedWeb of Science®Google Scholar 3 Iorio A, Oliovecchio E, Morfini M, Mannucci PM. Italian Registry of Haemophilia and Allied Disorders. Objectives, methodology and data analysis. Haemophilia 2008; 14: 444– 53. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Volume15, Issue2March 2009Pages 637-637 ReferencesRelatedInformation

Errata

HaemophiliaVolume 15, Issue 2 p. 637-637 Free Access Errata This article corrects the following: INTRODUCTORY NOTE J. OLDENBURG, S. ZUPANČIĆ ŠALEK, Volume 15Issue s1Haemophilia pages: 1-1 First Published online: December 24, 2008 First published: 23 March 2009 https://doi.org/10.1111/j.1365-2516.2009.02014_2.xAboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat In Oldenberg and ZupančićŠalek [2], the ‘Conflict of Interest’ statement was omitted from the article. The statement should read: J. Oldenburg has acted as a paid consultant and/or speaker (including symposia) for Bayer, Baxter, Biotest, Biovitrum, CLS Behring, NovoNordisk, Octapharma and Wyeth and has received funds for research from Baxter and NovoNordisk. Silva ZupančićŠalek has acted as a paid consultant and/or speaker (including symposia) for Bayer, Baxter and NovoNordisk. References 1 Den Uijl IEM, Fischer K, Van Der Bom JG, Grobbee DE, Rosendaal FR, Plug I. Clinical outcome of moderate haemophilia compared with severe and mild haemophilia. Haemophilia 2009; 15: 83– 90. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 2 Oldenberg J, ZupančićŠalek S. Introduction. Haemophilia 2009; 15(Suppl. 1): 1. Wiley Online LibraryWeb of Science®Google Scholar 3 Iorio A, Oliovecchio E, Morfini M, Mannucci PM. Italian Registry of Haemophilia and Allied Disorders. Objectives, methodology and data analysis. Haemophilia 2008; 14: 444– 53. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Volume15, Issue2March 2009Pages 637-637 ReferencesRelatedInformation

Clinical outcome of moderate haemophilia compared with severe and mild haemophilia

Information on outcome and treatment of patients with moderate haemophilia is scarce. In this study, we compared self-reported burden of disease in moderate haemophilia to severe and mild haemophilia. A nationwide questionnaire on bleeding pattern, treatment, impairment and quality of life was sent to 1567 Dutch patients with haemophilia. Out of 1066 respondents (response rate: 68%), 16% had moderate, 44% severe and 39% mild haemophilia. Median age was 36 years. Although overall outcome in moderate haemophilia was in between severe and mild haemophilia, moderate haemophilia patients did report a substantial burden of disease. The majority of patients with moderate haemophilia (73%) reported bleeds in the previous year; and a considerable proportion of moderate patients reported joint impairment (43%), chronic pain (15%), needed orthopaedic aids (24%) or were unemployed because of disability (27%). Within the group of moderate haemophilia patients, a large variation in bleeding pattern and outcome was observed. A quarter of patients with moderate haemophilia reported a more severe phenotype and intermittent use of prophylaxis. These patients reported frequent bleeding, with a median of eight bleeds per year, including two joint bleeds, and 68% reported joint impairment. Although outcome in moderate haemophilia is generally in between severe and mild haemophilia, moderate haemophilia patients reported a substantial burden of disease, and for more than 25% of patients with moderate haemophilia long term prophylaxis was implemented because of frequent bleeds.

Protecting the joints of mice and men

Meija-Carval et al. present a novel murine model for the study of haemophilic synovitis. The model appears suitable for assessing and quantifying joint disease in mice and the appropriate control animals are included. Thus, the results are likely reliable and of a high evidence grade. The study, however, can be questioned from an ethical point of view. The aims of the project were ‘…to test the hypothesis that a minimum number of haemarthroses negatively impacts on joint function and this would be reflected by decreased physical performance of experimental animals’. The results support the following conclusions: ‘(i) haemophilic mice can be trained to ambulate on a rotating rod; (ii) acute haemarthrosis temporarily impairs their ability to ambulate and (iii) following recovery from acute injury, mice developing synovitis demonstrated inferior physical ability compared with mice not developing synovitis’. The experimental animals were anaesthetized at time of the experimental injury but ‘on the third day were forced to exercise on the Rotarod’. The results show, as expected, higher morbidity among the experimental animals, i.e. they lose weight and perform less well in their physical function. Obviously, the animals are adversely affected. The discussion opens with the statement: ‘The data presented here demonstrate for the first time, the ability to monitor the impact on joint bleeding and the development of synovitis on physical performance’. I do not agree with the authors. The disease haemophilia was first described in the Babylonian Talmud, fourth century, Yevamoth 64 BC where it is stated: ‘For it was taught: if she circumcised her first child and he died (as a result of bleeding from the operation), and a second one also died, she must not circumcise her third child’ [1]. Thus, haemophilia is a very serious bleeding disorder with known consequences: acute joint bleeds with severe pain and physical impairment, other serious bleeding into the brain and viscera, and development of chronic joint disease resulting in serious handicap. In the beginning of the 1900s, the median life span among persons with haemophilia in Sweden was 11 years. As late as the period 1943–57, the median age at death was as low as 19 years [2]. Efficacious treatment during the last 50 years has been accompanied by increase in life expectancy [3]. With the introduction of prophylaxis in Europe during the late 1950s and early 1960s, joint outcome has markedly improved [4-7], benefiting quality of life and showing cost effectiveness [7, 8]. In Europe, the decades-long observation by clinicians of the obvious benefit of haemophilia treatment, notably the effectiveness of prophylaxis, has been supported by well-designed cohort studies. Thus, randomized clinical trials comparing prophylaxis with on demand therapy have never been performed, as they have been considered both unnecessary and unethical, and long-term outcome in haemophilia requires decades of follow-up in observational studies [9]. In some parts of North America, the European experience has not been accepted and therefore not only mice but also young children have suffered in the name of science [10]. The murine model described by Meja-Carvajal et al. may have a potential for further study of the pathophysiology of joint disease and the development of better treatment. However, the aims of their study and their results have been observed and confirmed in humans for decades, not to say thousands of years, in other parts of the world. Ethical awareness and readiness to learn from colleagues in other parts of the world must be the leading star for doctors treating patients. The author has stated that he has no interests which might be perceived as posing a conflict or bias.

Comparing two measures of quality of life for children with haemophilia: the CHO‐KLAT and the Haemo‐QoL

Disease-specific measures of quality of life (QoL) for children with haemophilia are now available for use in clinical studies [Haemophilia, 10, 2004, 9-16]. One of these measures, the Canadian Haemophilia Outcomes - Kids' Life Assessment Tool (CHO-KLAT), was developed in Canada with emphasis on the perspectives of children [Pediatr Blood Cancer, 47, 2006, 305-11; Haemophilia, 10, 2004, 34-43]. Another, the Haemo-QoL, was developed in Europe, with emphasis on the perspectives of clinicians [Haemophilia, 8, 2002, 47-54; Haemophilia, 10, 2004, 17-25]. While these two measures are unique and independent, researchers from both studies were collaboratively linked throughout development and testing. This study presents the results of a joint assessment of the two measures with respect to their strengths, limitations and unique contributions. The primary questions addressed were: 1 What is the relationship between the CHO-KLAT and the Haemo-QoL in terms of summary scores and item content? 2 What are the methodological strengths, limitations and unique contributions of each measure? We conducted a retrospective analysis of data from field testing of both measures. The analysis included a comparative assessment of the basic validity, reliability and items used in each measure. Overall, the CHO-KLAT and the Haemo-QoL are promising and valuable measures of QoL for children with haemophilia. Our analyses confirmed the basic psychometric properties of both tools, but identified some discrepancies between them. Additional data will allow for greater understanding of these discrepancies and lend clarity to how the tools should be used in clinical studies (separately or merged). The present recommendation is that the measures be run independently, but preferably concurrently in studies of children with haemophilia.

Development of a health-related quality of life measure for boys with haemophilia: the Canadian Haemophilia Outcomes--Kids Life Assessment Tool (CHO-KLAT).

Several measures of quality of life (QoL) are available for children with haemophilia. However, most are not disease-specific and few focus on children's perspectives. The purpose of this study was to develop a psychometrically sound measure of QoL that included the perspectives of boys with haemophilia. A list of potential items was developed from the literature, other measures, and input from five discussion sessions with adults with haemophilia, children with haemophilia and their parents and haemophilia nurses. The list was augmented with items generated by three focus groups with children and three focus groups with parents. These groups also prioritized items and recommended a domain structure. Supplemental information was gathered by surveying haematologists. Data from all sources were analysed to reduce the number of items using a two-step approach, based on rules that weighted the children's priorities most heavily. The remaining items were compiled into a questionnaire that was pilot tested with 10 children and their parents. The total item pool contained 228 potential items. Of these, 33 were removed based on three focus groups and survey responses, 72 were removed after the completion of all focus groups and 46 were removed due to redundancy. This resulted in a 77-item version of the CHO-KLAT. Pilot testing identified the need to subdivide two items, resulting in a 79-item CHO-KLAT. The CHO-KLAT is a promising disease-specific measure of QoL that reflects children's unique perspectives. This child-centric focus distinguishes the CHO-KLAT from alternative measures of QoL. Further research will assess the measurement properties of the CHO-KLAT.

When should prophylactic treatment in patients with haemophilia A and B start?--The German experience.

Radiological and orthopaedic outcome in severe and moderate haemophilia A and B patients undergoing long-term prophylactic treatment were prospectively investigated focusing on the age of onset of prophylaxis and the number of joint bleedings prior to treatment. We report on 21 patients with severe and moderate haemophilia A and B receiving prophylactic treatment of between 3.1 and 16.1 years' duration. Three patient groups were evaluated according to the age at onset of prophylaxis. In group I prophylactic treatment was initiated in the first 2 years of life. Patients in group II received prophylaxis at the age of 3-6 years. Late-onset or secondary prophylactic treatment was started at the age of 6 years and above in seven patients (group III). All patients received virus-inactivated F VIII or F IX concentrates at dosages of 30-50 IU/kg body weight i.v. three times per week for those with haemophilia A and twice per week for those with haemophilia B. Elbow, knee and ankle joints were investigated at 3-4-yearly intervals according to the radiological and orthopaedic scores recommended by the World Federation of Haemophilia. The total number of joint bleedings before and after start of prophylaxis were recorded in all patients. In group I 7/8 patients had unaffected joints with constant radiological and orthopaedic scores of zero or 1, after a median of 11.25 years of prophylactic treatment. One patient in this group demonstrated mild radiological alterations (score 4). Patients in group II showed neither radiological nor orthopaedic alterations at study entry. Surprisingly, worsening joint scores could be detected despite ongoing prophylaxis after the 3-year interval (median orthopaedic score 4, median radiological score 8). Treatment group III already showed considerable joint damage at study entry with a median radiological score of 11 (0-33) and a median orthopaedic score of 4 (0-11). Despite prophylactic treatment, both radiological (median 19.5, range 2-47) and orthopaedic scores (median 8, range 2-12) deteriorated after 3 years. Prior to onset of prophylaxis, no or only one joint bleeding occurred in treatment group I. In group II, a median of six joint bleeds (range 1-8) was reported before prophylaxis was started. Patients in group III usually experienced a median of more than 10 joint haemorrhages (range 6-10 or more). Under prophylactic treatment the number of joint bleedings decreased significantly in groups II and III. However, radiological and orthopaedic scores increased as a sign of progressing osteoarthropathic alterations in patients reporting more than five joint haemorrhages onset of prophylaxis whereas no joint alterations could be assessed in patients with no or only one joint bleeding episode prior to prophylaxis. Even a small number of joint bleedings seems to cause irreversible osteoarthropathic alterations leading to haemophilic arthropathy. Once apparent, further progression of joint damage could not be arrested despite of prophylactic treatment (groups II and III). In order to prevent haemophilic arthropathy, effective prophylaxis should be started before or at least after the first joint bleeding in severe haemophilia A and B.