| 1. |
- Halldén, Christer, 1957-, et al.
(författare)
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Investigation of disease-associated factors in haemophilia A patients without detectable mutations
- 2012
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Ingår i: Haemophilia. - : Blackwell. - 1351-8216 .- 1365-2516. ; 18:3, s. e132-e137
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Tidskriftsartikel (refereegranskat)abstract
- To investigate disease causing mechanism in haemophilia A patients without detectable mutation. Screening for F8 mutations in 307 haemophilia A patients using: re-sequencing and inversion PCR, reverse transcription (RT-PCR) of mRNA, MLPA analysis, haplotyping using SNP and microsatellite markers. No F8 mutations were detected in 9 of the 307 patients (2.9%) using re-sequencing and inversion PCR. MLPA analysis detected duplication in exon 6 in one patient and RT-PCR showed no products for different regions of mRNA in four other patients, indicating failed transcription. No obvious associations were observed between the phenotypes of the nine patients, their F8 haplotypes and the putative mutations detected. The mutation-positive patients carrying the same haplotypes as the mutation-negative patients show a multitude of different mutations, emphasizing the lack of associations at the haplotype level. VWF mutation screening and factor V measurements ruled out type 2N VWD and combined factor V and VIII deficiency respectively. To further investigate a possible role for FVIII interacting factors the haplotypes/diplotypes of F2, F9, F10 and VWF were compared. The nine patients had no specific haplotype/diplotype combination in common that can explain disease. Duplications and faulty transcription contribute to the mutational spectrum of haemophilia A patients where conventional mutation screening fail to identify mutations.
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| 2. |
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| 3. |
- Billström, Rolf, et al.
(författare)
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Anemier
- 2011
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Ingår i: Läkemedelsboken. - 9789197960502 ; , s. 239-251
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Bokkapitel (refereegranskat)
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| 4. |
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| 5. |
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| 6. |
- Aledort, Louis, et al.
(författare)
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Factor VIII therapy for hemophilia A: current and future issues
- 2014
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Ingår i: Expert Review of Hematology. - : Informa UK Limited. - 1747-4086 .- 1747-4094. ; 7:3, s. 373-385
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Forskningsöversikt (refereegranskat)abstract
- Hemophilia A is a congenital, recessive, X-linked bleeding disorder that is managed with infusions of plasma-derived or recombinant factor (F) VIII. The primary considerations in FVIII replacement therapy today are the: 1) immunogenicity of FVIII concentrates, 2) role of longer-acting FVIII products, 3) prophylactic use of FVIII in children and adults with severe hemophilia A, and 4) affordability and availability of FVIII products. Improving patient outcomes by increasing the use of FVIII prophylaxis, preventing or eliminating FVIII inhibitors, and expanding access to FVIII concentrates in developing countries are the major challenges confronting clinicians who care for patients with hemophilia A.
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| 7. |
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| 8. |
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| 9. |
- Andersson, Nadine G, et al.
(författare)
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Novel F8 and F9 gene variants from the PedNet Hemophilia Registry classified according to ACMG/AMP guidelines
- 2020
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 41:12, s. 2058-2072
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Tidskriftsartikel (refereegranskat)abstract
- In hemophilia A and B, analysis of the F8 and F9 gene variants enables carrier- and prenatal diagnosis and prediction of risk for development of inhibitors. The PedNet Registry collects clinical, genetic and phenotypic data prospectively on >2000 children with hemophilia. The genetic reports of F8/F9 gene variants were classified uniformly to HGVS nomenclature and re-evaluated using international population- and disease-specific databases, literature survey and, where applicable, computational predictive programs. We report 88 novel variants in the F8 and F9 genes, 80 fulfilling criteria for class 5 (pathogenic), six for class 4 (likely pathogenic) and two fulfilling criteria for class 3 (variant of unknown significance) of the ACMG (American College of Medical Genetics and Genomics)/AMP (Association for Molecular Pathology) guidelines together with information on the respective phenotype and inhibitor formation. The study highlights the need to re-evaluate and update earlier genetic reports in hemophilia both locally but also in variant databases in the light of changed nomenclature and new guidelines. This article is protected by copyright. All rights reserved.
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| 10. |
- Andersson, Nadine, et al.
(författare)
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Genetic screening of children with suspected inherited bleeding disorders
- 2020
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 26:2, s. 314-324
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Genetic screening using high-throughput DNA sequencing has become a tool in diagnosing patients with suspected inherited bleeding disorders (IBD). However, its usefulness and diagnostic efficacy in children is unclear.AIM: To evaluate the diagnostic efficacy of genetic screening for IBD in children and downstream further testing.METHODS: After informed consent, children (<18 years) with suspected IBD underwent genetic screening with 94 selected genes.RESULTS: A total of 68 heterozygous class 3-5 variants were detected in 30 children, 2.3 variants per patient. Directed specific functional testing was performed after genetic screening in a subset of patients. Adhering to the ACMG guidelines, the results of functional testing together with family history and previous publications classified three variants as likely disease causing (class 4) and two variants as disease causing (class 5), all in children with thrombocytopenia. The overall diagnostic rate was 16.7% (5/30). Children with thrombocytopenia had a significantly higher rate of significant genetic findings, 5/9 (55.6%) vs. 0/21 (0%; P = .0009).CONCLUSION: We conclude that performing genetic screening in children is an effective tool especially for children with inherited thrombocytopenia and has the possibility to diagnose platelet disorders adequately early in life. Children with bleeding diathesis, normal coagulation work-up and without thrombocytopenia are unlikely to be diagnosed by genetic screening. Ethical issues such as incidental findings, variants associated with cancer and the interpretation of the genetic results into clinical practice remain problematic.
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| 11. |
- Astermark, Jan, et al.
(författare)
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Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized
- 1999
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048. ; 105:4, s. 1109-1113
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Tidskriftsartikel (refereegranskat)abstract
- The frequency of joint bleeds and orthopaedic joint scores were evaluated in 121 patients with severe haemophilia who had started prophylactic treatment with clotting factor concentrates at least once weekly before the age of 10. 75 of the patients started before the age of 3, 31 at the age of 3-5 and 15 at the age of 6-9. Each subgroup was evaluated separately. In addition, a regimen of one infusion weekly was compared with that of two (haemophilia B) or three (haemophilia A) infusions weekly in each patient. A significant decrease in the overall number of joint bleeds per year was found after shortening the infusion interval (P<0.005), but the individual bleeding pattern varied. In survival analysis of the first pathologic joint score event, those who started prophylaxis before the age of 3 had a better outcome overall than those starting at later ages (P=0.001). However, in subgroup analysis, no significant difference was seen in the annual number of joint bleeds and the development of arthropathy between those starting with, or shifting to, the more intensive regimen before the age of 3 and those that were put on this regimen at the age of 3-5. Age at start of prophylaxis was found to be an independent predictor for the development of arthropathy (P=0.0002), whereas dose and infusion interval at start were not. Our data emphasize the importance of starting replacement therapy during the first years of life. However, it seems that when beginning the regimen it can be individualized and adjusted according to the bleeding pattern. In this way, the need for a venous access system may be assessed on an individual basis.
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| 12. |
- Auerswald, Guenter, et al.
(författare)
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Beyond patient benefit: clinical development in hemophilia
- 2012
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Ingår i: Hematology. - 1607-8454. ; 17:1, s. 1-8
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Forskningsöversikt (refereegranskat)abstract
- Historically in hemophilia, outcome measures have not been collected systematically. Hence, there are insufficient clearly defined, evidence-based measures that can be applied consistently across hemophilia trials. This review focuses on some key challenges to evaluating patient outcomes and performing trials identified by experts at the Fourth and Fifth Zurich Haemophilia Forums. As procedures appear inconsistent across Europe, guidelines require modification to be more appropriate and/or realistically achievable. The outcome measures utilized, and the timing of their collection, should also be standardized, and more objective measures used where feasible. Implementation of outcome measures could be refined through greater understanding of patient heterogeneity, and tailored to differentiate between hemophilia- and aging-related disease effects. Furthermore, robust outcome measures that can also inform health-economic decisions are increasingly needed. Lastly, as patient recruitment poses a challenge, the panel proposed a call for action to motivate physicians and patients to participate in clinical trials.
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| 13. |
- Auerswald, Günter, et al.
(författare)
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Pain and pain management in haemophilia
- 2016
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Ingår i: Blood Coagulation and Fibrinolysis. - 0957-5235. ; 27:8, s. 845-854
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Forskningsöversikt (refereegranskat)abstract
- Joint pain is common in haemophilia and may be acute or chronic. Effective pain management in haemophilia is essential to reduce the burden that pain imposes on patients. However, the choice of appropriate pain-relieving measures is challenging, as there is a complex interplay of factors affecting pain perception. This can manifest as differences in patients’ experiences and response to pain, which require an individualized approach to pain management. Prophylaxis with factor replacement reduces the likelihood of bleeds and bleed-related pain, whereas on-demand therapy ensures rapid bleed resolution and pain relief. Although use of replacement or bypassing therapy is often the first intervention for pain, additional pain relief strategies may be required. There is an array of analgesic options, but consideration should be paid to the adverse effects of each class. Nevertheless, a combination of medications that act at different points in the pain pathway may be beneficial. Nonpharmacological measures may also help patients and include active coping strategies; rest, ice, compression, and elevation; complementary therapies; and physiotherapy. Joint aspiration may also reduce acute joint pain, and joint steroid injections may alleviate chronic pain. In the longer term, increasing use of prophylaxis or performing surgery may be necessary to reduce the burden of pain caused by the degenerative effects of repeated bleeds. Whichever treatment option is chosen, it is important to monitor pain and adjust patient management accordingly. Beyond specific pain management approaches, ongoing collaboration between multidisciplinary teams, which should include physiotherapists and pain specialists, may improve outcomes for patients.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0
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| 14. |
- Benson, Gary, et al.
(författare)
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Diagnosis and care of patients with mild haemophilia : practical recommendations for clinical management
- 2018
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Ingår i: Blood Transfusion. - 1723-2007. ; , s. 535-544
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Forskningsöversikt (refereegranskat)abstract
- Mild haemophilia is defined by factor levels between 0.05 and 0.40 IU/mL and is characterised by traumatic bleeds. Major issues associated with mild haemophilia are that it may not present for many years after birth, and that awareness, even within families, may be low. Methodological problems exist in diagnosis, such as inconsistencies in results obtained from different assays used to measure factor levels in mild haemophilia. Advances in genetic testing provide insight into diagnosis as well as the likelihood of inhibitor development, which is not uncommon in patients with mild or moderate haemophilia and can increase morbidity. The management of patients with mild haemophilia is a challenge. This review includes suggestions around formulating treatment plans for these patients, encompassing the full spectrum from clinical care of the newly diagnosed neonate to that of the ageing patient with multiple comorbidities. Management strategies consider not only the vast differences in these patients' needs, but also risks of inhibitor development and approaches to optimally engage patients.
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| 15. |
- Benson, Gary, et al.
(författare)
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Immune tolerance induction in patients with severe hemophilia with inhibitors: expert panel views and recommendations for clinical practice.
- 2012
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Ingår i: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 88:5, s. 371-379
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Tidskriftsartikel (refereegranskat)abstract
- For hemophilia patients with inhibitors, immune tolerance induction (ITI) may help to restore clinical response to Factor (F) VIII or FIX concentrates. Several ITI regimens and protocols exist; however, despite 30 yr of progressive investigation, the ITI evidence base relies mainly on observational data. Expert opinion, experience, and interpretation of the available evidence are therefore valuable to support clinical decision-making. At the Sixth Zürich Haemophilia Forum an expert panel considered recent data and consensus to distill key practice points relating to ITI. The panel supported current recommendations that, where feasible, ITI should be offered early to children and adults (ideally ≤5 yr of inhibitor detection) when inhibitor titers are <10 Bethesda Units, and should be stopped when successful tolerance is achieved. For hemophilia A inhibitor patients, ITI can be founded on recombinant FVIII at high doses. The panel considered that patients with a high bleeding frequency should be offered additional prophylaxis with a bypassing agent. For hemophilia B patients, there may be a benefit to genetic testing to indicate the risk for inhibitors. ITI is often less effective and associated with a greater risk of side effects in these patients. For high-titer inhibitor (≥5 Bethesda Units) hemophilia B patients, the panel advised that bypassing agents could be offered on demand in addition to ITI. Within future ITI regimens there may be a role for additional immunosuppressant therapies. Participants agreed that research is needed to find alternatives to ITI therapy that offer durable and sustained effects and reduced rates of complications. © 2012 John Wiley & Sons A/S.
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| 16. |
- Berntorp, Erik, et al.
(författare)
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Centraliserad vård grundläggande i vårdprogram för blödarsjuka
- 1999
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Ingår i: Läkartidningen. - 0023-7205. ; 96:15, s. 1849-1852
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Tidskriftsartikel (refereegranskat)abstract
- Haemophilia is a rare and potentially life-threatening disease. In Sweden, with a population of approximately 8.5 million, about 350 people suffer from the more severe forms of haemophilia or von Willebrand disease. Meticulous management is important if the patients are to be spared chronic disability and serious treatment complications. The disease is lifelong and affects psychosocial aspects of life among patients and their families. With the help of a grant from the Swedish Board of Halth and Welfare, a care programme has been designed to guarantee Swedish haemophiliacs comparable and optimal care. The programme has been drawn up by representatives of the three haemophilia centres in Sweden (at University Hospital, Malmo, Sahlgrenska University Hospital, Gothenburg, and Karolinska Hospital, Stockholm) in co-operation with the World Federation of National Haemophilia Organisations. To ensure optimal individual application of the programme, individualised management strategies and patient information leaflets have been prepared.
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| 17. |
- Berntorp, Erik, et al.
(författare)
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Consensus perspectives on prophylactic therapy for haemophilia: summary statement.
- 2003
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 9:Suppl 1, s. 41278-41278
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Tidskriftsartikel (refereegranskat)abstract
- Participants in an international conference on prophylactic therapy for severe haemophilia developed a consensus summary of the findings and conclusions of the conference. In the consensus, participants agreed upon revised definitions for primary and secondary prophylaxis and also made recommendations concerning the need for an international system of pharmacovigilance. Considerations on starting prophylaxis, monitoring outcomes, and individualizing treatment regimens were discussed. Several research questions were identified as needing further investigation, including when to start and when to stop prophylaxis, optimal dosing and dose interval, and methods for assessment of long-term treatment effects. Such studies should include carefully defined cohorts, validated orthopaedic and quality-of-life assessment instruments, and cost-benefit analyses.
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| 18. |
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| 19. |
- Berntorp, Erik, et al.
(författare)
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The role of prophylaxis in bleeding disorders
- 2010
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 16:s5, s. 189-193
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Forskningsöversikt (refereegranskat)abstract
- The rationale for long-term prophylaxis in more severe forms of von Willebrand's disease (VWD) is obvious, as mucosal bleeding and haemophilia-like joint bleeds resulting in chronic morbidity may occur. However, the experience with prophylactic treatment in this group is scanty. An international VWD Prophylaxis Network (VWD PN) was established in 2006. The VWD PN will investigate prophylaxis with retrospective and prospective studies. Eighteen centres in Europe and North America are recruiting patients and an additional 40 centres are preparing for or evaluating participation. In the absence of randomized prospective studies for most rare bleeding disorders, guidelines for prophylaxis are a subject of controversy. In situations where there is a strong family history of bleeding, long-term prophylaxis is administered in selected cases. Short intervals of prophylaxis can also be given before some surgeries or during pregnancy. The benefits of prophylaxis must be balanced by the risk of side effects. Therefore, it is essential to delineate its management in a specialized comprehensive care environment. In haemophilia, decades of clinical experience and numerous retrospective and, recently, prospective studies clearly demonstrate that prophylactic treatment is superior to on-demand treatment, regardless of whether the outcome is the number of joint- or life-threatening bleeds, arthropathy evaluated by X-ray or MRI, or quality of life measured by generic or haemophilia-specific instruments. Optimal prophylactic treatment should be started early in life (primary prophylaxis) but various options exist for the dose and dose interval. These depend on the objective of treatment in the individual patient, which, in turn, is dependent on resources in the health care system.
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| 20. |
- Birgens, Henrik, et al.
(författare)
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The thalassaemia syndromes
- 2007
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Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 67:1, s. 41603-41603
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Forskningsöversikt (refereegranskat)abstract
- The thalassaemia syndromes, endemic in the Mediterranean area, the Middle East, the Indian subcontinent, the Far East and in tropical Africa, are the most common hereditary disorders in humans, and millions of people are affected by diseases. Due to a widespread population flow between continents in recent past centuries, the thalassaemias are now occurring with relatively high frequency in many non-endemic areas. In the Nordic countries, homozygous thalassaemia is still relatively rare, and most health-care personnel are not familiar with these diseases. This article focuses on two important issues, namely the biological and the clinical aspects of thalassaemia.
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| 21. |
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| 22. |
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| 23. |
- Blanchette, V S, et al.
(författare)
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Optimizing factor prophylaxis for the haemophilia population: where do we stand?
- 2004
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 10:4, s. 97-104
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Tidskriftsartikel (refereegranskat)abstract
- The hallmark of severe haemophilia, defined as a circulating level of factor (F) VIII (haemophilia A cases) or FIX (haemophilia B cases) of < 1%, is recurrent bleeding into muscles and joints (haemarthroses) from an early age of life. The inevitable result of such bleeding is progressive joint damage, leading to disabling arthritis that is typically evident within the first 2 decades of life in people with haemophilia who have limited or no access to regular factor replacement therapy, or those in whom factor replacement therapy is ineffective because of the presence of high-titre inhibitors. For children with severe haemophilia and no evidence of inhibitors, the unwanted musculoskeletal complications of severe haemophilia can be effectively prevented by the early initiation of a programme of long-term factor prophylaxis. In order to achieve the best outcome (a perfect musculoskeletal status for age) the programme of prophylaxis should be started before the onset of joint damage (primary prophylaxis). The gold standard primary prophylaxis regimen (the Malmo protocol) was pioneered and tested in Sweden and involves the infusion of 20-40 IU of FVIII per kg body weight on alternate days (minimum three times per week) for haemophilia A cases, and 20-40 IU kg(-1) of FIX twice weekly for haemophilia B cases. This protocol is, however, demanding on peripheral veins and very expensive. Modifications of the parent protocol such as starting primary prophylaxis with once-weekly infusions via peripheral veins with rapid escalation to full-dose prophylaxis or dose escalation based on frequency of bleeding are increasingly implemented in haemophilia treatment centres in countries that can afford the high cost of such programmes. These modified programmes can be achieved in the majority of young children with severe haemophilia without the need for central venous access devices (e.g. Port-a-Caths) and with avoidance of device-associated complications such as infection and thrombosis. In at least one centre, experience with arteriovenous fistulae as a strategy to ensure reliable venous access is being accumulated. The issues of compliance (adherence) to recommended prophylaxis protocols and when, if ever, to stop a programme of primary prophylaxis once started are real and require ongoing prospective studies. Such studies should incorporate outcome measures such as health-related quality-of-life and economic analyses.
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| 24. |
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| 25. |
- Carcao, Manuel D., et al.
(författare)
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Correlation between phenotype and genotype in a large unselected cohort of children with severe hemophilia A
- 2013
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 121:19, s. 3946-3952
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Tidskriftsartikel (refereegranskat)abstract
- Phenotypic variability is well recognized in severe hemophilia A. A few studies, mainly in adults treated lifelong on demand, suggest that bleeding phenotype correlates with factor VIII gene (F8) mutation type. Because treatment regimens influence outcomes to a large extent, examining bleeding phenotype during the first years of life may be the most suitable way to define this variability. We set out to analyze the very early phenotypic expression of severe hemophilia A in 621 consecutively enrolled, well-characterized previously untreated patients and to correlate this with patients' F8 mutation. Detailed information was collected on bleeds and treatment of the first 75 exposure days or until inhibitor development. F8 mutation type was known for 531 patients; 402 had null mutations and 129 had non-null mutations. Considering only patients who had not started prophylaxis or developed an inhibitor before select bleeding events, we found that patients with null mutations experienced their first bleed and first joint bleed at younger median ages than patients with non-null mutations (9.7 vs 10.9 months and 13.8 vs 16.1 months, respectively). We conclude that F8 mutation type accounts for only a small component of the significant phenotypic variability found among patients with severe hemophilia A.
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| 26. |
- Carcao, M., et al.
(författare)
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Devising a best practice approach to prophylaxis in boys with severe haemophilia: evaluation of current treatment strategies
- 2010
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Ingår i: Haemophilia. - 1351-8216. ; 16, s. 41373-41373
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Forskningsöversikt (refereegranskat)abstract
- Data from prospective studies clearly demonstrate the efficacy of prophylactic treatment of haemophilia in reducing joint- or life-threatening bleeding and the associated consequences for quality of life. Debate remains, however, regarding the optimal implementation of prophylaxis. Our aim in this review was to identify a best practice approach to factor replacement prophylaxis in boys with haemophilia. We evaluate prophylactic treatment regimens currently used in Swedish, Canadian and French centres and highlight key issues, including the optimal age for starting prophylaxis, the optimal treatment dosage/schedule and patient compliance.
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| 27. |
- Carlborg, E, et al.
(författare)
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The Malmo model for immune tolerance induction: impact of previous treatment on outcome
- 2000
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 6:6, s. 639-639
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Tidskriftsartikel (refereegranskat)abstract
- Ten patients, who had been treated according to the Malmo model for immune tolerance induction (ITI), were analysed regarding treatment with clotting factors and chemotherapy during the time period between inhibitor detection and ITI. Of the patients who were successfully rendered tolerant (n=6) all but one had received treatment with FVIII, either alone (n=1), or combined with cyclophosphamide (n=4). Of the patients who did not become tolerant, three of four had received treatment with FVIII during the inhibitor period but only one with FVIII and chemotherapy. The total amount of treatment received was in general much lower in the group that did not become tolerant. In individual cases, it appeared very clear that the inhibitor level and anamnestic response was substantially reduced prior to the ITI using the Malmo treatment model. We conclude that treatment of acute bleeds during the inhibitor period may be of importance for ITI and that the different response rates published for different immune tolerance regimens most likely do not reflect the true response rate for the respective regimen.
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| 28. |
- Chambost, H, et al.
(författare)
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Changing pattern of care of boys with haemophilia in western European centres
- 2005
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 11:2, s. 92-99
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Tidskriftsartikel (refereegranskat)abstract
- Haemophilia management is not uniform among countries, even within western Europe, that have close economic, social and cultural relationship. The European Paediatric Network PedNet aims to share experiences in the field of the care of boys with haemophilia. In 1998, a PedNet survey has shown significant disparities in 20 centres from 16 countries, particularly as regards the implementation of prophylaxis regimen. This survey has been updated in 2003 to describe the current status of haemophilia management in 22 centres and the changing pattern of care of boys with severe haemophilia in western Europe. Regular, continuous long-term prophylaxis is provided in all PedNet centres, more than 50% and 80-100% of boys being treated this way in 20/22 and 15/22 centres respectively. Twenty of the 22 centres (91%) recommend continuous prophylaxis (primary or secondary A) for a new patient. The use of recombinant factor VIII concentrates was already widespread in 1998 and a further expansion of recombinant products has been observed over the last 5 years. Recombinant FVIII is now used exclusively in nine centres and for more than 80% of boys with haemophilia A in nine other centres. The use of recombinant and plasma derived FIX is more balanced: among 18 centres where boys with haemophilia B are treated, 14 use recombinant FIX, and nine administer it to a majority of patients. Other modifications of practice have been stressed in this survey, such as more targeted use of central venous devices in the youngest boys and more extensive characterisation of genetic mutations.
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| 29. |
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| 30. |
- Dolan, Gerry, et al.
(författare)
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Haemophilia B : Where are we now and what does the future hold?
- 2018
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Ingår i: Blood Reviews. - : Elsevier BV. - 0268-960X. ; 32:1, s. 52-60
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Forskningsöversikt (refereegranskat)abstract
- Research has been lacking on the natural history, complications, and treatment of haemophilia B, which is less common than haemophilia A and was recognized as a distinct clinical entity in 1947. Although the two diseases share the same clinical manifestations, they differ in causative mutation, risk of inhibitor development, and patient quality of life. Frequently debated is whether haemophilia B is as clinically severe as haemophilia A, with much of the published data on overall and haemophilia-specific health outcomes suggesting that haemophilia B may have a less severe clinical phenotype. However, although fewer haemophilia B than haemophilia A patients appear to experience bleeding, bleeds are just as severe. We review distinguishing characteristics of haemophilia B and its treatment, including management strategies for neonates, therapeutic approaches for patients who develop inhibitors, pharmacokinetics of factor IX concentrates administered as replacement therapy, and potential future treatments.
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| 31. |
- Dolan, Gerry, et al.
(författare)
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Principles of Care for Acquired Hemophilia
- 2021
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Ingår i: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 106:6, s. 762-773
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To establish clear priorities for the care of patients with acquired hemophilia A (AHA) by proposing 10 key principles of practical, holistic AHA management.METHOD: These principles were developed by the Zürich Haemophilia Forum, an expert panel of European hemophilia specialists comprising physicians and nursing and laboratory specialists.RESULTS: The 10 proposed principles for AHA care are as follows: 1) Improving initial diagnosis of AHA; 2) Differential diagnosis of AHA: laboratory assessment of patients with unusual bleeding; 3) Effective communication between laboratories, physicians, and specialists; 4) Improving clinical care: networking between healthcare professionals in the treating hospital and specialist hemophilia centers; 5) Comprehensive assessment of bleeding; 6) Appropriate use of bypassing agents; 7) Long-term follow-up and monitoring for efficacy and safety of immunosuppressive treatment; 8) Inpatient/outpatient settings; 9) Access to innovative and disruptive treatments; 10) Promotion of international collaborative research.CONCLUSION: The proposed principles for holistic AHA care aim to ensure swift diagnosis and optimal patient management. Key to achieving this goal is training for healthcare personnel in non-specialist hospitals and collaboration between different specialists. We hope these principles will increase awareness of AHA in the wider medical community and catalyze efforts towards improving its practical, multidisciplinary management.
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| 32. |
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| 33. |
- Economou, Marina, et al.
(författare)
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Perinatal aspects of haemophilia
- 2014
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Ingår i: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 93, s. 21-25
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Forskningsöversikt (refereegranskat)abstract
- Haemophilia is an X-linked recessive genetic disease of haemostasis. Women carriers may present with a bleeding tendency similar to milder forms of the disease. Haemophilic newborns present risk factors and patterns of bleeding that are challenging. Identification of carriers and genetic counselling before conception is considered optimal to help decide on available conception options and during pregnancy to help minimise bleeding risks for both carrier mother and affected baby. Preimplantation genetic diagnosis is attractive to many couples at risk of having a child with haemophilia and relevant technology is becoming more available although it has both practical and ethical limitations. Pregnancy in carriers should be managed by a multidisciplinary team in a comprehensive treatment centre. The optimal mode of delivery for carriers expecting a baby known to have or being at risk of haemophilia is an issue of great debate. The general consensus among authors is avoidance of instrumental delivery, foetal scalp electrodes and blood sampling in pregnancies at risk of carrying an affected foetus, as well as early recourse to Caesarean section as guided by obstetric indications. Intracranial haemorrhage, although infrequent, is one the most devastating types of bleeding in haemophilic newborns and can occur regardless of the mode of delivery or the severity of haemophilia. Early screening is proposed for all infants with severe or moderate haemophilia who have had traumatic delivery and/or have evidence of extracranial haemorrhage. Women with postpartum haemorrhage should have a bleeding work-up.
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| 34. |
- Ekholm, C., et al.
(författare)
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Mild haemophilia in Sweden
- 2010
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Ingår i: Haemophilia. - 1351-8216. ; 16, s. 90-90
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Konferensbidrag (refereegranskat)
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| 35. |
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| 36. |
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| 37. |
- Fischer, Kathelijn, et al.
(författare)
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Intermediate- dose versus high-dose prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s
- 2013
-
Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 122:7, s. 1129-1136
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Tidskriftsartikel (refereegranskat)abstract
- Prophylactic treatment in severe hemophilia is very effective but is limited by cost issues. The implementation of 2 different prophylactic regimens in The Netherlands and Sweden since the 1970s may be considered a natural experiment. We compared the costs and outcomes of Dutch intermediate-and Swedish high-dose prophylactic regimens for patients with severe hemophilia (factor VIII/IX < 1 IU/dL) born between 1970 and 1994, using prospective standardized outcome assessment and retrospective collection of cost data. Seventy-eight Dutch and 50 Swedish patients, median age 24 years (range, 14-37 years), were included. Intermediate-dose prophylaxis used less factor concentrate (median: Netherlands, 2100 IU/kg per year [interquartile range (IQR), 1400-2900 IU/kg per year] vs Sweden, 4000 IU/kg per year [IQR, 3000-4900 IU/kg per year]); (P <.01). Clinical outcome was slightly inferior for the intermediate-dose regimen (P <.01) for 5-year bleeding (median, 1.3 [IQR, 0.8-2.7] vs 0 [IQR, 0.0-2.0] joint bleeds/y) and joint health (Haemophilia Joint Health Score > 10 of 144 points in 46% vs 11% of participants), although social participation and quality of life were similar. Annual total costs were 66% higher for high-dose prophylaxis (mean, 180 [95% confidence interval, 163 -196] 3 US$ 1000 for Dutch vs 298 [95% confidence interval, 271-325]) x US$ 1000 for Swedish patients; (P <.01). At group level, the incremental benefits of high-dose prophylaxis appear limited. At the patient level, prophylaxis should be tailored individually, and many patients may do well receiving lower doses of concentrate without compromising safety.
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| 38. |
- Fischer, Kathelijn, et al.
(författare)
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Primary prophylaxis in haemophilia care : Guideline update 2016
- 2017
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Ingår i: Blood Cells, Molecules, and Diseases. - : Elsevier BV. - 1079-9796. ; 67, s. 81-85
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Tidskriftsartikel (refereegranskat)abstract
- This paper reviews the current status on recommendations or guidelines for primary prophylaxis based on recent published papers from organizations or group of experts as well as some original key papers. A rather uniform view exists that prophylaxis should be initiated at an early age before or after no more than a single joint bleed and, if possible, preferably be continued for life. The dose and dose frequency of prophylaxis is dependent on the goal of treatment, bleeding phenotype, compliance, venous access and economic resources in the health care system and should be tailored individually based on clinical outcome and pharmacokinetics. For children, the effectiveness of prophylaxis is more dependent on maintaining minimum trough levels than in adults. Novel extended half-life products are being introduced, which should not affect the decision on when to start prophylaxis nor the initial dose, but which may be helpful for patients with difficult venous access and which may enable higher trough levels of factor VIII.
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| 39. |
- Fischer, K, et al.
(författare)
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Prophylaxis for severe haemophilia: clinical challenges in the absence as well as in the presence of inhibitors
- 2008
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 14:s3, s. 196-201
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Tidskriftsartikel (refereegranskat)abstract
- Prophylaxis is defined as the regular administration of clotting factor concentrates to prevent bleeding. Extensive data from observational studies and a recent randomized controlled trial (have established that early prophylactic treatment prevents bleeds and arthropathy in boys with severe haemophilia. The initiation of prophylaxis in young children remains challenging. To prevent arthropathy, prophylaxis should be started early, before the onset of joint damage. Alternative strategies of starting include starting before the age of 2 years, or starting before the third joint bleed. Dose and frequency vary between the original Swedish regime of 20-40 IU kg(-1) three times per week and lower dosed and step up regimes starting with 50 IU kg(-1) once weekly and rapidly increasing dose and frequency in case of bleeds. In the second decade, most patients on prophylaxis learn self-infusion. Self-management warrants confirmation of adequate knowledge of the disease. Increasing self-management concurring with major physical and psychological changes may cause reduced adherence. The challenge is to promote adherence and continue to prevent bleeds during this important period of rapid growth. The third decade of life often represents a change in lifestyle. Patients may get a job and periods of physical activity may be more confined. About two thirds of patients experiment with discontinuing prophylaxis in their early twenties, and 20-30% with mild bleeding patterns switch to on-demand treatment for prolonged periods or even permanently. The challenge is to optimize efficiency by individualizing prophylactic dose and frequency according to lifestyle and bleeding pattern. Inhibitors may develop in up to 30% of patients with severe haemophilia. Especially those with high titre inhibitors are at increased risk of developing target joints and severe arthropathy. The use of prophylactic treatment with bypassing agents in inhibitor patients is increasing. Early studies report in a significant reduction of bleeds, including intracranial bleeds, and improvement in quality of life. Data on results of primary prophylaxis in patients with inhibitors to prevent arthropathy are not yet available.
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| 40. |
- Fischer, K., et al.
(författare)
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Prospective observational cohort studies for studying rare diseases: the European PedNet Haemophilia Registry
- 2014
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 20:4, s. 280-286
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Tidskriftsartikel (refereegranskat)abstract
- Haemophilia is a rare disease. To improve knowledge, prospective studies of large numbers of subjects are needed. To establish a large well-documented birth cohort of patients with haemophilia enabling studies on early presentation, side effects and outcome of treatment. Twenty-one haemophilia treatment centres have been collecting data on all children with haemophilia with FVIII/IX levels up to 25% born from 2000 onwards. Another eight centres collected data on severe haemophilia A only. At baseline, details on delivery and diagnosis, gene mutation, family history of haemophilia and inhibitors are collected. For the first 75 exposure days, date, reason, dose and product are recorded for each infusion. Clinically relevant inhibitors are defined as follows: at least two positive inhibitor titres and a FVIII/IX recovery <66% of expected. For inhibitor patients, results of all inhibitor- and recovery tests are collected. For continued treatment, data on bleeding, surgery, prophylaxis and clotting factor consumption are collected annually. Data are downloaded for analysis annually. In May 2013, a total of 1094 patients were included: 701 with severe, 146 with moderate and 247 with mild haemophilia. Gene defect data were available for 87.6% of patients with severe haemophilia A. The first analysis, performed in May 2011, lead to two landmark publications. The outcome of this large collaborative research confirms its value for the improvement of haemophilia care. High-quality prospective observational cohorts form an ideal source to study natural history and treatment in rare diseases such as haemophilia.
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| 41. |
- Gedeborg, Rolf, et al.
(författare)
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Federated analyses of multiple data sources in drug safety studies
- 2023
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Ingår i: Pharmacoepidemiology and Drug Safety. - : John Wiley & Sons. - 1053-8569 .- 1099-1557. ; 32:3, s. 279-286
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Forskningsöversikt (refereegranskat)abstract
- PurposeStudies of rare side effects of new drugs with limited exposure may require pooling of multiple data sources. Federated Analyses (FA) allow real-time, interactive, centralized statistical processing of individual-level data from different data sets without transfer of sensitive personal data.MethodsWe review IT-architecture, legal considerations, and statistical methods in FA, based on a Swedish Medical Products Agency methodological development project.ResultsIn a review of all post-authorisation safety studies assessed by the EMA during 2019, 74% (20/27 studies) reported issues with lack of precision in spite of mean study periods of 9.3 years. FA could potentially improve precision in such studies. Depending on the statistical model, the federated approach can generate identical results to a standard analysis. FA may be particularly attractive for repeated collaborative projects where data is regularly updated. There are also important limitations. Detailed agreements between involved parties are strongly recommended to anticipate potential issues and conflicts, document a shared understanding of the project, and fully comply with legal obligations regarding ethics and data protection. FA do not remove the data harmonisation step, which remains essential and often cumbersome. Reliable support for technical integration with the local server architecture and security solutions is required. Common statistical methods are available, but adaptations may be required.ConclusionsFederated Analyses require competent and active involvement of all collaborating parties but have the potential to facilitate collaboration across institutional and national borders and improve the precision of postmarketing drug safety studies.
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| 42. |
- Gedeborg, Rolf, et al.
(författare)
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Validation of myocarditis diagnoses in the Swedish patient register for analyses of potential adverse reactions to COVID-19 vaccines
- 2023
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Ingår i: Upsala Journal of Medical Sciences. - : Upsala Medical Society. - 0300-9734 .- 2000-1967. ; 128:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Coronavirus disease 2019 (COVID-19) mRNA vaccines are associated with an increased risk of myocarditis using hospital discharge diagnoses as an outcome. The validity of these register-based diagnoses is uncertain.Methods: Patient records for subjects < 40 years of age and a diagnosis of myocarditis in the Swedish National Patient Register were manually reviewed. Brighton Collaboration diagnosis criteria for myocarditis were applied based on patient history, clinical examination, laboratory data, electrocardiograms, echocardiography, magnetic resonance imaging and myocardial biopsy. Poisson regression was used to estimate incidence rate ratios, comparing the register-based outcome variable to validated outcomes. Interrater reliability was assessed by a blinded re-evaluation.Results: Overall, 95.6% (327/342) of cases registered as myocarditis were confirmed (definite, probable or possible myocarditis according to Brighton Collaboration diagnosis criteria, positive predictive value 0.96 [95% CI 0.93–0.98]). Of the 4.4% (15/342) cases reclassified as no myocarditis or as insufficient information, two cases had been exposed to the COVID-19 vaccine no more than 28 days before the myocarditis diagnosis, two cases were exposed >28 days before admission and 11 cases were unexposed to the vaccine. The reclassification had only minor impact on incidence rate ratios for myocarditis following COVID-19 vaccination. In total, 51 cases were sampled for a blinded re-evaluation. Of the 30 randomly sampled cases initially classified as either definite or probably myocarditis, none were re-classified after re-evaluation. Of the in all 15 cases initially classified as no myocarditis or insufficient information, 7 were after re-evaluation re-classified as probable or possible myocarditis. This re-classification was mostly due to substantial variability in electrocardiogram interpretation.Conclusion: This validation of register-based diagnoses of myocarditis by manual patient record review confirmed the register diagnosis in 96% of cases and had high interrater reliability. Reclassification had only a minor impact on the incidence rate ratios for myocarditis following COVID-19 vaccination.
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| 43. |
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| 44. |
- Globe, Dennis, et al.
(författare)
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Measuring patient-reported outcomes in haemophilia clinical research
- 2009
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 15:4, s. 843-852
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Forskningsöversikt (refereegranskat)abstract
- Patient-reported outcome (PRO) measures have been used to assess quality of life and health state preferences from the patient's perspective. However, they have not been fully utilized in haemophilia clinical practice and research. A series of meetings were convened to review and document the state of the art in PROs relevant to haemophilia. Experts developed a process for selection of measures and identified published measures of health-related quality of life (HRQoL) relevant to patients with haemophilia. These were synthesized and reviewed. Patient preference measures were also identified and reviewed. Although the majority of measures were developed for and validated in adults, several measures were identified for use in paediatric populations. This paper recommends an approach to the selection of PROs for application in haemophilia clinical research and practice and identifies several potential measures relevant for application in haemophilia clinical research and practice.
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| 45. |
- Gouw, Samantha C., et al.
(författare)
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Factor VIII Products and Inhibitor Development in Severe Hemophilia A
- 2013
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 368:3, s. 231-239
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Tidskriftsartikel (refereegranskat)abstract
- Background For previously untreated children with severe hemophilia A, it is unclear whether the type of factor VIII product administered and switching among products are associated with the development of clinically relevant inhibitory antibodies (inhibitor development). Methods We evaluated 574 consecutive patients with severe hemophilia A (factor VIII activity, <0.01 IU per milliliter) who were born between 2000 and 2010 and collected data on all clotting-factor administration for up to 75 exposure days. The primary outcome was inhibitor development, which was defined as at least two positive inhibitor tests with decreased in vivo recovery of factor VIII levels. Results Inhibitory antibodies developed in 177 of the 574 children (cumulative incidence, 32.4%); 116 patients had a high-titer inhibitory antibody, defined as a peak titer of at least 5 Bethesda units per milliliter (cumulative incidence, 22.4%). Plasma-derived products conferred a risk of inhibitor development that was similar to the risk with recombinant products (adjusted hazard ratio as compared with recombinant products, 0.96; 95% confidence interval [CI], 0.62 to 1.49). As compared with third-generation full-length recombinant products (derived from the full-length complementary DNA sequence of human factor VIII), second-generation full-length products were associated with an increased risk of inhibitor development (adjusted hazard ratio, 1.60; 95% CI, 1.08 to 2.37). The content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. Conclusions Recombinant and plasma-derived factor VIII products conferred similar risks of inhibitor development, and the content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. Second-generation full-length recombinant products were associated with an increased risk, as compared with third-generation products. (Funded by Bayer Healthcare and Baxter BioScience.)
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| 46. |
- Gouw, Samantha C., et al.
(författare)
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Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study
- 2013
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 121:20, s. 4046-4055
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to examine the association of the intensity of treatment, ranging from high-dose intensive factor VIII (FVIII) treatment to prophylactic treatment, with the inhibitor incidence among previously untreated patients with severe hemophilia A. This cohort study aimed to include consecutive patients with a FVIII activity <0.01 IU/mL, born between 2000 and 2010, and observed during their first 75 FVIII exposure days. Intensive FVIII treatment of hemorrhages or surgery at the start of treatment was associated with an increased inhibitor risk (adjusted hazard ratio [aHR], 2.0; 95% confidence interval [CI], 1.3-3.0). High-dose FVIII treatment was associated with a higher inhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis was only associated with a decreased overall inhibitor incidence after 20 exposure days of FVIII. The association with prophylaxis was more pronounced in patients with low-risk F8 genotypes than in patients with high-risk F8 genotypes (aHR, 0.61, 95% CI, 0.19-2.0 and aHR, 0.85, 95% CI, 0.51-1.4, respectively). In conclusion, our findings suggest that in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk F8 mutations.
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| 47. |
- Gretenkort Andersson, Nadine, et al.
(författare)
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Intracranial haemorrhage in children and adolescents with severe haemophilia A or B - the impact of prophylactic treatment
- 2017
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048. ; 179:2, s. 298-307
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Tidskriftsartikel (refereegranskat)abstract
- The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH. We conducted a multicentre retrospective and prospective study that included 33 haemophilia centres from 20 countries. Inclusion criteria were children and adolescents born between 1993 and 2014, with severe haemophilia A or B without inhibitors. Participants were categorized by prophylaxis regimen: full, partial or none, based on dose and dose frequency of regular infusions. The cohort study included 1515 children: 29 cases of ICH over 8038 patient years were reported. The incidence of ICH in the prophylaxis group, 0·00033 cases of ICH/patient year, was significantly lower compared to the no prophylaxis group, 0·017 cases of ICH/patient year (RR 50·06; P < 0·001) and the partial prophylaxis group, 0·0050 cases of ICH/patient year (RR 14·92; P = 0·007). In the on-demand-group, 8% (2/24) children with ICH died and 33% had long-term sequelae, including intellectual and behavioural problems, paresis and epilepsy. Children on regular, frequent prophylaxis have a low risk of ICH compared to those using non-frequent or no prophylaxis.
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| 48. |
- Halldén, Christer, et al.
(författare)
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Investigation of disease-associated factors in haemophilia A patients without detectable mutations
- 2012
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Ingår i: Haemophilia. - : Wiley-Blackwell Publishing Ltd. - 1351-8216 .- 1365-2516. ; 18:3, s. e132-e137
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Tidskriftsartikel (refereegranskat)abstract
- To investigate disease causing mechanism in haemophilia A patients without detectable mutation. Screening for F8 mutations in 307 haemophilia A patients using: re-sequencing and inversion PCR, reverse transcription (RT-PCR) of mRNA, MLPA analysis, haplotyping using SNP and microsatellite markers. No F8 mutations were detected in 9 of the 307 patients (2.9%) using re-sequencing and inversion PCR. MLPA analysis detected duplication in exon 6 in one patient and RT-PCR showed no products for different regions of mRNA in four other patients, indicating failed transcription. No obvious associations were observed between the phenotypes of the nine patients, their F8 haplotypes and the putative mutations detected. The mutation-positive patients carrying the same haplotypes as the mutation-negative patients show a multitude of different mutations, emphasizing the lack of associations at the haplotype level. VWF mutation screening and factor V measurements ruled out type 2N VWD and combined factor V and VIII deficiencyrespectively. To further investigate a possible role for FVIII interacting factors the haplotypes/diplotypes of F2, F9, F10 and VWF were compared. The nine patients had no specific haplotype/diplotype combination in common that can explain disease. Duplications and faulty transcription contribute to the mutational spectrum of haemophilia A patients where conventional mutation screening fail to identify mutations.
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| 49. |
- Halldén, Christer, et al.
(författare)
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Origin of Swedish hemophilia A mutations
- 2012
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 10:12, s. 2503-2511
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Tidskriftsartikel (refereegranskat)abstract
- Background: Hemophilia A (HA) has a high level of variation within the disease class, with more than 1000 mutations being listed in the HAMSTeRS database. At the same time a number of F8 mutations are present in specific populations at high frequencies. Objectives: The simultaneous presence of large numbers of rare mutations and a small number of high-frequency mutations raises questions about the origins of HA mutations. The present study was aimed at describing the origins of HA mutations in the complete Swedish population. The primary issue was to determine what proportion of identical mutations are identical by descent (IBD) and what proportion are attributable to recurrent mutation events. The age of IBD mutations was also determined. Patients/Methods: In Sweden, the care of HA is centralized, and the Swedish HA population consists of 750 patients from > 300 families (35% severe, 15% moderate, and 50% mild). Identical haplotypes were defined by single-nucleotide polymorphism and microsatellite haplotyping, and the ages of the mutations were estimated with estiage. Results: Among 212 presumably unrelated patients with substitution mutations, 97 (46%) had mutations in common with other patients. Haplotyping of the 97 patients showed that 47 had IBD mutations (22%) with estimated ages of between two and 35 generations. The frequency of mild disease increased with an increasing number of patients sharing the mutations. Conclusions: A majority of the IBD mutations are mild and have age estimates of a few hundred years, but some could date back to the Middle Ages.
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| 50. |
- Halldén, Christer, et al.
(författare)
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Origin of Swedish hemophilia B mutations
- 2013
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 11:11, s. 2001-2008
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Tidskriftsartikel (refereegranskat)abstract
- Background More than 1100 mutations that cause hemophilia B (HB) have been identified. At the same time, specific F9 mutations are present at high frequencies in certain populations, which raise questions about the origin of HB mutations. ObjectivesTo describe the mutation spectrum of all HB families in Sweden and investigate if mutations appearing in several families are due to independent recurrent mutations (RMs) or to a common mutation event (i.e. are identical by descent (IBD)). Patients/MethodsThe registered Swedish HB population consists of patients from 86 families. Mutations were identified by resequencing and identical haplotypes were defined using 74 markers and a control population of 285 individuals. The ages of IBD mutations were estimated using ESTIAGE. ResultsOut of 77 presumably unrelated patients with substitution mutations, 47 patients (61%) had mutations in common with other patients. Haplotyping of the 47 patients showed that 24 patients had IBD mutations (51%) with estimated ages of between two and 23 generations. A majority of these patients had mild disease. Eight of the 15 mutations observed in more than one family were C>T transitions in CpG sites and all eight were RMs. ConclusionsThe association of IBD mutations with a mild phenotype is similar to what has been previously observed in hemophilia A. Noteworthy features of the mutations that are common to more than one family are the equal proportions of patients with RM and IBD mutations and the correlation between the occurrence of RMs and C>T transitions at CpG sites.
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