| 1. |
- Clausen, Niels, et al.
(författare)
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Similar bleeding phenotype in young children with haemophilia A or B : A cohort study
- 2014
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 20:6, s. 747-755
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Tidskriftsartikel (refereegranskat)abstract
- The bleeding phenotype has been suggested to differ between haemophilia A and B. More knowledge on the bleeding phenotype at initiation of treatment is important to optimize patient care. The aim of this study was to investigate the severity of the bleeding phenotype and the variation in bleeding in children with severe or moderate haemophilia A and B. Consecutive, previously untreated patients with severe or moderate haemophilia A and B (factor VIII or IX activity <0.01 or 0.01-0.05 IU mL-1 respectively) born between January 1st 2000 and January 1st 2010 were included. Primary outcome was severity of bleeding tendency. Secondary outcome was variation in bleeding pattern. A total of 582 patients with severe haemophilia A and 76 with severe haemophilia B did not differ in age at first exposure to clotting factor (0.81 vs. 0.88 years, P = 0.20), age at first bleed (0.82 vs. 0.88 years, P = 0.36), and age at first joint bleed (1.18 vs. 1.20 years, P = 0.59). Patients with moderate haemophilia were older compared to patients with severe haemophilia. In patients with moderate haemophilia there were no clear differences between haemophilia A and B. Severity and variation in bleeding phenotype are similar during the early stage of treatment in patients with severe and moderate haemophilia A and B respectively. The findings imply that children with haemophilia B should be observed and treated as vigilantly as those with haemophilia A.
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| 2. |
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| 3. |
- Berntorp, E., et al.
(författare)
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European retrospective study of real-life haemophilia treatment
- 2017
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 23:1, s. 105-114
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Haemophilia treatment varies significantly between individuals, countries and regions and details of bleed rates, factor consumption and injection frequency are often not available. Aim: To provide an overview of the FVIII/FIX treatment practice and outcome for patients with haemophilia A (HA) or haemophilia B (HB) across Europe. Methods: Non-interventional, 12-month retrospective study where anonymized data were retrieved from haemophilia centres/registers in Belgium, France, Germany, Italy, Spain, Sweden and the United Kingdom. Male patients (all ages) receiving coagulation factor treatment 24 months prior to the study, with basal FVIII/FIX levels ≤5 IU dL-1, without inhibitors, were included. Data were summarized descriptively. Results: In total, 1346 patients with HA and 312 with HB were included in the analysis; 75% and 57% had severe disease (FVIII/FIX < 1 IU dL-1) respectively. Prophylaxis was most common for severe haemophilia, especially for children, whereas on-demand treatment was more common for moderate haemophilia in most countries. The mean (SD) prescribed prophylactic treatment ranged from 67.9 (30.4) to 108.4 (78.1) (HA) and 32.3 (10.2) to 97.7 (32.1) (HB) IU kg-1 per week, across countries. Most patients on prophylaxis were treated ≥3 times/week (HA) or two times/week (HB). The median annual bleeding rate (ABR) for patients on prophylaxis ranged from 1.0 to 4.0 for severe HA, and from 1.0 to 6.0 for severe HB, while those with moderate haemophilia generally had slightly higher ABRs. Median ABRs for on-demand-treated severe HA ranged from 4.5 to 18.0, and for HB, 1.5 to 14.0. Conclusion: Treatment practice varied greatly between centres and countries and patients treated on-demand and prophylactically both experienced bleeds, emphasizing the need for further optimization of care.
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| 4. |
- Eckhardt, CL, et al.
(författare)
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Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A
- 2013
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 122:11, s. 1954-1962
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Tidskriftsartikel (refereegranskat)abstract
- The inhibitor incidence in nonsevere hemophilia A patients with certain F8 mutations approaches the inhibitor incidence in severe patients. These findings are highly relevant for clinical practice, as they facilitate identification of high-risk patients based on F8 genotype.
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| 5. |
- Hermans, C., et al.
(författare)
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Pharmacokinetic modelling and validation of the half-life extension needed to reduce the burden of infusions compared with standard factor VIII
- 2018
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 24:3, s. 376-384
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Currently, no universally accepted definition of extended half-life (EHL) recombinant FVIII (rFVIII) exists. Identifying the minimum half-life extension ratio required for a reduction in dosing frequency compared with standard rFVIII could enable a more practical approach to decisions around prophylaxis with EHL rFVIII. Aim: To identify the half-life extension ratio required to decrease rFVIII dosing frequency by at least 1 day while maintaining the proportion of patients with plasma rFVIII levels above 1 IU/dL and without increasing the total weekly dose. Methods: A previously published population pharmacokinetic model for standard rFVIII was used to estimate the percentage of patients with factor VIII (FVIII) levels always >1 IU/dL using various benchmark regimens. Using modelling, dosing frequency was reduced while rFVIII half-life was extended until the percentage of patients with FVIII >1 IU/dL equalled that of the benchmark regimen. Results: Benchmark 3×/wk dosing totalling 100 IU/kg/wk of rFVIII resulted in 56.6% of patients with FVIII levels always >1 IU/dL. With 2×/wk dosing, totalling 80 or 90 IU/kg/wk, half-life extensions required to maintain 56.6% of patients at FVIII levels >1 IU/dL were 1.30 and 1.26, respectively. A half-life extension ratio of 1.33 was required to change dosing from every 48 hours to every 72 hours (both at 105 IU/kg/wk) while maintaining 92.8% of patients with FVIII >1 IU/dL. Conclusion: Based on this investigation, EHL rFVIII products should have a minimum half-life extension ratio of 1.3 to provide a reduction in dosing frequency from 3× to 2×/wk compared with standard rFVIII products while maintaining the same minimum FVIII trough level.
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| 6. |
- Mahlangu, J., et al.
(författare)
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Defining extended half-life rFVIII-A critical review of the evidence
- 2018
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 24:3, s. 348-358
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Recent haemophilia treatment advances include new recombinant FVIII (rFVIII) products with improved pharmacokinetic (PK) properties that aim to reduce the burden of prophylaxis. These treatments are commonly referred to as extended half-life rFVIII products (EHL rFVIII). There is no uniform definition of what constitutes an EHL rFVIII. Such a definition would help physicians, patients and funders understand the properties of standard and EHL rFVIIIs and thus provide clarity when selecting an EHL in clinical settings. Aim: To critically assess the published evidence on new and emerging rFVIII products in order to propose a definition to classify EHL rFVIIIs. Methods: We systematically searched PubMed, EMBASE and regulatory authorities (FDA/EMA/Health Canada) websites for publications and regulatory submissions describing prospective crossover PK studies evaluating rFVIIIs that demonstrate improved PK parameters in adults and adolescents with severe haemophilia A. Results: Following critical analyses of the published data, we developed a holistic approach to defining rFVIIIs as EHLs, which requires all of the following: (i) using technology designed to extend rFVIII half-life; (ii) lacking bioequivalence with a standard rFVIII comparator-above the FDA/EMA cut-off of 125% for the 90% confidence intervals for area under the curve ratio; and (iii) having an extended half-life ratio measured in a PK comparator crossover study. Conclusion: In this systematic review, a pragmatic definition of EHL rFVIII has been proposed that should provide better clarity in clinical discussions surrounding the appropriate use of rFVIII products. At present, only products using PEGylation or Fc fusion half-life extension technology meet the proposed criteria for definition of EHL rFVIII.
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| 7. |
- Reipert, B M, et al.
(författare)
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The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development
- 2020
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 4:22, s. 5785-5796
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Tidskriftsartikel (refereegranskat)abstract
- Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products ("true PUPs") and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.
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| 8. |
- Rodriguez-Merchan, E. C., et al.
(författare)
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Joint protection in haemophilia
- 2011
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 17, s. 1-23
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Tidskriftsartikel (refereegranskat)abstract
- Haemarthroses (intra-articular haemorrhages) are a frequent finding typically observed in patients with haemophilia. Diagnosis and treatment of these bleeding episodes must be delivered as early as possible. Additionally, treatment should ideally be administered intensively (enhanced on-demand treatment) until the resolution of symptoms. Joint aspiration plays an important role in acute and profuse haemarthroses as the presence of blood in the joint leads to chondrocyte apoptosis and chronic synovitis, which will eventually result in joint degeneration (haemophilic arthropathy). Ultrasonography (US) is an appropriate diagnostic technique to assess the evolution of acute haemarthrosis in haemophilia, although magnetic resonance imaging remains the gold standard as far as imaging techniques are concerned. Some patients experience subclinical haemarthroses, which eventually tend to result in some degree of arthropathy, especially in the ankles. Nowadays, the most effective way of protecting these patients is primary prophylaxis, which in practice changes severe haemophilia into moderate haemophilia, preventing or at least minimizing the occurrence of haemarthrosis. If primary prophylaxis is, for whatever reason not an option, secondary prophylaxis and enhanced on demand treatment should be considered. Two alternatives are available for inhibitor patients: (i) control of haemostasis using by-passing agents (rFVIIa or aPCCs) either as enhanced on demand treatment or secondary prophylaxis, as appropriate, following the same basic principles used for non-inhibitor patients and (ii) immune tolerance induction (ITI) to eradicate the inhibitor.
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| 9. |
- Rodriguez-Merchan, E. C., et al.
(författare)
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Prevention of haemophilic arthropathy during childhood. May common orthopaedic management be extrapolated from patients without inhibitors to patients with inhibitors?
- 2008
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 14:Suppl. 6, s. 68-81
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Tidskriftsartikel (refereegranskat)abstract
- We recommend prophylaxis in haemophilic children with an inhibitor as a way of preventing the musculoskeletal impairment that is likely to affect them. This approach has been used for children without inhibitors with excellent results. If prophylaxis is not feasible, we suggest that intensive on-demand treatment should be given. Two agents, recombinant activated FVII (rFVIIa) and activated prothrombin complex concentrates (aPCC), are currently used to control haemostasis either for prophylaxis or intensive on-demand treatment. As it is recombinant, rFVIIa would seem more appropriate to be employed in children. aPCC could be used in adults, or in the event of an unsatisfactory response to rFVIIa. We recommend prophylaxis or, at least, intensive on-demand treatment in haemophilia children with inhibitors. Both rFVIIa and aPCC are being used for this purpose. It would seem that rFVIIa might be more appropriate for children as it is a recombinant product. Nevertheless, after skeletal maturity (in adults), both agents could be used indistinctively (taking into consideration that FEIBA is a plasma-derived product). We still need more well-designed comparative studies in order to be able to assert that our consensus-based conclusion is evidence based. In orthopaedic surgery, both aPCC and rFVIIa have been reported to be effective in controlling perioperative haemostasis, although in practice most centres have so far used rFVIIa for their orthopaedic procedures. We recommend rehabilitation programmes for all patients with inhibitors in order to mitigate the disabling and handicapping impact of their condition and thereby enable them to achieve social integration. Programmes for haemophilic children without inhibitors can be applied to children with inhibitors but should be individually tailored.
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| 10. |
- Salek, S. Z., et al.
(författare)
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The need for speed in the management of haemophilia patients with inhibitors
- 2011
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 17:1, s. 95-102
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Tidskriftsartikel (refereegranskat)abstract
- Rapid control of bleeding is the key to reducing bleeding complications and thereby preserving joint and musculoskeletal function in haemophilia patients with inhibitors. However, this requires early diagnosis following the onset of bleeding and strategies for rapid treatment in an outpatient setting. Overarching themes on the need for speed in managing bleeds in haemophilia patients were examined by a panel of clinicians experienced in managing inhibitor patients and joint disease during the Third Zurich Haemophilia Forum on 8 May 2009. This report summarizes the opinions of the panel on how to achieve rapid bleeding control in inhibitor patients and areas that were identified by the panel for future research or as needing new consensus guidelines. The consensus was that home treatment should be established for haemophilia patients with inhibitors, as it is associated with a faster time to treatment, as well as improvements in the quality of life of patients and their carers. In addition, as improved haemostatic control now allows inhibitor patients to participate in a wider range of physical activities, specific guidelines are required on which types of sport and work are appropriate. It was agreed that clear, systematic approaches are needed for early diagnosis of joint and muscle bleeds in inhibitor patients, which could facilitate rapid treatment. There may be opportunities for exploiting new diagnostic techniques from osteoarthritis to enable earlier diagnosis of haemophilic arthropathy. Overall, it was concluded that greater emphasis should be placed on education and patients' psychological needs, to enable inhibitor patients to cope up more effectively with their disease.
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| 11. |
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| 12. |
- Astermark, Jan, et al.
(författare)
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Clinical issues in inhibitors
- 2010
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 16, s. 54-60
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Forskningsöversikt (refereegranskat)abstract
- Anamestic inhibitors represent the major complication of haemophilia therapy now that clotting factor concentrates are virtually free of pathogen-transmission risk. Conventional clotting factor replacement is usually insufficient to prevent or treat bleeding in a haemophilia patient with a high responding inhibitor so that alternative treatment with bypassing agents is required. Despite their relative efficacy, their use does not achieve the same invariable haemostasis that patients without inhibitors do following treatment with factor concentrate replacement. This has led to the attempt to eradicate such inhibitors with immune tolerance induction. Success is not invariable, however, and many patients with long-term persistent high-titre inhibitors continue to experience great morbidity. Recently, this has given rise on a limited basis to attempts to use bypassing agents in prophylaxis regimens in an effort to alleviate this extreme morbidity. Each of these strategies is discussed in the context of their relative benefits and risks.
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| 13. |
- Berntorp, Erik, et al.
(författare)
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Pharmacokinetics, phenotype and product choice in haemophilia B: how to strike a balance?
- 2014
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 20, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- At the 7th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD) held in Brussels, Belgium, in February 2014, Pfizer sponsored a satellite symposium entitled: "Pharmacokinetics, phenotype and product choice in haemophilia B: How to strike a balance?" Co-chaired by Cedric Hermans (Cliniques Universitaires Saint Luc, Brussels, Belgium) and Mike Laffan (Imperial College, London, UK), the symposium provided an opportunity to debate whether pharmacokinetic (PK) parameters are good surrogates for clinical efficacy for haemophilia B in clinical practice, consider the perceptions and evidence of disease severity, and examine how these considerations can inform approaches to balancing the potential risks and benefits of the currently available treatment options for haemophilia B. PK parameters are routinely measured in clinical practice and are a requirement of regulatory bodies to demonstrate the clinical efficacy of products; however, the relationship between measured PK parameters and clinical efficacy is yet to be determined, an issue that was debated by Gerry Dolan (University Hospital, Queen's Medical Centre, Nottingham, UK) and Erik Berntorp (Lund University, Malmö Centre for Thrombosis and Haemostasis, Malmö, Sweden). Elena Santagostino (Universita degli Studi di Milano, Milano, Italy) reviewed how differing perceptions on the severity of haemophilia B compared with haemophilia A may have an impact on clinical decision-making. Finally, Andreas Tiede (Hannover Medical School, Hannover, Germany), examined the considerations for balancing the potential risks and benefits of the currently available treatment options for haemophilia B. Although the pathophysiology of haemophilia B has been widely studied and is largely understood, continued investigation and discussion around the optimal management course and appropriate therapeutic choice is warranted.
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| 14. |
- 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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| 15. |
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| 16. |
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| 17. |
- Matino, D., et al.
(författare)
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Switching clotting factor concentrates: considerations in estimating the risk of immunogenicity
- 2014
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 20:2, s. 200-206
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Tidskriftsartikel (refereegranskat)abstract
- The development of neutralizing antibodies to factor VIII (FVIII) is the most serious complication of therapy for haemophilia A. There is now excellent documentation that a large number of both genetic and environmental factors contribute to the risk of FVIII inhibitor incidence. One of the environmental factors that has been proposed as an influence on this complication is the occurrence of FVIII product switching. There are only a small number of clinical studies that have addressed this question, and thus, the amount of objective information available to assess this association is limited. In this review, in addition to summarizing past evidence pertinent to this subject, we present the results of a complementary strategy, a Delphi analysis, to add to the considerations of product switching and FVIII immunogenicity. With the imminent arrival in the clinic of several new FVIII products, the haemophilia community must be prepared to collect prospectively controlled data to better address this important management issue.
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| 18. |
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| 19. |
- Santagostino, E., et al.
(författare)
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Paediatric haemophilia with inhibitors: existing management options, treatment gaps and unmet needs
- 2009
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 15:5, s. 983-989
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Forskningsöversikt (refereegranskat)abstract
- Development of inhibitors is a severe complication of haemophilia posing many management challenges. While a long-term goal in inhibitor patients is eradication of inhibitors through immune tolerance induction, bypassing agents such as recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC) are essential for control of bleeding episodes. Paediatric patients with haemophilia and inhibitors are at particular risk of recurrent haemarthroses, and management of these patients should seek to avoid joint damage and support the child's full social and physical development. Current options for management of bleeding complications include on-demand treatment of acute bleeding episodes, secondary prophylaxis to avoid recurrent bleeds and surgery to treat affected joints. There is also a rationale for adopting prophylactic approaches to prevent bleeding in inhibitor patients, allowing this group similar opportunities for protection against arthropathy development as are given to non-inhibitor patients. This paper, based on a roundtable meeting of haematology experts at the first Zurich Haemophilia Forum in May 2008, reviews the current evidence supporting more intense and prophylactic approaches to manage bleeding risk in paediatric haemophilia patients with inhibitors, and highlights the need for investigations of primary prophylaxis in this vulnerable patient group, to support best long-term outcome.
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