| 1. |
- Berntorp, Erik, et al.
(author)
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Haemophilia
- 2021
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In: Nature Reviews Disease Primers. - : Springer Science and Business Media LLC. - 2056-676X. ; 7:1
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Research review (peer-reviewed)abstract
- Haemophilia A and B are rare congenital, recessive X-linked disorders caused by lack or deficiency of clotting factor VIII (FVIII) or IX (FIX), respectively. The severity of the disease depends on the reduction of levels of FVIII or FIX, which are determined by the type of the causative mutation in the genes encoding the factors (F8 and F9, respectively). The hallmark clinical characteristic, especially in untreated severe forms, is bleeding (spontaneous or after trauma) into major joints such as ankles, knees and elbows, which can result in the development of arthropathy. Intracranial bleeds and bleeds into internal organs may be life-threatening. The median life expectancy was ~30 years until the 1960s, but improved understanding of the disorder and development of efficacious therapy based on prophylactic replacement of the missing factor has caused a paradigm shift, and today individuals with haemophilia can look forward to a virtually normal life expectancy and quality of life. Nevertheless, the potential development of inhibitory antibodies to infused factor is still a major hurdle to overcome in a substantial proportion of patients. Finally, gene therapy for both types of haemophilia has progressed remarkably and could soon become a reality.
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| 2. |
- Björkman, Sven, et al.
(author)
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Population pharmacokinetics of recombinant factor VIII : the relationships of pharmacokinetics to age and body weight
- 2012
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 119:2, s. 612-618
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Journal article (peer-reviewed)abstract
- Comparison of the pharmacokinetics (PK) of a coagulation factor between groups of patients can be biased by differences in study protocols, in particular between blood sampling schedules. This could affect clinical dose tailoring, especially in children. The aim of this study was to describe the relationships of the PK of factor VIII (FVIII) with age and body weight by a population PK model. The potential to reduce blood sampling was also explored. A model was built for FVIII PK from 236 infusions of recombinant FVIII in 152 patients (1-65 years of age) with severe hemophilia A. The PK of FVIII over the entire age range was well described by a 2-compartment model and a previously reported problem, resulting from differences in blood sampling, to compare findings from children and adults was practically abolished. The decline in FVIII clearance and increase in half-life with age could be described as continuous functions. Retrospective reduction of blood sampling from 11 to 5 samples made no important difference to the estimates of PK parameters. The obtained findings can be used as a basis for PK-based dose tailoring of FVIII in clinical practice, in all age groups, with minimal blood sampling.
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| 3. |
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| 4. |
- Chowdary, Pratima, et al.
(author)
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Modeling to Predict Factor VIII Levels Associated with Zero Bleeds in Patients with Severe Hemophilia A Initiated on Tertiary Prophylaxis
- 2020
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In: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 120:5, s. 728-736
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Journal article (peer-reviewed)abstract
- Background: Factor VIII (FVIII) trough levels > 1 IU/dL in patients with severe hemophilia A receiving regular prophylaxis may optimize bleed protection. Objectives: In this post hoc analysis of patients receiving tertiary prophylaxis for approximately 1 year, the relationship between estimated FVIII levels and reported bleeds was investigated to predict the potential for zero bleeds. Methods: Sixty-three patients (median [range] age, 28 [7-59] years) with severe hemophilia A (229 bleeds) were included. FVIII levels at time of each bleed were estimated from single-dose individual pharmacokinetics. The highest estimated FVIII level at which patients experienced a bleed was considered the potentially effective trough level for that bleed type. Kaplan-Meier estimates of proportions of patients with no bleeds above certain estimated FVIII levels were determined. Those not experiencing a bleed in the trial were assumed to have a bleed at 0 IU/dL (pragmatic approach) or at their median trough level (conservative approach). Results: Kaplan-Meier estimates based on pragmatic approach predicted zero all bleeds, joint bleeds, and spontaneous joint bleeds in 1 year in 40, 43, and 63% of patients, respectively, when the potentially effective trough FVIII level was set at 1 IU/dL. Between 1 and 10 IU/dL, every 1 IU/dL rise in estimated FVIII level was associated with an additional 2% of patients having zero all bleeds. Conclusion: This post hoc analysis confirms benefits with trough levels of approximately 1 to 3 IU/dL in most patients starting tertiary prophylaxis; prophylaxis with higher trough levels may help patients to achieve zero bleeds.
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| 5. |
- Doria, Andrea S., et al.
(author)
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Quantitative versus semiquantitative MR imaging of cartilage in blood-induced arthritic ankles: preliminary findings
- 2014
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In: Pediatric Radiology. - : Springer Science and Business Media LLC. - 1432-1998 .- 0301-0449. ; 44:5, s. 576-586
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Journal article (peer-reviewed)abstract
- Recent advances in hemophilia prophylaxis have raised the need for accurate noninvasive methods for assessment of early cartilage damage in maturing joints to guide initiation of prophylaxis. Such methods can either be semiquantitative or quantitative. Whereas semiquantitative scores are less time-consuming to be performed than quantitative methods, they are prone to subjective interpretation. To test the feasibility of a manual segmentation and a quantitative methodology for cross-sectional evaluation of articular cartilage status in growing ankles of children with blood-induced arthritis, as compared with a semiquantitative scoring system and clinical-radiographic constructs. Twelve boys, 11 with hemophilia (A, n = 9; B, n = 2) and 1 with von Willebrand disease (median age: 13; range: 6-17), underwent physical examination and MRI at 1.5 T. Two radiologists semiquantitatively scored the MRIs for cartilage pathology (surface erosions, cartilage loss) with blinding to clinical information. An experienced operator applied a validated quantitative 3-D MRI method to determine the percentage area of denuded bone (dAB) and the cartilage thickness (ThCtAB) in the joints' MRIs. Quantitative and semiquantitative MRI methods and clinical-radiographic constructs (Hemophilia Joint Health Score [HJHS], Pettersson radiograph scores) were compared. Moderate correlations were noted between erosions and dAB (r = 0.62, P = 0.03) in the talus but not in the distal tibia (P > 0.05). Whereas substantial to high correlations (r range: 0.70-0.94, P < 0.05) were observed between erosions, cartilage loss, HJHS and Pettersson scores both at the distal tibia and talus levels, moderate/borderline substantial (r range: 0.55-0.61, P < 0.05) correlations were noted between dAB/ThCtAB and clinical-radiographic constructs. Whereas the semiquantitative method of assessing cartilage status is closely associated with clinical-radiographic scores in cross-sectional studies of blood-induced arthropathy, quantitative measures provide independent information and are therefore less applicable for that research design.
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| 6. |
- Globe, Dennis, et al.
(author)
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Measuring patient-reported outcomes in haemophilia clinical research
- 2009
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In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 15:4, s. 843-852
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Research review (peer-reviewed)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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| 7. |
- Kenet, Gili, et al.
(author)
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Continued benefit demonstrated with BAY 81-8973 prophylaxis in previously treated children with severe haemophilia A : Interim analysis from the LEOPOLD Kids extension study
- 2020
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In: Thrombosis Research. - : Elsevier BV. - 1879-2472 .- 0049-3848. ; 189, s. 96-101
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Journal article (peer-reviewed)abstract
- INTRODUCTION: BAY 81-8973 (Kovaltry®), a recombinant factor VIII (rFVIII) product, was efficacious and well tolerated in paediatric previously treated patients (PTPs) with severe haemophilia A for ≥50 exposure days (EDs) in the LEOPOLD Kids study. Because long-term prophylaxis (≥100 EDs) can provide substantial patient benefits, FVIII products should demonstrate long-term safety and efficacy.AIM: To demonstrate long-term (≥100 EDs) efficacy and safety of BAY 81-8973 in paediatric PTPs.METHODS: PTPs aged ≤12 years with severe haemophilia A without inhibitors could continue in the ongoing open-label extension study after completing ≥50 EDs in the LEOPOLD Kids main study. Patients received BAY 81-8973 for prophylaxis (25-50 IU/kg ≥2×/week), bleed treatment, and surgery. Bleeds were documented in electronic patient diaries. Inhibitor development was monitored every 6 months.RESULTS: At the August 2017 interim data cutoff, 46 patients (median [range] age at enrolment, 6.0 [1.0-11.0] years) had spent a median (range) of 602.5 (148-1069) EDs and 4.6 (1.0-5.9) years in the main plus extension studies. Median (quartile [Q]1; Q3) annualised bleeding rate for bleeds within 48 h after a prophylaxis infusion and total bleeds was 1.0 (0.2; 1.9) and 2.0 (0.4; 3.6), respectively. Most (>94%) bleeds were mild or moderate; 71.8% were treated with ≤1 infusion. BAY 81-8973 was also well tolerated with only one treatment-related adverse event (transient, low-titre inhibitor which did not require treatment adjustment).CONCLUSION: BAY 81-8973 was efficacious for prophylaxis and treatment of bleeds during >4.5 years in paediatric PTPs with severe haemophilia A.
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| 8. |
- Rodeghiero, Francesco, et al.
(author)
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Fundamentals for a Systematic Approach to Mild and Moderate Inherited Bleeding Disorders : An EHA Consensus Report
- 2019
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In: HemaSphere. - 2572-9241. ; 3:5
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Journal article (peer-reviewed)abstract
- Healthy subjects frequently report minor bleedings that are frequently 'background noise' of normality rather than a true disorder. Nevertheless, unexpected or unusual bleeding may be alarming. Thus, the distinction between normal and pathologic bleeding is critical. Understanding the underlying pathologic mechanism in patients with an excessive bleeding is essential for their counseling and treatment. Most of these patients with significant bleeding will result affected by non-severe inherited bleeding disorders (BD), collectively denominated mild or moderate BD for their relatively benign course. Unfortunately, practical recommendations for the management of these disorders are still lacking due to the current state of fragmented knowledge of pathophysiology and lack of a systematic diagnostic approach. To address this gap, an International Working Group (IWG) was established by the European Hematology Association (EHA) to develop consensus-based guidelines on these disorders. The IWG agreed that grouping these disorders by their clinical phenotype under the single category of mild-to-moderate bleeding disorders (MBD) reflects current clinical practice and will facilitate a systematic diagnostic approach. Based on standardized and harmonized definitions a conceptual unified framework is proposed to distinguish normal subjects from affected patients. The IWG proposes a provisional comprehensive patient-centered initial diagnostic approach that will result in classification of MBD into distinct clinical-pathological entities under the overarching principle of clinical utility for the individual patient. While we will present here a general overview of the global management of patients with MBD, this conceptual framework will be adopted and validated in the evidence-based, disease-specific guidelines under development by the IWG.
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| 9. |
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| 10. |
- Tolend, Mirkamal, et al.
(author)
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Critical appraisal of the International Prophylaxis Study Group magnetic resonance image scale for evaluating haemophilic arthropathy
- 2020
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In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 26:4, s. 565-574
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Journal article (peer-reviewed)abstract
- A goal of the International Prophylaxis Study Group (IPSG) is to provide an accurate instrument to measure MRI-based disease severity of haemophilic arthropathy at various time points, so that longitudinal changes in disease severity can be identified to support decisions on treatment management. We review and discuss in this paper the evaluative purpose of the IPSG MRI scale in relation to its development and validation processes so far. We also critically appraise the validity, reliability and responsiveness of using the IPSG MRI scale in different clinical and research settings, and whenever applicable, compare these clinimetric properties of the IPSG MRI scale with those of its precursors, the compatible additive and progressive MRI scales.
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