| 1. |
- Astermark, Jan, et al.
(författare)
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The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort.
- 2013
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 121:8, s. 1446-1454
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Tidskriftsartikel (refereegranskat)abstract
- Studies of determinants of development of inhibitory antibodies to factor VIII in people with hemophilia A indicate a complex process involving multiple factors. The Hemophilia Inhibitor Genetics Study Combined Cohort was formed to extend understanding of the genetic background of risk. The study group contains 833 subjects from three independent cohorts: brother pairs and singletons with and without a history of inhibitors, as well as 104 brother pairs discordant for inhibitor status. Using an Illumina iSelect platform, 13,331 SNPs from 1,081 genes, primarily immune response and immune modifier genes, were typed. Each cohort was analyzed separately with results combined using a meta-analytic technique. After adjustment for potential confounders, 53 SNPs were significant predictors of inhibitor status using the criteria of odds ratios (OR) in the same direction in all cohorts, or allowing for a 20% interval around an OR of 1 in one of the three, and significant in at least two. Of the 53, 13 markers had meta p-values of <0.001. Eight of the 53 were significant predictors among the discordant pairs. Results support the complexity of the immune response, and encourage further research with the goal of understanding the pathways involved.
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| 2. |
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| 3. |
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| 4. |
- Astermark, Jan, et al.
(författare)
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Arandomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study.
- 2009
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Ingår i: Gematologiâ i Transfuziologiâ. - 0234-5730. ; 54:5, s. 35-35
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Tidskriftsartikel (refereegranskat)abstract
- Arandomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. J. Astermark(1), Sh. M. Donfield(2), D. M. DiMichele(3), A. Gringeri(4), S. A. Gilbert(2), J. Waters(2), E. Berntorp(1), for the FENOC Study Group. Department for Hematology and Coagulation Disorders, Malmo, University Hospital, Malmo, Sweden(1); Department of Biostatistics, Rho, Chapel Hill, NC2; Department of Pediatrics, Weill Medical College, Cornell University, New York, NY3; Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, University of Milan, Italy(4). The development of inhibitory antibodies to factor VIII is a serious complication of hemophilia. FEIBA (factor VIII inhibitorbypassing activity), an activated prothrombin complex concentrate (aPCC), and NovoSeven, recombinant factor Vila (rFVIIa), are used as hemostatic bypassing agents in treating patients with inhibitors. The FENOC study was designed to test equivalence of the products in the treatment of ankle, knee, and elbow joint bleeding. A prospective, open-label, randomized, crossover, equivalency design was used. The parameters of interest were the percentage of patients who reported efficacy in response to FEIBA and the percentage that reported efficacy in response to NovoSeven. A difference in these percentages of no more than 15% was determined to be a clinically acceptable magnitude for equivalence of the 2 products. The primary outcome was evaluation 6 hours after treatment. Data for 96 bleeding episodes contributed by 48 participants were analyzed. The criterion for declaring the 2 products equivalent at 6 hours was not met; however, the confidence interval of the difference in percentages of efficacy reported for each product only slightly exceeded the 15% boundary (11.4-15.7%); p = 0.059. FEIBA and NovoSeven appear to exhibit a similar effect on joint bleeds, although the efficacy between products is rated differently by a substantial proportion of patients. This trial was registered at www.clinicaltrials.gov.
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| 5. |
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| 6. |
- Berntorp, Erik, et al.
(författare)
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Inhibitor treatment in haemophilas A and B: Summary statement for the 2006 International Consensus Conference
- 2006
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 12, s. 41281-41281
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Tidskriftsartikel (refereegranskat)abstract
- Participants in an international conference on the management of haemophilia patients with inhibitors developed a jointly authored summary of the findings and conclusions of the conference. Current knowledge of the genetic and immunologic mechanisms underlying inhibitor development was briefly summarized. Concerning the purported treatment-related risk factors, conference participants commented on the limitations of the available evidence and the need for more rigorous prospective research in a fully genotyped population. Other clinical considerations discussed included the unproved utility of routine surveillance, the need for assay standardization, the management of acute bleeding and approaches to joint disease prophylaxis and immune tolerance induction (ITI). A number of issues were identified as needing further investigation in larger prospective studies, ideally through international cooperation. Such studies should enrol cohorts that have been scrupulously defined in terms of mutation status and treatment exposure. Finally, conference participants urged their colleagues to participate in the currently ongoing international trials of ITI.
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| 7. |
- Dimichele, D M, et al.
(författare)
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Clinical trial design in haemophilia.
- 2012
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 18 Suppl 4, s. 18-23
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Tidskriftsartikel (refereegranskat)abstract
- Summary: Progress in the evidence-based care of haemophilia A and B worldwide has been historically challenged by the dearth of evaluable outcome data, including but not limited to the safety and effectiveness of therapeutic interventions. These challenges are partially rooted in the inherent difficulty of conducting prospective clinical trials and observational studies with statistically meaningful endpoints in a rare disease such as haemophilia. Despite the logistical barriers, the need for outcome data has never been more critical than in this time of expansive therapeutic advance tempered by the shrinking economic capacity to fund the rapidly increasing cost of treatment. Given that systematic analyses of published literature have been largely unsuccessful in compensating for the lack of rigorous and purposeful data collection, new approaches to clinical study design and statistical modelling are urgently needed. However, even as these are considered, the lack of broadly accepted and well-defined clinical outcome endpoints poses an additional barrier to progress. The three presentations encompassed by this paper highlight the timely need for quality data from the perspectives of the clinicians, regulatory agencies and health care funders, and describe the ongoing coordinated efforts by the international haemophilia community to further understand and dismantle the barriers to harmonized and standardized data collection on a global scale using well-defined clinical outcome endpoints.
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| 8. |
- Ljung, Rolf, et al.
(författare)
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Haemophilia in the first years of life.
- 2008
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 14 Suppl 3, s. 188-195
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Tidskriftsartikel (refereegranskat)abstract
- Surgery in infants and young children with haemophilia, when preceded by accurate diagnosis and accompanied by safe and effective factor prophylaxis, is not associated with a significant risk of haemorrhage. Haemophilic newborns undergoing circumcision or major surgery prior to diagnosis and in the absence of appropriate haemostatic prophylaxis remain as a concern. Inhibitor development has replaced haemorrhage as the major surgical complication in the developed world, largely because of the intensity of treatment used to secure haemostasis. For that reason only, essential surgery should be performed. Intracranial haemorrhage (ICH) during the neonatal period affects 3.5-4.0% of all haemophilia boys in countries with a good standard of health care, which is considerably (40-80 times) higher than expected in the normal population. Because of the high frequency of sporadic cases, ICH in the neonatal period can only be partially prevented by improved carrier diagnosis and counselling. Infections and thrombosis are the major serious complications of central venous lines. Large differences are seen in the frequency of these complications, the most plausible explanations are probably related to the protocol used for device care, the quality of education and the compliance of the users, an issue addressed in an on-going study.
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