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| 2. |
- Astermark, Jan, et al.
(author)
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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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In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 121:8, s. 1446-1454
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Journal article (peer-reviewed)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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| 3. |
- Gomperts, Edward D., et al.
(author)
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From theory to practice: Applying current clinical knowledge and treatment strategies to the care of hemophilia A patients with inhibitors
- 2008
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In: Blood Reviews. - 1532-1681. ; 22:Suppl 1, s. 1-11
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Research review (peer-reviewed)abstract
- Two bypassing agents are currently available to circumvent the need for factor FVIII in hemophilia A patients with inhibitors: the activated prothrombin complex FEIBA VH and recombinant activated factor VII (NovoSeven (R)). Both products are highly effective in controlling bleeding in the presence of inhibitory alloantibodies, yet their hemostatic efficacy can be unpredictable. As the results of the FEIBA NovoSeven (R) Comparative (FENOC) study illustrate, patients may respond better to one bypassing agent than the other. Furthermore, guidelines from an expert panel reflect that responsiveness to bypassing therapy may change from one bleed to the next in the same patient and even from hour to hour during the course of a single bleeding event. These findings underscore the need to have both bypassing products available to treat bleeding episodes in inhibitor patients, to frequently evaluate the efficacy of hemostasis during the course of a bleeding event, and to switch products early if the response to treatment is unsatisfactory. (C) 2008 Elsevier Ltd. All rights reserved.
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| 4. |
- Gomperts, Edward D, et al.
(author)
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The importance of genetic factors for the development of arthropathy : A longitudinal study of children and adolescents with haemophilia A
- 2017
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In: Thrombosis and Haemostasis. - 0340-6245. ; 117:2, s. 277-285
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Journal article (peer-reviewed)abstract
- Haemophilia A is a congenital bleeding disorder characterised by recurrent haemorrhages into the major joints. Haemophilic arthropathy is a well-established outcome of recurrent joint bleeding; however, it is clear that multiple factors determine the extent and severity of its occurrence. We sought to identify genetic factors related to abnormalities in range of motion (ROM) in the knees, ankles and elbows in a cohort of children and adolescents with haemophilia A not treated primarily with regular prophylaxis. Using data from the Haemophilia Growth and Development Study, we examined associations between 13,342 genetic markers and ROM scores measured at six-month intervals for up to seven years. As a first step, ordered logistic regression models were fit for each joint separately. A subset of SNP markers showing significant effects (p < 0.01) on the right and left sides for at least two joints were included in a full model fit using a multivariate generalised linear mixed model assuming an ordinal response. The models contained all ROM scores obtained at all visits. Twenty-five markers analysed in the full model showed either increased or decreased risk of ROM abnormalities at the p<0.001 level. Several genes identified at either the first or second stage of the analysis have been associated with arthritis in a variety of large studies. Our results support the likelihood that risk for haemophilic arthropathy is associated with genetic factors, the identification of which holds promise for further advancing the individualisation of treatment.
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