HTCN Investigators. Increased prevalence of inhibitors in Hispanic patients with severe haemophilia A enrolled in the Universal Data Collection database
Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO 64108, USA. Haemophilia
(Impact Factor: 2.6).
01/2012; 18(3):e260-5. DOI: 10.1111/j.1365-2516.2011.02739.x
Neutralizing inhibitors develop in 20-30% of patients with severe factor VIII (FVIII) deficiency. It is well established that Blacks have a higher prevalence of inhibitors than Whites. This is the first study to definitively demonstrate increased inhibitor prevalence in the Hispanic population. We compared inhibitor prevalence among various racial and ethnic groups in a cross-sectional analysis of 5651 males with severe haemophilia A that participated in the Universal Data Collection project sponsored by the Centers for Disease Control and Prevention. We used logistic regression analysis to control for potential confounding variables. We assigned as Hispanic those participants who were white and labelled themselves Hispanic. The prevalence of high-titre inhibitors in the Hispanic participants was 24.5% compared to 16.4% for White non-Hispanic patients (OR 1.4, 95% CI 1.1, 1.7). Possibilities as to the underlying cause of increased inhibitor prevalence in minority ethnic populations include polymorphisms in the FVIII molecule, HLA subtypes and differing inflammatory responses. A better understanding may lead to tailored treatment programmes, or other therapies, to decrease or prevent inhibitor development.
Available from: Judith R Baker
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ABSTRACT: Hemophilia is the most common inherited severe bleeding disorder. Although the most frequent complication of repeated hemorrhages is a crippling joint disease that begins in childhood, the extent of resultant joint functional impairment varies widely within the hemophilia population.
The goal of this exploratory analysis was to examine a national database that collects information on boys with hemophilia, an X-linked severe congenital bleeding disorder, to determine characteristics associated with increased risk of developing limitations in physical functioning as an outcome of recurrent hemorrhages.
A standard set of data is collected annually at ∼130 U.S. comprehensive hemophilia treatment centers (HTCs) in a voluntary surveillance program called the Universal Data Collection (UDC) program. Fifteen potential predictors for poor outcomes of physical functioning related to bleeding were examined for boys (aged ≤ 18 years) from 1998 to 2008. Bivariate and multivariate analyses of these predictors performed in 2009 examined associations with self-reported limitation of activities, absenteeism from work or school, and reliance on assistive devices for ambulation and mobility.
Multiple characteristics of underlying hemophilia severity and disease chronicity (in particular, increasing age, presence of joint bleeding, and inhibitor antibodies) were independently associated with increased risk of limitations of physical function. Nonwhite race/ethnicity was associated with each of the poorer functional outcomes in bivariate analyses. After controlling for the potential confounding effects of the multiple population characteristics on race, only African-American race was independently associated with activity restrictions, and African-American and Asian/Pacific Island ethnicity with absenteeism. With the exception of indicators of underlying disease severity, only obesity and medical insurance coverage with Medicaid rather than commercial insurance were independently associated with multiple poor outcomes.
Interventions focused on eliminating inhibitors, improving outcomes for African-American children with hemophilia, and maintaining healthy body weight are warranted. In addition, strategies are needed to assure adequate insurance coverage for all people with hemophilia to eliminate economic barriers to optimal functional outcomes.
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ABSTRACT: The review describes recent advances in our understanding of mechanisms leading to development of neutralizing antibodies following factor VIII (FVIII) replacement therapy for hemophilia A. Novel interventions with translational potential to lessen the incidence of these deleterious immune responses are discussed.
Genetic and environmental risk factors for inhibitor development, and cellular mechanisms leading to antibody production versus immune tolerance to FVIII, are increasingly coming into focus. Human and animal model studies are identifying T-cell and B-cell epitopes in FVIII and characterizing the presentation of naturally processed FVIII peptides on antigen-presenting cells (APCs). Novel methods to promote immune tolerance include decreasing FVIII uptake by APCs, modifying co-stimulatory pathways, inducing regulatory T-cell production, and presenting FVIII antigen to immature dendritic cells in a tolerance-promoting manner. A complementary approach to reduce inhibitor incidence is the design of less immunogenic FVIII proteins through epitope modification.
Studies of FVIII immunogenicity are revealing mechanisms of anti-FVIII immune responses, suggesting new approaches to reduce the incidence of inhibitors. Rational design of FVIII variants is producing less immunogenic proteins targeted to specific patient sub-populations. Future therapies will likely involve administration of less immunogenic FVIII proteins under conditions that promote immune tolerance.
Available from: europepmc.org
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ABSTRACT: Factor VIII (FVIII) replacement therapy is the foundation of treatment in hemophilia A and is effective unless a patient develops an alloantibody (inhibitor) against exogenous FVIII. Inhibitor development is currently the most significant treatment complication seen in patients with hemophilia and is associated with considerable morbidity and a decreased quality of life. The development of an inhibitor is the result of a complex interaction between a patient's immune system and genetic and environmental risk factors. The mainstay of treatment is the eradication of the inhibitor through immune tolerance. This review summarizes the current evidence regarding inhibitor risk factors, eradication, and hemostatic bypassing agents.
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