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Environmental and genetic factors influencing inhibitor development.
- Source :
-
Seminars in hematology [Semin Hematol] 2004 Jan; Vol. 41 (1 Suppl 1), pp. 82-8. - Publication Year :
- 2004
-
Abstract
- Inhibitor formation occurs at a frequency of 20% to 30% in severe hemophilia A, and 3% in hemophilia B. Today, it represents the major complication in patient care and renders classical substitution therapy ineffective. Genetic factors, such as factor VIII (FVIII) gene mutations and immune response genes, particularly the major histocompatibility complex, have been shown to constitute decisive risk factors for the development of inhibitors. In severe hemophilia A and B, those mutations that result in the absence or severe truncation of the FVIII/factor IX (FIX) proteins are associated with the highest risk for inhibitor formation, indicating that a major driving force in inhibitor development is the presentation of a novel antigen to the patient's immune system. An alternative pathomechanism may underlie inhibitor development in patients with mild hemophilia A. Missense mutations, especially those in the C1/C2 domains, may alter the immunogenicity of the FVIII protein, eliciting an inhibitor response against the mutated epitope. In some patients with hemophilia B, especially those with large deletions to the FIX gene, a severe allergic reaction occurs simultaneously with inhibitor onset. Despite the obviously strong genetic predisposition, discordant inhibitor status in monozygotic hemophilia A twins demonstrates that environmental factors also play a role in the development of inhibitors.
- Subjects :
- Alleles
Antibodies blood
Blood Coagulation Factor Inhibitors genetics
Environmental Exposure adverse effects
Epitopes genetics
Epitopes immunology
Factor IX genetics
Factor IX immunology
Factor VIII adverse effects
Factor VIII genetics
Factor VIII immunology
Factor VIII therapeutic use
Genes, MHC Class I immunology
Genes, MHC Class II immunology
Hemophilia A blood
Hemophilia A etiology
Hemophilia B blood
Hemophilia B etiology
Humans
Mutation immunology
Blood Coagulation Factor Inhibitors immunology
Hemophilia A genetics
Hemophilia A immunology
Hemophilia B genetics
Hemophilia B immunology
Subjects
Details
- Language :
- English
- ISSN :
- 0037-1963
- Volume :
- 41
- Issue :
- 1 Suppl 1
- Database :
- MEDLINE
- Journal :
- Seminars in hematology
- Publication Type :
- Academic Journal
- Accession number :
- 14872427
- Full Text :
- https://doi.org/10.1053/j.seminhematol.2003.11.016