Inhibitors in hemophilia A: mechanisms of inhibition, management and perspectives
Factor VIII (FVIII) replacement therapy remains the mainstay in hemophilia A care. The major complication of replacement therapy is formation of antibodies, which inhibit FVIII activity, thus dramatically reducing treatment efficiency. The present review summarizes the accumulated knowledge on epito...
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Published in | Blood coagulation & fibrinolysis Vol. 15; no. 2; p. 109 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
01.03.2004
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Abstract | Factor VIII (FVIII) replacement therapy remains the mainstay in hemophilia A care. The major complication of replacement therapy is formation of antibodies, which inhibit FVIII activity, thus dramatically reducing treatment efficiency. The present review summarizes the accumulated knowledge on epitopes of FVIII inhibitors and mechanisms of their inhibitory effects. FVIII inhibitors most frequently target the A2, C2 and A3 domains of FVIII and interfere with important interactions of FVIII at various stages of its functional pathway; a class of FVIII inhibitors inactivates FVIII by proteolysis. We discuss therapeutic approaches currently used for treatment of hemophilia A patients with inhibitors and analyze the factors that influence the outcome. The choice between options should depend on the level of inhibitors and consideration of efficacy, safety, and availability of particular regimens. Advances of basic science open avenues for alternative targeted, specific and long-lasting treatments, such as the use of peptide decoys for blocking FVIII inhibitors, bypassing them with human/porcine FVIII hybrids, neutralizing FVIII-reactive CD4 T cells with anti-clonotypic antibodies, or inducing immune tolerance to FVIII with the use of universal CD4 epitopes or by genetic approaches. |
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AbstractList | Factor VIII (FVIII) replacement therapy remains the mainstay in hemophilia A care. The major complication of replacement therapy is formation of antibodies, which inhibit FVIII activity, thus dramatically reducing treatment efficiency. The present review summarizes the accumulated knowledge on epitopes of FVIII inhibitors and mechanisms of their inhibitory effects. FVIII inhibitors most frequently target the A2, C2 and A3 domains of FVIII and interfere with important interactions of FVIII at various stages of its functional pathway; a class of FVIII inhibitors inactivates FVIII by proteolysis. We discuss therapeutic approaches currently used for treatment of hemophilia A patients with inhibitors and analyze the factors that influence the outcome. The choice between options should depend on the level of inhibitors and consideration of efficacy, safety, and availability of particular regimens. Advances of basic science open avenues for alternative targeted, specific and long-lasting treatments, such as the use of peptide decoys for blocking FVIII inhibitors, bypassing them with human/porcine FVIII hybrids, neutralizing FVIII-reactive CD4 T cells with anti-clonotypic antibodies, or inducing immune tolerance to FVIII with the use of universal CD4 epitopes or by genetic approaches. |
Author | Hauser, Charlotte A E Shima, Midori Lacroix-Desmazes, Sebastien Khrenov, Alexey V Saenko, Evgueni L Ananyeva, Natalya M Ovanesov, Mikhail V |
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SubjectTerms | Animals Antibodies, Anti-Idiotypic - therapeutic use Antibodies, Catalytic - immunology Antibody Specificity Antigen Presentation Autoantibodies - biosynthesis Autoantibodies - immunology Blood Coagulation Factors - therapeutic use Desensitization, Immunologic Epitope Mapping Epitopes - immunology Factor VIII - antagonists & inhibitors Factor VIII - genetics Factor VIII - immunology Factor VIII - therapeutic use Genetic Therapy Hemophilia A - drug therapy Hemophilia A - immunology Hemorrhage - etiology Hemorrhage - prevention & control Humans Immune Tolerance Isoantibodies - biosynthesis Isoantibodies - immunology Lymphocyte Subsets - immunology Mice Mice, Inbred C57BL Peptide Fragments - chemical synthesis Peptide Fragments - immunology Peptide Fragments - therapeutic use Protein Structure, Tertiary Structure-Activity Relationship Swine |
Title | Inhibitors in hemophilia A: mechanisms of inhibition, management and perspectives |
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