TY - JOUR
T1 - Inhibitors in hemophilia A
T2 - Mechanisms of inhibition, management and perspectives
AU - Ananyeva, Natalya M.
AU - Lacroix-Desmazes, Sebastien
AU - Hauser, Charlotte
AU - Shima, Midori
AU - Ovanesov, Mikhail V.
AU - Khrenov, Alexey V.
AU - Saenko, Evgueni L.
PY - 2004/3/1
Y1 - 2004/3/1
N2 - 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.
AB - 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.
KW - Anti-idiotypic antibodies
KW - Epitope
KW - Factor VIII
KW - Hemophilia A
KW - Immune response
KW - Inhibitory antibody
KW - Inhibitory mechanism
KW - Peptide decoy
KW - T cell
KW - T-cell co-stimulatory interactions
KW - Universal CD4 epitope
KW - Xase complex
UR - http://www.scopus.com/inward/record.url?scp=1642356200&partnerID=8YFLogxK
U2 - 10.1097/00001721-200403000-00001
DO - 10.1097/00001721-200403000-00001
M3 - Review article
C2 - 15090997
AN - SCOPUS:1642356200
SN - 0957-5235
VL - 15
SP - 109
EP - 124
JO - Blood Coagulation and Fibrinolysis
JF - Blood Coagulation and Fibrinolysis
IS - 2
ER -