title: Catalytic activity of antibodies against factor VIII in patients with hemophilia A.
abstract: Hemophilia A is an X chromosome-linked recessive disorder resulting in defective or deficient factor VIII (FVIII) molecules, which, in its severe form, is a life-threatening and crippling hemorrhagic disease. Infusion of homologous FVIII to patients with severe hemophilia A results, in 25% of patients, in the emergence of alloantibodies against FVIII (inhibitors)( ref. 1) that inhibit FVIII procoagulant activity by steric hindrance of the interaction of FVIII either with stabilizing molecules, with molecules essential for its activity or with activating molecules. Here, we report on the proteolysis of FVIII by alloantibodies of two patients with severe hemophilia A, demonstrating a previously unknown mechanism by which FVIII inhibitors may prevent the pro-coagulant function of FVIII. The kinetic parameters of FVIII hydrolysis indicate a functional role for the catalytic immune response in the inactivation of FVIII in vivo. The characterization of alloantibodies against FVIII as site-specific proteases may provide new approaches to the treatment of FVIII inhibitors.
authors.affiliation: INSERM U430 and Université Pierre et Marie Curie, Hôpital Broussais, 75014 Paris, France. kaveri@hbroussais.fr
authors.forename: S
authors.initials: S
authors.lastname: Lacroix-Desmazes
authors.forename: A
authors.initials: A
authors.lastname: Moreau
authors.lastname: Sooryanarayana
authors.forename: C
authors.initials: C
authors.lastname: Bonnemain
authors.forename: N
authors.initials: N
authors.lastname: Stieltjes
authors.forename: A
authors.initials: A
authors.lastname: Pashov
authors.forename: Y
authors.initials: Y
authors.lastname: Sultan
authors.forename: J
authors.initials: J
authors.lastname: Hoebeke
authors.forename: M D
authors.initials: MD
authors.lastname: Kazatchkine
authors.forename: S V
authors.initials: SV
authors.lastname: Kaveri
mesh_terms: D017151:Antibodies, Catalytic / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D001667:Binding, Competitive; D010450:Endopeptidases / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D005169:Factor VIII / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D006467:Hemophilia A / Q000201:enzymology / Q000276:immunology*; D006801:Humans; D006868:Hydrolysis; D007074:Immunoglobulin G / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism; D007518:Isoantibodies / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*; D007700:Kinetics; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D017151:Antibodies, Catalytic; D007074:Immunoglobulin G; D007518:Isoantibodies; D014841:von Willebrand Factor; D005169:Factor VIII; D010450:Endopeptidases