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Previous Volume 346:662-667 February 28, 2002 Number 9 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Editorial by Stollar, B. D. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Factor VIII inhibitors are IgG alloantibodies that arise during replacement therapy in 25 to 50 percent of patients with severe hemophilia A. The hydrolysis of factor VIII by anti–factor VIII antibodies has been proposed as a mechanism of inactivation of factor VIII.

Methods We purified IgG from patients with severe hemophilia A. The proteolytic activity of the antibodies was assessed by incubating the IgG with biotinylated human factor VIII and analyzing patterns of factor VIII cleavage by sodium dodecyl sulfate–polyacrylamide-gel electrophoresis and immunoblotting. The controls were normal human IgG and IgG purified from plasma of patients with hemophilia who did not have inhibitory antibodies.

Results Significant proteolytic activity was detected in IgG from 13 of 24 inhibitor-positive patients. No hydrolytic activity was detected in control antibodies of IgG from patients without inhibitors. The rate of hydrolysis of factor VIII by purified IgG correlated positively with the factor VIII–neutralizing activity of IgG in plasma (r²=0.67, P=0.029). Principal-component analysis of migration profiles of digestion fragments demonstrated the heterogeneity of the catalytic potential of factor VIII inhibitors among patients.

Conclusions Proteolysis is a mechanism by which IgG antibodies against factor VIII can inactivate factor VIII.

Source Information

From INSERM Unité 430 and Université Pierre et Marie Curie, Hôpital Broussais, Paris (S.L.-D., J.B., N.M., M.P.H., A.P., M.D.K., S.V.K.); Unité Mixte de Recherche 5094, Centre National de la Recherche Scientifique, Faculté de Pharmacie, Montpellier, France (S.V.); Centre des Hémophiles, Hôpital Cochin et Bicêtre, Paris (N.S., R.O.); the Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, Leuven, Belgium (J.-M.S.-R.); and Unité Propre de Recherche 9021, Centre National de la Recherche Scientifique, Institut de Biologie Moleculaire et Cellulaire, Strasbourg, France (J.H.).

Other authors were Joseph Reinbolt, Ph.D. (Unité Propre de Recherche 9002, Centre National de la Recherche Scientifique, IBMC, Strasbourg, France), and Dipika Mohanty, M.D., Ph.D. (Institute of Immunohaematology, Mumbai, India).

Address reprint requests to Dr. Lacroix-Desmazes at INSERM Unité 430, Hôpital Broussais, 96 rue Didot, Paris 75014, France, or at sebastien.lacroix{at}brs.ap-hop-paris.fr.

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