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Catalytic activity of antibodies against factor VIII in patients with hemophilia A

Nature Medicine volume 5, pages 1044–1047 (1999)Cite this article

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 molecules2, with molecules essential for its activity3,4 or with activating molecules5. 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.

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Figure 1: Hydrolysis of 125I-labeled FVIII by affinity-purified IgG antibodies against FVIII of hemophilia A patients.
Figure 2: Dose- and time-dependency of proteolysis of 125I-labeled FVIII by affinity-purified antibodies against FVIII from hemophilia A patients.
Figure 3: Hydrolysis of 125I-labeled FVIII by IgG antibodies against FVIII IgG in the presence of increasing amounts of unlabeled FVIII.

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Acknowledgements

The authors thank Drs. J.-P. Bouvet, V. Frémaux-Bacchi and T. Croughs for suggestions and J. Reinbolt and C. Lichté for help in microsequencing. This work was supported by Institut National de la Santé et de la Recherche Médicale (INSERM) and Centre National de la Recherche Scientifique (CNRS), France and by the Bayer Pharma, France. S.L.D. is a recipient of a grant from Bayer Pharma. A.M. is a recipient of a fellowship from the Ministère de la Recherche et de la Technologie, France. A.P. is a recipient of a fellowship from NATO.

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Authors and Affiliations

  1. INSERM U430 and Université Pierre et Marie Curie, Hôpital Broussais, Paris, 75014, France

    Sébastien Lacroix-Desmazes, Alexandre Moreau,  Sooryanarayana, Cécile Bonnemain, Anastas Pashov, Michel D. Kazatchkine & Srinivas V. Kaveri

  2. Natalie Stieltjes, Centre des hémophiles, Hôpital Cochin, Paris, France

    Natalie Stieltjes & Yvette Sultan

  3. UPR 9021 CNRS, IBMC, Strasbourg, France

    Johan Hoebeke

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  1. Sébastien Lacroix-Desmazes
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Correspondence to Srinivas V. Kaveri.

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Lacroix-Desmazes, S., Moreau, A., Sooryanarayana et al. Catalytic activity of antibodies against factor VIII in patients with hemophilia A. Nat Med 5, 1044–1047 (1999). https://doi.org/10.1038/12483

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