Von Willebrand Factor Modulates Factor VIII Immunogenicity: Comparative Study of Different Factor VIII Concentrates in a Haemophilia A Mouse Model

Mathias Behrmann; John Pasi; Jean-Marie R. Saint-Remy; Ronald Kotitschke; Michael Kloft

doi:10.1055/s-0037-1613191

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2002; 88(02): 221-229
DOI: 10.1055/s-0037-1613191

In Focus

Schattauer GmbH

Von Willebrand Factor Modulates Factor VIII Immunogenicity: Comparative Study of Different Factor VIII Concentrates in a Haemophilia A Mouse Model

Mathias Behrmann

¹Institute for Biophysical Chemistry and Biochemistry, Johann-Wolfgang-Goethe-University, Frankfurt am Main, Germany

,

John Pasi

²Division of Haematology, University of Leicester, Leicester, UK

,

Jean-Marie R. Saint-Remy

³Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium

,

Ronald Kotitschke

⁴Biotest Pharma GmbH, Dreieich, Germany

,

Michael Kloft

⁴Biotest Pharma GmbH, Dreieich, Germany

› Institutsangaben

Abstract

Summary

The development of an immune response towards factor VIII (FVIII) remains the major complication of haemophilia A replacement therapy. Product-related risk factors have recently been identified on the basis of epidemiological studies, but the mechanism is not understood. To this end, various commercially available FVIII concentrates were administered by the IV route to FVIII-knockout mice and the resulting immune response was characterised. Significantly higher inhibitor titres (Bethesda assay) were observed for one recombinant FVIII and one plasma-derived FVIII product depleted in von Willebrand factor (VWF). Inhibitor titres were reduced upon pre-incubation of FVIII with purified VWF. Epitope specificity of anti-FVIII IgG was characterised using FVIII-fragments produced in E. coli. Concentrates with no or reduced VWF-level elicited antibodies recognising predominantly the acidic a1 and a3 regions. Addition of VWF prior to injection also modified the epitope specificity. FVIII concentrates, therefore, show qualitative and quantitative variations in immunogenicity, which are at least partly modulated by VWF.

Keywords

Haemophilia A - factor VIII - von Willebrand factor - animal model - immunogenicity

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Referenzen

References
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