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Blood, 1 January 2004, Vol. 103, No. 1, pp. 155-157. Prepublished online as a Blood First Edition Paper on September 11, 2003; DOI 10.1182/blood-2003-04-1321. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-04-1321v1 103/1/155    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by d'Oiron, R. Articles by Jacquemin, M. Search for Related Content PubMed PubMed Citation Articles by d'Oiron, R. Articles by Jacquemin, M. Related Collections Hemostasis, Thrombosis, and Vascular Biology Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Brief report Deletion of alanine 2201 in the FVIII C2 domain results in mild hemophilia A by impairing FVIII binding to VWF and phospholipids and destroys a major FVIII antigenic determinant involved in inhibitor development Roseline d'Oiron, Jean-Maurice Lavergne, Renaud Lavend'homme, Abdellah Benhida, Jean-Claude Bordet, Claude Negrier, Kathelijne Peerlinck, Jos Vermylen, Jean-Marie Saint-Remy, and Marc Jacquemin From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium; Hôpital de Bicêtre, le Kremlin-Bicêtre, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U331, Laboratoire d'Hemobiologie-Faculte de Medecine RTH Laennec, Lyon, France; INSERM U143, Hôpital de Bicêtre, le Kremlin-Bicêtre, France. The C2 domain of factor VIII (FVIII) mediates FVIII binding to von Willebrand factor (VWF) and phospholipids (PLs), thereby determining the stability and the activity of FVIII. A deletion of Ala2201 (Del2201) was identified in the FVIII C2 domain of 2 unrelated patients with mild hemophilia A (FVIII:C 11%-33%). This mutation prevents FVIII binding to a human monoclonal antibody recognizing the C2 domain and inhibiting FVIII binding to VWF and phospholipids. By comparison to healthy FVIII, Del2201 FVIII had a significantly reduced binding to VWF, which likely contributes to reduced FVIII levels in plasma. Del2201 FVIII interaction with phospholipids was evaluated in an FXa generation assay, using various concentrations of synthetic phospholipid vesicles mimicking an activated platelet surface. At the lowest phospholipid concentration allowing FXa generation, Del2201 FVIII activity was reduced 3-fold. This is the first report of a mutation altering FVIII binding to phospholipids and occurring in patients with hemophilia A. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. C. Spiegel, P. Murphy, and B. L. Stoddard Surface-exposed Hemophilic Mutations across the Factor VIII C2 Domain Have Variable Effects on Stability and Binding Activities J. Biol. Chem., December 17, 2004; 279(51): 53691 - 53698. [Abstract] [Full Text] [PDF] J. G. G. Gilles, S. C. Grailly, M. De Maeyer, M. G. Jacquemin, L. P. VanderElst, and J.-M. R. Saint-Remy In vivo neutralization of a C2 domain-specific human anti-Factor VIII inhibitor by an anti-idiotypic antibody Blood, April 1, 2004; 103(7): 2617 - 2623. [Abstract] [Full Text] [PDF]

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