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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1704-1712. Prepublished online as a Blood First Edition Paper on June 16, 2008; DOI 10.1182/blood-2008-01-133181. This Article Full Text (PDF) All Versions of this Article: blood-2008-01-133181v1 112/5/1704    most recent Alert me when this article is cited Alert me if a correction is posted 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 van Schooten, C. J Articles by Lenting, P. J Search for Related Content PubMed PubMed Citation Articles by van Schooten, C. J Articles by Lenting, P. J Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 10, 2008 Accepted May 27, 2008 Macrophages contribute to the cellular uptake of von Willebrand factor and factor VIII in vivo Carina J van Schooten, Shirin Shahbazi, Evelyn Groot, Beatrijs D Oortwijn, H. Marijke van den Berg, Cecile V Denis, and Peter J Lenting* Dept. of Clinical Chemistry & Haematology, University Medical Center Utrecht, Utrecht, Netherlands U770, INSERM, Le Kremlin-Bicetre, France Van Creveld Clinic, University Medical Center Utrecht, Utrecht, Netherlands Dept. of Protein Discovery, Crucell Holland BV, Leiden, Netherlands * Corresponding author; email: p.j.lenting{at}umcutrecht.nl. Von Willebrand Factor (VWF) and factor VIII (FVIII) circulate in a tight non-covalent complex. At present, the cells that contribute to the removal of FVIII and VWF are of unknown identity. Here, we analyzed spleen and liver tissue-sections of VWF-deficient mice infused with recombinant VWF or recombinant FVIII. This analysis revealed that both proteins were targeted to cells of macrophage origin. When applied as a complex, both proteins were co-directed to the same macrophages. Chemical inactivation of macrophages using gadolinium-chloride resulted in doubling of endogenous FVIII levels in VWF-null mice, and of VWF levels in wild-type mice. Moreover, the survival of infused VWF was prolonged almost 2-fold in VWF-deficient mice after gadolinium-chloride treatment. VWF and FVIII also bound to primary human macrophages in in vitro tests. In addition, radiolabelled VWF bound to human THP1-macrophages in a dose-dependent, specific and saturable manner (half-maximal binding at 0.014 mg/ml). Binding to macrophages was followed by a rapid uptake and subsequent degradation of the internalised protein. This process was also visualized using a VWF-green fluorescent protein fusion protein. In conclusion, our data strongly indicate that macrophages play a prominent role in the clearance of the VWF/FVIII complex. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Where does von Willebrand factor go? Gary E. Gilbert Blood 2008 112: 1549-1550. [Full Text] [PDF] This article has been cited by other articles: A. L. Sorensen, V. Rumjantseva, S. Nayeb-Hashemi, H. Clausen, J. H. Hartwig, H. H. Wandall, and K. M. Hoffmeister Role of sialic acid for platelet life span: exposure of {beta}-galactose results in the rapid clearance of platelets from the circulation by asialoglycoprotein receptor-expressing liver macrophages and hepatocytes Blood, August 20, 2009; 114(8): 1645 - 1654. [Abstract] [Full Text] [PDF] S. F. De Meyer, H. Deckmyn, and K. Vanhoorelbeke von Willebrand factor to the rescue Blood, May 21, 2009; 113(21): 5049 - 5057. [Abstract] [Full Text] [PDF]

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