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Blood, 10 September 2009, Vol. 114, No. 11, pp. 2307-2314. Prepublished online as a Blood First Edition Paper on June 30, 2009; DOI 10.1182/blood-2009-03-209031. This Article Full Text Full Text (PDF) Supplemental Methods and Figure All Versions of this Article: blood-2009-03-209031v1 114/11/2307    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 CrossRef Google Scholar Articles by Saller, F. Articles by Angelillo-Scherrer, A. PubMed PubMed Citation Articles by Saller, F. Articles by Angelillo-Scherrer, A. Related Collections Thrombosis and Hemostasis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  THROMBOSIS AND HEMOSTASIS Generation and phenotypic analysis of protein S–deficient mice François Saller1, Anne C. Brisset1, Svetlana N. Tchaikovski2, Monica Azevedo1, Roman Chrast3, José A. Fernández4, Marc Schapira1, Tilman M. Hackeng2, John H. Griffin4, and Anne Angelillo-Scherrer1 1 Service and Central Laboratory of Hematology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; 2 Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands; 3 Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; and 4 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA Protein S (PS) is an important natural anticoagulant with potentially multiple biologic functions. To investigate further the role of PS in vivo, we generated Pros+/– heterozygous mice. In the null (–) allele, the Pros exons 3 to 7 have been excised through conditional gene targeting. Pros+/– mice did not present any signs of spontaneous thrombosis and had reduced PS plasma levels and activated protein C cofactor activity in plasma coagulation and thrombin generation assays. Tissue factor pathway inhibitor cofactor activity of PS could not be demonstrated. Heterozygous Pros+/– mice exhibited a notable thrombotic phenotype in vivo when challenged in a tissue factor–induced thromboembolism model. No viable Pros–/– mice were obtained through mating of Pros+/– parents. Most E17.5 Pros–/– embryos were found dead with severe intracranial hemorrhages and most likely presented consumptive coagulopathy, as demonstrated by intravascular and interstitial fibrin deposition and an increased number of megakaryocytes in the liver, suggesting peripheral thrombocytopenia. A few E17.5 Pros–/– embryos had less severe phenotype, indicating that life-threatening manifestations might occur between E17.5 and the full term. Thus, similar to human phenotypes, mild heterozygous PS deficiency in mice was associated with a thrombotic phenotype, whereas total homozygous deficiency in PS was incompatible with life. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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