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Blood, 1 June 2004, Vol. 103, No. 11, pp. 4173-4179. Prepublished online as a Blood First Edition Paper on February 19, 2004; DOI 10.1182/blood-2003-10-3578. This Article Full Text (PDF) All Versions of this Article: 2003-10-3578v1 103/11/4173    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 Castoldi, E. Articles by Rosing, J. Search for Related Content PubMed PubMed Citation Articles by Castoldi, E. Articles by Rosing, J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Submitted October 20, 2003 Accepted February 6, 2004 Impaired APC-cofactor activity of factor V plays a major role in the APC resistance associated with the factor V Leiden (R506Q) and R2 (H1299R) mutations Elisabetta Castoldi*, Jeroen M Brugge, Gerry A Nicolaes, Domenico Girelli, Guido Tans, and Jan Rosing Department of Biochemistry, Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands Department of Clinical and Experimental Medicine, University of Verona, Verona, Italy * Corresponding author; email: e.castoldi{at}bioch.unimaas.nl. APC resistance is a major risk factor for venous thrombosis. Factor V (FV) gene mutations like FVLeiden (R506Q) and FVR2 (H1299R) may cause APC resistance either by reducing the susceptibility of FVa to APC-mediated inactivation or by interfering with the cofactor activity of FV in APC-catalysed FVIIIa inactivation. We quantified the APC-cofactor activity expressed by FVLeiden and FVR2, and determined the relative contributions of reduced susceptibility and impaired APC-cofactor activity to the APC resistance associated with these mutations. Plasmas containing varying concentrations of normal FV, FVLeiden or FVR2 were assayed with the Immunochrom®APC Response test, which specifically measures the APC-cofactor activity of FV, and with the Coatest®APCTMResistance assay, which probes both the susceptibility and APC-cofactor components. FVR2 expressed 73% of the APC-cofactor activity of normal FV, whereas FVLeiden exhibited no cofactor activity in FVIIIa inactivation. Poor susceptibility to APC and impaired APC-cofactor activity contributed equally to FVLeiden-associated APC resistance, while FVR2-associated APC resistance was entirely due to the reduced APC-cofactor activity of FVR2. Thrombin generation assays confirmed the importance of the anticoagulant activity of FV and indicated that FVLeiden homozygotes are exposed to a higher thrombotic risk than heterozygotes because their plasma lacks normal FV acting as an anticoagulant protein. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Anticoagulant factor V and thrombosis risk Bjorn Dahlback Blood 2004 103: 3995. [Full Text] [PDF] This article has been cited by other articles: H. Sun, X. Wang, J. L. Degen, and D. Ginsburg Reduced thrombin generation increases host susceptibility to group A streptococcal infection Blood, February 5, 2009; 113(6): 1358 - 1364. [Abstract] [Full Text] [PDF] P. Simioni, E. Castoldi, B. Lunghi, D. Tormene, J. Rosing, and F. Bernardi An underestimated combination of opposites resulting in enhanced thrombotic tendency Blood, October 1, 2005; 106(7): 2363 - 2365. [Abstract] [Full Text] [PDF] A. C. Parker, L. V. Mundada, A. H. Schmaier, and W. P. Fay Factor VLeiden Inhibits Fibrinolysis In Vivo Circulation, December 7, 2004; 110(23): 3594 - 3598. [Abstract] [Full Text] [PDF]

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