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Blood, 1 December 2003, Vol. 102, No. 12, pp. 4028-4034. Prepublished online as a Blood First Edition Paper on August 7, 2003; DOI 10.1182/blood-2003-05-1560. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-05-1560v1 102/12/4028    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 Mushunje, A. Articles by Huntington, J. A. Search for Related Content PubMed PubMed Citation Articles by Mushunje, A. Articles by Huntington, J. A. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Heparin-induced substrate behavior of antithrombin Cambridge II Alec Mushunje, Aiwu Zhou, Robin W. Carrell, and James A. Huntington From the Department of Haematology, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, United Kingdom. Cambridge II (A384S) is a highly prevalent antithrombin variant in the British population (1.14 per 1000) and predisposes carriers to a mild but significant increased risk of thrombosis. To determine if the association of Cambridge II with thrombophilia is due to a perturbation of the antithrombin inhibitory mechanism, we expressed and characterized the variant. Antithrombin Cambridge II was found to be normal in its affinity for heparin, its ability to form sodium dodecyl sulfate-stable complexes with factor Xa and thrombin, and its uncatalyzed stoichiometries and rates of inhibition. However, in the presence of full-length heparin there was a 3- and 7-fold increase in stoichiometry of inhibition of factor Xa and thrombin. The stoichiometries were not affected by pentasaccharides, indicating that the inhibitory mechanism of antithrombin Cambridge II is perturbed only in the presence of a bridging glycosaminoglycan. Thus, the vascular localization of antithrombin Cambridge II would render the carrier slightly thrombophilic. The high occurrence of this mutation and its possible propagation from a few founders suggests an evolutionary advantage, perhaps in decreasing postpartum bleeding. (Blood. 2003;102:4028-4034) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Corral, D. Hernandez-Espinosa, J. M. Soria, R. Gonzalez-Conejero, A. Ordonez, J. R. Gonzalez-Porras, E. Perez-Ceballos, R. Lecumberri, I. Sanchez, V. Roldan, et al. Antithrombin Cambridge II (A384S): an underestimated genetic risk factor for venous thrombosis Blood, May 15, 2007; 109(10): 4258 - 4263. [Abstract] [Full Text] [PDF] D. J. D. Johnson, J. Langdown, W. Li, S. A. Luis, T. P. Baglin, and J. A. Huntington Crystal Structure of Monomeric Native Antithrombin Reveals a Novel Reactive Center Loop Conformation J. Biol. Chem., November 17, 2006; 281(46): 35478 - 35486. [Abstract] [Full Text] [PDF] J. Langdown, D. J. D. Johnson, T. P. Baglin, and J. A. Huntington Allosteric Activation of Antithrombin Critically Depends upon Hinge Region Extension J. Biol. Chem., November 5, 2004; 279(45): 47288 - 47297. [Abstract] [Full Text] [PDF] D. J. D. Johnson and J. A. Huntington The Influence of Hinge Region Residue Glu-381 on Antithrombin Allostery and Metastability J. Biol. Chem., February 6, 2004; 279(6): 4913 - 4921. [Abstract] [Full Text] [PDF]

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