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Blood, 1 October 2009, Vol. 114, No. 14, pp. 3092-3100. Prepublished online as a Blood First Edition Paper on May 4, 2009; DOI 10.1182/blood-2009-02-203661. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2009-02-203661v1 114/14/3092    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 Buyue, Y. Articles by Sheehan, J. P. PubMed PubMed Citation Articles by Buyue, Y. Articles by Sheehan, J. P. Related Collections Thrombosis and Hemostasis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  THROMBOSIS AND HEMOSTASIS Fucosylated chondroitin sulfate inhibits plasma thrombin generation via targeting of the factor IXa heparin-binding exosite Yang Buyue1, and John P. Sheehan1 1 Departments of Medicine/Hematology-Oncology and Pathology, University of Wisconsin-Madison Depolymerized holothurian glycosaminoglycan (DHG) is a fucosylated chondroitin sulfate with antithrombin-independent antithrombotic properties. Heparin cofactor II (HCII)-dependent and -independent mechanisms for DHG inhibition of plasma thrombin generation were evaluated. When thrombin generation was initiated with 0.2 pM tissue factor (TF), the half maximal effective concentration (EC50) for DHG inhibition was identical in mock- or HCII-depleted plasma, suggesting a serpin-independent mechanism. In the presence of excess TF, the EC50 for DHG was increased 13- to 27-fold, suggesting inhibition was dependent on intrinsic tenase (factor IXa-factor VIIIa) components. In factor VIII–deficient plasma supplemented with 700 pM factor VIII or VIIIa, and factor IX–deficient plasma supplemented with plasma-derived factor IX or 100 pM factor IXa, the EC50 for DHG was similar. Thus, cofactor and zymogen activation did not contribute to DHG inhibition of thrombin generation. Factor IX–deficient plasma supplemented with mutant factor IX(a) proteins demonstrated resistance to DHG inhibition of thrombin generation [factor IX(a) R233A > R170A > WT] that inversely correlated with protease-heparin affinity. These results replicate the effect of these mutations with purified intrinsic tenase components, and establish the factor IXa heparin-binding exosite as the relevant molecular target for inhibition by DHG. Glycosaminoglycan-mediated intrinsic tenase inhibition is a novel antithrombotic mechanism with physiologic and therapeutic applications. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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