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Blood, 15 October 2008, Vol. 112, No. 8, pp. 3234-3241. Prepublished online as a Blood First Edition Paper on July 22, 2008; DOI 10.1182/blood-2008-01-136820. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-01-136820v1 112/8/3234    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 Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY The heparin-binding exosite of factor IXa is a critical regulator of plasma thrombin generation and venous thrombosis Yang Buyue1,*, Herbert C. Whinna2, and John P. Sheehan1 1 Departments of Medicine/Hematology-Oncology and Pathology, University of Wisconsin-Madison; and 2 Department of Pathology, University of North Carolina at Chapel Hill The role of the factor IXa heparin-binding exosite in coagulation was assessed with mutations that enhance (R170A) or reduce (R233A) stability of the protease-factor VIIIa A2 domain interaction. After tissue factor (TF) addition to reconstituted factor IX-deficient plasma, factor IX R170A supported a 2-fold increase in velocity index (slope) and peak thrombin concentration, whereas factor IX R233A had a 4- to 10-fold reduction relative to factor IX wild-type. In the absence of TF, 5 to 100 pM of factor IXa increased thrombin generation to approach TF-stimulated thrombin generation at 100% factor IX. Factor IXa R170A demonstrated a 2- to 3-fold increase in peak thrombin concentration and 5-fold increase in velocity index, whereas the response for factor IXa R233A was blunted and delayed relative to wild-type protease. In hemophilia B mice, factor IX replacement reduced the average time to hemostasis after saphenous vein incision, and the time to occlusion after FeCl3-induced saphenous vein injury. At 5% factor IX, the times to occlusion for factor IX wild-type, R170A, and R233A were 15.7 minutes, 9.1 minutes (P .003), and more than 45 minutes. These data support the role of the factor IXa heparin-binding exosite as a critical regulator of coagulation and novel antithrombotic target. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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