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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 (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 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 Buyue, Y. Articles by Sheehan, J. P. Search for Related Content PubMed PubMed Citation Articles by Buyue, Y. Articles by Sheehan, J. P. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 30, 2008 Accepted July 1, 2008 The heparin-binding exosite of factor IXa is a critical regulator of plasma thrombin generation and venous thrombosis Yang Buyue, Herbert C. Whinna, and John P. Sheehan* Dept. of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States Pathology and Laboratory Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, United States * Corresponding author; email: jps{at}medicine.wisc.edu. The role of the factor IXa heparin-binding exosite in coagulation was assessed with mutations that selectively enhance (R170A) or reduce (R233A) stability of the protease-factor VIIIa A2 domain interaction. Following 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, while factor IX R233A had a 4-10 fold reduction relative to factor IX wild type. In the absence of TF, 5-100 pM factor IXa increased thrombin generation to approach TF-stimulated thrombin generation at 100% factor IX. Factor IXa R170A demonstrated a 2-3 fold increase in peak thrombin concentration and up to 5-fold increase in velocity index, while 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 (ATTH) following saphenous vein incision, and the time to occlusion (TTO) following FeCl3-induced saphenous vein injury. At 5% factor IX, the TTO for factor IX wild type, R170A, and R233A were 15.7, 9.1 (P 0.003), and > 45 min. 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? This article has been cited by other articles: P. Simioni, D. Tormene, G. Tognin, S. Gavasso, C. Bulato, N. P. Iacobelli, J. D. Finn, L. Spiezia, C. Radu, and V. R. Arruda X-Linked Thrombophilia with a Mutant Factor IX (Factor IX Padua) N. Engl. J. Med., October 22, 2009; 361(17): 1671 - 1675. [Abstract] [Full Text] [PDF] Y. Buyue and J. P. Sheehan Fucosylated chondroitin sulfate inhibits plasma thrombin generation via targeting of the factor IXa heparin-binding exosite Blood, October 1, 2009; 114(14): 3092 - 3100. [Abstract] [Full Text] [PDF]

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