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Blood, 15 May 2005, Vol. 105, No. 10, pp. 3902-3909. Prepublished online as a Blood First Edition Paper on January 27, 2005; DOI 10.1182/blood-2004-11-4435. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-11-4435v1 105/10/3902    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 Chen, H.-H. Articles by Wun, T.-C. Search for Related Content PubMed PubMed Citation Articles by Chen, H.-H. Articles by Wun, T.-C. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Fusion proteins comprising annexin V and Kunitz protease inhibitors are highly potent thrombogenic site-directed anticoagulants Hsiu-Hui Chen, Cristina P. Vicente, Li He, Douglas M. Tollefsen, and Tze-Chein Wun From the Division of Hematology, Department of Medicine, Washington University School of Medicine, St Louis, MO; and EVAS Therapeutics, Ballwin, MO. The anionic phospholipid, phosphatidyl-L-serine (PS), is sequestered in the inner layer of the plasma membrane in normal cells. Upon injury, activation, and apoptosis, PS becomes exposed on the surfaces of cells and sheds microparticles, which are procoagulant. Coagulation is initiated by formation of a tissue factor/factor VIIa complex on PS-exposed membranes and propagated through the assembly of intrinsic tenase (factor VIIIa/factor IXa), prothrombinase (factor Va/factor Xa), and factor XIa complexes on PS-exposed activated platelets. We constructed a novel series of recombinant anticoagulant fusion proteins by linking annexin V (ANV), a PS-binding protein, to the Kunitz-type protease inhibitor (KPI) domain of tick anticoagulant protein, an aprotinin mutant (6L15), amyloid -protein precursor, or tissue factor pathway inhibitor. The resulting ANV-KPI fusion proteins were 6- to 86-fold more active than recombinant tissue factor pathway inhibitor and tick anticoagulant protein in an in vitro tissue factor–initiated clotting assay. The in vivo antithrombotic activities of the most active constructs were 3- to 10-fold higher than that of ANV in a mouse arterial thrombosis model. ANV-KPI fusion proteins represent a new class of anticoagulants that specifically target the anionic membrane-associated coagulation enzyme complexes present at sites of thrombogenesis and are potentially useful as antithrombotic agents. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. Stoll, N. Bassler, C. E. Hagemeyer, S. U. Eisenhardt, Y. C. Chen, R. Schmidt, M. Schwarz, I. Ahrens, Y. Katagiri, B. Pannen, et al. Targeting Ligand-Induced Binding Sites on GPIIb/IIIa via Single-Chain Antibody Allows Effective Anticoagulation Without Bleeding Time Prolongation Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1206 - 1212. [Abstract] [Full Text] [PDF]

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