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Blood, 1 April 2007, Vol. 109, No. 9, pp. 3733-3740. Prepublished online as a Blood First Edition Paper on January 16, 2007; DOI 10.1182/blood-2006-07-035147. This Article Full Text (PDF) All Versions of this Article: blood-2006-07-035147v1 109/9/3733    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 Gruber, A. Articles by Hanson, S. R. Search for Related Content PubMed PubMed Citation Articles by Gruber, A. Articles by Hanson, S. R. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 13, 2006 Accepted December 5, 2006 Relative antithrombotic and antihemostatic effects of protein C activator versus low molecular weight heparin in primates Andras Gruber*, Ulla M. Marzec, Leslie Bush, Enrico Di Cera, Jose A. Fernandez, Michelle A. Berny, Erik I. Tucker, Owen J.T. McCarty, John H. Griffin, and Stephen R. Hanson Dept of Biomedical Engineering, Oregon Health & Science University, Portland, OR Dept of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO Dept of Molecular & Experimental Medicine, The Scripps Research Institute, La Jolla, CA * Corresponding author; email: grubera{at}ohsu.edu. The anticoagulant and antiinflammatory enzyme, activated protein C (APC), naturally controls thrombosis without affecting hemostasis. We therefore evaluated whether the integrity of primary hemostasis was preserved during limited pharmacological antithrombotic protein C activator (PCA) treatment in baboons. The double mutant thrombin (Trp215Ala/Glu217Ala) with less than 1% procoagulant activity was used as a relatively selective PCA and compared to systemic anticoagulation by APC and low molecular weight heparin (LMWH) at doses that inhibited fibrin deposition on thrombogenic segments of arterio-venous shunts. As expected, both systemic anticoagulants, APC (0.028 or 0.222 mg/kg/70 min) and LMWH (0.325 to 2.6 mg/kg/70 min), were antithrombotic and prolonged the template bleeding time. In contrast, PCA at doses (0.0021 to 0.0083 mg/kg/70 min) that had antithrombotic effects comparable to LMWH did not demonstrably impair primary hemostasis. PCA bound to platelets and leukocytes, and accumulated in thrombi. APC infusion at higher circulating APC levels was less antithrombotic than PCA infusion at lower circulating APC levels. The observed dissociation of antithrombotic and antihemostatic effects during PCA infusion thus appeared to emulate the physiological regulation of intravascular blood coagulation (thrombosis) by the endogenous protein C system. Our data suggest that limited pharmacological protein C activation might exhibit considerable thrombosis-specificity. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. S. Gandhi, M. J. Page, Z. Chen, L. Bush-Pelc, and E. Di Cera Mechanism of the Anticoagulant Activity of Thrombin Mutant W215A/E217A J. Biol. Chem., September 4, 2009; 284(36): 24098 - 24105. [Abstract] [Full Text] [PDF] A. Bah, C. J. Carrell, Z. Chen, P. S. Gandhi, and E. Di Cera Stabilization of the E* Form Turns Thrombin into an Anticoagulant J. Biol. Chem., July 24, 2009; 284(30): 20034 - 20040. [Abstract] [Full Text] [PDF] E. I. Tucker, U. M. Marzec, T. C. White, S. Hurst, S. Rugonyi, O. J. T. McCarty, D. Gailani, A. Gruber, and S. R. Hanson Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI Blood, January 22, 2009; 113(4): 936 - 944. [Abstract] [Full Text] [PDF] P. S. Gandhi, Z. Chen, F. S. Mathews, and E. Di Cera Structural identification of the pathway of long-range communication in an allosteric enzyme PNAS, February 12, 2008; 105(6): 1832 - 1837. [Abstract] [Full Text] [PDF] M. C. Berndt and R. K. Andrews New Direction for WE Thrombin Arterioscler Thromb Vasc Biol, February 1, 2008; 28(2): 205 - 207. [Full Text] [PDF] M. A. Berny, T. C. White, E. I. Tucker, L. A. Bush-Pelc, E. Di Cera, A. Gruber, and O. J.T. McCarty Thrombin Mutant W215A/E217A Acts as a Platelet GPIb Antagonist Arterioscler Thromb Vasc Biol, February 1, 2008; 28(2): 329 - 334. [Abstract] [Full Text] [PDF] L. A. Bush-Pelc, F. Marino, Z. Chen, A. O. Pineda, F. S. Mathews, and E. Di Cera Important Role of the Cys-191 Cys-220 Disulfide Bond in Thrombin Function and Allostery J. Biol. Chem., September 14, 2007; 282(37): 27165 - 27170. [Abstract] [Full Text] [PDF]

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