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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.
Next Article 
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates
András Gruber1,
Ulla M. Marzec1,
Leslie Bush2,
Enrico Di Cera2,
José A. Fernández3,
Michelle A. Berny1,
Erik I. Tucker1,
Owen J. T. McCarty1,
John H. Griffin3, and
Stephen R. Hanson1
1 Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR;
2 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO; and
3 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA
The anticoagulant and anti-inflammatory 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 with systemic anticoagulation by APC and low-molecular-weight heparin (LMWH) at doses that inhibited fibrin deposition on thrombogenic segments of arteriovenous shunts. As expected, both systemic anticoagulants, APC (0.028 or 0.222 mg/kg for 70 minutes) and LMWH (0.325 to 2.6 mg/kg for 70 minutes), were antithrombotic and prolonged the template bleeding time. In contrast, PCA at doses (0.0021 to 0.0083 mg/kg for 70 minutes) that had antithrombotic effects comparable with 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.
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