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.
