title: Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates.
abstract: 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.
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA. grubera@ohsu.edu
authors.forename: András
authors.initials: A
authors.lastname: Gruber
authors.forename: Ulla M
authors.initials: UM
authors.lastname: Marzec
authors.forename: Leslie
authors.initials: L
authors.lastname: Bush
authors.forename: Enrico
authors.initials: E
authors.lastname: Di Cera
authors.forename: José A
authors.initials: JA
authors.lastname: Fernández
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Berny
authors.forename: Erik I
authors.initials: EI
authors.lastname: Tucker
authors.forename: Owen J T
authors.initials: OJ
authors.lastname: McCarty
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Hanson
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000925:Anticoagulants / Q000493:pharmacokinetics / Q000494:pharmacology*; D001760:Bleeding Time; D004353:Drug Evaluation, Preclinical; D006487:Hemostasis / Q000187:drug effects*; D006490:Hemostatics / Q000493:pharmacokinetics / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D020125:Mutation, Missense; D010215:Papio; D011486:Protein C / Q000819:agonists / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology; D013917:Thrombin / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy*
chemical_list: D000925:Anticoagulants; D006490:Hemostatics; D006495:Heparin, Low-Molecular-Weight; D011486:Protein C; D011994:Recombinant Proteins; D013917:Thrombin