Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates

András Gruber, Ulla M. Marzec, Leslie Bush, Enrico Di Cera, José A. Fernández, Michelle A. Berny, Erik I. Tucker, Owen J.T. McCarty, John H. Griffin, Stephen R. Hanson

Research output: Contribution to journalArticle

41 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3733-3740
Number of pages8
JournalBlood
Volume109
Issue number9
DOIs
StatePublished - May 1 2007

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of 'Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates'. Together they form a unique fingerprint.

  • Cite this