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, José A. Fernández, Michelle A. Berny, Erik Tucker, Owen McCarty, John H. Griffin, Stephen R. Hanson

Research output: Contribution to journalArticle

40 Citations (Scopus)

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

Fingerprint

Low Molecular Weight Heparin
Protein C
Primates
Thrombosis
Hemostasis
Anticoagulants
Pharmacology
Bleeding Time
Papio
Blood Coagulation
Platelets
Coagulation
Fibrin
Thrombin
Leukocytes
Blood
Anti-Inflammatory Agents

ASJC Scopus subject areas

  • Hematology

Cite this

Gruber, A., Marzec, U. M., Bush, L., Di Cera, E., Fernández, J. A., Berny, M. A., ... Hanson, S. R. (2007). Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates. Blood, 109(9), 3733-3740. https://doi.org/10.1182/blood-2006-07-035147

Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates. / Gruber, Andras; Marzec, Ulla M.; Bush, Leslie; Di Cera, Enrico; Fernández, José A.; Berny, Michelle A.; Tucker, Erik; McCarty, Owen; Griffin, John H.; Hanson, Stephen R.

In: Blood, Vol. 109, No. 9, 01.05.2007, p. 3733-3740.

Research output: Contribution to journalArticle

Gruber, Andras ; Marzec, Ulla M. ; Bush, Leslie ; Di Cera, Enrico ; Fernández, José A. ; Berny, Michelle A. ; Tucker, Erik ; McCarty, Owen ; Griffin, John H. ; Hanson, Stephen R. / Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates. In: Blood. 2007 ; Vol. 109, No. 9. pp. 3733-3740.
@article{7af6a4c2d19249f5a14262047b4a4165,
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.",
author = "Andras Gruber and Marzec, {Ulla M.} and Leslie Bush and {Di Cera}, Enrico and Fern{\'a}ndez, {Jos{\'e} A.} and Berny, {Michelle A.} and Erik Tucker and Owen McCarty and Griffin, {John H.} and Hanson, {Stephen R.}",
year = "2007",
month = "5",
day = "1",
doi = "10.1182/blood-2006-07-035147",
language = "English (US)",
volume = "109",
pages = "3733--3740",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "9",

}

TY - JOUR

T1 - Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates

AU - Gruber, Andras

AU - Marzec, Ulla M.

AU - Bush, Leslie

AU - Di Cera, Enrico

AU - Fernández, José A.

AU - Berny, Michelle A.

AU - Tucker, Erik

AU - McCarty, Owen

AU - Griffin, John H.

AU - Hanson, Stephen R.

PY - 2007/5/1

Y1 - 2007/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=34247379463&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34247379463&partnerID=8YFLogxK

U2 - 10.1182/blood-2006-07-035147

DO - 10.1182/blood-2006-07-035147

M3 - Article

VL - 109

SP - 3733

EP - 3740

JO - Blood

JF - Blood

SN - 0006-4971

IS - 9

ER -