Inhibition of repetitive thrombus formation in the stenosed canine coronary artery by enoxaparin, but not by unfractionated heparin.
Experiments were designed to compare the antithrombotic efficacy of enoxaparin and unfractionated heparin (UH) in a model of platelet-dependent cyclic flow reductions (CFRs) in the stenosed canine circumflex coronary artery. Low-molecular-weight heparins (LMWHs) are safe and effective in the prevention and treatment of venous thromboembolism. The present experiments were designed to evaluate the potential use of LMWHs in arterial thrombotic indications by comparing the antithrombotic effect of an LMWH with that of UH in an animal model of unstable angina. After establishment of consistent CFRs by experimentally induced vascular stenosis and damage, vehicle (saline), enoxaparin, or UH was administered intravenously as a loading dose plus a continuous infusion for 1 hour. The inhibition of CFRs was taken as an indicator of antithrombotic efficacy. Enoxaparin inhibited repetitive platelet thrombus formation in a dose-dependent manner, with significant inhibition of CFRs achieved at 0.5 mg/kg + 5 microg/kg per minute. This dose of enoxaparin resulted in anti-Xa levels of 0.9 to 1.0 IU/mL, anti-IIa levels of 0.2 to 0.3 IU/mL, activated partial thromboplastin time (APTT) of 1.3-fold over baseline, and a 1.4-fold increase (NS) in template bleeding time. Near-complete abolishment of CFRs was achieved with enoxaparin at 1.0 mg/kg + 10 microg/kg per minute. This dose of enoxaparin produced anti-Xa levels of 2 to 2.2 IU/mL, anti-IIa levels of 0.5 to 0.6 IU/mL, an increase in APTT of 1.4- to 1.5-fold over baseline, and a 1.9-fold increase (P<0.05) in template bleeding time. In contrast, UH had no significant effect on CFRs at a dose (100 U/kg + 10 U/kg per minute) that resulted in anti-Xa levels of 1.2 to 1.6 IU/mL, anti-IIa levels of 1.8 to 2.4 IU/mL, an increase in APTT greater than 10-fold over baseline, and a 2.5-fold increase (P<0.05) in template bleeding time. Compared with the vehicle group, circulating platelet count and hematocrit were not changed significantly by any dose of enoxaparin or UH tested. Enoxaparin, unlike UH, prevented repetitive platelet-dependent thrombus formation in the dog, thereby supporting the potential use of enoxaparin as a replacement for heparin in the treatment of arterial thrombotic disorders such as unstable angina.
Leadley
R J
RJ
Cardiovascular Drug Discovery, Rhône-Poulenc Rorer, Collegeville, PA 19426, USA. robert.leadley@rp-rorer.com
Kasiewski
C J
CJ
Bostwick
J S
JS
Bentley
R
R
Dunwiddie
C T
CT
Perrone
M H
MH
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D003328:Coronary Thrombosis / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D003331:Coronary Vessels; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D017984:Enoxaparin / Q000627:therapeutic use*; D015951:Factor Xa / Q000378:metabolism; D005260:Female; D006439:Hemodynamics; D006493:Heparin / Q000627:therapeutic use*; D008297:Male; D010314:Partial Thromboplastin Time; D011516:Prothrombin / Q000378:metabolism; D011517:Prothrombin Time; D012008:Recurrence
D000925:Anticoagulants; D017984:Enoxaparin; D011516:Prothrombin; C025337:Factor IIa; D006493:Heparin; D015951:Factor Xa