Leadley R J, Kasiewski C J, Bostwick J S, Bentley R, Dunwiddie C T, Perrone M H
Cardiovascular Drug Discovery, Rhône-Poulenc Rorer, Collegeville, PA 19426, USA.
Arterioscler Thromb Vasc Biol. 1998 Jun;18(6):908-14. doi: 10.1161/01.atv.18.6.908.
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.
实验旨在比较依诺肝素和普通肝素（UH）在犬回旋支冠状动脉狭窄模型中血小板依赖性循环血流减少（CFR）模型中的抗血栓形成疗效。低分子量肝素（LMWHs）在预防和治疗静脉血栓栓塞方面是安全有效的。本实验旨在通过比较低分子量肝素与普通肝素在不稳定型心绞痛动物模型中的抗血栓形成作用，评估低分子量肝素在动脉血栓形成适应症中的潜在用途。通过实验性诱导血管狭窄和损伤建立一致的CFR后，静脉注射载体（生理盐水）、依诺肝素或普通肝素作为负荷剂量加持续输注1小时。CFR的抑制被视为抗血栓形成疗效的指标。依诺肝素以剂量依赖性方式抑制重复性血小板血栓形成，在0.5mg/kg + 5μg/kg每分钟时实现了对CFR的显著抑制。该剂量的依诺肝素导致抗Xa水平为0.9至1.0IU/mL，抗IIa水平为0.2至0.3IU/mL，活化部分凝血活酶时间（APTT）比基线增加1.3倍，模板出血时间增加1.4倍（无统计学意义）。依诺肝素在1.0mg/kg + 10μg/kg每分钟时几乎完全消除了CFR。该剂量的依诺肝素产生的抗Xa水平为2至2.2IU/mL，抗IIa水平为0.5至0.6IU/mL，APTT比基线增加1.4至1.5倍，模板出血时间增加1.9倍（P<0.05）。相比之下，普通肝素在剂量为100U/kg + 10U/kg每分钟时对CFR没有显著影响，该剂量导致抗Xa水平为1.2至1.6IU/mL，抗IIa水平为1.8至2.4IU/mL，APTT比基线增加超过10倍，模板出血时间增加2.5倍（P<0.05）。与载体组相比，任何测试剂量的依诺肝素或普通肝素均未显著改变循环血小板计数和血细胞比容。与普通肝素不同，依诺肝素可预防犬体内重复性血小板依赖性血栓形成，从而支持依诺肝素在治疗动脉血栓形成疾病如不稳定型心绞痛中作为肝素替代品的潜在用途。
