Jun L, Arnout J, Vanhove P, Dol F, Lormeau J C, Herbert J M, Collen D, Van de Werf F
Laboratory of Experimental Cardiology, University of Leuven, Belgium.
Coron Artery Dis. 1995 Mar;6(3):257-63.
Low-molecular-weight heparins may have a higher benefit to risk ratio than unfractionated heparin in preventing perioperative thrombosis. The antithrombotic effects of low-molecular-weight heparins, given as adjunctive therapy to alteplase and aspirin, have not previously been compared with those of unfractionated heparin in experimental models of coronary artery thrombosis.
Occlusive coronary thrombosis was induced in 5 groups of 10 dogs by placing a copper coil into the left anterior descending coronary artery. After 1 h of occlusion, intravenous alteplase (0.1 mg/kg bolus followed by 0.01 mg/kg/min for 30 min), and aspirin (bolus of 5 mg/kg) were administered in combination with one of the following study treatments given intravenously for 2 h: placebo (group 1); unfractionated heparin (200 IU/kg bolus followed by 100 IU/kg/h, group II); the low-molecular weight heparin, nadroparin calcium, in three different doses (100 IU/kg bolus followed by 50 IU/kg/h, group III; 200 IU/kg bolus followed by 100 IU/kg/h, group IV; and 300 IU/kg followed by 150 IU/kg/h, group V). Coronary patency was assessed with angiography at 10 min intervals and hemostasis parameters were measured at baseline, after 1 h of occlusion, and 30 and 120 min after commencing drug administration.
Optimal reperfusion [Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 without reocclusion] was more frequently observed in groups II (6/10), IV (8/10) and V (9/10) than in groups I (1/10) and III (3/10) (P < 0.05). Groups II and IV had similar patency rates (P = NS) and were therefore assumed to represent equivalent antithrombotic doses. Both nadroparin calcium and unfractionated heparin effectively prevented new thrombin generation as shown by repeated measurements of thrombin-antithrombin III complex levels in plasma. At equivalent antithrombotic doses, nadroparin calcium (group IV) was associated with significantly lower steady state values than standard heparin (group II) for activated partial thromboplastin time (41.3 +/- 48.9 versus 134.7 +/- 61.6 s), anti-Xa levels (2.4 +/- 0.5 vs 3.4 +/- 0.9 U/ml) and anti-IIa levels (0.8 +/- 0.1 versus 2.1 +/- 0.7 U/ml).
Both nadroparin calcium and unfractionated heparin significantly enhance alteplase-induced thrombolysis in aspirin-treated dogs. At equivalent antithrombotic doses, nadroparin calcium was associated with less prolongation of the activated partial thromboplastin time and lower steady-state anti-Xa and anti-IIa activities.
在预防围手术期血栓形成方面，低分子量肝素可能比普通肝素具有更高的效益风险比。在冠状动脉血栓形成的实验模型中，低分子量肝素作为阿替普酶和阿司匹林辅助治疗的抗血栓作用，此前尚未与普通肝素进行比较。
将5组，每组10只犬的左冠状动脉前降支放置铜圈诱导闭塞性冠状动脉血栓形成。闭塞1小时后，静脉注射阿替普酶（0.1mg/kg推注，随后以0.01mg/kg/min持续30分钟）和阿司匹林（5mg/kg推注），并与以下研究治疗之一静脉联合给药2小时：安慰剂（第1组）；普通肝素（200IU/kg推注，随后100IU/kg/h，第2组）；三种不同剂量的低分子量肝素那屈肝素钙（100IU/kg推注，随后50IU/kg/h，第3组；200IU/kg推注，随后100IU/kg/h，第4组；300IU/kg推注，随后150IU/kg/h，第5组）。每隔10分钟通过血管造影评估冠状动脉通畅情况，并在基线、闭塞1小时后以及开始给药后30分钟和120分钟测量止血参数。
与第1组（1/10）和第3组（3/10）相比，第2组（6/10）、第4组（8/10）和第5组（9/10）更频繁地观察到最佳再灌注[心肌梗死溶栓（TIMI）血流分级3级且无再闭塞]（P<0.05）。第2组和第4组的通畅率相似（P=无显著性差异），因此被认为代表等效的抗血栓剂量。血浆中凝血酶 - 抗凝血酶III复合物水平的重复测量表明，那屈肝素钙和普通肝素均能有效预防新的凝血酶生成。在等效抗血栓剂量下，那屈肝素钙（第4组）与标准肝素（第2组）相比，活化部分凝血活酶时间（41.3±48.9对134.7±61.6秒）、抗Xa水平（2.4±0.5对3.4±0.9U/ml）和抗IIa水平（0.8±0.1对2.1±0.7U/ml）的稳态值显著更低。
那屈肝素钙和普通肝素均能显著增强阿替普酶在阿司匹林治疗犬中诱导的溶栓作用。在等效抗血栓剂量下，那屈肝素钙与活化部分凝血活酶时间延长较少以及较低的稳态抗Xa和抗IIa活性相关。
