We compared the direct thrombin inhibitor, desulfatohirudin (REVASC) and the indirect thrombin inhibitor, heparin, as adjuncts to thrombolytic therapy with reteplase in a canine model of coronary artery thrombosis. 2. Reteplase (BM 06.022) is a recombinant unglycosylated variant of human tissue-type plasminogen activator. Thrombus formation in anaesthetized open chest dogs was induced by electrical injury. Left circumflex coronary artery blood flow was monitored for 210 min with an electromagnetic flow probe. Twenty eight dogs were randomized to receive i.v. heparin (120 iu kg-1 bolus plus 80 iu kg-1 per h) or i.v. hirudin (2.0 mg kg-1 bolus plus 2.0 mg kg-1 per h) 10 min before thrombolysis preceded by i.v. acetylsalicyclic acid (20 mg kg-1) 5 min prior to anticoagulation. Every dog received an i.v. double bolus injection of 0.14 + 0.14 u kg-1 ( = 0.24 + 0.24 mg kg-1) reteplase, 30 min apart, 1 h after thrombus formation. 3. At comparable reperfusion rates (12 out of 12 vs. 15 out of 16 dogs), hirudin enhanced time to reperfusion (14.3 +/- 1.4 vs. 23.2 +/- 3.4 min; P < 0.05) and completely prevented reocclusion after reperfusion in contrast to heparin (0 out of 11 vs. 7 out of 11 dogs; P < 0.05). Coronary blood flow quality was improved by hirudin as shown by a higher maximum blood flow after reperfusion (130 +/- 14.3 vs. 83 +/- 9.3% of baseline; P < 0.05), a higher blood flow level at 20, 30, 40, and 50 min after onset of thrombolysis (P < 0.05) and a longer cumulative patency time (195 +/- 1.7 vs. 166 +/- 12 min; P < 0.05). Activated partial thromboplastin time and buccal mucosa bleeding time were prolonged (P < 0.05) by either anticoagulant, but did not differ significantly between groups. 4. The direct thrombin inhibitor, desulfatohirudin, enhanced thrombolysis, prevented reocclusion and increased blood flow as compared with the indirect thrombin inhibitor, heparin, when investigated at one dose level each and used in conjunction with reteplase.
摘要
在犬冠状动脉血栓形成模型中，我们比较了直接凝血酶抑制剂去硫酸水蛭素（REVASC）和间接凝血酶抑制剂肝素作为瑞替普酶溶栓治疗辅助药物的效果。2. 瑞替普酶（BM 06.022）是重组的非糖基化人组织型纤溶酶原激活剂变体。通过电损伤诱导麻醉开胸犬形成血栓。用电磁血流探头监测左旋冠状动脉血流210分钟。28只犬被随机分为两组，在溶栓前10分钟静脉注射肝素（120国际单位/千克负荷量加80国际单位/千克每小时）或静脉注射水蛭素（2.0毫克/千克负荷量加2.0毫克/千克每小时），在抗凝前5分钟静脉注射乙酰水杨酸（20毫克/千克）。每只犬在血栓形成后1小时，分两次静脉注射0.14 + 0.14单位/千克（相当于0.24 + 0.24毫克/千克）瑞替普酶，间隔30分钟。3. 在再灌注率相当的情况下（12只犬中有12只 vs. 16只犬中有15只），与肝素相比，水蛭素延长了再灌注时间（14.3 +/- 1.4分钟 vs. 23.2 +/- 3.4分钟；P < 0.05），并完全防止了再灌注后的再闭塞（11只犬中有0只 vs. 11只犬中有7只；P < 0.05）。水蛭素改善了冠状动脉血流质量，表现为再灌注后最大血流更高（130 +/- 14.3% vs. 83 +/- 9.3%基线；P < 0.05），溶栓开始后20、30、40和50分钟时血流水平更高（P < 0.05），以及累积通畅时间更长（195 +/- 1.7分钟 vs. 166 +/- 12分钟；P < 0.05）。两种抗凝剂均延长了活化部分凝血活酶时间和口腔黏膜出血时间（P < 0.05），但两组之间无显著差异。4. 当以每种一种剂量水平进行研究并与瑞替普酶联合使用时，直接凝血酶抑制剂去硫酸水蛭素与间接凝血酶抑制剂肝素相比，增强了溶栓效果，防止了再闭塞并增加了血流。
