Chen L Y, Nichols W W, Mattsson C, Teger-Nilson A C, Wallin R, Saldeen T G, Mehta J L
Department of Medicine, University of Florida College of Medicine, Gainesville, USA.
Cardiovasc Res. 1995 Dec;30(6):866-74.
Coronary artery often reoccludes after thrombolytic therapy with recombinant tissue-plasminogen activator (rt-PA). This reocclusion is thought to be due to in situ platelet activation mediated by thromboxane (Tx) A2 and thrombin; hence, aspirin and thrombin inhibitors are often used in patients with acute myocardial infarction. This study was designed to examine the modulation of coronary artery reocclusion by a novel low molecular weight direct thrombin inhibitor inogatran with or without aspirin.
22 dogs with electrically-induced occlusive intracoronary thrombus were treated with saline (n = 7, group A), or high dose inogatran (0.25 mg/kg bolus followed by 0.6 mg/kg per h for 2 h, n = 5, group B), or low dose inogatran (0.125 mg/kg bolus followed by 0.3 mg/kg per h for 2 h, n = 5, group C), or aspirin+low dose inogatran (n = 5, Group D). Recombinant tissue-plasminogen activator (rt-PA) was infused for 20 min starting 2 min after the bolus in all dogs. Coronary artery blood flow was monitored for 120 min after rt-PA administration.
Reperfusion rates were similar in all groups, but the time to reperfusion was shortest in group B dogs (18 +/- 2 min vs. 32 +/- 7 min in group A dogs, P < 0.05). Reocclusion rates were 80%, 0%, 50%, and 60% in groups A, B, C, and D dogs, respectively. The restored blood flow persisted for 19 +/- 10, > 120 min, 71 +/- 30 and 54 +/- 26 min in groups A, B, C, and D dogs, respectively. At the end of rt-PA infusion, prothrombin time (PT) and activated partial thromboplastin time (APTT) were increased 1.3-2 times the control value, and the changes in PT and APTT were similar in all groups. Thrombin generation and activity, assessed by rise in thrombin-antithrombin complex and fibrinopeptide A levels, and decrease in fibrinogen levels were most marked in group A dogs, and less so in group B, C and D dogs.
These data show that high dose of direct thrombin inhibitor inogatran shortens time to reflow and abolishes coronary artery reocclusion. However, aspirin does not potentiate the effect of suboptimal doses of inogatran.
使用重组组织型纤溶酶原激活剂（rt-PA）进行溶栓治疗后，冠状动脉常出现再闭塞。这种再闭塞被认为是由于血栓素（Tx）A2和凝血酶介导的原位血小板激活所致；因此，阿司匹林和凝血酶抑制剂常用于急性心肌梗死患者。本研究旨在探讨新型低分子量直接凝血酶抑制剂依诺加群单独或联合阿司匹林对冠状动脉再闭塞的调节作用。
将22只电诱导冠状动脉内闭塞性血栓形成的犬分为生理盐水组（n = 7，A组）、高剂量依诺加群组（0.25 mg/kg静脉推注，随后以0.6 mg/kg每小时持续2小时，n = 5，B组）、低剂量依诺加群组（0.125 mg/kg静脉推注，随后以0.3 mg/kg每小时持续2小时，n = 5，C组）或阿司匹林+低剂量依诺加群组（n = 5，D组）。所有犬在静脉推注后2分钟开始输注重组组织型纤溶酶原激活剂（rt-PA）20分钟。rt-PA给药后监测冠状动脉血流120分钟。
所有组的再灌注率相似，但B组犬的再灌注时间最短（18±2分钟，A组犬为32±7分钟，P<0.05）。A、B、C和D组犬的再闭塞率分别为80%、0%、50%和60%。A、B、C和D组犬恢复的血流分别持续19±10分钟、>120分钟、71±30分钟和54±26分钟。在rt-PA输注结束时，凝血酶原时间（PT）和活化部分凝血活酶时间（APTT）增加至对照值的1.3 - 2倍，且所有组PT和APTT的变化相似。通过凝血酶 - 抗凝血酶复合物和纤维蛋白肽A水平升高以及纤维蛋白原水平降低评估的凝血酶生成和活性在A组犬中最为显著，在B、C和D组犬中则较弱。
这些数据表明，高剂量直接凝血酶抑制剂依诺加群可缩短再灌注时间并消除冠状动脉再闭塞。然而，阿司匹林不能增强次优剂量依诺加群的效果。
