PILOT-STUDY OF THE EFFICACY OF A THROMBIN INHIBITOR FOR USE DURING CARDIOPULMONARY BYPASS
PILOT-STUDY OF THE EFFICACY OF A THROMBIN INHIBITOR FOR USE DURING CARDIOPULMONARY BYPASS
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DOI：
10.1016/0003-4975(94)92206-3
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发表时间：
1994-08-01
影响因子：
4.6
通讯作者：
MILLER, DC
中科院分区：
文献类型：
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作者：
DEANDA, A;COUTRE, SE;MILLER, DC
肝素通常用于体外循环（CPB）期间的抗凝，但有肝素诱导的血小板减少症、肝素引起的血栓形成或两者兼有病史的患者禁用肝素。肝素治疗也可能由于肝素抵抗而无效。一种短效的，基于阿托伐他汀的凝血酶抑制剂（凝血酶适体）可能在这些和其他临床情况下作为肝素的替代品。我们在犬CPB中试研究中测试了一种新型凝血酶适体，以确定其抗凝效力、凝血变量的变化以及适体清除机制和药代动力学。最初研究了7只狗：4只接受不同剂量的适体（以建立药代动力学特征），3只接受肝素。随后，其他4只犬接受CPB，在CPB前接受适体的恒定输注（以表征基线凝血状态），在60分钟的总CPB期间进行部分CPB和血液稀释，最后在2小时恢复期后。在mg.kg-1）.min（-1）剂量下，随着适体输注，活化凝血时间从106 +/-12秒上升到187 +/-8秒（+/- 1标准差）（p = 0.014），血液稀释后进一步增加（至259 +/- 41秒; p = 0.017），并且在总CPB期间甚至更长（> 1，500秒; p < 0.001）。活化凝血时间的这种后期增加导致全CPB期间凝血酶适体的血浆浓度升高，如通过高效液相色谱法测定的。计算的血浆适体消除半衰期从基线条件期间的1.9分钟增加到全旁路期间的7.7分钟，表明肺血管系统在适体清除中起作用。重要的是，在停止适体输注的5分钟内，凝血特征恢复到正常水平。与肝素相比，血小板或纤维蛋白原消耗量无差异。术后出血（胸管排出量）极轻微（2小时内95 - 150 mL），血清化学特征正常。这些初步试验数据表明，这种凝血酶适体是安全的，并且使用常规抗凝措施，在这种短期犬CPB模型中作为抗凝剂是有效的，并且其药代动力学是可预测的。此外，肺循环似乎在适体的清除中起主要作用。
Heparin is normally used for anticoagulation during cardiopulmonary bypass (CPB), but its use is contraindicated in patients with a history of heparin-induced thrombocytopenia, heparin-provoked thrombosis, or both. Heparin therapy can also be ineffective due to heparin resistance. A short-acting, oligonucleotide-based thrombin inhibitor (thrombin aptamer) may potentially serve as a substitute for heparin in these and other clinical situations. We tested a novel thrombin aptamer in a canine CPB pilot study to determine its anticoagulant efficacy, the resultant changes in coagulation variables, and the aptamers clearance mechanisms and pharmacokinetics. Seven dogs were studied initially: Four received varied doses of the aptamer (to establish the pharmacokinetic profile) and 3 received heparin. Subsequently, 4 other dogs underwent CPB, receiving a constant infusion of the aptamer before CPB (to characterize the baseline coagulation status), with partial CPB and hemodilution, during 60 minutes of total CPB, and, finally, after a 2-hour recovery period. At a 0.5 mg.kg(-1).min(-1) dose, the activated clotting time rose with aptamer infusion from 106 +/- 12 seconds to 187 +/- 8 seconds (+/- 1 standard deviation) (p = 0.014), increased further with hemodilution (to 259 +/- 41 seconds; p = 0.017), and was even more prolonged during total CPB (> 1,500 seconds; p < 0.001). This later increase in the activated clotting time paralleled a rise in the plasma concentration of the thrombin aptamer during total CPB, as determined by high-performance liquid chromatography. The calculated plasma aptamer elimination half-life increased from 1.9 minutes during baseline conditions to 7.7 minutes during total bypass, suggesting that the pulmonary vasculature plays a role in aptamer clearance. Importantly, the coagulation profile returned to normal levels within 5 minutes of halting aptamer infusion. There was no difference in platelet or fibrinogen consumption versus those of heparin. Postoperative bleeding (chest tube output) was minimal (95 to 150 mL over a 2-hour period), and serum chemistry profiles were normal. These preliminary pilot data indicate that this thrombin aptamer is both safe and, using conventional measures of anticoagulation, effective as an anticoagulant in this short-term canine CPB model, and that its pharmacokinetics are predictable. Furthermore, the pulmonary circulation appears to play a major role in the clearance of the aptamer.