Mickelson J K, Simpson P J, Cronin M, Homeister J W, Laywell E, Kitzen J, Lucchesi B R
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109.
Circulation. 1990 Feb;81(2):617-27. doi: 10.1161/01.cir.81.2.617.
Coronary artery rethrombosis can complicate initially effective thrombolytic therapy. Platelets interacting with injured vascular endothelium in a region along the coronary artery with reduced luminal cross-sectional area contribute to rethrombosis. The purpose of this study was to investigate the potential of the F(ab')2 fragment of the murine monoclonal antibody 7E3 [7E3 F(ab')2] to prevent rethrombosis after intracoronary clot lysis with recombinant tissue-type plasminogen activator (rt-PA) in an experimental model. The 7E3 F(ab')2 binds to the platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), thereby preventing platelet-fibrinogen interaction and intravascular thrombus formation. Experimental coronary artery thrombosis was produced in the anesthetized dog by application of direct anodal current to the intimal surface of the left circumflex coronary artery in the region of an external stenosis. Lysis of the established intracoronary thrombus was achieved with the intravenous administration of rt-PA (25 mg) after which the animals were randomized into two groups. Group 1 (n = 10) served as the control, receiving the saline diluent, and group 2 (n = 9) received 7E3 F(ab')2, given as a single intravenous injection (0.8 mg/kg). The times required for occlusive thrombus formation, rt-PA-induced thrombolysis, and rethrombosis (if it occurred) were similar in the animals treated with saline and those treated with 7E3 F(ab')2. The initial left circumflex coronary artery blood flow was similar in both groups but decreased to a negligible level in group 1. In group 2, left circumflex coronary artery blood flow declined modestly (24 +/- 2 to 10 +/- 2 ml/min). Rethrombosis occurred in all animals in group 1 but in only two of nine animals in group 2 (p less than 0.05). Oscillations in coronary blood flow preceded rethrombosis in group 1, whereas 7E3 F(ab')2 stabilized left circumflex coronary artery blood flow patterns during the course of teh experimental protocol (5.2 +/- 0.9 vs. 0.7 +/- 0.4 oscillations, respectively; p less than 0.05). Thrombus mass recovered from the left circumflex coronary artery at the conclusion of each experiment was greater in group 1 as compared with group 2 (7.0 +/- 2.3 vs. 1.5 +/- 0.7 mg, respectively; p less than 0.05). The area of left ventricle at risk for infarction was similar in both groups but infarct size, infarction/at risk assessed histochemically, was larger in group 1 than group 2 (35 +/- 9% vs. 6 +/- 4%, respectively; p less than 0.05). Platelet aggregation induced by ADP and arachidonic acid was similar at baseline for all of the animals.(ABSTRACT TRUNCATED AT 400 WORDS)
冠状动脉再血栓形成可使最初有效的溶栓治疗变得复杂。血小板与冠状动脉腔内横截面积减小区域的受损血管内皮相互作用，会导致再血栓形成。本研究的目的是在实验模型中，研究鼠单克隆抗体7E3的F(ab')2片段[7E3 F(ab')2]预防重组组织型纤溶酶原激活剂(rt-PA)冠状动脉内血栓溶解后再血栓形成的潜力。7E3 F(ab')2与血小板糖蛋白IIb/IIIa复合物(GPIIb/IIIa)结合，从而阻止血小板与纤维蛋白原相互作用以及血管内血栓形成。通过向左回旋支冠状动脉外狭窄区域的内膜表面施加直流电，在麻醉犬身上产生实验性冠状动脉血栓形成。静脉注射rt-PA(25mg)使已形成的冠状动脉血栓溶解，之后将动物随机分为两组。第1组(n = 10)作为对照组，接受生理盐水稀释剂，第2组(n = 9)接受7E3 F(ab')2，单次静脉注射(0.8mg/kg)。用生理盐水治疗的动物和用7E3 F(ab')2治疗的动物，闭塞性血栓形成、rt-PA诱导的溶栓以及再血栓形成(如果发生)所需时间相似。两组最初的左回旋支冠状动脉血流相似，但第1组血流降至可忽略不计的水平。在第2组中，左回旋支冠状动脉血流适度下降(从24±2降至10±2ml/min)。第1组所有动物均发生再血栓形成，而第2组9只动物中只有2只发生再血栓形成(p<0.05)。第1组冠状动脉血流振荡先于再血栓形成，而7E3 F(ab')2在实验过程中稳定了左回旋支冠状动脉血流模式(分别为5.2±0.9次振荡与0.7±0.4次振荡；p<0.05)。每次实验结束时，从左回旋支冠状动脉回收的血栓量，第1组比第2组大(分别为7.0±2.3mg与1.5±0.7mg；p<0.05)。两组左心室梗死危险区域面积相似，但经组织化学评估，第1组梗死面积、梗死/危险区域比值大于第2组(分别为35±9%与6±4%；p<0.05)。所有动物在基线时，由ADP和花生四烯酸诱导的血小板聚集相似。(摘要截于400字)
