Roux S P, Sakariassen K S, Turitto V T, Baumgartner H R
Pharma Division, Preclinical Research/PRPV, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Arterioscler Thromb. 1991 Sep-Oct;11(5):1182-91. doi: 10.1161/01.atv.11.5.1182.
Thrombosis on the damaged or ruptured vascular wall in a stenotic coronary artery is believed to be the precipitating factor leading to unstable angina. Little is known about the nature of the interactions among platelets, fluid dynamic factors, and vessel wall properties under such conditions. In the present investigation we have compared two experimental models of thrombosis simultaneously in anesthetized dogs. The first was an in vivo model of unstable angina, in which a fixed circumflex coronary artery stenosis was produced and the resultant cyclic blood flow reductions (CFRs) through the vessel were investigated after infusion of aspirin and a combination of aspirin and epinephrine. As previously reported, aspirin inhibited the CFRs, but the continuous infusion of epinephrine reestablished the appearance of CFRs. The second was an ex vivo model, in which thrombus formation on a type III collagen surface was investigated in a parallel-plate perfusion system under controlled conditions of exposure time and flow; morphological evaluation of thrombus volume, platelet adhesion, and fibrin deposition was performed. The chamber was positioned in an extracorporeal shunt between the carotid artery and the jugular vein of anesthetized dogs and exposed to nonanticoagulated blood at a shear rate of 1,600 sec-1. Thirty minutes after establishment of the CFRs, a blood sample for platelet aggregation was collected and a bleeding time and a first ex vivo perfusion were performed. At the end of this perfusion, animals were subjected either to no treatment (n = 10) or to an intravenous bolus of 10 mg/kg aspirin (n = 7), and a second perfusion was conducted 30 minutes later. Additional untreated animals (n = 6) were given aspirin followed by a continuous intravenous infusion of 10 micrograms/ml epinephrine, and a third perfusion was conducted. Results with respect to platelet adhesion, thrombus volume, and fibrin deposition were similar in the two perfusions in untreated animals. Treatment with aspirin abolished the CFRs in all dogs and concomitantly reduced the ex vivo thrombus volume by 84% (p less than 0.01) without affecting platelet adhesion and fibrin deposition. Bleeding time increased by 40% (p less than 0.05), and collagen-induced platelet aggregation was virtually abolished (p less than 0.01). However, infusion of epinephrine in dogs after aspirin treatment restored the CFRs, and the ex vivo thrombus volumes were not statistically different from predrug values. Thus, the ex vivo model satisfactorily reflects the more complicated in vivo model events with respect to intracoronary thrombosis and substantiates the view that aspirin interrupts coronary thrombogenesis in the dog by interfering with platelet cohesion.
人们认为，在狭窄的冠状动脉中，受损或破裂血管壁上形成的血栓是导致不稳定型心绞痛的诱发因素。在这种情况下，血小板、流体动力学因素和血管壁特性之间相互作用的本质鲜为人知。在本研究中，我们在麻醉犬身上同时比较了两种血栓形成的实验模型。第一种是不稳定型心绞痛的体内模型，通过制造固定的左旋冠状动脉狭窄，然后在输注阿司匹林以及阿司匹林与肾上腺素的组合后，研究通过该血管产生的周期性血流减少（CFR）情况。如先前报道，阿司匹林可抑制CFR，但持续输注肾上腺素可使CFR再次出现。第二种是体外模型，在平行板灌注系统中，在暴露时间和血流的可控条件下，研究III型胶原表面的血栓形成；对血栓体积、血小板黏附及纤维蛋白沉积进行形态学评估。该腔室置于麻醉犬颈动脉与颈静脉之间的体外分流中，以1600秒-1的剪切速率暴露于未抗凝的血液中。在建立CFRs 30分钟后，采集用于血小板聚集的血样，并进行出血时间测定和首次体外灌注。在此次灌注结束时，对动物进行如下处理：不治疗（n = 10）或静脉推注10 mg/kg阿司匹林（n = 7），30分钟后进行第二次灌注。另外未治疗的动物（n = 6）先给予阿司匹林，然后持续静脉输注10微克/毫升肾上腺素，之后进行第三次灌注。在未治疗动物的两次灌注中，血小板黏附、血栓体积和纤维蛋白沉积方面的结果相似。用阿司匹林治疗可消除所有犬的CFRs，并使体外血栓体积同时减少84%（p < 0.01），而不影响血小板黏附和纤维蛋白沉积。出血时间增加40%（p < 0.05），胶原诱导的血小板聚集几乎完全被消除（p < 0.01）。然而，在阿司匹林治疗后的犬中输注肾上腺素可恢复CFRs，且体外血栓体积与给药前的值无统计学差异。因此，体外模型在冠状动脉内血栓形成方面令人满意地反映了更复杂的体内模型事件，并证实了阿司匹林通过干扰血小板凝聚来阻断犬冠状动脉血栓形成的观点。
