Makkar R R, Litvack F, Eigler N L, Nakamura M, Ivey P A, Forrester J S, Shah P K, Jordan R E, Kaul S
Department of Medicine, Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Circulation. 1997 Feb 18;95(4):1015-21. doi: 10.1161/01.cir.95.4.1015.
Thrombosis is an important limitation of metallic coronary stents, especially in smaller vessels in which shear rates are high. Monoclonal antibody to platelet glycoprotein IIb/IIIa receptor (7E3) has been shown to inhibit shear-induced platelet aggregation. In this study, we compared the effects of 7E3, heparin, and aspirin on stent thrombosis in an ex vivo arteriovenous shunt model of high-shear blood flow.
An ex vivo arteriovenous shunt was created in 10 anesthetized dogs. Control rough-surface slotted-tube nitinol stents (n = 72) expanded to 2 mm in diameter in a tubular perfusion chamber were interposed in the shunt and exposed to flowing arterial blood at a shear rate of 2100s-1 for 20 minutes. The animals were treated with intravenous murine 7E3 (Fab')2 (0.2, 0.4, and 0.8 mg/kg), heparin (100 U/kg), or aspirin (10 mg/kg). Effects of the test agents on thrombus weight, platelet aggregation, platelet P-selectin expression, bleeding time, and activated clotting time (ACT) were quantified. 7E3 reduced stent thrombosis by 95% (20 +/- 1 to 1 +/- 1 mg, P < .001) and platelet aggregation by 94% (14 +/- 2 to 1 +/- 1 omega, P < .001) at the highest dose (0.8 mg/kg). 7E3 significantly prolonged bleeding time but had no effect on ACT and platelet P-selectin expression. Heparin prolonged ACT but had no significant effect on stent thrombosis or platelet aggregation. Aspirin, although it inhibited platelet aggregation by 65%, had no effect on stent thrombosis (19 +/- 2 versus 20 +/- 1 mg in controls).
7E3 produced a dose-dependent inhibition of acute stent thrombosis under high-shear flow conditions. Stent thrombosis was resistant to heparin and aspirin. Thus, 7E3 may be an effective agent for preventing stent thrombosis.
血栓形成是金属冠状动脉支架的一个重要局限性，尤其是在剪切率较高的小血管中。血小板糖蛋白IIb/IIIa受体单克隆抗体（7E3）已被证明可抑制剪切诱导的血小板聚集。在本研究中，我们在高剪切血流的体外动静脉分流模型中比较了7E3、肝素和阿司匹林对支架血栓形成的影响。
在10只麻醉犬中建立体外动静脉分流。将对照的粗糙表面开槽管镍钛合金支架（n = 72）在管状灌注室中扩张至直径2 mm，置于分流中，并以2100s-1的剪切率暴露于流动的动脉血中20分钟。动物接受静脉注射鼠源性7E3（Fab'）2（0.2、0.4和0.8 mg/kg）、肝素（100 U/kg）或阿司匹林（10 mg/kg）治疗。对受试药物对血栓重量、血小板聚集、血小板P-选择素表达、出血时间和活化凝血时间（ACT）的影响进行定量分析。在最高剂量（0.8 mg/kg）时，7E3使支架血栓形成减少95%（从20±1 mg降至1±1 mg，P <.001），血小板聚集减少94%（从14±2 Ω降至1±1 Ω，P <.001）。7E3显著延长出血时间，但对ACT和血小板P-选择素表达无影响。肝素延长ACT，但对支架血栓形成或血小板聚集无显著影响。阿司匹林虽然抑制血小板聚集65%，但对支架血栓形成无影响（对照组为19±2 mg，阿司匹林组为20±1 mg）。
在高剪切流条件下，7E3对急性支架血栓形成产生剂量依赖性抑制作用。支架血栓形成对肝素和阿司匹林有抵抗性。因此，7E3可能是预防支架血栓形成的有效药物。
