A structural and dynamic investigation of the facilitating effect of glycoprotein IIb/IIIa inhibitors in dissolving platelet-rich clots
A structural and dynamic investigation of the facilitating effect of glycoprotein IIb/IIIa inhibitors in dissolving platelet-rich clots
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DOI：
10.1161/hh0402.105095
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发表时间：
2002-03-08
影响因子：
20.1
通讯作者：
Weisel, JW
中科院分区：
文献类型：
--
作者：
Collet, JP;Montalescot, G;Weisel, JW
糖蛋白IIb/IIIa （GP IIb/IIIa）抑制剂最近被证明可以促进药物溶栓的速度和程度。然而，它们与rtPA在溶解血栓性血管闭塞方面的协同潜力尚不完全清楚。因此，我们开发了一种动态和结构的方法来分析纤维蛋白溶解，以评估血小板的抑制作用和GPIIb/IIIa抑制剂在溶解富血小板凝块（prc）中的促进作用。荧光rtPA法研究了细胞的结构。来追踪rtPA结合锋的进展。用共聚焦显微镜测量裂解前沿速度。与血小板贫乏区相比，prc的纤溶抵抗与血小板丰富区rtPA结合速度和溶前速度的降低有关（在血小板丰富区和血小板贫乏区，rtPA结合速度分别为2.4+/-0.2和3.5+/-0.4妈妈/分钟，P=0.04；溶前速度分别为1.2+/-0.6和2.8+/-0.2妈妈/分钟，P=0.008）。纤维蛋白溶解呈异质性，使血小板丰富的区域未被溶解。凝血前添加药物浓度的阿昔单抗（0.068 mumol/L）或依替巴肽（I mumol/L）可使富血小板区平均表面积分别降低64% （P=0.0005）和72% （P=0.0007）。在血小板丰富区和血小板贫乏区之间，rtPA结合率和rtPA结合前沿速度的平衡导致阿昔单抗- prc （P=0.006）或依替巴肽- prc （P=0.03）在血小板丰富区溶出前沿速度增加3倍。处理后的prc的总裂解率比对照prc提高了74% (P
Glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors were shown recently to facilitate the rate and the extent of pharmacological thrombolysis. However, their synergistic potential with rtPA in dissolving thrombotic vaso-occlusions is not fully understood. We have therefore developed a dynamic and structural approach for analysis of fibrinolysis to assess the inhibiting effect of platelets and the facilitating effect of GPIIb/IIIa inhibitors in dissolving platelet-rich clots (PRCs). Fluorescent rtPA was used to study the architecture of PRCs. to follow the progression of the rtPA binding front. and to measure the lysis-front velocity using confocal microscopy. Fibrinolysis resistance of PRCs was related to a reduction of both rtPA binding and lysis-front velocities of platelet-rich areas compared with platelet-poor areas (2.4+/-0.2 versus 3.5+/-0.4 mum/min for rtPA binding velocity, P=0.04, and 1.2+/-0.6 versus 2.8+/-0.2 mum/min for lysis-front velocity, P=0.008, in platelet-rich and platelet-poor areas, respectively). Fibrinolysis appeared heterogeneous, leaving platelet-rich areas un-lysed. Adding pharmacological concentrations of abciximab (0.068 mumol/L) or eptifibatide (I mumol/L) before clotting decreased the average surface of platelet-rich areas by 64% (P=0.0005) and 72% (P=0.0007), respectively. The resulting equalization of rtPA binding rate and rtPA binding-front velocity between platelet-rich and platelet-poor areas led to a 3-fold increase of the lysis-front velocity in platelet-rich areas of either abciximab-PRC (P=0.006) or eptifibatide-PRC (P=0.03). The overall lysis rate of treated-PRC was increased by 74% compared with control-PRC (P