Serebruany Victor L, Malinin Alex I, Callahan Kevin P, Binbrek Azan, Van De Werf Frans, Alexander John H, Granger Christopher B, Gurbel Paul A
Sinai Hospital, Johns Hopkins University, Baltimore, Md, USA.
Am Heart J. 2003 Apr;145(4):636-42. doi: 10.1067/mhj.2003.210.
Platelets play a pivotal role in the pathogenesis of acute myocardial infarction, as well as in the occurrence of coronary artery reocclusion and bleeding events. Therefore, the success of fibrinolytic therapy may be dependent on its direct effects on platelets.
We sought to determine how tenecteplase (TNK) and alteplase (tPA) affect platelets in vitro in human volunteers and ex vivo by use of patient data from the Assessment of the Safety and Efficacy of a New Thrombolytic Agent (ASSENT-2) trial. For the in vitro studies, whole blood from 9 healthy volunteers was incubated with 30 mg TNK and 60 mg tPA. Platelet function was measured by conventional aggregometry, bedside point-of-care devices, and sensitive flow cytometry techniques. For the ex vivo study, 41 patients were selected from the ASSENT-2 trial: 21 had received TNK and 20 had received tPA. Each patient underwent 7 serial blood draws every 30 minutes for 3 hours. Levels of platelet endothelial cell adhesion molecule-1 (PECAM-1), vascular cell adhesion molecule-1 (VCAM-1), P-selectin, beta-thromboglobulin, platelet factor 4, thromboxane, and prostacyclin were measured by enzyme-linked immunosorbent assay. Significant inhibition of conventional and whole blood aggregation and reduced platelet function by point-of-care analyzers were observed for both agents, but mostly in the TNK-treated samples. After incubation with TNK, flow cytometry revealed decreased expression of glycoprotein IIb/IIIa, PECAM-1, vitronectin receptor, CD151, and formation of the platelet-monocyte aggregates. Serial samples from patients in the ASSENT-2 trial showed a significant decrease of soluble platelet-endothelial biomarkers in the TNK group. There was a trend toward decreased platelet function characteristics with tPA; however, these differences were much smaller than those observed with TNK.
Both tPA and TNK were shown to affect platelet function in human volunteers and in patients with AMI early after thrombolysis. The antiplatelet properties of TNK were shown to be more profound than those of tPA. These findings are relevant to ongoing investigations of combination therapy with fibrinolytic and antiplatelet agents in patients with AMI.
血小板在急性心肌梗死的发病机制以及冠状动脉再闭塞和出血事件的发生中起关键作用。因此，溶栓治疗的成功可能取决于其对血小板的直接作用。
我们试图通过使用来自新型溶栓剂安全性和有效性评估（ASSENT-2）试验的患者数据，确定替奈普酶（TNK）和阿替普酶（tPA）在体外对人类志愿者血小板以及在体内的影响。对于体外研究，将9名健康志愿者的全血与30mg TNK和60mg tPA一起孵育。通过传统的凝集测定法、床边即时检测设备和灵敏的流式细胞术技术测量血小板功能。对于体内研究，从ASSENT-2试验中选取41例患者：21例接受TNK治疗，20例接受tPA治疗。每位患者在3小时内每隔30分钟进行7次连续采血。通过酶联免疫吸附测定法测量血小板内皮细胞黏附分子-1（PECAM-1）、血管细胞黏附分子-1（VCAM-1）、P-选择素、β-血小板球蛋白、血小板因子4、血栓素和前列环素的水平。两种药物均观察到对传统和全血凝集有显著抑制作用，且即时检测分析仪显示血小板功能降低，但主要在TNK治疗的样本中。与TNK孵育后，流式细胞术显示糖蛋白IIb/IIIa、PECAM-1、玻连蛋白受体、CD151的表达降低，以及血小板-单核细胞聚集体的形成。ASSENT-2试验中患者的系列样本显示TNK组中可溶性血小板-内皮生物标志物显著降低。tPA治疗有使血小板功能特征降低的趋势；然而，这些差异比TNK治疗所观察到的差异小得多。
tPA和TNK均显示在溶栓后早期对人类志愿者和急性心肌梗死患者的血小板功能有影响。TNK的抗血小板特性比tPA更显著。这些发现与正在进行的急性心肌梗死患者溶栓与抗血小板联合治疗的研究相关。
