Hennan James K, Swillo Robert E, Morgan Gwen A, Leik Courtney E, Brooks Jonathan M, Shaw Gray D, Schaub Robert G, Crandall David L, Vlasuk George P
Cardiovascular and Metabolic Disease Research, Philadelphia, PA 19101, USA.
Thromb Haemost. 2006 Mar;95(3):469-75. doi: 10.1160/TH05-09-0640.
Under high shear arterial blood flow von Willebrand Factor (vWF) binds the platelet receptor glycoprotein (GP) Ibalpha, leading to platelet adhesion, activation and thrombosis. Blockade of vWF-GPIb alpha interactions by GPG-290 was investigated in a canine model of coronary artery thrombosis alone and in combination with clopidogrel. GPG-290 (100 microg/kg, n=6; 500 microg/kg, n=6) prolonged time to thrombotic occlusion (TTO) to 105+/-34 and 156+/-23 (p<0.05) min, respectively compared to the saline treated control group (32+/-6 min, n=6). Patency of the injured vessel was sustained in 1/6 (100 microg/kg) and 3/6 vessels (500 microg/kg) 4 hours after injury, in contrast to 0/6 in the control group. There was an increase in bleeding after the 500 microg/kg dose, but only at the 1 hr time point. Clopidogrel was studied in two dosing regimens representing either a clinical pretreatment regimen (PTR) of 4.3 mg/kg on day -2 followed by 1.1 mg/kg daily for 2 days prior to the procedure or pre-procedural loading dose regimen (LDR) of 4.3 mg/kg 3 hr pre-procedure. The PTR and LDR clopidogrel treatments prolonged TTO to 98.2+/-30.0 min and 136.1+/-39.5 min (p<0.05), and sustained patency in 1/6 and 4/8 vessels, respectively. However, template bleeding time in the LDR clopidogrel group was sustained higher than the control group. The combination of PTR clopidogrel and GPG-290 (100 microg/kg) prolonged TTO equivalent to LDR clopidogrel alone (141.4 +/- 35.1 min) and sustained patency in 3/7 dogs, without increased bleeding while LDR clopidogrel combined with 100 microg/kg GPG-290 prevented occlusion in 5/8 dogs and further prolonged TTO (173.5+/-32.6 min) but was associated with increased bleeding compared to control. GPG-290 is an antithrombotic agent that may be combined with lower doses of clopidogrel to yield similar antithrombotic efficacy as higher loading doses.
在高剪切力的动脉血流状态下，血管性血友病因子（vWF）与血小板受体糖蛋白（GP）Ibalpha结合，导致血小板黏附、活化及血栓形成。在犬冠状动脉血栓形成模型中，单独及联合氯吡格雷研究了GPG - 290对vWF - GPIbα相互作用的阻断作用。与生理盐水处理的对照组（32±6分钟，n = 6）相比，GPG - 290（100微克/千克，n = 6；500微克/千克，n = 6）使血栓闭塞时间（TTO）分别延长至105±34分钟和156±23分钟（p<0.05）。损伤后4小时，1/6（100微克/千克）和3/6（500微克/千克）的损伤血管保持通畅，而对照组为0/6。500微克/千克剂量后出血增加，但仅在1小时时间点。氯吡格雷研究了两种给药方案，一种是临床预处理方案（PTR），在第-2天给予4.3毫克/千克，然后在手术前2天每天给予1.1毫克/千克；另一种是术前负荷剂量方案（LDR），在手术前3小时给予4.3毫克/千克。PTR和LDR氯吡格雷治疗使TTO分别延长至98.2±30.0分钟和136.1±39.5分钟（p<0.05），分别使1/6和4/8的血管保持通畅。然而，LDR氯吡格雷组的模板出血时间持续高于对照组。PTR氯吡格雷与GPG - 290（100微克/千克）联合使用使TTO延长至与单独使用LDR氯吡格雷相当的水平（141.4±35.1分钟），并使3/7只犬的血管保持通畅，且无出血增加；而LDR氯吡格雷与100微克/千克GPG - 290联合使用可防止5/8只犬发生闭塞，并进一步延长TTO（173.5±32.6分钟），但与对照组相比出血增加。GPG - 290是一种抗血栓形成药物，可与较低剂量的氯吡格雷联合使用，以产生与较高负荷剂量相似的抗血栓形成疗效。
