Summary

Under high shear arterial blood flow von Willebrand Factor(vWF) binds the platelet receptor glycoprotein (GP) Iba ,leadingto platelet adhesion, activation and thrombosis. Blockade ofvWF-GPIba interactions by GPG-290 was investigated in a caninemodel of coronary artery thrombosis alone and in combinationwith clopidogrel. GPG-290 (100 µg/kg, n=6; 500 µg/kg,n=6) prolonged time to thrombotic occlusion (TTO) to 105±34and 156±23 (p<0.05) min, respectively compared to the salinetreated control group (32±6min, n=6). Patency of the injuredvessel was sustained in 1/6 (100µg/kg) and 3/6 vessels (500µg/kg) 4 hours after injury, in contrast to 0/6 in the controlgroup. There was an increase in bleeding after the 500 µg/kgdose, but only at the 1 hr time point. Clopidogrel was studied intwo dosing regimens representing either a clinical pretreatmentregimen (PTR) of 4.3 mg/kg on day –2 followed by 1.1 mg/kgdaily for 2 days prior to the procedure or pre-procedural loading dose regimen (LDR) of 4.3 mg/kg 3 hr pre-procedure.ThePTR and LDR clopidogrel treatments prolonged TTO to98.2±30.0 min and 136.1±39.5 min (p<0.05), and sustained patencyin 1/6 and 4/8 vessels, respectively. However, templatebleeding time in the LDR clopidogrel group was sustained higherthan the control group.The combination of PTR clopidogrel andGPG-290 (100 µg/kg) prolonged TTO equivalent to LDR clopidogrelalone (141.4±35.1 min) and sustained patency in 3/7dogs, without increased bleeding while LDR clopidogrel combinedwith 100 µg/kg GPG-290 prevented occlusion in 5/8 dogsand further prolonged TTO (173.5±32.6 min) but was associatedwith increased bleeding compared to control. GPG-290 isan antithrombotic agent that may be combined with lowerdoses of clopidogrel to yield similar antithrombotic efficacy ashigher loading doses.