Antithrombotic effects and bleeding time prolongation with synthetic platelet GPIIb/IIIa inhibitors in animal models of platelet-mediated thrombosis
Collen, D.; Lu, H.R.; Stassen, J.M.; Vreys, I.; Yasuda, T.; Bunting, S.; Gold, H.K.
Thrombosis and Haemostasis 71(1): 95-102
1994
ISSN/ISBN: 0340-6245 PMID: 8165652 Document Number: 423132
Cyclic Arg-Gly-Asp (RGD) containing synthetic peptides such as L-cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-alpha-aspartyl-cyclic (1 fwdarw 5)-sulfide, 5-oxide (G4120) and acetyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-arginyl-glycyl-L-alpha-aspartyl-(0-methyltyrosyl)-L-arginyl-L-cysteinamide, cyclic 1 fwdarw 9-sulfide (TP9201) bind with high affinity to the platelet GPIIb/IIIa receptor. The relationship between antithrombotic effect, ex vivo platelet aggregation and bleeding time prolongation with both agents was studied in hamsters with a standardized femoral vein endothelial cell injury predisposing to platelet-rich mural thrombosis, and in dogs with a carotid arterial eversion graft inserted in the femoral artery. Intravenous administration of G4120 in hamsters inhibited in vivo thrombus formation with a 50% inhibitory bolus dose (ID-50) of approximately 20 mu-g/kg, ex vivo ADP-induced platelet aggregation with ID-50 of 10 mu-g/kg, and bolus injection of 1 mg/kg prolonged the bleeding time from 38 +- 9 to 1,100 +- 330s. Administration of TP9201 in hamsters inhibited in vivo thrombus formation with ID-50 of 30 mu-g/kg, ex vivo platelet aggregation with an ID-50 of 50 mu-g/kg and bolus injection of 1 mg/kg did not prolong the template bleeding time. In the dog eversion graft model, infusion of 100 mu-g/kg of G4120 over 60 min did not fully inhibit platelet-mediated thrombotic occlusion but was associated with inhibition of ADP-induced ex vivo platelet aggregation and with prolongation of the template bleeding time from 1.3 +- 0.4 to 12 +- 2 min. Infusion of 300 mu-g/kg of TP9201 over 60 min completely prevented thrombotic occlusion, inhibited ex vivo platelet aggregation, but was not associated with prolongation of the template bleeding time. TP9201, unlike G4120, inhibits in vivo platelet-mediated thrombus formation without associated prolongation of the template bleeding time.