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Thromb Haemost 1994; 71(01): 095-102
DOI: 10.1055/s-0038-1642390
Review Article
Schattauer GmbH Stuttgart

Antithrombotic Effects and Bleeding Time Prolongation with Synthetic Platelet GPIIb/llla Inhibitors in Animal Models of Platelet-Mediated Thrombosis

Désiré Collen
The Center for Thrombosis and Vascular Research, University of Leuven, Leuven, Belgium
,
Hua Rong Lu
The Center for Thrombosis and Vascular Research, University of Leuven, Leuven, Belgium
,
Jean-Marie Stassen
The Center for Thrombosis and Vascular Research, University of Leuven, Leuven, Belgium
,
Ingrid Vreys
The Center for Thrombosis and Vascular Research, University of Leuven, Leuven, Belgium
,
Tsunehiro Yasuda
1   Cardiac Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
,
Stuart Bunting
2   Department of Cardiovascular Pharmacology, Genentech Inc., South San Francisco, CA, USA
,
Herman K Gold
1   Cardiac Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
› Author Affiliations
Further Information

Publication History

Received: 14 April 1993

Accepted after revision 01 October 1993

Publication Date:
12 July 2018 (online)

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Summary

Cyclic Arg-Gly-Asp (RGD) containing synthetic peptides such as L-cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-a-aspartyl-cyclic (1→5)-sulfide, 5-oxide (G4120) and acetyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-arginyl-glycyl-L-α-aspartyl-[0-methyltyrosyl]-L-arginyl-L-cysteinamide, cyclic 1→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 (ID50) of approximately 20 μg/kg, ex vivo ADP-induccd platelet aggregation with ID50 of 10 μg/kg, and bolus injection of 1 mg/kg prolonged the bleeding time from 38 ± 9 to 1,100 ± 330 s. Administration of TP9201 in hamsters inhibited in vivo thrombus formation with ID50 of 30 μg/kg, ex vivo platelet aggregation with an ID50 of 50 μg/kg and bolus injection of 1 mg/kg did not prolong the template bleeding time. In the dog eversion graft model, infusion of 100 μg/kg of G4120 over 60 min did not fully inhibit platelet-mediated thrombotic occlusion but was associated with inhibition of ADP-induccd ex vivo platelet aggregation and with prolongation of the template bleeding time from 1.3 ± 0.4 to 12 ± 2 min. Infusion of 300 μg/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.

 

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