New RGD analogue inhibits human platelet adhesion and aggregation and eliminates platelet deposition on canine vascular grafts

Brian G. Rubin, Daniel J. McGraw, Gregorio A. Sicard, Samuel A. Santoro

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Platelet adhesion and aggregation are mediated by fibrinogen via the receptor glycoprotein IIb/IIIa, which recognizes the arginine-glycine-aspartic (RGD) amino-acid sequence. We investigated the ability of 8-guanidino-octanoyl-Asp-Phe (SC-49992), an intravenously infused, stable RGD analogue, to inhibit human platelet function in vitro and to reduce in vivo canine platelet deposition on prosthetic grafts. Human platelet aggregation induced by 10 μmol/L adenosine diphosphate was inhibited in a concentration dependent manner with an ED50 of 1 μg/ml of SC-49992. Adenosine diphosphate-induced secretion, which is dependent on fibrinogen occupancy of the glycoprotein IIb/IIIa receptor, was reduced in a concentration dependent manner, also with an ED50 of 1 μg/ml. Thrombin-induced secretion, which is independent of fibrinogen binding, was unaffected. Activation-dependent platelet adhesion to fibrinogen substrates was reduced in a concentration-dependent manner by SC-49992. Platelet adhesion to fibronectin substrates was also reduced by the analogue, but to a lesser extent. SC-49992 effectively eluted glycoprotein IIb/IIIa bound to RGD derivatized sepharose. Eight thrombosis-prone dogs had polytetrafluoroethylene femoral artery grafts placed. Dogs received the RGD analogue or a normal saline infusion during their first graft procedure. One week later a second contralateral femoral graft with infusion of the other agent was performed. Aggregometry during RGD analogue infusion demonstrated inhibition of induced aggregation, whereas normal saline infusion had no effect. As measured by the adherence of platelets labeled with indium III 8-guanidino-octanoyl-Asp-Phe reduced platelet deposition on vascular grafts by more than 90% (p = 0.0006, log transformed data, paired t test). Histologic examination demonstrated marked reduction or complete elimination of platelet thrombus on the luminal surface of the grafts under drug-treated conditions. Previous attempts to block platelet aggregation have been of limited success. 8-guanidino-octanoyl-Asp-Phe represents a novel class of glycoprotein IIb/IIIa inhibitors, which act at the final common pathway of platelet aggregation. Although the specific role of RGD inhibition in the clinical setting remains undefined, a broad range of platelet-mediated primary and recurrent thromboembolic conditions may potentially benefit from therapeutic intervention with this compound.

Original languageEnglish
Pages (from-to)683-692
Number of pages10
JournalJournal of Vascular Surgery
Volume15
Issue number4
DOIs
StatePublished - Apr 1992

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