title: Selective alpha IIb beta 3 receptor blockage with peptide TP9201 prevents platelet uptake on Dacron vascular grafts without significant effect on bleeding time.
abstract: Synthetic vascular prostheses lack the uniquely low thrombogenicity provided by the endothelial cell lining of autogenous saphenous vein or artery grafts. The thrombogenic nature of the synthetic graft surface becomes a major determinant of early prosthetic graft patency. We demonstrate in a baboon ex vivo synthetic graft model that modification of the host's platelet interaction with the graft surface results in inhibition of platelet thrombus formation and thereby, a possible enhancement of early prosthetic graft patency. This was achieved by selective blockage of the platelet alpha IIb beta 3 receptor by the arginine-glycine-aspartic acid-containing synthetic peptide TP9201. Platelet thrombus formation on a Dacron graft indicated by accumulation of indium III-oxine-labeled autologous platelets was measured by gamma camera imaging. After 60 minutes of circulation, TP9201 at a bolus of 125 micrograms/kg; infusion of 3 micrograms/kg/min, bolus of 190 micrograms/kg; infusion of 5 micrograms/kg/min, bolus of 250 micrograms/kg; infusion of 6 micrograms/kg/min, and bolus of 500 micrograms/kg; infusion of 12 micrograms/kg/min decreased platelet uptake on the graft to 50%, 40%, 30%, and 10% of control uptake, respectively. Forelimb template bleeding times were not found to be significantly prolonged at doses that effectively inhibit ex vivo platelet aggregation. As a result of drug treatment, no changes in hemodynamic parameters or hematologic profile, including platelet number and clotting time, were observed. We demonstrate here that the arginine-glycine-aspartic acid-containing peptide TP9201, which competitively inhibits the alpha IIb beta 3 integrin-fibrinogen interaction, significantly decreased the accumulation of platelets on a Dacron vascular graft. Molecules like peptide TP9201, because of its unique activity profile, may represent a superior approach to the control of platelet accumulation on thrombogenic surfaces.
authors.affiliation: Surgical Research Laboratory, New England Medical Center, Boston.
authors.forename: C
authors.initials: C
authors.lastname: Mazur
authors.forename: J F
authors.initials: JF
authors.lastname: Tschopp
authors.forename: E C
authors.initials: EC
authors.lastname: Faliakou
authors.forename: K E
authors.initials: KE
authors.lastname: Gould
authors.forename: J T
authors.initials: JT
authors.lastname: Diehl
authors.forename: M D
authors.initials: MD
authors.lastname: Pierschbacher
authors.forename: R J
authors.initials: RJ
authors.lastname: Connolly
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D001807:Blood Vessel Prosthesis; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D016023:Integrins / Q000037:antagonists & inhibitors*; D008297:Male; D010215:Papio; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011093:Polyethylene Terephthalates / Q000378:metabolism*; D014654:Vascular Patency / Q000187:drug effects
chemical_list: D016023:Integrins; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011093:Polyethylene Terephthalates; C085362:TP 9201