Selective alpha IIb beta 3 receptor blockage with peptide TP9201 prevents platelet uptake on Dacron vascular grafts without significant effect on bleeding time.
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.
Mazur
C
C
Surgical Research Laboratory, New England Medical Center, Boston.
Tschopp
J F
JF
Faliakou
E C
EC
Gould
K E
KE
Diehl
J T
JT
Pierschbacher
M D
MD
Connolly
R J
RJ
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
D016023:Integrins; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011093:Polyethylene Terephthalates; C085362:TP 9201