Inhibition of coronary artery reocclusion after thrombolysis with an RGD-containing peptide with no significant effect on bleeding time

BACKGROUND: A synthetic RGD-containing cyclic peptide, TP9201, specific for the platelet alpha IIb beta 3 receptor complex, was tested for its ability to accelerate thrombolysis and prevent reocclusion in experimentally induced coronary artery thrombosis. METHODS: Anesthetized, open-chest dogs with occlusive thrombi received tissue plasminogen activator with TP9201 (113 micrograms/kg bolus; 2.7 micrograms/kg/min infusion, n = 7) or saline control (n = 9). RESULTS: A 2.8-fold increase in the duration of vessel patency from 52.7 +/- 63.7 min to 149.1 +/- 63.7 min (P < 0.05) was observed with TP9201 treatment. The mean duration of vessel occlusion was reduced 2.4-fold from 172.4 +/- 81.1 min to 71.7 +/- 63.7 min (P < 0.05). Administration of TP9201 reduced the mean time to lysis from 76.6 +/- 42.9 min to 54.4 +/- 42.9 min, but thrombolysis was not significantly accelerated. Persistent patency was observed in four out of seven of the treated dogs compared with none of the nine in the control group (P < 0.05). Administration of TP9201 inhibited ex-vivo platelet aggregation stimulated by ADP (30 microM) or collagen (10 micrograms/ml). No thrombocytopenia or changes in hemodynamic parameters were observed in the treated group compared with the control group. Peptide TP9201 had no effect on bleeding time and the inhibitory effect on ex-vivo platelet aggregation was rapid and reversible. The pharmacodynamic half-life of TP9201 was approximately 1 h with ex-vivo platelet activity returning to baseline within 2 h of discontinuation of treatment. CONCLUSIONS: TP9201 may be an effective therapy for the prevention of re-thrombosis after thrombolytic therapy without adversely affecting hemostasis.