Combination of a direct thrombin inhibitor and a platelet glycoprotein IIb/IIIa blocking peptide facilitates and maintains reperfusion of platelet-rich thrombus with alteplase

We sought to determine the efficacy of the combination of argatroban, a dir ect thrombin inhibitor, and G4120, a platelet glycoprotein (GP) IIb/IIIa bl ocker, to enhance thrombolysis with alteplase. Platelet-rich thrombus in th e rabbit arterial thrombosis model is relatively resistant to alteplase des pite the addition of aspirin and heparin. The adjunctive use of either dire ct thrombin inhibitors or GP IIb/IIIa inhibitors in thrombolysis has been i nvestigated with encouraging, but limited, success. The usefulness of combi ning both agents as adjunctive therapy to thrombolysis has not been fully e xplored. Following platelet-rich thrombus formation in the rabbit, argatrob an (3 mg/kg), G4120 (0.5 mg/kg), G4120 plus heparin (200 U/kg), or G4120 pl us argatroban were intravenously infused over 60 minutes. Alteplase was giv en as intravenous boluses (0.45 mg/kg) at 15-minute intervals up to 4 doses or until reperfusion. Blood flow and bleeding time were monitored for 2 ho urs. The combination of G4120 plus argatroban resulted in a persistent pate ncy in 5 of 7 animals compared with 0 of 6 for argatroban alone (p = 0.02), 1 of 6 for G4120 alone (p = 0.08), and 2 of 6 for G4120 plus heparin (p = 0.2). Although during the infusion the bleeding times were longer in the gr oups that received G4120 (26 +/- 7.7 minutes vs. 14 +/- 10 minutes, p < 0.0 5), by the end of the experiment there were no statistically significant di fferences. Similarly, during the infusion the activated partial thromboplas tin times (aPTT) was higher in groups that received heparin or argatroban ( 99 +/- 51 seconds vs. 32 +/- 7.6 seconds, p < 0.001), but by the end of the experiment the aPTTs had returned to close to baseline in all groups excep t the G4120 plus heparin group. These results suggest that lysis of platele t-rich thrombus with alteplase requires the addition of both potent platele t and thrombin inhibitors. Specifically designed agents, G4120 and argatrob an, are effective without additional increased risk for bleeding.