Background We evaluated the effects of a novel platelet fibrinogen receptor antagonist, Integrelin, and a direct thrombin inhibitor, recombinant hirudin, given together with recombinant tissue plasminogen activator (rTPA) in a canine experimental model of intracoronary thrombosis. We tested the hypothesis that combination of both agents at low doses would have an additive antithrombotic effect, resulting in a significant improvement in the efficacy of rTPA.Methods and Results Thirty-two dogs with an electrically induced coronary thrombus were treated with rTPA (1 mg/kg over 20 minutes) together with one of the following adjunctive treatments in a random fashion. Eight dogs received saline for 90 minutes; Integrelin (5 micrograms x kg sup -1 x min sup -1 for 90 minutes) was given to 8 dogs; 8 dogs received recombinant hirudin (20 micrograms x kg sup -1 x min sup -1 for 90 minutes); and 8 dogs were treated with a low-dose combination of Integrelin (2.5 micrograms x kg sup -1 x min sup -1) plus recombinant hirudin (10 micrograms x kg sup -1 x min sup -1) for 90 minutes. Integrelin or recombinant hirudin, when given as single adjunct to rTPA, enhanced the lysis of the occlusive thrombus, causing full restoration of coronary blood flow (100% of its baseline value) for 29+-16 and 26+-5 minutes, respectively, whereas coronary blood flow was fully restored for only 5+-1 minutes in dogs receiving rTPA plus saline (both P<.05). However, either Integrelin or recombinant hirudin failed to modify the reocclusion rate (57% and 63%, respectively) compared with saline (83%; all P=NS). Conversely, the low-dose combination therapy led to complete restoration of coronary blood flow for 92+-19 minutes (P<.01 versus all treatments) and significantly reduced the reocclusion rate (25%; P<.05 versus saline).Conclusions These data show that inhibition of specific pathways of platelet and thrombin activity improves the extent and duration of rTPA-induced thrombolysis in the electrolytic canine model. Furthermore, our findings suggest that low doses of platelet IIb/IIIa and direct thrombin antagonists in combination may be used successfully during thrombolysis. (Circulation. 1994;89:1802-1809.)