ENDARTERECTOMY: PREVENTION OF THROMBOSIS & RESTENOSIS

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To enhance thrombolytic responses without increasing hemorrhagic risks, the antithrombotic effects of recombinant Lys-plasminogen (r-LysPgn), a prothrombolytic plasminogen intermediate, have been examined in baboon models of thrombus formation and dissolution. The dose-response effects of r-LysPgn, alone or in combination with sub-threshold dosing of tissue plasminogen activator (tPA), have been measured with respect to the accumulation of 111In-platelets and 125I-fibrin in thrombus forming on endovascular metallic stents, or thrombogenic segments of vascular graft interposed in exteriorized chronic arteriovenous (AV) femoral shunts. Thrombolytic losses have also been determined for preformed, stable, 111In-platelet and 125I-fibrin labeled graft thrombus and corresponding propagated thrombotic tails, together with changes in blood tests of thrombosis, thrombolysis and hemostasis. Escalating doses of bolus intravenous r-LysPgn (2, 4 or 8 mg/kg) increased circulating plasmin ogen levels in a dose-dependent manner, was removed by log-linear clearance with T50 of 120 min, and reciprocally decreased the accumulating thrombus on metallic stents and segments of vascular graft (p<0.001in all cases for 8 mg/kg doses). r-LysPgn also impaired platelet aggregatory responses to physiologic agonists in vitro, but not ex vivo. Prethrombosis administration of low-dose r-LysPgn (2 mg/kg) greatly enhanced the lysis of radiolabeled non-occluding thrombus by a sub-threshold dose of tPA (0.1 mg/kg) compared with tPA-only controls (p=0.03). Elective bolus injections of r-LysPgn prior to stent deployment decrease the amount of thrombus formed without compromising hemostasis by facilitating endogenous tPA thrombolysis. r-LysPgn may provide effective and safe antithrombotic therapy for Interventional vascular procedures.