REDUCTION IN STENT AND VASCULAR GRAFT THROMBOSIS AND ENHANCEMENT OF THROMBOLYSIS BY RECOMBINANT LYS-PLASMINOGEN IN NONHUMAN-PRIMATES

Background To enhance thrombolytic responses without increasing hemorr hagic risks, the antithrombotic effects of recombinant Lys-plasminogen (r-LysPgn), a prothrombolytic plasminogen intermediate, were examined in baboon models of thrombus formation and dissolution. Methods and R esults The dose-response effects of r-LysPgn, alone or in combination with subthreshold dosing of tissue plasminogen activator (TPA), were m easured with respect to the accumulation of In-111-labeled platelets a nd I-125-fibrin in thrombus forming on endovascular metallic stents or thrombogenic segments of vascular graft interposed in exteriorized lo ng-term arteriovenous (AV) femoral shunts. Thrombolytic losses have al so been determined for preformed, stable, In-111-platelet- and I-125-f ibrin-labeled graft thrombus and corresponding propagated thrombotic t ails, together with changes in blood tests of thrombosis, thrombolysis , and hemostasis. Bolus intravenous r-LysPgn in escalating doses (2, 4 , or 8 mg/kg) increased circulating plasminogen levels in a dose-depen dent manner, was removed by log-linear clearance with a T-50 of 120 mi nutes, and reciprocally decreased the accumulating thrombus on metalli c stents and segments of vascular graft (P<.001 in all cases for 8-mg/ kg doses). r-LysPgn also impaired platelet aggregatory responses to ph ysiological agonists in vitro but not ex vivo. Prethrombosis administr ation of low-dose r-LysPgn (2 mg/kg) greatly enhanced the lysis of rad iolabeled nonoccluding thrombus by a subthreshold dose of TPA (0.1 mg/ kg) compared with TPA-only controls (P=.03). Conclusions Elective bolu s injections of r-LysPgn before stent deployment decrease the amount o f thrombus formed without compromising hemostasis by facilitating endo genous TPA thrombolysis. r-LysPgn may provide effective and safe antit hrombotic therapy for interventional vascular procedures.