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(Circulation. 1997;96:941-948.)
© 1997 American Heart Association, Inc.

Articles

Reduction in Stent and Vascular Graft Thrombosis and Enhancement of Thrombolysis by Recombinant Lys-Plasminogen in Nonhuman Primates

I. Birgitta Sundell, PhD; Ulla M. Marzec, MS; Andrew B. Kelly, DVM; Nicolas A. F. Chronos, MD; Lars C. Petersen, PhD; Stephen R. Hanson, PhD; Ulla Hedner, MD; ; Laurence A. Harker, MD

From the Division of Hematology-Oncology, Department of Medicine, Yerkes Regional Primate Research Center, Emory University School of Medicine, Atlanta, Ga, and Vessel Wall Biology, NovoNordisk A/S, Genetofte, Denmark (L.C.P., U.H.).

Correspondence to Laurence A. Harker, MD, Division of Hematology and Oncology, Emory University School of Medicine, 1639 Pierce Dr, Room 1003, Atlanta, GA 30322.

Background To enhance thrombolytic responses without increasing hemorrhagic 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 Results The dose-response effects of r-LysPgn, alone or in combination with subthreshold dosing of tissue plasminogen activator (TPA), were measured with respect to the accumulation of ¹¹¹In-labeled platelets and ¹²⁵I-fibrin in thrombus forming on endovascular metallic stents or thrombogenic segments of vascular graft interposed in exteriorized long-term 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. Bolus intravenous r-LysPgn in escalating doses (2, 4, or 8 mg/kg) increased circulating plasminogen levels in a dose-dependent manner, was removed by log-linear clearance with a T₅₀ of 120 minutes, and reciprocally decreased the accumulating thrombus on metallic stents and segments of vascular graft (P<.001 in all cases for 8-mg/kg doses). r-LysPgn also impaired platelet aggregatory responses to physiological agonists in vitro but not ex vivo. Prethrombosis administration of low-dose r-LysPgn (2 mg/kg) greatly enhanced the lysis of radiolabeled nonoccluding thrombus by a subthreshold dose of TPA (0.1 mg/kg) compared with TPA-only controls (P=.03).

Conclusions Elective bolus injections of r-LysPgn before 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.

Key Words: plasminogen • platelets • thrombolysis • plasminogen activators

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