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 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.


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 (111)In-labeled platelets and (125)I-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, (111)In-platelet- and (125)I-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.
Sundell
I B
IB
Department of Medicine, Yerkes Regional Primate Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Marzec
U M
UM
Kelly
A B
AB
Chronos
N A
NA
Petersen
L C
LC
Hanson
S R
SR
Hedner
U
U
Harker
L A
LA
D000818:Animals; D001807:Blood Vessel Prosthesis / Q000009:adverse effects*; D004357:Drug Synergism; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D008297:Male; D010215:Papio; D010446:Peptide Fragments / Q000493:pharmacokinetics / Q000494:pharmacology*; D010958:Plasminogen / Q000493:pharmacokinetics / Q000494:pharmacology*; D011994:Recombinant Proteins; D015607:Stents / Q000009:adverse effects*; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
D005343:Fibrinolytic Agents; D010446:Peptide Fragments; D011994:Recombinant Proteins; C018998:lysyl-plasminogen; D010958:Plasminogen; D010959:Tissue Plasminogen Activator