title: Recombinant lys-plasminogen given before, but not after, recombinant tissue-type plasminogen activator markedly improves coronary thrombolysis in dogs: relationship of thrombolytic efficacy with parameters of fibrinolysis.
abstract: Recombinant tissue-type plasminogen activator (rt-PA) administration rapidly restores blood flow in thrombosed coronary arteries, but coronary arteries often reocclude after initial thrombolysis. This occurs because of the short half-life of rt-PA and rapid increase in plasminogen activator inhibitor (PAI-1) and alpha2-antiplasmin levels in plasma. We hypothesized that administration of lys-plasminogen, which binds to fibrin with 10 times greater affinity and results in a loose fibrin structure (as compared with native glu-plasminogen), before rt-PA would enhance the thrombolytic efficacy of rt-PA and modulate parameters of fibrinolysis. To examine this hypothesis, dogs with electrically induced stable thrombus in the left anterior descending coronary artery (LAD) were treated with saline (group A, n = 9) or lys-plasminogen (group B, 2 mg/kg, n = 5), followed 10 min later by rt-PA (1 mg/kg in 20 min). Four other dogs with occlusive LAD thrombus were first given rt-PA, followed by lys-plasminogen (2 mg/kg) 50 min later (group C). Lys-plasminogen given before rt-PA restored flow in all dogs in 14 +/- 4 min (vs. 22 +/- 9 min in group A, p < 0.05), continuing > 2 h (vs. 41 +/- 15 min in group A, p < 0.02). Lys-plasminogen given after rt-PA did not potentiate the effect of rt-PA. Plasma t-PA antigen concentrations were highest in group B dogs at 2 h after rt-PA infusion. PAI-1 and alpha2-antiplasmin plasma levels were suppressed in all dogs receiving lys-plasminogen whether it was given before or after rt-PA. Therefore, lys-plasminogen given before rt-PA markedly potentiates the effect of rt-PA and alters the parameters of fibrinolysis. In contrast, lys-plasminogen given after rt-PA does not influence the thrombolytic effect of rt-PA, whereas it suppresses PAI-1 and alpha2-antiplasmin levels in plasma. This study also suggests that binding of plasminogen to the clot is more important than the plasma levels of PAI-1 and alpha2-antiplasmin.
authors.affiliation: Department of Medicine, University of Florida College of Medicine, Gainesville 32610-0277, USA.
authors.forename: L Y
authors.initials: LY
authors.lastname: Chen
authors.forename: W W
authors.initials: WW
authors.lastname: Nichols
authors.forename: T G
authors.initials: TG
authors.lastname: Saldeen
authors.forename: J L
authors.initials: JL
authors.lastname: Mehta
mesh_terms: D000818:Animals; D000933:Antifibrinolytic Agents / Q000008:administration & dosage; D003328:Coronary Thrombosis / Q000097:blood / Q000628:therapy*; D004285:Dogs; D004334:Drug Administration Schedule; D005260:Female; D005342:Fibrinolysis; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage*; D010958:Plasminogen / Q000008:administration & dosage*; D010960:Plasminogen Activators / Q000008:administration & dosage* / Q000097:blood; D015424:Reperfusion; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000097:blood
chemical_list: D000933:Antifibrinolytic Agents; D010446:Peptide Fragments; C018998:lysyl-plasminogen; D010958:Plasminogen; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator