Thrombolytic efficacy of recombinant human microplasmin in a canine model of copper coil-induced coronary artery thrombosis.
We investigated the in vitro fibrinolytic properties of microplasmin, the isolated proteinase domain of plasmin, and its thrombolytic efficacy in a coronary artery thrombosis model in dogs. The amidolytic and fibrinolytic activity of recombinant microplasmin was compared with natural human plasmin. The thrombolytic efficacy of microplasmin was studied in a canine model of copper coil induced coronary artery thrombosis. Animals were randomly assigned to one of six treatment regimens, each with five animals per cohort. Four treatment groups received an intravenous bolus of microplasmin followed by an intravenous infusion of microplasmin for 1 h (1 mg/kg + 1.5 mg/kg/h with or without abciximab or 2 mg/kg + 3 mg/kg/h). In two treatment groups, microplasmin was administered intracoronary. Bolus administration was followed by a 1-h infusion if coronary flow was incompletely restored after the initial bolus administration (1 mg/kg + 1.5 mg/kg/h or 2 mg/kg + 3 mg/kg/h, respectively). The thrombolytic efficacy was documented by repeated angiographies and the coronary perfusion was assessed with the Thrombolysis in Myocardial Infarction (TIMI) grading. No significant differences between plasmin and microplasmin were observed with respect to the catalytic efficiencies towards the synthetic chromogenic substrates S-2403 or S-2444. The concentration required for 50% lysis of purified fibrin clots in 3 h, was approximately 100 nM for microplasmin compared to 20 nM for natural plasmin. Intravenous bolus administration of microplasmin restored TIMI 3 coronary flow in 0/5, 0/5, 1/5 and 2/5, respectively, whereas intracoronary bolus administration restored TIMI 3 coronary flow in 1/5 and 4/5 (1 mg/kg and 2 mg/kg, respectively) (ANOVA P < 0.05). TIMI 3 coronary flow was obtained in 0/5, 2/5, 2/5 and 3/5, respectively, during subsequent intravenous administration and in 5/5 and 4/5 in case of intracoronary administration (ANOVA P < 0.05). When compared to natural plasmin, the catalytic efficiency of microplasmin towards chromogenic substrates was similar, but the fibrinolytic potency of microplasmin towards fibrin clots was lower. Intracoronay administration of microplasmin effectively lysed coronary thrombosis.
Dommke
Christophe
C
Department of Cardiology, University Hospital Gasthuisberg, Leuven, Belgium.
Turschner
Oliver
O
Stassen
Jean-Marie
JM
Van de Werf
Frans
F
Lijnen
H Roger
HR
Verhamme
Peter
P
D000792:Angiography; D000818:Animals; D003328:Coronary Thrombosis / Q000188:drug therapy*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005341:Fibrinolysin / Q000008:administration & dosage* / Q000627:therapeutic use; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D009842:Oligopeptides; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000627:therapeutic use; D015912:Thrombolytic Therapy / Q000379:methods*; D016896:Treatment Outcome
D009842:Oligopeptides; D010446:Peptide Fragments; C110926:S 2403; C054561:microplasmin; D005341:Fibrinolysin