Plasmin-dependent
thrombolytic agents are potentially prothrombotic and proinflammatory.
Alfimeprase, a
zinc-containing
metalloproteinase, degrades
fibrin directly and achieves thrombolysis independent of
plasmin formation. This study examines the hypothesis that thrombolysis in the absence of
plasmin generation results in improved myocardial salvage on reperfusion. The thrombolytic effects of recombinant
tissue plasminogen activator [rt-PA; 0.022 mg/kg, 1/10 of which was administered as a loading dose; the rest (9/10) was infused over 60 min by intracoronary (ic) administration] or
alfimeprase (0.5 mg/kg over 1 min ic) were evaluated in a canine model of arterial
thrombosis involving electrolytic injury of the left circumflex (LCX) coronary artery. Both agents induced thrombolysis, with onset of reperfusion being more rapid after
alfimeprase compared with rt-PA (1.5 +/- 0.6 vs. 10.1 +/- 2.1 min). In the absence of adjunctive
therapy, time to reocclusion after
alfimeprase was 3.2 +/- 0.5 min compared with 77.5 +/- 31.9 min with rt-PA. The
glycoprotein IIb/IIIa platelet receptor antagonist
CRL-42796 prolonged reperfusion time after thrombolysis with
alfimeprase or rt-PA. The effect of each lytic agent on
myocardial infarct size was examined in a separate group of dogs subjected to 60 min of LCX coronary artery
ligation and 4 h of reperfusion.
Myocardial infarct size, expressed as percentage of the risk region, was larger (32.16 +/- 3.95%) after rt-PA compared with
alfimeprase (19.85 +/- 3.61%) or that of the saline control group (18.46 +/- 3.34%). rt-PA in contrast to
alfimeprase, a direct-acting
fibrinolytic agent, is associated with an increase in myocyte
reperfusion injury.