SUPPRESSION OF THROMBOLYSIS IN A CANINE MODEL OF PULMONARY-EMBOLISM

Background The brisk fibrinolytic response of canines has impaired eff orts to develop a canine model of chronic thromboembolic pulmonary hyp ertension. Difficulties in retaining chronic embolic residuals were pa rtially overcome by administration of tranexamic acid (TXA) (Circulati on. 1991;83:1272-1279.). In this study, we used type 1 plasminogen act ivator inhibitor (PAI-1), a major inhibitor of the endogenous fibrinol ytic system, to determine its efficacy in the suppression of thromboly sis in canines. Methods and Results Thrombus was induced in the inferi or vena cava of anesthetized mongrel dogs with thrombin and a special double-balloon catheter; 2 hours later, the thrombus was embolized. In one group of dogs, activated type 1 plasminogen activator inhibitor ( PAI-1) (130 mu g) was delivered directly into the forming thrombus; in another, TXA (110 mg/kg) was given intravenously before thrombus form ation; in controls, thrombus was induced without inhibitors. Crosslink ed fibrin degradation product (D-dimer) appeared in the blood of contr ol animals within 1 hour of thrombus induction (176+/-62.5 versus 1.02 +/-0.39 ng/mL baseline; mean+/-SEM), was maximal by 4 hours (413+/-110 ng/mL) and remained elevated at 24 hours (90.8+/-19.5 ng/mL). Compare d with controls, PAI-1 and TXA suppressed D-dimer release by 80% and 8 5%, respectively, over the first 24 hours. One week later, animals wer e killed, and residual emboli were harvested. Perfusion scan defects p ersisted in all animals at this time, but there were no scan defect di fferences among groups. However, emboli recovered from animals receivi ng PAI-1 still harbored immunoreactive PAI-1 and were, on average, mor e than twofold greater in mass (393+/-56 mg) than emboli recovered fro m either controls (183+/-76 mg) or animals receiving TXA (180+/-80 mg) . Conclusions Intravenous TXA and intrathrombus PAI-1 effectively supp ress thrombolysis for 24 hours in canines. Thromboemboli enriched with PAI-1 appear to resist lysis for longer periods of time (up to 1 week ). These findings are consistent with the hypothesis that PAI-1 remain s associated with the embolus, where it continues to inhibit lysis, wh ereas TXA eventually diffuses out of the embolus, allowing lysis to en sue.