Augmented experimental pulse-spray thrombolysis with tissue plasminogen activator, enabling dose reduction by one or more orders of magnitude

PURPOSE: To critically evaluate and optimize methodologic details of pulse- spray thrombolysis with tissue plasminogen activator (tPA) in a subacute ra bbit inferior vena cava thrombosis model. MATERIALS AND METHODS: Occlusive inferior vena cava thrombi were produced i n 104 rabbits and 2 days later were treated for 1 hour with pulse-spray thr ombolysis using tPA, Methodologic variables included pulse frequency, conce ntration and amount of tPA, infusion versus pulse therapy, and admixture of heparin, After the rabbits were killed, residual thrombus was weighed. RESULTS: The authors' earlier standard regimen (3 mg of tPA in 6 mt of hepa rinized saline, 0.2-mL hand pulses, frequency 1 pulse per 2 minutes) produc ed 60% mean lysis, Optimization involved increasing the pulse frequency to two per minute and decreasing tPA concentration by 98% to 0.01 mg/mL, modif ications that produced 22% more thrombolysis, despite 92% reduction in amou nt of tPA to 0.25 mg. CONCLUSION: Consistent with the in vitro work of other investigators, a rou ghly bell-shaped dose-response curve was elicited in vivo for pulse-spray w ith tPA. By diluting tPA to an optimal level, and increasing pulse frequenc y to two per minute, thrombolysis was markedly augmented, These results sug gest that the conventional dose of tPA used for clinical pulse-spray thromb olysis can be reduced by one to two orders of magnitude, possibly markedly reducing procedural risk.