Augmented Experimental Pulse-Spray Thrombolysis with Tissue Plasminogen Activator, Enabling Dose Reduction by One or More Orders of Magnitude

Abstract

To critically evaluate and optimize methodologic details of pulse-spray thrombolysis with tissue plasminogen activator (tPA) in a subacute rabbit inferior vena cava thrombosis model. Occlusive inferior vena cava thrombi were produced in 104 rabbits and 2 days later were treated for 1 hour with pulse-spray thrombolysis using tPA. Methodologic variables included pulse frequency, concentration and amount of tPA, infusion versus pulse therapy, and admixture of heparin. After the rabbits were killed, residual thrombus was weighed. The authors' earlier standard regimen (3 mg of tPA in 6 mL of heparinized saline, 0.2-mL hand pulses, frequency 1 pulse per 2 minutes) produced 60% mean lysis. Optimization involved increasing the pulse frequency to two per minute and decreasing tPA concentration by 98% to 0.01 mg/mL, modifications that produced 22% more thrombolysis, despite 92% reduction in amount of tPA to 0.25 mg. Consistent with the in vitro work of other investigators, a roughly bell-shaped dose-response curve was elicited in vivo for pulse-spray with tPA. By diluting tPA to an optimal level, and increasing pulse frequency to two per minute, thrombolysis was markedly augmented. These results suggest that the conventional dose of tPA used for clinical pulse-spray thrombolysis can be reduced by one to two orders of magnitude, possibly markedly reducing procedural risk.