Pulse-Spray Thrombolysis with Reteplase: Optimization and Comparison with tPA in a Rabbit Model

Abstract

To critically evaluate and optimize methodology for pulse-spray thrombolysis with reteplase in a rabbit inferior vena cava (IVC) thrombosis model and to compare results with optimized parameters for the use of tissue plasminogen activator (tPA). Occlusive IVC thrombus was produced in 102 rabbits and treated 2 days later for 1 hour with pulse-spray thrombolysis using reteplase. Methodologic variables included pulse frequency, concentration and amount of reteplase, infusion versus pulse therapy, and admixture of heparin. After the rabbits were killed, residual thrombus was weighed and percent lysis was estimated on the basis of previous control values. Results were compared with those achieved with tPA in 18 additional rabbits and also with previous tPA results. As in earlier tPA studies, pulse-spray methods were far more effective than constant infusion. Pulses at 30-second intervals produced better results than pulses at 2-minute intervals. At the optimal concentration of 0.02 U/mL (molarity 90 x 10(-8) ), reteplase produced 79% lysis. At two-fold higher or lower concentrations, lysis was reduced by approximately 25%, and at eight-fold higher or six-fold lower concentrations, lysis was reduced by approximately 50%. Optimal concentration of tPA was 0.02 mg/mL, yielding 78% lysis. Admixture of reteplase with heparin suggested improvement, but differences were statistically insignificant. When used with pulse-spray methodology, reteplase demonstrated a steep bell-shaped response-concentration curve similar in pitch and amplitude to that of tPA. The optimal molar concentration of reteplase was approximately three times that of tPA. However, at their respective optimal concentrations, reteplase and tPA were equally effective.