Plasminogen-enriched Pulse-Spray Thrombolysis with tPA: Further Developments

Abstract

To further improve methods for pulsed plasminogen-enriched thrombolysis and to compare results with the best obtainable with use of tissue plasminogen activator (tPA) alone. Parameters of plasminogen-enriched pulse-spray thrombolysis were manipulated in groups of rabbits with inferior vena cava thrombosis, and weights of 1-hour residual thrombus were compared. Variables evaluated were (i) tPA pulse frequency, (ii) amount of plasminogen used for enrichment, (iii) tPA concentration and amount, (iv) pulsed versus infused tPA, and (v) admixture versus separation of plasminogen and tPA. With use of 3 mg of tPA and approximately 0.9 mg plasminogen enrichment, efficacy varied directly with pulse frequency over a pulse range of every 15 minutes to every 30 seconds. With use of 30-second pulses of tPA at a concentration 0.125 mg/mL, efficacy also correlated directly with increasing plasminogen enrichment up to, but not beyond, approximately 1.8 mg per 1.24 g of clot. Optimized methodology yielded 89% lysis in 1 hour, as compared to 74% lysis previously reported with use of optimized low-concentration (0.01 mg/ mL) tPA alone. Plasminogen enrichment in conjunction with low concentrations of tPA, admixture of tPA and plasminogen, and fractionation of the plasminogen enrichment all proved to be nonproductive or counterproductive. Optimized in vivo postthrombotic plasminogen enrichment significantly accelerated thrombolysis of experimental clots compared to use of optimized tPA alone.