Comparative lytic efficacy of rt-PA and intermittent ultrasound in porcine versus human clots

Abstract

Porcine thrombi are employed routinely in preclinical models of ischemic stroke. In this study, we examined the differential lytic susceptibility of porcine and human whole blood clots to recombinant tissue-plasminogen activator (rt-PA) and the adjuvant use of an echo contrast agent, Definity®, and intermittent 120 kHz ultrasound to enhance thrombolysis. An in vitro system equipped with time-lapse microscopy was used to evaluate rt-PA lysis of porcine and human clots in same species or cross species plasma. The rt-PA lytic efficacy observed for porcine clots in porcine plasma was 22 times lower than for human clots in human plasma. Porcine clots did not exhibit increased lysis with adjuvant Definity® and ultrasound exposure. However, the rt-PA lytic susceptibility of the porcine clots in human plasma was similar to that of human clots in human plasma. Human clots perfused with porcine plasma did not respond to rt-PA, but adjuvant use of Definity® and ultrasound enhanced lysis. These results reveal considerable differences in lytic susceptibility of porcine clots and human clots to rt-PA, and highlight the limitations of current porcine models used to develop clinical thrombolytic therapies.