Distributed intraclot thrombolysis: Mechanism of accelerated thrombolysis with encapsulated plasminogen activators

Background: The delivery of encapsulated plasminogen activators has demonstrated enhanced thrombolysis in vivo in several models. The mechanism of such improvement has not previously been established. Objectives. We explored in vitro the mechanism by which microencapsulation of streptokinase in polymeric microparticles accelerates clot digestion and reduces reperfusion times by as much as an order of magnitude in vivo. Methods: The efficacy of microencapsulated streptokinase (MESK) was directly compared with identical dosages of unencapsulated streptokinase (FREE SK) at three initial pressure drops using clots formed of plasma or whole blood in 0.2-cm inner diameter glass capillary tubes. Results: MESK demonstrated accelerated flow restoration compared with FREE SK for each condition in plasma (23.8 ± 4.5% faster) and whole blood clots (17.2 ± 9.2% faster). Images collected by fight microscopy show sites of thrombolysis internal to the clot only with MESK while the spatial distribution of fluorescently labeled streptokinase by confocal microscopy confirms greater penetration of the encapsulated agent compared with unencapsulated streptokinase. Digestion thus proceeds in three dimensions rather than restricted to a two-dimensional lysis front. Conclusions: The improved clot penetration with MESK establishes enhanced transport with encapsulation and the concept of distributed intraclot thrombolysis as a basis for the accelerated dissolution observed with encapsulated plasminogen activators in vivo.