Ultrasound-enhanced Fibrinolysis Pro-fibrinolytic and Non-beneficial Effects Of Ultrasound Exposure

Abstract: The aim of this study was to further clarify the pro-fibrinolytic effects, and to explore the possible non-beneficial effects in ischemic organs, during exposure to pulsed ultrasound. This was accomplished by studies of the effects of different intensities of pulsed ultrasound exposure on the fibrinolytic properties of streptokinase and reteplase. Measurements were performed both following pre-exposure of the drugs and clots to pulsed ultrasound, and following concomitant exposure of clots and drugs.

In the exploration of pro-fibrinolytic effects during ultrasound exposure it was shown that exposure of the streptokinase molecule to low-intensity, pulsed high frequency ultrasound modulates its fibrinolytic properties. The effects were present following ultrasound exposure of streptokinase solution and during ultrasound exposure of clots and streptokinase solution concomitantly. Depending on its intensity, modulation was observed as both increased and decreased fibrinolytic effects. Pre-exposure of reteplase solution to low-intensity ultrasound induced changes in the function of the reteplase molecule associated with enhanced fibrinolytic effects. Enhancement effects were also seen when the clots were pre-exposed to high intensities of ultrasound before or concomitantly with exposure to reteplase solution, suggesting that two different intensity-dependent mechanisms are involved in ultrasound-enhanced reteplase fibrinolysis. No decreased fibrinolytic effect of reteplase depending on ultrasound exposure could be seen.

In an initial study of the fibrinolytic effects induced by a combination of Sonazoid® microbubbles and ultrasound, the effects of various ultrasound parameters on the microbubble destruction-rate was studied. It was shown that, at the same intensity level, the destruction-rate was faster outside the resonance frequency range. Five pulses were needed to achieve a fast destruction-rate. An ultrasound intensity of 0.5 W/cm2 was shown to be the lowest intensity yielding a fast destruction-rate of Sonazoid® microbubbles.

The possible non-beneficial effects in ischemic organs of ultrasound with characteristics used to enhance fibrinolysis in vivo were studied in two different models, one using non-perfused myocardia in pigs, and one using non-perfused brain tissue in rats. It was shown that prolonged exposure of low intensity pulsed ultrasound might increase instantaneous myocardial damage. However, the same frequency, intensity and duration of pulsed ultrasound did not seem to enhance ischemic damage in non-perfused rat brain or induce any damage in the perfused rat brain.

In conclusion, ultrasound-enhanced fibrinolysis is induced by multiple mechanisms and drug specific reactions, and this study shows the importance of evaluating the effects of exposure on ischemic tissue, aiming at ultrasound-enhanced fibrinolysis.