Augmentation of in-stent clot dissolution by low frequency ultrasound combined with aspirin and heparin. An ex-vivo canine shunt study.
ABSTRACT Ultrasound can accelerate clot dissolution in vitro and in vivo. We used an ex vivo canine shunt to investigate low frequency ultrasound effects on platelet-rich stent thrombosis.
Nitinol stents were expanded to 2 mm in diameter in two perfusion chambers in a parallel shunt and exposed to flowing arterial blood at 2100 s(-1) to generate stent thrombi (n=224 perfusion runs). Dethrombotic effects were assessed during treatment with saline and combined treatment with aspirin and heparin. One stent was exposed to ultrasound (27 kHz, 1.4 W/cm2), while the other was not. Stent thrombi were weighed before and after treatment. There was no significant effect of ultrasound during saline infusion. Treatment with aspirin+heparin alone reduced thrombus weight by 37+/-25% (18.9+/-6.1 to 11.8+/-7.7 mg, p<0.0001). Combined treatment with aspirin+heparin+ultrasound produced a 49+/-23% reduction in thrombus weight (19.0+/-6.3 to 9.6+/-7.8 mg, p<0.0001). The reduction in thrombus weight was significantly greater in aspirin+heparin+ultrasound compared with aspirin+heparin alone (p=0.04).
Transcutaneous ultrasound significantly enhances dethrombotic effect of aspirin plus heparin on preformed stent thrombi. These findings suggest the potential of ultrasound as an adjunct to antithrombotic therapy to improve effectiveness without increasing the risk of bleeding complications during treatment of vascular thrombosis.
- SourceAvailable from: Robert J Siegel[show abstract] [hide abstract]
ABSTRACT: We examined the effectiveness of the microbubbles of an echo contrast agent, dodecafluoropentane (DDFP) emulsion, to enhance low frequency ultrasound clot disruption in vitro and in vivo. Ultrasound is reported to facilitate clot dissolution, and microbubbles could theoretically enhance ultrasound clot dissolution by augmenting cavitational effects. In vitro studies: The disruption rate of fresh human clots by ultrasound (24 kHz, 2.9 W/cm2) was examined in saline and DDFP emulsion. In vivo studies: Using a rabbit iliofemoral thrombotic occlusion model, recanalization rate and histopathologic findings were compared among groups treated with DDFP emulsion alone, transcutaneous ultrasound (20 kHz, 1.5 W/cm2) alone and with DDFP emulsion and ultrasound combined. The ultrasound clot disruption rate was significantly (p < 0.01) increased, from 72 +/- 18% (mean +/- SD) in saline to 98 +/- 4% in DDFP emulsion in 3 min in vitro. No vessel was recanalized by DDFP emulsion alone (0%), and only a single artery was patent after ultrasound treatment alone (9%). In contrast, 82% of iliofemoral arteries were angiographically recanalized after ultrasound treatment with DDFP emulsion. Histologically, the patent arteries had only minimal focal mural thrombus, with no evidence of vessel wall damage. However, substantial damage was observed in rabbit dermis and subcutaneous tissue. 1) DDFP emulsion, an echo contrast agent, significantly enhances the clot-disrupting effect of low frequency ultrasound in vitro and in an in vivo rabbit iliofemoral occlusion model. 2) This simple combination therapy has potential for clinical application in patients with thrombotic arterial occlusions.Journal of the American College of Cardiology 08/1997; 30(2):561-8. · 14.09 Impact Factor
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ABSTRACT: Ultrasound (US) accelerates enzymatic fibrinolysis in vitro and in animal models, and may be a useful adjunctive therapy for clinical thrombolysis. Successful clinical application will depend on the selection of appropriate US parameters to optimize fibrinolytic enhancement while limiting adverse effects, including heating. Most studies have been done at megahertz frequencies, but tissue penetration is better and heating less at lower frequencies. We have, therefore, now investigated the effects of continuous-wave and pulsed US on fibrinolysis at midkilohertz frequencies. Fibrinolysis with tissue plasminogen activator (t-PA) was measured by solubilization of radiolabeled fibrin exposed to a calibrated US field in a temperature-controlled water bath. There was significant enhancement of fibrinolysis at frequencies of 27, 40 and 100 kHz, with the greatest effect observed at 27 kHz. The largest effect was observed with continuous-wave US, but significant acceleration was also observed with peak intensities of 1 W/cm(2) duty cycles of 10% and 1%. At a 10% duty cycle, there was approximately 60% of the fibrinolytic enhancement observed with continuous-wave exposure, indicating a clear advantage of pulsing to optimize fibrinolytic effect and limit exposure. We conclude that US in the range of 27 to 100 kHz is effective in accelerating fibrinolysis at intensities and pulsing conditions that minimize the probability of heating and cavitation in clinical applications.Ultrasound in Medicine & Biology 04/2002; 28(3):377-82. · 2.46 Impact Factor
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ABSTRACT: The purpose of this study was to determine whether different components of human atherosclerotic plaques exposed to flowing blood resulted in different degrees of thrombus formation. It is likely that the nature of the substrate exposed after spontaneous or angioplasty-induced plaque rupture is one factor determining whether an unstable plaque proceeds rapidly to an occlusive thrombus or persists as a nonocclusive mural thrombus. Although observational data show that plaque rupture is a potent stimulus for thrombosis, and exposed collagen is suggested to have a predominant role in thrombosis, the relative thrombogenicity of different components of human atherosclerotic plaques is not well established. We investigated thrombus formation on foam cell-rich matrix (obtained from fatty streaks), collagen-rich matrix (from sclerotic plaques), collagen-poor matrix without cholesterol crystals (from fibrolipid plaques), atheromatous core with abundant cholesterol crystals (from atheromatous plaques) and segments of normal intima derived from human aortas at necropsy. Specimens were mounted in a tubular chamber placed within an ex vivo extracorporeal perfusion system and exposed to heparinized porcine blood (mean [+/- SEM] activated partial thromboplastin time ratio 1.5 +/- 0.04) for 5 min under high shear rate conditions (1,690 s-1). Thrombus was quantitated by measurement of indium-labeled platelets and morphometric analysis. Under similar conditions, substrates were perfused with heparinized human blood (2 IU/ml) in an in vitro system, and thrombus formation was similarly evaluated. Thrombus formation on atheromatous core was up to sixfold greater than that on other substrates, including collagen-rich matrix (p = 0.0001) in both heterologous and homologous systems. Although the atheromatous core had a more irregular exposed surface and thrombus formation tended to increase with increasing roughness, the atheromatous core remained the most thrombogenic substrate when the substrates were normalized by the degree of irregularity as defined by the roughness index (p = 0.002). The atheromatous core is the most thrombogenic component of human atherosclerotic plaques. Therefore, plaques with a large atheromatous core content are at high risk of leading to acute coronary syndromes after spontaneous or mechanically induced rupture because of the increased thrombogenicity of their content.Journal of the American College of Cardiology 07/1994; 23(7):1562-9. · 14.09 Impact Factor