Thrombosis Research
Volume 121, Issue 2 , Pages 193-202, 2007

Pulsed-high intensity focused ultrasound enhanced tPA mediated thrombolysis in a novel in vivo clot model, a pilot study☆

  • Michael J. Stone

      Affiliations

    • Diagnostic Radiology Department, Clinical Center, National Institutes of Health, Building 10, Room 1N306a, 10 Center Drive, Bethesda, MD 20892, USA
    • Howard Hughes Medical Institute Research Scholars Program, USA
    • ,
  • Victor Frenkel

      Affiliations

    • Diagnostic Radiology Department, Clinical Center, National Institutes of Health, Building 10, Room 1N306a, 10 Center Drive, Bethesda, MD 20892, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1 301 402 5710; fax: +1 301 496 9933.
    • ,
  • Sergio Dromi

      Affiliations

    • Diagnostic Radiology Department, Clinical Center, National Institutes of Health, Building 10, Room 1N306a, 10 Center Drive, Bethesda, MD 20892, USA
    • ,
  • Peter Thomas

      Affiliations

    • Division of Bioengineering and Physical Science, Office of Research Services, National Institutes of Health, Bethesda, MD, USA
    • ,
  • Ryan P. Lewis

      Affiliations

    • Diagnostic Radiology Department, Clinical Center, National Institutes of Health, Building 10, Room 1N306a, 10 Center Drive, Bethesda, MD 20892, USA
    • ,
  • King C.P. Li

      Affiliations

    • Diagnostic Radiology Department, Clinical Center, National Institutes of Health, Building 10, Room 1N306a, 10 Center Drive, Bethesda, MD 20892, USA
    • ,
  • McDonald Horne III

      Affiliations

    • Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA
    • ,
  • Bradford J. Wood

      Affiliations

    • Diagnostic Radiology Department, Clinical Center, National Institutes of Health, Building 10, Room 1N306a, 10 Center Drive, Bethesda, MD 20892, USA

Received 12 January 2007; received in revised form 8 March 2007; accepted 9 March 2007.

Abstract 

Introduction

Thrombotic disease continues to account for significant morbidity and mortality. Ultrasound energy has been investigated as a potential primary and adjunctive treatment for thrombotic disease. We have previously shown that pulsed-high intensity focused ultrasound (HIFU) enhances thrombolysis induced by tissue plasminogen activator (tPA) in vitro, including describing the non-destructive mechanism by which tPA availability and consequent activity are increased. In this study we aimed to determine if the same effects could be achieved in vivo.

Materials and methods

In this study, pulsed-HIFU exposures combined with tPA boluses were compared to treatment with tPA alone, HIFU alone and control in a novel in vivo clot model. Clots were formed in the rabbit marginal ear vein and verified using venography and infrared imaging. The efficacy of thrombolytic treatment was monitored via high resolution ultrasonography for 5 h post-treatment. The cross-sectional area of clots at 4 points along the vein was measured and normalized to the pre-treatment size.

Results

At 5 h the complete recanalization of clots treated with pulsed-HIFU and tPA was significantly different from the partial recanalization seen with tPA treatment alone. tPA treatment alone showed a significant decrease in clot versus control, where HIFU was not significantly different than control. Histological analysis of the vessel walls in the treated veins showed no apparent irreversible damage to endothelial cells or extravascular tissue.

Conclusions

This study demonstrates that tPA mediated thrombolysis can be significantly enhanced when combined with non-invasive pulsed-HIFU exposures.

Abbreviations: tissue plasminogen activator, tPA, high intensity focused ultrasound, HIFU

Keywords: High intensity focused ultrasound (HIFU), Thrombolysis, Tissue plasminogen activator (tPA), Clot model, Rabbit ear vein

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☆ Supported in part by the Intramural Research Program, Clinical Center, National Institutes of Health; Howard Hughes Medical Institute Research Scholars Program (MJS).

PII: S0049-3848(07)00125-9

doi:10.1016/j.thromres.2007.03.023

Thrombosis Research
Volume 121, Issue 2 , Pages 193-202, 2007

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