title: Pulsed-high intensity focused ultrasound enhanced tPA mediated thrombolysis in a novel in vivo clot model, a pilot study.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Diagnostic Radiology Department, Clinical Center, National Institutes of Health, Building 10, Room 1N306a, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Stone
authors.forename: Victor
authors.initials: V
authors.lastname: Frenkel
authors.forename: Sergio
authors.initials: S
authors.lastname: Dromi
authors.forename: Peter
authors.initials: P
authors.lastname: Thomas
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Lewis
authors.forename: King C P
authors.initials: KC
authors.lastname: Li
authors.forename: McDonald
authors.initials: M
authors.lastname: Horne
authors.forename: Bradford J
authors.initials: BJ
authors.lastname: Wood
mesh_terms: D000818:Animals; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D023421:Models, Animal; D010865:Pilot Projects; D011817:Rabbits; D015912:Thrombolytic Therapy / Q000379:methods*; D013927:Thrombosis / Q000188:drug therapy / Q000628:therapy*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D016896:Treatment Outcome; D014464:Ultrasonic Therapy; D014465:Ultrasonics
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator