title: Ultrasound-enhanced tissue plasminogen activator thrombolysis in an in vitro porcine clot model.
abstract: BACKGROUND
  Thrombolytics such as recombinant tissue plasminogen activator (rt-PA) have advanced the treatment of ischemic stroke, myocardial infarction, deep vein thrombosis and pulmonary embolism.
  
  
  OBJECTIVE
  To improve the efficacy of this thrombolytic therapy, the synergistic effect of rt-PA and 120 kHz or 1.0 MHz ultrasound was assessed in vitro using a porcine clot model.
  
  
  METHODS
  Fully retracted whole blood clots prepared from fresh porcine blood were employed to compare rt-PA thrombolytic treatment with and without exposure to 120-kHz or 1-MHz ultrasound. For sham studies (without ultrasound), clot mass loss was measured as a function of rt-PA concentration from 0.003 to 0.107 mg/ml. For combined ultrasound and rt-PA treatments, peak-to-peak pressure amplitudes of 0.35, 0.70 or 1.0 MPa were employed. The range of duty cycles varied from 10% to 100% (continuous wave) and the pulse repetition frequency was fixed at 1.7 KHz.
  
  
  RESULTS
  For rt-PA alone, the mass loss increased monotonically as a function of rt-PA concentration up to approximately 0.050 mg/ml. With ultrasound and rt-PA exposure, clot mass loss increased by as much as 104% over rt-PA alone. Ultrasound without the presence of rt-PA did not significantly enhance thrombolysis compared to control treatment. The ultrasound-mediated clot mass loss enhancement increased with the square root of the overall treatment duration.
  
  
  CONCLUSIONS
  Both 120-kHz and 1-MHz pulsed and CW ultrasound enhanced rt-PA thrombolysis in a porcine whole blood clot model in vitro. No clear dependence of the observed thrombolytic enhancement on ultrasound duty cycle was evident. The lack of duty cycle dependence suggests a more complex mechanism that could not be sustained by merely increasing the pulse duration.
authors.affiliation: Department of Biomedical Engineering, University of Cincinnati, Medical Science Building, Rm. 6167, 231 Albert Sabin Way, Cincinnati, OH 45267-0586, USA. Christy.Holland@uc.edu
authors.forename: Christy K
authors.initials: CK
authors.lastname: Holland
authors.forename: Sampada S
authors.initials: SS
authors.lastname: Vaidya
authors.forename: Saurabh
authors.initials: S
authors.lastname: Datta
authors.forename: Constantin-C
authors.initials: CC
authors.lastname: Coussios
authors.forename: George J
authors.initials: GJ
authors.lastname: Shaw
mesh_terms: D000818:Animals; D011994:Recombinant Proteins / Q000627:therapeutic use; D013552:Swine; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D014464:Ultrasonic Therapy
chemical_list: D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator