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The Effect of 120-kHz Ultrasound on Thrombolytic Efficacy in Porcine Thromboembolism Models

Huang, Shenwen
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511884862297255

Abstract Details

2017, PhD, University of Cincinnati, Engineering and Applied Science: Biomedical Engineering.
Ischemic stroke affects nearly 700,000 patients in the United States each year and is the fifth most common cause of death. In less than 6% of ischemic stroke patients, lysis of the occlusive clot is attempted with recombinant tissue-plasminogen activator (rt-PA). The addition of Definity® microbubbles and 120-kHz ultrasound to rt-PA treatment has been shown to enhance lytic activity in vitro and ex vivo. However, preclinical trials must be completed in an animal model such as pigs prior to human clinical trials. One porcine thrombosis model is the intracerebral hemorrhage model, in which an intracerebral hemorrhage is treated with a lytic and exposed to ultrasound. An assay for a biochemical marker of clot breakdown, D-dimer, was evaluated for quantification of thrombolysis in this model. A porcine D-dimer purification protocol was developed and the identity of the purified D-dimer was confirmed by immunoblotting and MALDI TOF-TOF analysis. We evaluated a commercially available D-dimer ELISA kit and 5 commercially available D-dimer antibodies for development of an in-house ELISA protocol. In porcine samples produced in an in vitro thrombolysis system, D-dimer concentration was shown to correlate with mass loss. However, no current assay is known to be able to quantitate D-dimer with adequate sensitivity (10 ng/mL). To create an arterial thromboembolism model of ischemic stroke, porcine ascending pharyngeal arteries (APA) were occluded bilaterally. Most arteries were occluded with a single clot chosen to be about 1 mm larger than the inner diameter of the target artery. However, intraarterial treatment of the occluded arteries with rt-PA was ineffective and did not recanalize any of the occluded arteries. A protocol for post-mortem APA excision from swine was also developed. The lack of rt-PA efficacy in the porcine arterial thromboembolism model suggested that porcine clots were resistant to rt-PA thrombolysis. In vitro evaluation of the lytic response of porcine and human clots showed that the presence of human plasminogen either intercalated within the clot or in the surrounding plasma allows for more humanoid rt-PA thrombolytic efficacy. When perfused with human plasma, porcine clots and human clots showed equivalent fractional clot loss when treated with plasma alone, rt-PA, or rt-PA with Definity and adjuvant ultrasound exposure. Human whole blood clots perfused with porcine plasma exhibited less rt PA lysis than human clots perfused with human plasma. However, adjuvant ultrasound exposure increased lysis to the same extent as in human clots perfused with human plasma. Porcine clots doped with barium sulfate (BaSO4) were evaluated for rt-PA thrombolytic efficacy. Non-doped and BaSO4-doped porcine clots demonstrated a similar degree of thrombolysis when treated with plasma alone, rt-PA, and rt-PA with adjuvant ultrasound exposure. However, the reduced susceptibility of porcine blood clots to rt-PA was evident. Porcine clots doped with human plasminogen showed increased rt-PA lysis compared to plasma alone, and US exposure adjuvant to rt-PA treatment showed US enhancement of rt-PA lysis. The resistance to rt-PA lysis in porcine clots suggest that biochemical alteration of porcine clots may be required to better mimic human hemostasis.
Christy Holland, Ph.D. (Committee Chair)
Todd Abruzzo, Ph.D. (Committee Member)
Kevin Haworth, Ph.D. (Committee Member)
Andrew Herr, Ph.D. (Committee Member)
Daria Narmoneva, Ph.D. (Committee Member)
144 p.
Biomedical Research
sonothrombolysis; ultrasound; porcine models; therapeutic ultrasound; D-dimer

Recommended Citations

Citations

  • Huang, S. (2017). The Effect of 120-kHz Ultrasound on Thrombolytic Efficacy in Porcine Thromboembolism Models [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511884862297255

    APA Style (7th edition)

  • Huang, Shenwen. The Effect of 120-kHz Ultrasound on Thrombolytic Efficacy in Porcine Thromboembolism Models. 2017. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511884862297255.

    MLA Style (8th edition)

  • Huang, Shenwen. "The Effect of 120-kHz Ultrasound on Thrombolytic Efficacy in Porcine Thromboembolism Models." Doctoral dissertation, University of Cincinnati, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511884862297255

    Chicago Manual of Style (17th edition)

ucin1511884862297255
298
© 2017, some rights reserved.Creative Commons License The Effect of 120-kHz Ultrasound on Thrombolytic Efficacy in Porcine Thromboembolism Models by Shenwen Huang is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.