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Augmentation of In-Vitro Clot Dissolution by Low Frequency High-Intensity Ultrasound Combined with Antiplatelet and Antithrombotic Drugs

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Abstract

Background: Glycoprotein IIb/IIIa antagonists and heparin are increasingly used for treatment of acute coronary syndromes. There is no data on the effect of these drugs on clot dissolution when combined with low frequency high-intensity ultrasonic energy. We examined a possible additive effect of low frequency high-intensity ultrasound with an antithrombotic, an antiplatelet and a fibrinolytic agent alone or in combinations for in vitro blood clot dissolution.

Methods: Human blood clots were incubated for 10′, 15′ and 30′ in normal saline containing commonly used concentrations of heparin, tirofiban, t-PA and Optison (echocardiographic contrast agent) alone and in combinations. Clots were then randomly exposed to low frequency high-intensity ultrasound (27[emsp3 ]kHz) for 5 minutes. The percent difference in clot weight and the incremental effect of ultrasound energy were calculated.

Results: The most significant additive effect of ultrasound energy was detected with the combination of tirofiban and heparin (39±2% augmentation after 10′ of incubation, p<0.0001). The greatest magnitude of percent clot weight reduction was observed with ultrasound energy combined with either t-PA alone (72±1% after 30′ incubation, p=0.0016) or with the combination of t-PA, tirofiban, heparin and Optison (68±4% after 30′ incubation, p=0.015).

Conclusions: Application of low frequency high-intensity ultrasound has an additive effect to antiplatelet, antithrombotic and fibrinolytic drugs, specifically with the combination of tirofiban and heparin or with t-PA; this effect is observed after a short incubation period.

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References

  1. Topol EJ, Byzova TV, Plow EF. Platelet GP IIb-IIIa blockers. Lancet 1999;353:227–231.

    Article  PubMed  Google Scholar 

  2. Braunwald E, Maseri A, Armstrong PW, et al. Rationale and clinical evidence for the use of GP IIb=IIIa inhibitors in acute coronary syndromes. Eur Heart J 1998;19 Suppl D:D22–30.

    PubMed  Google Scholar 

  3. Ferguson JJ, Lau TK.New antiplatelet agents for acute coronary syndromes. Am Heart J 1998;135: S194–200.

    PubMed  Google Scholar 

  4. The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997;96:1445–1453.

    Google Scholar 

  5. Kereiakes DJ, Kleiman NS, Ambrose J, et al. Randomized, double-blind, placebo-controlled dose-ranging study of tirofiban (MK-383) platelet IIb/IIIa blockade in high risk patients undergoing coronary angioplasty. J Am Coll Cardiol 1996;27:536–542.

    Article  PubMed  Google Scholar 

  6. The PRISM Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998;338:1498–1505.

    Google Scholar 

  7. The PRISM-PLUS Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofi-ban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998;338:1488–1497.

    Google Scholar 

  8. Barrett JS, Murphy G, Peerlinck K, et al. Pharmacokinetics and pharmacodynamics of MK-383, a selective non-peptide platelet glycoprotein-IIb/IIIa receptor antagonist, in healthy men. Clin Pharmacol Ther 1994;56:377–388.

    PubMed  Google Scholar 

  9. Lynch JJ, Jr., Cook JJ, Sitko GR, et al. Nonpeptide glycoprotein IIb/IIIa inhibitors. 5. Antithrombotic effects of MK-0383. J Pharmacol Exp Ther 1995;272: 20–32.

    PubMed  Google Scholar 

  10. Peerlinck K, De Lepeleire I, Goldberg M, et al. MK-383 (L-700,462), a selective nonpeptide platelet glycoprotein IIb/IIIa antagonist, is active in man. Circulation 1993;88:1512–1517.

    PubMed  Google Scholar 

  11. Luo H, Steffen W, Cercek B, Arunasalam S, Maurer G, Siegel RJ. Enhancement of thrombolysis by external ultrasound. Am Heart J 1993;125:1564–1569.

    Article  PubMed  Google Scholar 

  12. Hamm CW, Steffen W, Terres W, et al. Intravascular therapeutic ultrasound thrombolysis in acute myocardial infarctions. Am J Cardiol 1997;80:200–204.

    Article  PubMed  Google Scholar 

  13. Harpaz D, Chen X, Francis CW, Marder VJ, Meltzer RS. Ultrasound enhancement of thrombolysis and reperfusion in vitro. J Am Coll Cardiol 1993;21: 1507–1511.

    PubMed  Google Scholar 

  14. Lauer CG, Burge R, Tang DB, Bass BG, Gomez ER, Alving BM. Effect of ultrasound on tissue-type plasminogen activator-induced thrombolysis. Circulation 1992;86:1257–1264.

    PubMed  Google Scholar 

  15. Rosenschein U, Roth A, Rassin T, Basan S, Laniado S, Miller HI. Analysis of coronary ultrasound thrombolysis endpoints in acute myocardial infarction (ACUTE trial). Results of the feasibility phase. Circulation 1997;95:1411–1416.

    PubMed  Google Scholar 

  16. Shlansky-Goldberg RD, Cines DB, Sehgal CM. Catheter-delivered ultrasound potentiates in vitro thrombolysis. J Vasc Interv Radiol 1996;7:313–320.

    PubMed  Google Scholar 

  17. Sehgal CM, Leveen RF, Shlansky-Goldberg RD. Ultrasound-assisted thrombolysis. Invest Radiol 1993; 28:939–943.

    PubMed  Google Scholar 

  18. Trubestein G, Engel C, Etzel F, Sobbe A, Cremer H, Stumpff U. Thrombolysis by ultrasound. Clin Sci Mol Med Suppl 1976;3:697s–698s.

    PubMed  Google Scholar 

  19. Tachibana K, Tachibana S. Albumin microbubble echo-contrast material as an enhancer for ultrasound accelerated thrombolysis. Circulation 1995;92:1148–1150.

    PubMed  Google Scholar 

  20. Kornowski R, Meltzer RS, Chernine A, Vered Z, Battler A. Does external ultrasound accelerate thrombolysis? Results from a rabbit model. Circulation 1994;89:339–344.

    PubMed  Google Scholar 

  21. Blinc A, Francis CW, T rudnowski JL, Carstensen EL. Characterization of ultrasound-potentiated fibrinolysis in vitro. Blood 1993;81:2636–2643.

    PubMed  Google Scholar 

  22. Francis CW, Blinc A, Lee S, Cox C. Ultrasound accelerates transport of recombinant tissue plasminogen activator into clots. Ultrasound Med Biol 1995;21: 419–424.

    Article  PubMed  Google Scholar 

  23. Blinc A, Kennedy SD, Bryant RG, Marder VJ, Francis CW. Flow through clots determines the rate and pattern of fibrinolysis. Thromb Haemost 1994;71: 230–235.

    PubMed  Google Scholar 

  24. Blinc A, Planinsic G, K eber D, et al. Dependence of blood clot lysis on the mode of transport of urokinase into the clot-a magnetic resonance imaging study in vitro. Thromb Haemost 1991;65:549–552.

    PubMed  Google Scholar 

  25. Siddiqi F, Blinc A, Braaten J, Francis CW. Ultrasound increases flow through fibrin gels. Thromb Haemost 1995;73:495–498.

    PubMed  Google Scholar 

  26. Shebuski RJ, Stabilito IJ, Sitko GR, Polokoff MH. Acceleration of recombinant tissue-type plasminogen activator-induced thrombolysis and prevention of reocclusion by the combination of heparin and the Arg-Gly-Asp-containing peptide bitistatin in a canine model of coronary thrombosis. Circulation 1990;82: 169–177.

    PubMed  Google Scholar 

  27. Gold HK, Coller BS, Yasuda T, et al. Rapid and sustained coronary artery recanalization with combined bolus injection of recombinant tissue-type plasminogen activator and monoclonal antiplatelet GPIIb/IIIa antibody in a canine preparation. Circulation 1988;77:670–677.

    PubMed  Google Scholar 

  28. Suchkova V, Siddiqi FN, Carstensen EL, Dalecki D, Child S, Francis CW. Enhancement of fibrinolysis with 40-kHz ultrasound. Circulation 1998;98:1030–1035.

    PubMed  Google Scholar 

  29. Luo H, Birnbaum Y, Fishbein MC, et al. Enhancement of thrombolysis in vivo without skin and soft tissue damage by transcutaneous ultrasound. Thromb Res 1998;89:171–177.

    Article  PubMed  Google Scholar 

  30. Luo H, Nishioka T, Fishbein MC, et al. Transcutaneous ultrasound augments lysis of arterial thrombi in vivo. Circulation 1996;94:775–778.

    PubMed  Google Scholar 

  31. Nishioka T, Luo H, Fishbein MC, et al. Dissolution of thrombotic arterial occlusion by high intensity, low frequency ultrasound and dodecafluoropentane emulsion: an in vitro and in vivo study. J Am Coll Cardiol 1997;30:561–568.

    Article  PubMed  Google Scholar 

  32. Birnbaum Y, Luo H, Nagai T, et al. Noninvasive in vivo clot dissolution without a thrombolytic drug: recanalization of thrombosed iliofemoral arteries by transcutaneous ultrasound combined with intravenous infusion of microbubbles. Circulation 1998;97: 130–134.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California, USA

    Shaul Atar, Huai Luo, Tomoo Nagai & Robert J. Siegel

  2. Rabin Medical Center, Petah-Tikva, Israel

    Yochai Birnbaum

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  1. Shaul Atar
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  2. Huai Luo
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  3. Yochai Birnbaum
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  4. Tomoo Nagai
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  5. Robert J. Siegel
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Atar, S., Luo, H., Birnbaum, Y. et al. Augmentation of In-Vitro Clot Dissolution by Low Frequency High-Intensity Ultrasound Combined with Antiplatelet and Antithrombotic Drugs. J Thromb Thrombolysis 11, 223–228 (2001). https://doi.org/10.1023/A:1011912920777

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