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. 1994 May;112(1):272–276. doi: 10.1111/j.1476-5381.1994.tb13063.x

Comparative effects of anti-platelet agents as adjuncts to tissue plasminogen activator in a dog model of occlusive coronary thrombosis.

S J McAuliffe 1, J A Moors 1, H B Jones 1
PMCID: PMC1910308  PMID: 8032650

Abstract

1. This study compares a cyclo-oxygenase inhibitor (aspirin), a 5-HT2 antagonist (ZM170809) and a combined thromboxane synthase inhibitor/receptor antagonist (ZD1542) as adjuncts to tissue plasminogen activator (rt-PA). 2. Application of an anodal current (332 +/- 4.1 microA) to the stenosed left circumflex coronary artery of 20 anaesthetized dogs produced a stable platelet-rich occlusive thrombus. 3. After initial i.v. administration of recombinant human tissue type plasminogen activator (rt-PA, 3 mg bolus +2 mg kg-1 h-1 for 30 min) thrombolysis occurred in 15 out of 20 dogs. All 15 dogs reoccluded. 4. The second i.v. administration of rt-PA in the presence of either aspirin, ZM170809, ZD1542 or saline resulted in thrombolysis in all 20 dogs. 5. Both the combined thromboxane synthase inhibitor/receptor antagonist (ZD1542) and 5-HT2 antagonist (ZM170809) significantly (P < 0.05) reduced the time taken to lyse the thrombus compared with the saline group. The times were 14.4 +/- 2.7 min, 18.0 +/- 3.9 min and 36.8 +/- 6.2 min for ZD1542, ZM170809 and saline respectively. 6. Aspirin did not offer any additional benefit to using rt-PA alone. The times to thrombolysis were 36.8 +/- 8.4 min for aspirin and 36.8 +/- 6.2 min for the saline group. 7. The number of dogs in which the circumflex coronary artery reoccluded within 60 min of terminating the second infusion of rt-PA were five for saline, four for aspirin, two for ZD1542 and two for ZM170809. 8. These results indicate that both ZD1542 and ZM170809 are more effective adjuncts than aspirin in thrombolysis and may provide an improvement in current clinical practice.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Coller B. S. Platelets and thrombolytic therapy. N Engl J Med. 1990 Jan 4;322(1):33–42. doi: 10.1056/NEJM199001043220107. [DOI] [PubMed] [Google Scholar]
  2. De Clerck F., Xhonneux B., Leysen J., Janssen P. A. Evidence for functional 5-HT2 receptor sites on human blood platelets. Biochem Pharmacol. 1984 Sep 1;33(17):2807–2811. doi: 10.1016/0006-2952(84)90699-3. [DOI] [PubMed] [Google Scholar]
  3. Eisenberg P. R., Sherman L. A., Jaffe A. S. Paradoxic elevation of fibrinopeptide A after streptokinase: evidence for continued thrombosis despite intense fibrinolysis. J Am Coll Cardiol. 1987 Sep;10(3):527–529. doi: 10.1016/s0735-1097(87)80194-8. [DOI] [PubMed] [Google Scholar]
  4. Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation. 1985 Apr;71(4):699–708. doi: 10.1161/01.cir.71.4.699. [DOI] [PubMed] [Google Scholar]
  5. Fitzgerald D. J., Wright F., FitzGerald G. A. Increased thromboxane biosynthesis during coronary thrombolysis. Evidence that platelet activation and thromboxane A2 modulate the response to tissue-type plasminogen activator in vivo. Circ Res. 1989 Jul;65(1):83–94. doi: 10.1161/01.res.65.1.83. [DOI] [PubMed] [Google Scholar]
  6. Gold H. K., Leinbach R. C., Garabedian H. D., Yasuda T., Johns J. A., Grossbard E. B., Palacios I., Collen D. Acute coronary reocclusion after thrombolysis with recombinant human tissue-type plasminogen activator: prevention by a maintenance infusion. Circulation. 1986 Feb;73(2):347–352. doi: 10.1161/01.cir.73.2.347. [DOI] [PubMed] [Google Scholar]
  7. Golino P., Ashton J. H., Glas-Greenwalt P., McNatt J., Buja L. M., Willerson J. T. Mediation of reocclusion by thromboxane A2 and serotonin after thrombolysis with tissue-type plasminogen activator in a canine preparation of coronary thrombosis. Circulation. 1988 Mar;77(3):678–684. doi: 10.1161/01.cir.77.3.678. [DOI] [PubMed] [Google Scholar]
  8. Golino P., Ashton J. H., McNatt J., Glas-Greenwalt P., Yao S. K., O'Brien R. A., Buja L. M., Willerson J. T. Simultaneous administration of thromboxane A2- and serotonin S2-receptor antagonists markedly enhances thrombolysis and prevents or delays reocclusion after tissue-type plasminogen activator in a canine model of coronary thrombosis. Circulation. 1989 Apr;79(4):911–919. doi: 10.1161/01.cir.79.4.911. [DOI] [PubMed] [Google Scholar]
  9. Jang I. K., Gold H. K., Ziskind A. A., Fallon J. T., Holt R. E., Leinbach R. C., May J. W., Collen D. Differential sensitivity of erythrocyte-rich and platelet-rich arterial thrombi to lysis with recombinant tissue-type plasminogen activator. A possible explanation for resistance to coronary thrombolysis. Circulation. 1989 Apr;79(4):920–928. doi: 10.1161/01.cir.79.4.920. [DOI] [PubMed] [Google Scholar]
  10. Kerins D. M., Roy L., FitzGerald G. A., Fitzgerald D. J. Platelet and vascular function during coronary thrombolysis with tissue-type plasminogen activator. Circulation. 1989 Dec;80(6):1718–1725. doi: 10.1161/01.cir.80.6.1718. [DOI] [PubMed] [Google Scholar]
  11. Lucore C. L., Sobel B. E. Interactions of tissue-type plasminogen activator with plasma inhibitors and their pharmacologic implications. Circulation. 1988 Mar;77(3):660–669. doi: 10.1161/01.cir.77.3.660. [DOI] [PubMed] [Google Scholar]
  12. McAuliffe S. J., Moors J. A., Snow H. M., Wayne M., Jessup R. Redirection of arachidonic acid metabolism by ICI D1542: effects on thrombus formation in the coronary artery of the anaesthetized dog. Br J Pharmacol. 1993 Apr;108(4):901–906. doi: 10.1111/j.1476-5381.1993.tb13484.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. McAuliffe S. J., Snow H. M., Cox B., Smith C. C., Noble M. I. Interaction between the effects of 5-hydroxytryptamine and adrenaline on the growth of platelet thrombi in the coronary artery of the anaesthetized dog. Br J Pharmacol. 1993 Jun;109(2):405–410. doi: 10.1111/j.1476-5381.1993.tb13583.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Romson J. L., Haack D. W., Lucchesi B. R. Electrical induction of coronary artery thrombosis in the ambulatory canine: a model for in vivo evaluation of anti-thrombotic agents. Thromb Res. 1980 Mar 15;17(6):841–853. doi: 10.1016/0049-3848(80)90249-2. [DOI] [PubMed] [Google Scholar]
  15. Shebuski R. J., Storer B. L., Fujita T. Effect of thromboxane synthase inhibition on the thrombolytic action of tissue-type plasminogen activator in a rabbit model of peripheral arterial thrombosis. Thromb Res. 1988 Dec 1;52(5):381–392. doi: 10.1016/0049-3848(88)90022-9. [DOI] [PubMed] [Google Scholar]
  16. Van de Werf F., Ludbrook P. A., Bergmann S. R., Tiefenbrunn A. J., Fox K. A., de Geest H., Verstraete M., Collen D., Sobel B. E. Coronary thrombolysis with tissue-type plasminogen activator in patients with evolving myocardial infarction. N Engl J Med. 1984 Mar 8;310(10):609–613. doi: 10.1056/NEJM198403083101001. [DOI] [PubMed] [Google Scholar]
  17. Yao S. K., Benedict C. R., Rosolowsky M., McNatt J., Falinska B., Campbell W. B., Buja L. M., Willerson J. T. Effect of aspirin on local prostaglandin production and serotonin accumulation in a canine model with coronary cyclic flow variations or thrombosis. J Mol Cell Cardiol. 1991 Apr;23(4):473–482. doi: 10.1016/0022-2828(91)90171-h. [DOI] [PubMed] [Google Scholar]

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