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Dynamic nature of thrombin generation, fibrin formation, and platelet activation in unstable angina and non-Q-wave myocardial infarction

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Abstract

Background

Thrombin and platelets are directly involved in arterial thrombosis, typically occurring at sites of atherosclerotic plaque rupture among patients with acute coronary syndromes. Understanding the dynamic nature of pathologic thrombosis has important clinical implications.

Methods

Fibrinopeptide A (FPA), thrombin-antithrombin complexes (TAT), and prothrombin activation fragment 1.2 (F1.2), plasma markers of fibrin formation (thrombin activity) and thrombin generation, and platelet activation, determined by the recognition of a surface-expressed platelet α-granule protein, P-selectin, using flow cytometry, were measured in 36 consecutive patients with unstable angina and non-Q-wave myocardial infarction participating in the Thrombolysis In Myocardial Ischemia (TIMI) III B trial.

Results

Thrombin generation (TAT 12.1 ± 17.8 ng/ml vs. 3.4 ± 1.0 ng/ml; F1.2 0.19 ± 0.14 nmol/1 vs. 0.12 ± 0.8 nmol/1), fibrin formation (FPA 15.8 ± 23.5 ng/ml vs. 7.5 ± 2.3 ng/ ml), and platelet activation) 10.6 ± 2.4% vs. 2.5 ± 2.0%) were increased significantly in patients compared with healthy, age-matched controls (p < 0.01). Fibrin formation, represented by plasma FPA levels, did not correlate with the percentage of activated platelets (r=− .10, p=0.69). Thrombin generation and platelet activation also did not correlate. A statistically insignificant trend between TAT and platelet activation was observed (r=.42, p=0.07); however, even with TAT levels in excess of 20 ng/ml (nearly sixfold greater than normal healthy controls) platelet activation was increased by only 1.7-fold.

Conclusions

Thrombin generation, fibrin formation, and platelet activation are increased modestly among patients with unstable angina and non-Q-wave myocardial infarction. Despite the involvement of platelets and coagulation proteins in arterial thrombotic processes, their relative contributions may vary, providing a pathophysiologic basis for the dynamic expression of disease and response to treatment observed commonly in clinical practice.

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References

  1. 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;75:699–708.

    Google Scholar 

  2. Davies MJ, Thomas AC, Knapman PA, Hangartner JR. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death.Circulation 1986;73:418–427.

    Google Scholar 

  3. Fernández-Ortiz A, Badimon JJ, Falk E, et al. Characterization of the relative thrombogenicity of atherosclerotic plaque components: Implications for consequences of plaque rupture.J Am Coll Cardiol 1994;23:1562–1569.

    Google Scholar 

  4. Théroux P, Ouimet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina.N Engl J Med 1988; 319:1105–1111.

    Google Scholar 

  5. Lewis HD, Davis JW, Archibald DG, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina.N Engl J Med 1983;309:396–403.

    Google Scholar 

  6. Cairns J, Gent M, Singer J, et al. Aspirin sulfmpyrazone, or both in unstable angina: Results of a Canadian Multicenter Trial.N Engl J Med 1985;313:1369–1375.

    Google Scholar 

  7. Antiplatelet Trialists' Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment.Br Med J 1988;296:320–331.

    Google Scholar 

  8. Chesbro JH, Webster MWI, Zoldhelyi P, Roche PC, Badimon L, Badimon JJ. Antithrombotic therapy and progression of coronary artery disease. Antiplatelet versus antithrombins.Circulation 1992;86(Suppl III):III100-III111.

    Google Scholar 

  9. Tracy RP, Bovill EG, Stump DC, Lin T, Gorrol T, Collen D, Mann KG. Reduction of in vitro artifact during blood collection in the Thrombolysis In Myocardial Infarction Trial, Phase II.Blood 1988;78(Suppl 1):376.

    Google Scholar 

  10. Becker RC, Tracy RP, Bovill EG, Mann KG, Ault K. The clinical use of flow cytometry for assessing platelet activation in acute coronary syndromes.Coro Art Dis 1994;5: 339–345.

    Google Scholar 

  11. Carmody MW, Ault KA, Mitchell JG, Rose NS, Ng A-K. Production of monoclonal antibodies specific for platelet activation antigens and their use in evaluating platelet function.Hybridoma 1990;9:631–641.

    Google Scholar 

  12. Bevers EM, Comfurius P, Van Rijn JLML, Hemker HC, Zwaal RFA. Generation of prothrombin-converting activity and the exposure of phosphatidylserine at the outer surface of platelets.Eur J Biochem 1982;122:429–436.

    Google Scholar 

  13. Bevers EM, Comfurius P, Zwaal RFA. Changes in membrane phospholipid distribution during platelet activation.Biochim Biophys Acta 1983;736:57–66.

    Google Scholar 

  14. Zwaal RFA, Bevers EM. Platelet phospholipid asymmetry and its significance in hemostasis.Subcell Biochem 1983;9: 299–334.

    Google Scholar 

  15. Bevers EM, Rosing J, Zwaal RFA. Development of procoagulant binding sites on the platelet surface.Adv Exp Med Biol 1985;192:359–371.

    Google Scholar 

  16. Sandberg H, Andersson LO, Hoglund S. Isolation and characterization of lipid-protein particles containing platelet factor 3 released from human platelets.Biochem J 1982;203: 303–311.

    Google Scholar 

  17. Simms P, Wiedmer T, Esmon CT, Weiss HJ, Shatil SJ. Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane.J. Biol Chem 1989;264:17049–17053.

    Google Scholar 

  18. Coughlin SR, Vu T-KH, Hung DT, Whaton VI. Characterization of the cloned platelet thrombin receptor: Issues and opportunities.JClin Invest 1992;89:351–355.

    Google Scholar 

  19. Dohlman HG, Thorner J, Caron MG, Lefkowitz RJ. Model systems for the study of seven transmembrane segment receptors.Annu Rev Biochem 1992;60:651–688.

    Google Scholar 

  20. Badimon L, Badimon J-J, Galvez A, Chesebro JH, Fuster V. Influence of arterial damage and wall shear rate on platelet deposition: Ex vivo study in a swine model.Arteriosclerosis 1986;6:312–320.

    Google Scholar 

  21. Badimon L, Turitto VT, Rosemark JA, Badimon JJ, Fuster V. Characterization of a tubular flow chamber for studying platelet interaction with biological and prosthetic materials: Deposition of 111 indium-labeled platelets on collagen, subendothelium, and Gortex®.JLabClin Med 1987;110: 706–718.

    Google Scholar 

  22. Badimon L, Badimon JJ. Mechanisms of arterial thrombosis in nonparallel streamlines: Platelet thrombi grow on the apex of stenotic severely injured vessel wall.JClin Invest 1989;84:1134–1144.

    Google Scholar 

  23. Lassila R, Badimon JJ, Vallabhajosula S, Badimon L. Dynamic monitoring of platelet deposition on severely damaged vessel wall in flowing blood: Effects of different stenosis on thrombus growth.Arteriosclerosis 1990;10:306–315.

    Google Scholar 

  24. Badimon L, Chesebro JH, Badimon JJ. Thrombus formation on ruptured atherosclerotic plaques and rethrombosis on evolving thrombi.Circulation 1992;86(Suppl III): III74-III85.

    Google Scholar 

  25. Gast A, Tschopp TB, Baumgartner HR. Thrombin plays a key role in late platelet thrombus growth and/or stability. Effect of a specific thrombin inhibitor on thrombogenesis induced by aortic subendothelium exposed to flowing rabbit blood.Arterio and Thrombos 1994;14:1466–1474.

    Google Scholar 

  26. Kragel AH, Gertz SD, Roberts WC. Morphologic comparison of frequency and types of acute lesions in the major epicardial coronary arteries in unstable angina pectoris, sudden coronary death and acute myocardial infarction.J Am Coll Cardiol 1991;18:801–808.

    Google Scholar 

  27. Sherman CT, Litvack F, Grundfest W. Coronary angioscopy in patients with unstable angina pectoris.N Engl J Med 1986;315:913–919.

    Google Scholar 

  28. Mixuno K, Satomura K, Miyamoto A, et al. Angioscopic evaluation of coronary-artery thrombi in acute coronary syndromes.N Engl J Med 1992;326:287–291.

    Google Scholar 

  29. Uchida Y, Masuo M, Tomaru T, Kato A, Sugimoto T. Fiberoptic observation of thrombosis and thrombolysis in isolated human coronary arteries.Am Heart J 1986;112:691–696.

    Google Scholar 

  30. The TIMI IIIA Investigators. Early effects of tissue-type plasminogen activator added to conventional therapy on the culprit coronary lesion in patients presenting with ischemie cardiac pain at rest: Results of the Thrombolysis In Myocardial Ischemia (TIMI IIIA) Trial.Circulation 1993;87:38–52.

    Google Scholar 

  31. Eisenberg PR, Sherman LA, Schectman K, Perez J, Sobel BE, Jaffe AS. Fibrinopeptide A: A marker of acute coronary thrombosis.Circulation 1985;71:912–918.

    Google Scholar 

  32. Eisenberg PR, Kenzora JL, Sobel BE, Ludbrook PA, Jaffe AS. Relation between ST segment shifts during ischemia and thrombin activity in patients with unstable angina.J Am Coll Cardiol 1991;18:898–903.

    Google Scholar 

  33. Ardissino D, Gamba MG, Merlini PA, et al. Fibrinopeptide A excretion in urine: A marker of the cumulative thrombin activity in stable versus unstable angina patients.Am J Cardiol 1991;68:58B-63B.

    Google Scholar 

  34. Wilensky RL, Seller JA, Wish M, Tulchinsky M. Urinary fibrinopeptide A levels in ischemic heart disease.Am J Cardiol 1989;14:597–603.

    Google Scholar 

  35. Hamm CW, Lorenz RL, Bleifeld W, Kupper W, Wober W, Weber PC. Biochemical evidence of platelet activation in patients with persistent unstable angina.Am J Cardiol 1987;10:998–104.

    Google Scholar 

  36. Fitzgerald DJ, Roy L, Catella F, Fitzgerald GA. Platelet activation in unstable coronary disease.N Engl J Med 1986; 315:983–989.

    Google Scholar 

  37. Willerson JT, Golino P, Eidt J, Campbell WB, Buja M. Specific platelet mediators and unstable coronary artery lesions: Experimental evidence and potential clinical implications.Circulation 1989;80:198–206.

    Google Scholar 

  38. Théroux P, Latour JG, Léger-Gauthier C, De Lara J. Fibrinopeptide A and platelet factor levels in unstable angina pectoris.Circulation 1987;75:156–162.

    Google Scholar 

  39. Wilensky RL, Bourdillon V, Vix VA, Zeller JA. Intracoronary artery thrombus formation in unstable angina: A clinical, biochemical and angiographic correlation.J Am Coll Cardiol 1993;21:692–699.

    Google Scholar 

  40. Becker RC, Tracy RP, Bovill EG, et al. Platelet activation determined by flow cytometry persists despite antithrombotic therapy in patients with unstable angina and non-Q wave myocardial infarction.J Thromb Thrombolys 1994;1: 101–107.

    Google Scholar 

  41. Aronson DL, Chang P, Kessler CM. Platelet-dependent thrombin generation after in vitro fibrinolytic treatment.Circulation 1992;85:1706–1712.

    Google Scholar 

  42. Galvani M, Abendschein DR, Ferrini D, Ottani F, Rusticali F, Eisenberg PR. Failure of fixed dose intravenous heparin to suppress increases in thrombin activity after coronary thrombolysis with streptokinase.J Am Coll Cardiol 1994;24:1145–1452.

    Google Scholar 

  43. Willerson JT, Campbell WB, Winniford MD, et al. Conversion from chronic to acute coronary artery disease: Speculation regarding mechanisms.Am J Cardiol 1984;54:1349–1354.

    Google Scholar 

  44. Willerson JT, Hillis LD, Winniford MD, Buja LM. Speculations regarding mechanisms responsible for acute ischemie heart disease syndromes.J Am Coll Cardiol 1986;8:245–250.

    Google Scholar 

  45. Itoh Y, Yanagisawa M, Ohkubo S, et al. Cloning and sequence analysis of cDNA encoding the precursor of a human endothelium-derived vasoconstrictor peptide, endothelin: Identity of human and porcine endothelia.FEBS Lett 1988; 231:440–444.

    Google Scholar 

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Authors and Affiliations

  1. Thrombosis Research Center, Clinical Trials Section, Laboratory for Vascular Biology Research, University of Massachusetts Medical School, Worcester, MA

    Richard C. Becker M.D.

  2. Biochemistry Research Laboratory, University of Vermont Medical School, Burlington, VT

    Kenneth G. Mann & Russell P. Tracy

  3. Department of Pathology, University of Vermont Medical School, Burlington, VT

    Edwin G. Bovill

  4. Cytometry Research Institute, Maine Medical Center, Portland, MB

    Kenneth Ault

Authors
  1. Richard C. Becker M.D.
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  2. Edwin G. Bovill
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  3. Jeanne M. Corrao
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  4. Steven P. Ball
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  5. Kenneth Ault
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  6. Kenneth G. Mann
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  7. Russell P. Tracy
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Becker, R.C., Bovill, E.G., Corrao, J.M. et al. Dynamic nature of thrombin generation, fibrin formation, and platelet activation in unstable angina and non-Q-wave myocardial infarction. J Thromb Thrombol 2, 57–63 (1995). https://doi.org/10.1007/BF01063163

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  • DOI: https://doi.org/10.1007/BF01063163

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