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. 1987 Jun;79(6):1749–1755. doi: 10.1172/JCI113015

Tissue plasminogen activator promotes platelet disaggregation in plasma.

J Loscalzo, D E Vaughan
PMCID: PMC424517  PMID: 2438305

Abstract

We studied the disaggregation of human platelets by tissue-type plasminogen activator (t-PA). When added to a suspension of human platelets induced to aggregate in plasma with adenosine 5'-diphosphate, t-PA promoted disaggregation of platelets over several minutes. Addition of fresh plasma or purified human fibrinogen to disaggregated platelets facilitated (reversible) aggregation and subsequent disaggregation. Aspirin treatment of platelets markedly potentiated the ability of t-PA to induce disaggregation. Disaggregation was inhibited by alpha-2-antiplasmin. Comparative analysis of the rate of proteolysis of platelet-bound fibrinogen with that of ambient plasma fibrinogen suggested that fibrinogenolysis of cohesive fibrinogen occurred more rapidly than fibrinogenolysis of ambient fibrinogen. These data demonstrate that t-PA facilitates platelet disaggregation in plasma through kinetically selective proteolysis of cohesive fibrinogen by plasmin, and suggest that thrombolytic mechanisms may serve both to remove platelets from platelet-fibrin thrombi and to disperse circulating platelet aggregates.

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Selected References

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

  1. Adelman B., Michelson A. D., Loscalzo J., Greenberg J., Handin R. I. Plasmin effect on platelet glycoprotein Ib-von Willebrand factor interactions. Blood. 1985 Jan;65(1):32–40. [PubMed] [Google Scholar]
  2. Astrup T. Tissue activators of plasminogen. Fed Proc. 1966 Jan-Feb;25(1):42–51. [PubMed] [Google Scholar]
  3. BORN G. V., CROSS M. J. THE AGGREGATION OF BLOOD PLATELETS. J Physiol. 1963 Aug;168:178–195. doi: 10.1113/jphysiol.1963.sp007185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bennett J. S., Vilaire G. Exposure of platelet fibrinogen receptors by ADP and epinephrine. J Clin Invest. 1979 Nov;64(5):1393–1401. doi: 10.1172/JCI109597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bowry S. K., Prentice C. R., Courtney J. M. A modification of the Wu and Hoak method for the determination of platelet aggregates and platelet adhesion. Thromb Haemost. 1985 Jun 24;53(3):381–385. [PubMed] [Google Scholar]
  6. Collen D., Stassen J. M., Marafino B. J., Jr, Builder S., De Cock F., Ogez J., Tajiri D., Pennica D., Bennett W. F., Salwa J. Biological properties of human tissue-type plasminogen activator obtained by expression of recombinant DNA in mammalian cells. J Pharmacol Exp Ther. 1984 Oct;231(1):146–152. [PubMed] [Google Scholar]
  7. Connellan J. M., Thurlow P. J., Barlow B., Lowe M., McKenzie I. F. Investigation of alternative mechanisms of collagen-induced platelet activation by using monoclonal antibodies to glycoprotein IIb-IIIa and fibrinogen. Thromb Haemost. 1986 Apr 30;55(2):153–157. [PubMed] [Google Scholar]
  8. Davies M. J., Thomas A. C., Knapman P. A., Hangartner J. R. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation. 1986 Mar;73(3):418–427. doi: 10.1161/01.cir.73.3.418. [DOI] [PubMed] [Google Scholar]
  9. Dougherty J. H., Jr, Levy D. E., Weksler B. B. Platelet activation in acute cerebral ischaemia. Serial measurements of platelet function in cerebrovascular disease. Lancet. 1977 Apr 16;1(8016):821–824. doi: 10.1016/s0140-6736(77)92774-x. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Friberger P., Knös M., Gustavsson S., Aurell L., Claeson G. Methods for determination of plasmin, antiplasmin and plasminogen by means of substrate S-2251. Haemostasis. 1978;7(2-3):138–145. doi: 10.1159/000214252. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Guccione M. A., Kinlough-Rathbone R. L., Packham M. A., Harfenist E. J., Rand M. L., Greenberg J. P., Perry D. W., Mustard J. F. Effects of plasmin on rabbit platelets. Thromb Haemost. 1985 Feb 18;53(1):8–14. [PubMed] [Google Scholar]
  14. Haerem J. W. Mural platelet microthrombi and major acute lesions of main epicardial arteries in sudden coronary death. Atherosclerosis. 1974 May-Jun;19(3):529–541. doi: 10.1016/s0021-9150(74)80017-1. [DOI] [PubMed] [Google Scholar]
  15. Haerem J. W. Platelet aggregates in intramyocardial vessels of patients dying suddenly and unexpectedly of coronary artery disease. Atherosclerosis. 1972 Mar-Apr;15(2):199–213. doi: 10.1016/0021-9150(72)90070-6. [DOI] [PubMed] [Google Scholar]
  16. Hoylaerts M., Rijken D. C., Lijnen H. R., Collen D. Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin. J Biol Chem. 1982 Mar 25;257(6):2912–2919. [PubMed] [Google Scholar]
  17. Kinlough-Rathbone R. L., Mustard J. F., Perry D. W., Dejana E., Cazenave J. P., Packham M. A., Harfenist E. J. Factors influencing the deaggregation of human and rabbit platelets. Thromb Haemost. 1983 Jun 28;49(3):162–167. [PubMed] [Google Scholar]
  18. Kohanna F. H., Smith M. H., Salzman E. W. Do patients with thromboembolic disease have circulating platelet aggregates? Blood. 1984 Jul;64(1):205–209. [PubMed] [Google Scholar]
  19. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  20. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  21. Le Breton G. C., Venton D. L. Thromboxane A2 receptor antagonism selectively reverses platelet aggregation. Adv Prostaglandin Thromboxane Res. 1980;6:497–503. [PubMed] [Google Scholar]
  22. Loscalzo J., Inbal A., Handin R. I. von Willebrand protein facilitates platelet incorporation in polymerizing fibrin. J Clin Invest. 1986 Oct;78(4):1112–1119. doi: 10.1172/JCI112668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lowe G. D., Reavey M. M., Johnston R. V., Forbes C. D., Prentice C. R. Increased platelet aggregates in vascular and nonvascular illness: correlation with plasma fibrinogen and effect of ancrod. Thromb Res. 1979 Feb-Mar;14(2-3):377–386. doi: 10.1016/0049-3848(79)90246-9. [DOI] [PubMed] [Google Scholar]
  24. Marguerie G. A., Edgington T. S., Plow E. F. Interaction of fibrinogen with its platelet receptor as part of a multistep reaction in ADP-induced platelet aggregation. J Biol Chem. 1980 Jan 10;255(1):154–161. [PubMed] [Google Scholar]
  25. Mehta P., Mehta J. Platelet function studies in coronary artery disease. V. Evidence for enhanced platelet microthrombus formation activity in acute myocardial infarction. Am J Cardiol. 1979 Apr;43(4):757–760. doi: 10.1016/0002-9149(79)90075-4. [DOI] [PubMed] [Google Scholar]
  26. Merskey C., Kleiner G. J., Johnson A. J. Quantitative estimation of split products of fibrinogen in human serum, relation to diagnosis and treatment. Blood. 1966 Jul;28(1):1–18. [PubMed] [Google Scholar]
  27. Merskey C., Lalezari P., Johnson A. J. A rapid, simple, sensitive method for measuring fibrinolytic split products in human serum. Proc Soc Exp Biol Med. 1969 Jul;131(3):871–875. doi: 10.3181/00379727-131-33998. [DOI] [PubMed] [Google Scholar]
  28. Miles L. A., Ginsberg M. H., White J. G., Plow E. F. Plasminogen interacts with human platelets through two distinct mechanisms. J Clin Invest. 1986 Jun;77(6):2001–2009. doi: 10.1172/JCI112529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Miles L. A., Plow E. F. Binding and activation of plasminogen on the platelet surface. J Biol Chem. 1985 Apr 10;260(7):4303–4311. [PubMed] [Google Scholar]
  30. Miller J. L., Katz A. J., Feinstein M. B. Plasmin inhibition of thrombin-induced platelet aggregation. Thromb Diath Haemorrh. 1975 Apr 30;33(2):286–309. [PubMed] [Google Scholar]
  31. Nachman R. L., Hubbard A., Ferris B. Iodination of the human platelet membrane. Studies of the major surface glycoprotein. J Biol Chem. 1973 Apr 25;248(8):2928–2936. [PubMed] [Google Scholar]
  32. Niewiarowski S., Senyi A. F., Gillies P. Plasmin-induced platelet aggregation and platelet release reaction. Effects on hemostasis. J Clin Invest. 1973 Jul;52(7):1647–1659. doi: 10.1172/JCI107345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Peerschke E. I. The platelet fibrinogen receptor. Semin Hematol. 1985 Oct;22(4):241–259. [PubMed] [Google Scholar]
  34. Peerschke E. I., Wainer J. A. Examination of irreversible platelet-fibrinogen interactions. Am J Physiol. 1985 May;248(5 Pt 1):C466–C472. doi: 10.1152/ajpcell.1985.248.5.C466. [DOI] [PubMed] [Google Scholar]
  35. Phillips D. R. Effect of trypsin on the exposed polypeptides and glycoproteins in the human platelet membrane. Biochemistry. 1972 Nov 21;11(24):4582–4588. doi: 10.1021/bi00774a025. [DOI] [PubMed] [Google Scholar]
  36. Prazich J. A., Rapaport S. I., Samples J. R., Engler R. Platelet aggregate ratios--standardization of technique and test results in patients with myocardial ischemia and patients with cerebrovascular disease. Thromb Haemost. 1977 Oct 31;38(3):597–605. [PubMed] [Google Scholar]
  37. Radomski M., Swies J., Gryglewski R. J. Disaggregatory action of phosphodiesterase inhibitors. Pharmacol Res Commun. 1981 Jan;13(1):41–47. doi: 10.1016/s0031-6989(81)80037-9. [DOI] [PubMed] [Google Scholar]
  38. Rampling M. W., Gaffney P. J. The sulphite precipitation method for fibrinogen measurement; its use on small samples in the presence of fibrinogen degradation products. Clin Chim Acta. 1976 Feb 16;67(1):43–52. doi: 10.1016/0009-8981(76)90215-1. [DOI] [PubMed] [Google Scholar]
  39. Rao G. H., Reddy K. R., White J. G. The influence of epinephrine on prostacyclin (PGI2) induced dissociation of ADP aggregated plateletes. Prostaglandins Med. 1980 Jun;4(6):385–397. doi: 10.1016/0161-4630(80)90047-6. [DOI] [PubMed] [Google Scholar]
  40. Rao G. H., White J. G. Disaggregation and reaggregation of 'irreversibly' aggregated platelets: a method for more complete evaluation of anti-platelet drugs. Agents Actions. 1985 Jul;16(5):425–434. doi: 10.1007/BF01982884. [DOI] [PubMed] [Google Scholar]
  41. Rijken D. C., Wijngaards G., Zaal-de Jong M., Welbergen J. Purification and partial characterization of plasminogen activator from human uterine tissue. Biochim Biophys Acta. 1979 Sep 29;580(1):140–153. doi: 10.1016/0005-2795(79)90205-8. [DOI] [PubMed] [Google Scholar]
  42. Schafer A. I., Adelman B. Plasmin inhibition of platelet function and of arachidonic acid metabolism. J Clin Invest. 1985 Feb;75(2):456–461. doi: 10.1172/JCI111720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Schafer A. I., Maas A. K., Ware J. A., Johnson P. C., Rittenhouse S. E., Salzman E. W. Platelet protein phosphorylation, elevation of cytosolic calcium, and inositol phospholipid breakdown in platelet activation induced by plasmin. J Clin Invest. 1986 Jul;78(1):73–79. doi: 10.1172/JCI112576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Stricker R. B., Wong D., Shiu D. T., Reyes P. T., Shuman M. A. Activation of plasminogen by tissue plasminogen activator on normal and thrombasthenic platelets: effects on surface proteins and platelet aggregation. Blood. 1986 Jul;68(1):275–280. [PubMed] [Google Scholar]
  45. Tandon N., Harmon J. T., Rodbard D., Jamieson G. A. Thrombin receptors define responsiveness of cholesterol-modified platelets. J Biol Chem. 1983 Oct 10;258(19):11840–11845. [PubMed] [Google Scholar]
  46. Teger-Nilsson A. C., Friberger P., Gyzander E. Determination of a new rapid plasmin inhibitor in human blood by means of a plasmin specific tripeptide substrate. Scand J Clin Lab Invest. 1977 Sep;37(5):403–409. [PubMed] [Google Scholar]
  47. Willerson J. T., Campbell W. B., Winniford M. D., Schmitz J., Apprill P., Firth B. G., Ashton J., Smitherman T., Bush L., Buja L. M. Conversion from chronic to acute coronary artery disease: speculation regarding mechanisms. Am J Cardiol. 1984 Dec 1;54(10):1349–1354. doi: 10.1016/s0002-9149(84)80095-8. [DOI] [PubMed] [Google Scholar]
  48. Wiman B., Collen D. Molecular mechanism of physiological fibrinolysis. Nature. 1978 Apr 6;272(5653):549–550. doi: 10.1038/272549a0. [DOI] [PubMed] [Google Scholar]
  49. Wu K. K., Barnes R. W., Hoak J. C. Platelet hyperaggregability in idiopathic recurrent deep vein thrombosis. Circulation. 1976 Apr;53(4):687–691. doi: 10.1161/01.cir.53.4.687. [DOI] [PubMed] [Google Scholar]
  50. Wu K. K., Hoak J. C. A new method for the quantitative detection of platelet aggregates in patients with arterial insufficiency. Lancet. 1974 Oct 19;2(7886):924–926. doi: 10.1016/s0140-6736(74)91131-3. [DOI] [PubMed] [Google Scholar]

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