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. 1974 Oct;54(4):782–791. doi: 10.1172/JCI107818

Resolution of Experimental Pulmonary Emboli with Heparin and Streptokinase in Different Dosage Regimens

J F Cade 1,2,3,4, J Hirsh 1,2,3,4, E Regoeczi 1,2,3,4, M Gent 1,2,3,4, M R Buchanan 1,2,3,4, D M Hynes 1,2,3,4
PMCID: PMC301618  PMID: 4430712

Abstract

Thrombolytic agents may be useful in acute pulmonary embolism, but their optimal dosage remains uncertain. We have examined the relative efficacy of heparin and different doses of streptokinase, either alone or in combination, in acute experimental pulmonary embolism. A standardized massive embolus of autologous blood clot incorporating canine [125I]-fibrinogen was given to 40 dogs; the degree of resolution after 24 h was quantitated by measuring the radioactivity in the lungs and was compared with detailed postmortem observations.

The amount of residual embolus was 49% in control animals, 28% after heparin (200 U/kg loading dose and 800 U/kg/24 h maintenance dose), and 6% after high dose streptokinase (250,000 U loading dose and 100,000 U/h maintenance dose); it was 31% after low dose streptokinase (25,000 U loading dose and 10,000 U/h maintenance dose), 7% after low dose streptokinase with heparin, 14% after very low dose streptokinase (5,000 U/h without a loading dose) with heparin, and 9% after short course streptokinase (250,000 U loading dose and no maintenance dose) with heparin.

The combination of heparin and low doses or brief courses of streptokinase appeared to be synergistic and produced as much resolution as did standard high dose streptokinase alone. The enhanced resolution of pulmonary emboli in heparin-treated animals may have been due to the prevention by heparin of further deposition of fibrin on the embolus. It appears that dosage regimens of thrombolytic therapy other than those in current use may be worthy of clinical examination.

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Selected References

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  1. ALKJAERSIG N., FLETCHER A. P., SHERRY S. The mechanism of clot dissolution by plasmin. J Clin Invest. 1959 Jul;38(7):1086–1095. doi: 10.1172/JCI103885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. ALLISON P. R., DUNNILL M. S., MARSHALL R. Pulmonary embolism. Thorax. 1960 Dec;15:273–283. doi: 10.1136/thx.15.4.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. ASTRUP T., BRAKMAN P., NISSEN U. THE ESTIMATION OF FIBRINOGEN. A REVISION. Scand J Clin Lab Invest. 1965;17:57–65. doi: 10.3109/00365516509077284. [DOI] [PubMed] [Google Scholar]
  4. BARRITT D. W., JORDAN S. C. Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet. 1960 Jun 18;1(7138):1309–1312. doi: 10.1016/s0140-6736(60)92299-6. [DOI] [PubMed] [Google Scholar]
  5. BAUER G. CLINICAL EXPERIENCES OF A SURGEON IN THE USE OF HEPARIN. Am J Cardiol. 1964 Jul;14:29–35. doi: 10.1016/0002-9149(64)90101-8. [DOI] [PubMed] [Google Scholar]
  6. BRECHER G., CRONKITE E. P. Morphology and enumeration of human blood platelets. J Appl Physiol. 1950 Dec;3(6):365–377. doi: 10.1152/jappl.1950.3.6.365. [DOI] [PubMed] [Google Scholar]
  7. BROWSE N. L., JAMES D. C. STREPTOKINASE AND PULMONARY EMBOLISM. Lancet. 1964 Nov 14;2(7368):1039–1043. doi: 10.1016/s0140-6736(64)90991-2. [DOI] [PubMed] [Google Scholar]
  8. BUCKELL M. The effect of citrate on euglobulin methods of estimating fibrinolytic activity. J Clin Pathol. 1958 Sep;11(5):403–405. doi: 10.1136/jcp.11.5.403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Baillie A. J., Sim A. K. Activation of the fibrinolytic enzyme system in laboratory animals and in man. A comparative study. Thromb Diath Haemorrh. 1971 Jun 30;25(3):499–506. [PubMed] [Google Scholar]
  10. Basu D., Gallus A., Hirsh J., Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med. 1972 Aug 17;287(7):324–327. doi: 10.1056/NEJM197208172870703. [DOI] [PubMed] [Google Scholar]
  11. Bishop R., Ekert H., Gilchrist G., Shanbrom E., Fekete L. The preparation and evaluation of a standardized fibrin plate for the assessment of fibrinolytic activity. Thromb Diath Haemorrh. 1970 May 31;23(2):202–210. [PubMed] [Google Scholar]
  12. CAREY L. C., WILLIAMS R. D. Comparative effects of dicoumarol, tromexan, and heparin on thrombus propagation. Ann Surg. 1960 Nov;152:919–922. doi: 10.1097/00000658-196011000-00022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cade J. F., Hynes D. M., Garnett E. S., Regoeczi E., Hirsh J. Hot clot scan. A method for the accurate identification of experimental pulmonary emboli. Invest Radiol. 1974 Jan-Feb;9(1):32–36. [PubMed] [Google Scholar]
  14. Dalen J. E., Mathur V. S., Evans H., Haynes F. W., Pur-Shahriari A. A., Stein P. D., Dexter L. Pulmonary angiography in experimental pulmonary embolism. Am Heart J. 1966 Oct;72(4):509–520. doi: 10.1016/0002-8703(66)90108-6. [DOI] [PubMed] [Google Scholar]
  15. Dellenback R. J., Chien S. The quantitation of isotope loss with tyrosine loss in the canine fibrinogen-fibrin transformation. Proc Soc Exp Biol Med. 1971 Jul;137(3):751–758. doi: 10.3181/00379727-137-35659. [DOI] [PubMed] [Google Scholar]
  16. FLETCHER A. P., ALKJAERSIG N., SHERRY S. Fibrinolytic mechanisms and the development of thrombolytic therapy. Am J Med. 1962 Nov;33:738–752. doi: 10.1016/0002-9343(62)90251-6. [DOI] [PubMed] [Google Scholar]
  17. FLETCHER A. P., ALKJAERSIG N., SHERRY S. The maintenance of a sustained thrombolytic state in man. I. Induction and effects. J Clin Invest. 1959 Jul;38(7):1096–1110. doi: 10.1172/JCI103886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. FLETCHER A. P., SHERRY S., ALKJAERSIG N., SMYRNIOTIS F. E., JICK S. The maintenance of a sustained thrombolytic state in man. II. Clinical observations on patients with myocardial infarction and other thromboembolic disorders. J Clin Invest. 1959 Jul;38(7):1111–1119. doi: 10.1172/JCI103887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. FREIMAN D. G., WESSLER S., LERTZMAN M. Experimental pulmonary embolism with serum-induced thrombi aged in vivo. Am J Pathol. 1961 Jul;39:95–102. [PMC free article] [PubMed] [Google Scholar]
  20. Fitz Gerald D. E., Szeto I. L., Spero J., Lewis J. H. The thrombolytic effect of heparin and a heparin-like substance, SP 54. Thromb Diath Haemorrh. 1967 May 31;17(3-4):418–422. [PubMed] [Google Scholar]
  21. GUREWICH V., THOMAS D., STEIN M., WESSLER S. Bronchoconstriction in the presence of pulmonary embolism. Circulation. 1963 Mar;27:339–345. doi: 10.1161/01.cir.27.3.339. [DOI] [PubMed] [Google Scholar]
  22. Genton E., Wolf P. S. Experimental pulmonary embolism: effects of urokinase therapy on organizing thrombi. J Lab Clin Med. 1967 Aug;70(2):311–325. [PubMed] [Google Scholar]
  23. Genton E., Wolf P. S. Urokinase therapy in pulmonary thromboembolism. Am Heart J. 1968 Nov;76(5):628–637. doi: 10.1016/0002-8703(68)90161-0. [DOI] [PubMed] [Google Scholar]
  24. Gurewich V., Cohen M. L., Thomas D. P. Humoral factors in massive pulmonary embolism: an experimental study. Am Heart J. 1968 Dec;76(6):784–794. doi: 10.1016/0002-8703(68)90264-0. [DOI] [PubMed] [Google Scholar]
  25. Hirsh J., Hale G. S., McDonald I. G., McCarthy R. A., Cade J. F. Resolution of acute massive pulmonary embolism after pulmonary arterial infusion of streptokinase. Lancet. 1967 Sep 16;2(7516):593–597. doi: 10.1016/s0140-6736(67)90741-6. [DOI] [PubMed] [Google Scholar]
  26. Hirsh J., Hale G. S., McDonald I. G., McCarthy R. A., Pitt A. Streptokinase therapy in acute major pulmonary embolism: effectiveness and problems. Br Med J. 1968 Dec 21;4(5633):729–734. doi: 10.1136/bmj.4.5633.729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hirsh J., McDonald I. G., Hale G. A., O'Sullivan E. F., Jelinek V. M. Comparison of the effects of streptokinase and heparin on the early rate of resolution of major pulmonary embolism. Can Med Assoc J. 1971 Mar 20;104(6):488–passim. [PMC free article] [PubMed] [Google Scholar]
  28. Hirsh J., O'Sullivan E. F., Martin M. Evaluation of a standard dosage schedule with streptokinase. Blood. 1970 Mar;35(3):341–349. [PubMed] [Google Scholar]
  29. JOHNSON A. J., McCARTY W. R. The lysis of artificially induced intravascular clots in man by intravenous infusions of streptokinase. J Clin Invest. 1959 Sep;38:1627–1643. doi: 10.1172/JCI103941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. JOHNSON A. J., TILLETT W. S. The lysis in rabbits of intravascular blood clots by the streptococcal fibrinolytic system (streptokinase). J Exp Med. 1952 May 1;95(5):449–464. doi: 10.1084/jem.95.5.449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. JUST-VIERA J. O., YEAGER G. H. MASSIVE PULMONARY EMBOLISM: II. PREDICTABLE MORTALITY AND CARDIOPULMONARY CHANGES IN DOGS BREATHING ROOM AIR. Ann Surg. 1964 Apr;159:636–644. doi: 10.1097/00000658-196415940-00024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Johnson A. J., Kline D. L., Alkjaersig N. Assay methods and standard preparations for plasmin, plasminogen and urokinase in purified systems, 1967-1968. Thromb Diath Haemorrh. 1969 Apr 30;21(2):259–272. [PubMed] [Google Scholar]
  33. LEWIS J. H., KERBER C. W., WILSON J. H. EFFECTS OF FIBRINOLYTIC AGENTS AND HEPARIN ON INTRAVASCULAR CLOT LYSIS. Am J Physiol. 1964 Nov;207:1044–1048. doi: 10.1152/ajplegacy.1964.207.5.1044. [DOI] [PubMed] [Google Scholar]
  34. Marshall R., Dunnill M. S. Experimental pulmonary embolism by platelet agglutinates in dogs. Thorax. 1966 Jul;21(4):372–381. doi: 10.1136/thx.21.4.372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. 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]
  36. Miller G. A., Gibson R. V., Honey M., Sutton G. C. Treatment of pulmonary embolism with streptokinase. A preliminary report. Br Med J. 1969 Mar 29;1(5647):812–815. doi: 10.1136/bmj.1.5647.812. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Moser K. M., Harsanyi P., Rius-Garriga G., Guisan M., Landis G. A., Miale A., Jr Assessment of pulmonary photoscanning and angiography in experimental pulmonary embolism. Circulation. 1969 May;39(5):663–674. doi: 10.1161/01.cir.39.5.663. [DOI] [PubMed] [Google Scholar]
  38. Moser K. M., Miale A., Jr Interpretive pitfalls in lung photoscanning. Am J Med. 1968 Mar;44(3):366–376. doi: 10.1016/0002-9343(68)90108-3. [DOI] [PubMed] [Google Scholar]
  39. Niewiarowski S., Gurewich V. Laboratory identification of intravascular coagulation. The serial dilution protamine sulfate test for the detection of fibrin monomer and fibrin degradation products. J Lab Clin Med. 1971 Apr;77(4):665–676. [PubMed] [Google Scholar]
  40. O'Sullivan E. F., Hirsh J., McCarthy R. A., de Gruchy G. C. Heparin in the treatment of venous thrombo-embolic disease: administration, control and results. Med J Aust. 1968 Jul 27;2(4):153–159. doi: 10.5694/j.1326-5377.1968.tb29378.x. [DOI] [PubMed] [Google Scholar]
  41. Olwin J. H., Koppel J. L. Little publicized aspects of thromboembolism. Med Clin North Am. 1967 Jan;51(1):151–159. doi: 10.1016/s0025-7125(16)33090-5. [DOI] [PubMed] [Google Scholar]
  42. PROCTOR R. R., RAPAPORT S. I. The partial thromboplastin time with kaolin. A simple screening test for first stage plasma clotting factor deficiencies. Am J Clin Pathol. 1961 Sep;36:212–219. doi: 10.1093/ajcp/36.3.212. [DOI] [PubMed] [Google Scholar]
  43. Regoeczi E. Fibrinogen catabolism: kinetics of catabolism following sudden elevation of the pool with exogenous fibrinogen. Clin Sci. 1970 Jan;38(1):111–121. doi: 10.1042/cs0380111. [DOI] [PubMed] [Google Scholar]
  44. Regoeczi E., Walton P. L. Effects of clotting on the label in iodinated fibrinogen in different species. Thromb Diath Haemorrh. 1967 Feb 28;17(1-2):237–246. [PubMed] [Google Scholar]
  45. SHERRY S., FLETCHER A. P., ALKJAERSIG N. Developments in fibrinolytic therapy for thrombo-embolic disease. Ann Intern Med. 1959 Mar;50(3):560–570. doi: 10.7326/0003-4819-50-3-560. [DOI] [PubMed] [Google Scholar]
  46. SHERRY S., LINDEMEYER R. I., FLETCHER A. P., ALKJAERSIG N. Studies on enhanced fibrinolytic activity in man. J Clin Invest. 1959 May;38(5):810–822. doi: 10.1172/JCI103863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. SHERRY S., TITCHENER A., GOTTESMAN L., WASSERMAN P., TROLL W. The enzymatic dissolution of experimental arterial thrombi in the dog by trypsin, chymotrypsin and plasminogen activators. J Clin Invest. 1954 Oct;33(10):1303–1313. doi: 10.1172/JCI103006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Sasahara A. A., Cannilla J. E., Belko J. S., Morse R. L., Criss A. J. Urokinase therapy in clinical pulmonary embolism. A new thrombolytic agent. N Engl J Med. 1967 Nov 30;277(22):1168–1173. doi: 10.1056/NEJM196711302772203. [DOI] [PubMed] [Google Scholar]
  49. Sautter R. D., Emanuel D. A., Fletcher F. W., Wenzel F. J., Matson J. I. Urokinase for the treatment of acute pulmonary thromboembolism. JAMA. 1967 Oct 16;202(3):215–218. [PubMed] [Google Scholar]
  50. Sherry S. Fibrinolysis. Annu Rev Med. 1968;19:247–268. doi: 10.1146/annurev.me.19.020168.001335. [DOI] [PubMed] [Google Scholar]
  51. Silver D., Hall J. H. Effect of heparin on the fibrinolytic system. Surg Forum. 1966;17:11–13. [PubMed] [Google Scholar]
  52. Stein P. D., O'Connor J. F., Dalen J. E., Pur-Shahriari A. A., Hoppin F. G., Jr, Hammond D. T., Haynes F. W., Fleischner F. G., Dexter L. The angiographic diagnosis of acute pulmonary embolism: evaluation of criteria. Am Heart J. 1967 Jun;73(6):730–741. doi: 10.1016/0002-8703(67)90224-4. [DOI] [PubMed] [Google Scholar]
  53. Streptokinase therapy in acute major pulmonary embolism. Am Heart J. 1970 Apr;79(4):574–578. doi: 10.1016/0002-8703(70)90269-3. [DOI] [PubMed] [Google Scholar]
  54. THOMAS D., STEIN M., TANABE G., REGE V., WESSLER S. MECHANISM OF BRONCHOCONSTRICTION PRODUCED BY THROMBOEMBOLI IN DOGS. Am J Physiol. 1964 Jun;206:1207–1212. doi: 10.1152/ajplegacy.1964.206.6.1207. [DOI] [PubMed] [Google Scholar]
  55. Thomas D. P., Gurewich V., Ashford T. P. Platelet adherence to thromboemboli in relation to the pathogenesis and treatment of pulmonary embolism. N Engl J Med. 1966 Apr 28;274(17):953–956. doi: 10.1056/NEJM196604282741709. [DOI] [PubMed] [Google Scholar]
  56. Vellar I. D., O'Sullivan E. F. Comparison of the action of heparin and streptokinase on experimental pulmonary emboli in the dog. Cardiovasc Res. 1972 Nov;6(6):734–740. doi: 10.1093/cvr/6.6.734. [DOI] [PubMed] [Google Scholar]
  57. Verstraete M., Vermylen J., Amery A., Vermylen C. Thrombolytic therapy with streptokinase using a standard dosage scheme. Br Med J. 1966 Feb 19;1(5485):454–456. doi: 10.1136/bmj.1.5485.454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. WESSLER S., FREIMAN D. G., BALLON J. D., KATZ J. H., WOLFF R., WOLF E. Experimental pulmonary embolism with serum-induced thrombi. Am J Pathol. 1961 Jan;38:89–101. [PMC free article] [PubMed] [Google Scholar]
  59. WRIGHT H. P., KUBIK M. M., HYDEN M. Influence of anticoagulant administration on the rate of recanalization of experimentally thrombosed veins. Br J Surg. 1952 Sep;40(160):163–166. doi: 10.1002/bjs.18004016016. [DOI] [PubMed] [Google Scholar]
  60. Walker R. H., Goodwin J., Jackson J. A. Resolution of pulmonary embolism. Br Med J. 1970 Oct 17;4(5728):135–139. doi: 10.1136/bmj.4.5728.135. [DOI] [PMC free article] [PubMed] [Google Scholar]

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