I
ANGIOLOGY The Journal
of Vascular
Official Journal of the
Diseases
College of Angiology College of Angiology
American
and the International
Published under the auspices of
THE ANGIOLOGY RESEARCH FOUNDATION, INC.
THEORETICAL AND PRACTICAL ASPECTS OF THROMBOLYTIC THERAPY JACK HIRSH, M.D. Ontario, Canada THEORETICAL ASPECTS
Thrombolytic agents The
feasibility of producing dissolution of thrombi and emboli by the plasminogen activators streptokinase and urokinase is now well demonstrated. Streptokinase is available in a highly purified form. It has the disadvantage of being antigenic to man; however, pyrogenicity formerly a major difficulty is no longer a serious problem provided that corticosteroids are used with streptokinase.’ Streptokinase also has the advantage of being considerably less expensive than urokinase and more readily available. On the other hand, urokinase is nonantigenic and does not appear to be associated with allergic or pyrogenic reactions.’ The plasminogen activators produce fibrinolysis by converting the proenzyme plasminogen into the active enzyme plasmin.’ Streptokinase is not a direct activator of plasminogen. It first combines with plasminogen in an equimolar ratio, and the complex of streptokinase and plasminogen then activates plasminogen enzymatically to form plasmin.3 Fibrin, which has not been cross-linked, is much more susceptible to dissolution by plasmin than fibrin, which has been covalently bonded through the action of factor XIII.4-s Mechanism
of Thrombolysis A number of mechanisms have been postulated for thrombolysis. These have to explain how plasmin, formed in vivo, can selectively digest fibrin without producing a marked plasma proteolytic state. Alkjaersig and associates’ proposed that plasminogen activator diffuses into the thrombus where it converts plasminogen to plasmin close to its substrate, fibrin. It was further proposed that plasmin present in the thrombus is protected from inactivation by its inhibitor. On the other hand, the Presented at the Sixteenth Annual
Meeting
of the International
College of Angiology, Montreal,
Quebec, Canada.
1
Downloaded from ang.sagepub.com at Bobst Library, New York University on May 23, 2015
2
plasminogen that is converted to plasmin in plasma is rapidly inactivated by an excess of plasma antiplasmin and so fibrinogen and other clotting factors are protected from proteolysis. This hypothesis explains a number of the observed effects of thrombolytic therapy with plasminogen activators ; however, it is difficult to reconcile this theory with the observation that plasminogen is not concentrated in the thrombus in significant quan-
tities.88 A second hypothesis, suggested by Chesterman and colleagues,’ is that activator, rather than plasminogen, is adsorbed onto fibrin, and that this activator activates plasminogen which is present in the plasma circulating around and in the interstices of the thrombus. The implications of this hypothesis are that thrombolysis is dependent on the level of circulating plasminogen. In support for this hypothesis is the evidence that thrombolysis is achieved more effectively by regimens that do not produce complete depletion of circulating plasma plasminogen.&dquo; Another hypothesis proposed by Ambrus and associatesll is that plasmin circulates in plasma complexed with antiplasmin and that this complex is dissociated in the presence of fibrin allowing thrombolysis to occur
specifically. Recent evidence from Harpel and Mosessonl2 indicates that plasmin complexed with a2-macroglobulin in the circulation does have fibrinogenolytic activity; however, it is not known if this complex also has fibrino-
lytic activity. Relative Susceptibility
of Venous and Arterial Thrombi Theoretically, venous thrombi might be considered to be more susceptible to thrombolytic therapy than arterial thrombi since venous thrombi are composed largely of fibrin whereas arterial thrombi have a much larger platelet component. However, fibrin has an important role in stabilizing the platelet aggregates that make up arterial thrombi&dquo; and lysis of this fibrin results in dissolution of these thrombi.14 In addition, as arterial thrombi age, the platelets undergo autolysis and are replaced by fibrin which is susceptible to therapeutic fibrinolysis.l3
Bleeding Caused by Thrombolytic Therapy The major side effect of thrombolytic therapy is bleeding.’ Bleeding particularly occurs in patients who have been exposed to recent surgery or trauma. A number of factors contribute to this hemorrhagic tendency. These include lysis of fibrin in hemostatic plugs and wounds, the coagulation defect produced by plasma proteolysis of fibrinogen and other clotting factors, and the anticoagulant effects of fibrin/fibrinogen proteolysis products. These proteolysis products have been shown to inhibit fibrin polymerization and certain species of these proteolysis products also act as antithrombins and others have been shown to inhibit platelet function.
Streptokinase A ntibodies The main problem associated with the antigenicity of streptokinase is caused by the fact that streptococcal antibodies cross-react with streptokiDownloaded from ang.sagepub.com at Bobst Library, New York University on May 23, 2015
3 These antibodies, the result of previous streptococcal infection, are most patients and must be neutralized before thrombolysis can be produced.15 The streptococcal antibodies combine with and inactivate streptokinase, and the streptokinase-antibody complex which is thus formed is rapidly cleared from the bloodstream.16 The neutralizing dose of streptokinase cannot be predicted with any certainty because the concentration of the streptococcal antibodies varies widely from patient to patient.’ For this reason, it has been recommended that a streptokinase resistance test should be performed before commencing treatment to determine the inducing dose of streptokinase-that is, the dose that is necessary to neutralize the antibodies and rapidly produce a thrombolytic state. In addition, because of its antigenicity, streptokinase treatment cannot be repeated during a 3 to 6 month period after the initial treatment.1.15 Allergic reactions have also been reported with streptokinase, but these are uncommon and impossible to predict since they are not necessarily associated with a high streptococcal antibody titer.1 nase.
present in
Dosage Regimens dosage schedules have been used in an to to overcome the need attempt perform a streptokinase resistance test on each patient before beginning treatment with streptokinase.&dquo;&dquo; With this approach, it is inevitable that some patients will recieve an inducing dose in excess of their minimal requirements and others a dose that fails to neutralize the streptokinase antibodies. High inducing doses which exceed the patient’s streptokinase resistance are safe and effective, presumably because they produce rapid lowering of circulating plasminogen.17,18 On the other hand, inducing doses which fail to neutralize the circulating antibodies are pharmacologically ineffective. The optimal standard inducing dose varies according to the range and distribution of streptokinase resistance in the patient population. A number of studies have now demonstrated that routine use of a standard dosage schedule is acceptable provided that it has been shown by appropriate testing that a thrombolytic state could be achieved in a high percentage of the community in question with an acceptable inducing dose. A standard dosage regimen should not be used in patients who have had a recent streptococcal infection or who have recently been treated with streptokinase. In these circumstances a resistance test should be performed, and the appropriate dose given. In recent years, various standard
PRACTICAL ASPECTS
Indications The definite and less definite indications for thrombolytic therapy are shown in Table I. There is now good evidence that thrombolytic therapy with either streptokinase or urokinase accelerates the rate of lysis of acute major pulmonary emboli.19-22 A number of studies have shown that the majority of pulmonary emboli undergo spontaneous lysis over a period of weeks to months,23 and there is good evidence that most patients with acute major pulmonary embolism who survive long enough to have the Downloaded from ang.sagepub.com at Bobst Library, New York University on May 23, 2015
4 TABLE I
Indications for Thrombolytic Therapy
clinical diagnosis confirmed by either angiography or lung scanning continue to survive, provided that recurrent embolism is prevented by adequate heparin therapy.24 However, defective spontaneous lysis of pulmonary emboli may occur in patients with underlying heart or lung disease, and this group in particular could benefit from thrombolytic
therapy.25 There is now good evidence from controlled trials that, when compared with heparin, streptokinase accelerates the rate of lysis of acute venous thrombi.26 Follow-up studies have also demonstrated that provided that complete lysis is achieved, normal venous valve function is maintained.&dquo; For this reason, the use of thrombolytic therapy should be considered in any patient with acute popliteal, femoral, or iliac vein thrombosis provided that there are no contraindications to such treatment. The effectiveness of streptokinase decreases with the age of the thrombus, and lysis is unlikely to be achieved if the thrombus has been present for more than 96 hours.&dquo; Although no controlled trials have been performed, evidence from a large number of well-studied cases suggests that streptokinase induces lysis of acute arterial thrombi.28-32 Surgery is the first line of approach for the treatment of acute arterial thrombosis, but if surgery is contraindicated, thrombolytic therapy should be considered. Although streptokinase has been shown to produce dissolution of thrombi in arteriovenous shunts, mechanical measures are usually successful, and this is not an important indication for thrombolytic therapy. Less certain indications for thrombolytic therapy include patients with chronic arterial thrombosis, in whom streptokinase is reported to induce lysis in about 10% of cases; patients with myocardial infarction, in whom studies with streptokinase have been inconclusive; and patients with retinal vascular occlusions, in whom the clinical results have been somewhat
inconclusive. Contraindications The contraindications for thrombolytic therapy include recent surgery or trauma, severe hypertension, peptic ulcer, carcinoma with metastases,
Downloaded from ang.sagepub.com at Bobst Library, New York University on May 23, 2015
5
generalized hemostatic defect, carotid artery thrombosis, and cardiac thrombosis with systemic embolism. Dosage Regimens It has now been demonstrated that successful thrombolysis can be achieved using a standard dosage regimen.1,17 The usual loading dose is 250,000 units given over a half hour followed by 100,000 units/hr. Local low-dose streptokinase therapy has been used successfully in acute arterial thrombosis,32 and a combination of low-dose streptokinase and full-dose heparin therapy has been shown to produce lysis of pulmonary emboli and venous
thrombi.33
Laboratory Monitoring A number of studies have now demonstrated that monitoring of streptokinase therapy can be achieved by performing a thrombin time, the aim being to maintain the results of this test at about two to four times the control value.I.34 Two approaches have been recommended if the thrombin time becomes elevated above the upper limit of this range. Treatment can be stopped for 2 to 3 hours, thus allowing the fibrin split products to be cleared, or the dose of streptokinase can be increased to produce rapid plasminogen depletion, which would then decrease the possibility of further plasma proteolysis. It should be recalled, however, that thrombolysis may be compromised if there is complete plasminogen depletion. If mild bleeding occurs, local measures can be tried. If the bleeding is severe, treatment should be stopped, and if it is very severe and there is evidence of hypofibrinogenemia or a coagulation defect, fresh frozen plasma or fibrinogen should be administered. If bleeding is potentially lifethreatening, c-aminocaproic acid should be given in addition to replacement therapy with fresh frozen plasma; however, this is rarely necessary. J. Hirsh, M. D.
Professor of Pathology and Medicine McMaster University St. Joseph’s Hospital 50 Charlton A venue East Hamilton, Ontario Canada REFERENCES
O’Sullivan, E. F., and Martin, M.: Evaluation of a standard dosage schedule with streptokinase. Blood, 35: 341, 1970. Fletcher, A. P., Alkjaersig, N., Sherry, S., Genton, E., Hirsh, J., and Bachman, F.: The development of urokinase as a thrombolytic agent: Maintenance of a sustained thromboembolic state in man by its intravenous infusion. J. Lab. Clin. Med., 65: 713, 1965. Sherry, S.: Fibrinolysis. Ann. Rev. Med. 19: 247, 1968. Bruner-Lorand, J., and Pilkington, R. E.: Inhibitors of fibrin cross-linking: Relevance for thrombolysis. Nature, 210: 1273, 1966. Henderson, K. W., and Nussbaum, M.: The mechanism of enhanced streptokinase-induced clot lysis following in-vitro Factor XIII inactivation. Br. J. Haematol., 17 : 445, 1969. Feddersen, C., and Gormsen, J.: Plasma digestion of stabilized and non-stabilized fibrin illustrated by pH-stat titration and thromboelastography. Scand. J. Clin. Lab. Invest., 27: 175, 1971.
1. Hirsh, J., 2.
3. 4. 5. 6.
.
Downloaded from ang.sagepub.com at Bobst Library, New York University on May 23, 2015
6’ 7. 8. 9.
10.
11. 12.
13. 14. 15. 16.
17. 18. 19.
20.
21. 22. 23. 24.
25. 26. 27. 28.
29. 30.
31.
32.
33.
34.
Alkjaersig, N., Fletcher, A. P., and Sherry, S.: The mechanism of clot dissolution by plasmin. J. Clin. Invest., 38: 1086, 1959. Hedner, V., Nilsson, I. M., and Robertson, B.: Determination of plasminogen in clots and thrombi. Thromb. Diath. Haemorrh., 16: 38, 1966. Chesterman, C. N., Allington, M. J., and Sharp, A. A.: Relationship of plasminogen activator to fibrin. Nature, 238: 15, 1972. Amery, A., Donati, M. B., Vermylen, J., and Verstraete, M.: Comparison between the changes in the plasma fibrinogen and plasminogen levels induced by a moderate or high initial dose of streptokinase. Thromb. Diath. Haemorrh., 23: 504, 1970. Ambrus, C. M., and Markus, G.: Plasmin-Antiplasmin complex as a reservoir of fibrinolytic enzymes. Am. J. Physiol. 199: 491, 1960. Harpel, P. C., and Mosesson, M. W.: Degradation of human fibrinogen by plasma α2 macroglobulin-enzyme complexes. J. Clin. Invest., 52: Jørgensen, L., Rowsell, H. C., Hovig, T., and Mustard, J. F.: Resolution and organization of 51: 681, 1967. platelet-rich mural thrombi in carotid arteries of swine. Am. J. Pathol., Hirsh, J., Buchanan, M., Glynn, M. F., and Mustard, J. F.: Effect of activation of the fibrinolytic mechanism on experimental platelet-rich thrombi. J. Lab. Clin. Med., 72: 245, 1968. Fletcher, A. P., Alkjaersig, N., and Sherry, S.: The maintenance of a sustained thrombolytic state in man. I. Induction and effects. J. Clin. Invest., 38: 1096, 1959. Fletcher, A. P., Alkjaersig, N., and Sherry, S.: The clearance of heterologous protein from the circulation of normal and immunized man. J. Clin. Invest., 37: 1306, 1958. Verstraete, M., Vermylen, M., Amery, A., and Vermylen, C.: Thrombolytic therapy with streptokinase using a standard dosage scheme. Br. Med. J., 1: 454, 1966. Fletcher, A. P., Alkjaersig, M., and Sherry, S.: Fibrinolytic mechanisms and the development of thrombolytic therapy. Am. J. Med., 33: 738, 1962. Hirsh, J., Hale, G., MacDonald, I., McCarthy, R., and Pitt, A.: Streptokinase therapy in acute major pulmonary embolism: Effectiveness and problems. Br. Med. J., 21: 729, 1968. Hirsh, J., McDonald, I., and O’Sullivan, E.: Comparison of the effects of streptokinase and heparin on the early rate of resolution of major pulmonary embolism. Can. Med. Assoc. J., 104: 488 & 516, 1971. Miller, G., Sutton, G., Kerr, I., Gibson, R., and Honey, M.: Comparison of streptokinase and heparin in treatment of isolated acute massive pulmonary embolism. Br. Med. J., 2: 681, 1971. The urokinase pulmonary embolism Trial: Circulation (Suppl. II), 47 & 48: 1, 1973. Tow, D., Wagner, H., Jr., and Holmes, R.: Urokinase in pulmonary embolism. N. Engl. J. Med., 1161, 1967. 277: Donald, G. A., Williams, G., Scannell, J. G., and Shaw, R. S.: A reappraisal of the application of the Trendelenburg operation to massive fetal pulmonary embolism. N. Engl. J. Med., 268 : 171, 1963. Chait, A., Summers, D., Krasinow, N., and Wechsler, B. M.: Observations on the fate of large pulmonary emboli. Am. J. Roentgenol., 100: 364, 1967. Kakkar, V., Flanc, C., Howe, C., O’Shea, M., and Flute, P.: Treatment of deep vein thrombosis: A trial of heparin, streptokinase and Arvin. Br. Med. J., 1: 806, 1969. Kakkar, V., Flanc, C., O’Shea, M., Flute, P., Howe, C., and Clarke, M.: Treatment of deep vein thrombosis with streptokinase. Br. J. Surg., 56: 178, 1969. Schmutzler, R., and Koller, F.: Thrombolytic therapy. In: Poller, L. (ed.), Recent Advances in Blood Coagulation, p. 299. Little, Brown, Boston, 1969. Salmon, J.: Fibrinolyse et Pathologie Vasculaire, p. 207. Arscia, S., Bruxelles and Maloine, S. (eds.), Paris, 1964. Verstraete, M., Amery, A., and Vermylen, J.: Feasibility of adequate thrombolytic therapy with streptokinase and peripheral arterial occlusions. I. Clinical and arteriographic results. Br. Med. J., 1: 1499, 1963. Verstraete, M., Vermylen, J., and Donati, M.: The effect of streptokinase infusion on chronic arterial occlusions and stenoses. Ann. Intern. Med., 74: 377, 1971. Hirsh, J., O’Sullivan, E. F., Gallus, A. S., and Gilford, E. J.: Arterial thrombosis in a patient with chronic thrombocytopenia: Successful treatment with intra-arterial infusion of streptokinase. Med. J. Aust., 2: 1304, 1969. Gallus, A. S., and Hirsh, J.: Combined use of low dose streptokinase and full dose heparin. Proceedings of the Fifteenth Congress of the International Society of Hematology, Jerusalem, (In press) 1974. Sherry, S.: Streptokinase therapy for thromboembolic vascular occlusive vascular disease. Ann. Intern. Med., 74: 437, 1971.
Downloaded from ang.sagepub.com at Bobst Library, New York University on May 23, 2015
ANGIOLOGY The Journal
of Vascular
Official Journal of the
Diseases
College of Angiology College of Angiology
American
and the International
Published under the auspices of
THE ANGIOLOGY RESEARCH FOUNDATION, INC.
THEORETICAL AND PRACTICAL ASPECTS OF THROMBOLYTIC THERAPY JACK HIRSH, M.D. Ontario, Canada THEORETICAL ASPECTS
Thrombolytic agents The
feasibility of producing dissolution of thrombi and emboli by the plasminogen activators streptokinase and urokinase is now well demonstrated. Streptokinase is available in a highly purified form. It has the disadvantage of being antigenic to man; however, pyrogenicity formerly a major difficulty is no longer a serious problem provided that corticosteroids are used with streptokinase.’ Streptokinase also has the advantage of being considerably less expensive than urokinase and more readily available. On the other hand, urokinase is nonantigenic and does not appear to be associated with allergic or pyrogenic reactions.’ The plasminogen activators produce fibrinolysis by converting the proenzyme plasminogen into the active enzyme plasmin.’ Streptokinase is not a direct activator of plasminogen. It first combines with plasminogen in an equimolar ratio, and the complex of streptokinase and plasminogen then activates plasminogen enzymatically to form plasmin.3 Fibrin, which has not been cross-linked, is much more susceptible to dissolution by plasmin than fibrin, which has been covalently bonded through the action of factor XIII.4-s Mechanism
of Thrombolysis A number of mechanisms have been postulated for thrombolysis. These have to explain how plasmin, formed in vivo, can selectively digest fibrin without producing a marked plasma proteolytic state. Alkjaersig and associates’ proposed that plasminogen activator diffuses into the thrombus where it converts plasminogen to plasmin close to its substrate, fibrin. It was further proposed that plasmin present in the thrombus is protected from inactivation by its inhibitor. On the other hand, the Presented at the Sixteenth Annual
Meeting
of the International
College of Angiology, Montreal,
Quebec, Canada.
1
Downloaded from ang.sagepub.com at Bobst Library, New York University on May 23, 2015
2
plasminogen that is converted to plasmin in plasma is rapidly inactivated by an excess of plasma antiplasmin and so fibrinogen and other clotting factors are protected from proteolysis. This hypothesis explains a number of the observed effects of thrombolytic therapy with plasminogen activators ; however, it is difficult to reconcile this theory with the observation that plasminogen is not concentrated in the thrombus in significant quan-
tities.88 A second hypothesis, suggested by Chesterman and colleagues,’ is that activator, rather than plasminogen, is adsorbed onto fibrin, and that this activator activates plasminogen which is present in the plasma circulating around and in the interstices of the thrombus. The implications of this hypothesis are that thrombolysis is dependent on the level of circulating plasminogen. In support for this hypothesis is the evidence that thrombolysis is achieved more effectively by regimens that do not produce complete depletion of circulating plasma plasminogen.&dquo; Another hypothesis proposed by Ambrus and associatesll is that plasmin circulates in plasma complexed with antiplasmin and that this complex is dissociated in the presence of fibrin allowing thrombolysis to occur
specifically. Recent evidence from Harpel and Mosessonl2 indicates that plasmin complexed with a2-macroglobulin in the circulation does have fibrinogenolytic activity; however, it is not known if this complex also has fibrino-
lytic activity. Relative Susceptibility
of Venous and Arterial Thrombi Theoretically, venous thrombi might be considered to be more susceptible to thrombolytic therapy than arterial thrombi since venous thrombi are composed largely of fibrin whereas arterial thrombi have a much larger platelet component. However, fibrin has an important role in stabilizing the platelet aggregates that make up arterial thrombi&dquo; and lysis of this fibrin results in dissolution of these thrombi.14 In addition, as arterial thrombi age, the platelets undergo autolysis and are replaced by fibrin which is susceptible to therapeutic fibrinolysis.l3
Bleeding Caused by Thrombolytic Therapy The major side effect of thrombolytic therapy is bleeding.’ Bleeding particularly occurs in patients who have been exposed to recent surgery or trauma. A number of factors contribute to this hemorrhagic tendency. These include lysis of fibrin in hemostatic plugs and wounds, the coagulation defect produced by plasma proteolysis of fibrinogen and other clotting factors, and the anticoagulant effects of fibrin/fibrinogen proteolysis products. These proteolysis products have been shown to inhibit fibrin polymerization and certain species of these proteolysis products also act as antithrombins and others have been shown to inhibit platelet function.
Streptokinase A ntibodies The main problem associated with the antigenicity of streptokinase is caused by the fact that streptococcal antibodies cross-react with streptokiDownloaded from ang.sagepub.com at Bobst Library, New York University on May 23, 2015
3 These antibodies, the result of previous streptococcal infection, are most patients and must be neutralized before thrombolysis can be produced.15 The streptococcal antibodies combine with and inactivate streptokinase, and the streptokinase-antibody complex which is thus formed is rapidly cleared from the bloodstream.16 The neutralizing dose of streptokinase cannot be predicted with any certainty because the concentration of the streptococcal antibodies varies widely from patient to patient.’ For this reason, it has been recommended that a streptokinase resistance test should be performed before commencing treatment to determine the inducing dose of streptokinase-that is, the dose that is necessary to neutralize the antibodies and rapidly produce a thrombolytic state. In addition, because of its antigenicity, streptokinase treatment cannot be repeated during a 3 to 6 month period after the initial treatment.1.15 Allergic reactions have also been reported with streptokinase, but these are uncommon and impossible to predict since they are not necessarily associated with a high streptococcal antibody titer.1 nase.
present in
Dosage Regimens dosage schedules have been used in an to to overcome the need attempt perform a streptokinase resistance test on each patient before beginning treatment with streptokinase.&dquo;&dquo; With this approach, it is inevitable that some patients will recieve an inducing dose in excess of their minimal requirements and others a dose that fails to neutralize the streptokinase antibodies. High inducing doses which exceed the patient’s streptokinase resistance are safe and effective, presumably because they produce rapid lowering of circulating plasminogen.17,18 On the other hand, inducing doses which fail to neutralize the circulating antibodies are pharmacologically ineffective. The optimal standard inducing dose varies according to the range and distribution of streptokinase resistance in the patient population. A number of studies have now demonstrated that routine use of a standard dosage schedule is acceptable provided that it has been shown by appropriate testing that a thrombolytic state could be achieved in a high percentage of the community in question with an acceptable inducing dose. A standard dosage regimen should not be used in patients who have had a recent streptococcal infection or who have recently been treated with streptokinase. In these circumstances a resistance test should be performed, and the appropriate dose given. In recent years, various standard
PRACTICAL ASPECTS
Indications The definite and less definite indications for thrombolytic therapy are shown in Table I. There is now good evidence that thrombolytic therapy with either streptokinase or urokinase accelerates the rate of lysis of acute major pulmonary emboli.19-22 A number of studies have shown that the majority of pulmonary emboli undergo spontaneous lysis over a period of weeks to months,23 and there is good evidence that most patients with acute major pulmonary embolism who survive long enough to have the Downloaded from ang.sagepub.com at Bobst Library, New York University on May 23, 2015
4 TABLE I
Indications for Thrombolytic Therapy
clinical diagnosis confirmed by either angiography or lung scanning continue to survive, provided that recurrent embolism is prevented by adequate heparin therapy.24 However, defective spontaneous lysis of pulmonary emboli may occur in patients with underlying heart or lung disease, and this group in particular could benefit from thrombolytic
therapy.25 There is now good evidence from controlled trials that, when compared with heparin, streptokinase accelerates the rate of lysis of acute venous thrombi.26 Follow-up studies have also demonstrated that provided that complete lysis is achieved, normal venous valve function is maintained.&dquo; For this reason, the use of thrombolytic therapy should be considered in any patient with acute popliteal, femoral, or iliac vein thrombosis provided that there are no contraindications to such treatment. The effectiveness of streptokinase decreases with the age of the thrombus, and lysis is unlikely to be achieved if the thrombus has been present for more than 96 hours.&dquo; Although no controlled trials have been performed, evidence from a large number of well-studied cases suggests that streptokinase induces lysis of acute arterial thrombi.28-32 Surgery is the first line of approach for the treatment of acute arterial thrombosis, but if surgery is contraindicated, thrombolytic therapy should be considered. Although streptokinase has been shown to produce dissolution of thrombi in arteriovenous shunts, mechanical measures are usually successful, and this is not an important indication for thrombolytic therapy. Less certain indications for thrombolytic therapy include patients with chronic arterial thrombosis, in whom streptokinase is reported to induce lysis in about 10% of cases; patients with myocardial infarction, in whom studies with streptokinase have been inconclusive; and patients with retinal vascular occlusions, in whom the clinical results have been somewhat
inconclusive. Contraindications The contraindications for thrombolytic therapy include recent surgery or trauma, severe hypertension, peptic ulcer, carcinoma with metastases,
Downloaded from ang.sagepub.com at Bobst Library, New York University on May 23, 2015
5
generalized hemostatic defect, carotid artery thrombosis, and cardiac thrombosis with systemic embolism. Dosage Regimens It has now been demonstrated that successful thrombolysis can be achieved using a standard dosage regimen.1,17 The usual loading dose is 250,000 units given over a half hour followed by 100,000 units/hr. Local low-dose streptokinase therapy has been used successfully in acute arterial thrombosis,32 and a combination of low-dose streptokinase and full-dose heparin therapy has been shown to produce lysis of pulmonary emboli and venous
thrombi.33
Laboratory Monitoring A number of studies have now demonstrated that monitoring of streptokinase therapy can be achieved by performing a thrombin time, the aim being to maintain the results of this test at about two to four times the control value.I.34 Two approaches have been recommended if the thrombin time becomes elevated above the upper limit of this range. Treatment can be stopped for 2 to 3 hours, thus allowing the fibrin split products to be cleared, or the dose of streptokinase can be increased to produce rapid plasminogen depletion, which would then decrease the possibility of further plasma proteolysis. It should be recalled, however, that thrombolysis may be compromised if there is complete plasminogen depletion. If mild bleeding occurs, local measures can be tried. If the bleeding is severe, treatment should be stopped, and if it is very severe and there is evidence of hypofibrinogenemia or a coagulation defect, fresh frozen plasma or fibrinogen should be administered. If bleeding is potentially lifethreatening, c-aminocaproic acid should be given in addition to replacement therapy with fresh frozen plasma; however, this is rarely necessary. J. Hirsh, M. D.
Professor of Pathology and Medicine McMaster University St. Joseph’s Hospital 50 Charlton A venue East Hamilton, Ontario Canada REFERENCES
O’Sullivan, E. F., and Martin, M.: Evaluation of a standard dosage schedule with streptokinase. Blood, 35: 341, 1970. Fletcher, A. P., Alkjaersig, N., Sherry, S., Genton, E., Hirsh, J., and Bachman, F.: The development of urokinase as a thrombolytic agent: Maintenance of a sustained thromboembolic state in man by its intravenous infusion. J. Lab. Clin. Med., 65: 713, 1965. Sherry, S.: Fibrinolysis. Ann. Rev. Med. 19: 247, 1968. Bruner-Lorand, J., and Pilkington, R. E.: Inhibitors of fibrin cross-linking: Relevance for thrombolysis. Nature, 210: 1273, 1966. Henderson, K. W., and Nussbaum, M.: The mechanism of enhanced streptokinase-induced clot lysis following in-vitro Factor XIII inactivation. Br. J. Haematol., 17 : 445, 1969. Feddersen, C., and Gormsen, J.: Plasma digestion of stabilized and non-stabilized fibrin illustrated by pH-stat titration and thromboelastography. Scand. J. Clin. Lab. Invest., 27: 175, 1971.
1. Hirsh, J., 2.
3. 4. 5. 6.
.
Downloaded from ang.sagepub.com at Bobst Library, New York University on May 23, 2015
6’ 7. 8. 9.
10.
11. 12.
13. 14. 15. 16.
17. 18. 19.
20.
21. 22. 23. 24.
25. 26. 27. 28.
29. 30.
31.
32.
33.
34.
Alkjaersig, N., Fletcher, A. P., and Sherry, S.: The mechanism of clot dissolution by plasmin. J. Clin. Invest., 38: 1086, 1959. Hedner, V., Nilsson, I. M., and Robertson, B.: Determination of plasminogen in clots and thrombi. Thromb. Diath. Haemorrh., 16: 38, 1966. Chesterman, C. N., Allington, M. J., and Sharp, A. A.: Relationship of plasminogen activator to fibrin. Nature, 238: 15, 1972. Amery, A., Donati, M. B., Vermylen, J., and Verstraete, M.: Comparison between the changes in the plasma fibrinogen and plasminogen levels induced by a moderate or high initial dose of streptokinase. Thromb. Diath. Haemorrh., 23: 504, 1970. Ambrus, C. M., and Markus, G.: Plasmin-Antiplasmin complex as a reservoir of fibrinolytic enzymes. Am. J. Physiol. 199: 491, 1960. Harpel, P. C., and Mosesson, M. W.: Degradation of human fibrinogen by plasma α2 macroglobulin-enzyme complexes. J. Clin. Invest., 52: Jørgensen, L., Rowsell, H. C., Hovig, T., and Mustard, J. F.: Resolution and organization of 51: 681, 1967. platelet-rich mural thrombi in carotid arteries of swine. Am. J. Pathol., Hirsh, J., Buchanan, M., Glynn, M. F., and Mustard, J. F.: Effect of activation of the fibrinolytic mechanism on experimental platelet-rich thrombi. J. Lab. Clin. Med., 72: 245, 1968. Fletcher, A. P., Alkjaersig, N., and Sherry, S.: The maintenance of a sustained thrombolytic state in man. I. Induction and effects. J. Clin. Invest., 38: 1096, 1959. Fletcher, A. P., Alkjaersig, N., and Sherry, S.: The clearance of heterologous protein from the circulation of normal and immunized man. J. Clin. Invest., 37: 1306, 1958. Verstraete, M., Vermylen, M., Amery, A., and Vermylen, C.: Thrombolytic therapy with streptokinase using a standard dosage scheme. Br. Med. J., 1: 454, 1966. Fletcher, A. P., Alkjaersig, M., and Sherry, S.: Fibrinolytic mechanisms and the development of thrombolytic therapy. Am. J. Med., 33: 738, 1962. Hirsh, J., Hale, G., MacDonald, I., McCarthy, R., and Pitt, A.: Streptokinase therapy in acute major pulmonary embolism: Effectiveness and problems. Br. Med. J., 21: 729, 1968. Hirsh, J., McDonald, I., and O’Sullivan, E.: Comparison of the effects of streptokinase and heparin on the early rate of resolution of major pulmonary embolism. Can. Med. Assoc. J., 104: 488 & 516, 1971. Miller, G., Sutton, G., Kerr, I., Gibson, R., and Honey, M.: Comparison of streptokinase and heparin in treatment of isolated acute massive pulmonary embolism. Br. Med. J., 2: 681, 1971. The urokinase pulmonary embolism Trial: Circulation (Suppl. II), 47 & 48: 1, 1973. Tow, D., Wagner, H., Jr., and Holmes, R.: Urokinase in pulmonary embolism. N. Engl. J. Med., 1161, 1967. 277: Donald, G. A., Williams, G., Scannell, J. G., and Shaw, R. S.: A reappraisal of the application of the Trendelenburg operation to massive fetal pulmonary embolism. N. Engl. J. Med., 268 : 171, 1963. Chait, A., Summers, D., Krasinow, N., and Wechsler, B. M.: Observations on the fate of large pulmonary emboli. Am. J. Roentgenol., 100: 364, 1967. Kakkar, V., Flanc, C., Howe, C., O’Shea, M., and Flute, P.: Treatment of deep vein thrombosis: A trial of heparin, streptokinase and Arvin. Br. Med. J., 1: 806, 1969. Kakkar, V., Flanc, C., O’Shea, M., Flute, P., Howe, C., and Clarke, M.: Treatment of deep vein thrombosis with streptokinase. Br. J. Surg., 56: 178, 1969. Schmutzler, R., and Koller, F.: Thrombolytic therapy. In: Poller, L. (ed.), Recent Advances in Blood Coagulation, p. 299. Little, Brown, Boston, 1969. Salmon, J.: Fibrinolyse et Pathologie Vasculaire, p. 207. Arscia, S., Bruxelles and Maloine, S. (eds.), Paris, 1964. Verstraete, M., Amery, A., and Vermylen, J.: Feasibility of adequate thrombolytic therapy with streptokinase and peripheral arterial occlusions. I. Clinical and arteriographic results. Br. Med. J., 1: 1499, 1963. Verstraete, M., Vermylen, J., and Donati, M.: The effect of streptokinase infusion on chronic arterial occlusions and stenoses. Ann. Intern. Med., 74: 377, 1971. Hirsh, J., O’Sullivan, E. F., Gallus, A. S., and Gilford, E. J.: Arterial thrombosis in a patient with chronic thrombocytopenia: Successful treatment with intra-arterial infusion of streptokinase. Med. J. Aust., 2: 1304, 1969. Gallus, A. S., and Hirsh, J.: Combined use of low dose streptokinase and full dose heparin. Proceedings of the Fifteenth Congress of the International Society of Hematology, Jerusalem, (In press) 1974. Sherry, S.: Streptokinase therapy for thromboembolic vascular occlusive vascular disease. Ann. Intern. Med., 74: 437, 1971.
Downloaded from ang.sagepub.com at Bobst Library, New York University on May 23, 2015
