Synonyms: Estreptoquinasa; Plasminokinase; Sterptokinasum; Streptokinaasi; Streptokinas; Streptokinasum; Sztreptokináz.
Cyrillic synonym: Стрептокиназа.

💊 Chemical information

CAS — 9002-01-1.
ATC — B01AD01.
ATC Vet — QB01AD01.


Eur. includes a concentrated solution.

Ph. Eur. 6.2

(Streptokinase Concentrated Solution; Streptokinasi Solutio Concentrata). A preparation of a protein obtained from culture filtrates of certain strains of haemolytic Streptococcus group C. It has the property of combining with human plasminogen to form plasminogen activator. The potency is not less than 510 international units per microgram of nitrogen. A clear, colourless liquid. pH 6.8 to 7.5. Store in airtight containers at a temperature of −20°. Protect from light.


The incorporation of albumin in commercial preparations of streptokinase has reduced the incidence of flocculation with streptokinase solutions. However, flocculation has occurred with small volumes prepared with sodium chloride 0.9% in sterilised glass containers apparently because of residual acid buffers that remain in empty evacuated containers after sterilisation. 1 1. Thibault L. Streptokinase flocculation in evacuated glass bottles. Am J Hosp Pharm 1985; 42: 278.

💊 Units

The potency of streptokinase is expressed in international units and preparations are assayed using the second International Standard (1989). The Christensen unit is the quantity of streptokinase that will lyse a standard blood clot completely in 10 minutes and is equivalent to the international unit.

💊 Adverse Effects

In common with other thrombolytics streptokinase may cause haemorrhage, particularly from puncture sites; severe internal bleeding has occurred and may be difficult to control. Streptokinase is antigenic, and allergic reactions ranging from rashes to rarer anaphylactoid and serum-sickness-like symptoms have occurred. Fever, sometimes high, and associated symptoms such as chills and back or abdominal pain are quite frequent. Nausea and vomiting may occur. There have been a few reports of Guillain-Barré syndrome. Streptokinase infusion may be associated with hypotension, both direct or as a result of reperfusion; bradycardia and arrhythmias may also occur due to reperfusion. The break-up of existing clots may occasionally produce emboli elsewhere; pulmonary embolism and acute renal failure due to cholesterol embolisation have been reported.

Back pain.

Streptokinase infusion has been associated with the development of very severe low back pain, which resolves within a few minutes of stopping the infusion, and may be severe enough to warrant opioid analgesia.1-4 The back pain may represent a hypersensitivity reaction. Providing that the pain is controlled and that dissecting aortic aneurysm is not suspected, it may still be possible to complete the streptokinase infusion.4,5Alternatively, immediate substitution with a different thrombolytic has been suggested.6 There have also been a few reports of low back pain associated with anistreplase infusion.7,8
1. Shah M, Taylor RT. Low back pain associated with streptokinase. BMJ 1990; 301: 1219
2. Dickinson RJ, Rosser A. Low back pain associated with streptokinase. BMJ 1991; 302: 111–12.
3. Porter NJ, Nikoletatos K. Low back pain associated with streptokinase. BMJ 1991; 302: 112
4. Pinheiro RF, et al. Low back pain during streptokinase infusion. Arq Bras Cardiol 2002; 78: 233–5
5. Lear J, et al. Low back pain associated with streptokinase. Lancet 1992; 340: 851
6. Fishwick D, et al. Thrombolysis and low back pain. BMJ 1995; 310: 504
7. Hannaford P, Kay CR. Back pain and thrombolysis. BMJ 1992; 304: 915
8. Lear J, Rajapakse R. Low back pain associated with anistreplase. BMJ 1993; 306: 896.

Effects on the blood.

Although falls in the haemoglobin value of patients receiving thrombolytics are most likely to be due to blood loss from haemorrhage, there has been a report of a patient who had signs of haemolytic anaemia after intravenous infusion of streptokinase.1 In a subsequent test in vitro the patient’s serum caused strong agglutination of streptokinase-treated red blood cells, supporting the view that streptokinase was responsible for the haemolysis.
1. Mathiesen O, Grunnet N. Haemolysis after intravenous streptokinase. Lancet 1989; i: 1016–17.

Effects on the eyes.

Acute uveitis1,2 and iritis,3,4 associated with transient renal impairment in one patient,3 have followed treatment of myocardial infarction with intravenous streptokinase. In one case uveitis was associated with serum sickness2 and in all of them hypersensitivity to streptokinase was suspected.
1. Kinshuck D. Bilateral hypopyon and streptokinase. BMJ 1992; 305: 1332
2. Proctor BD, Joondeph BC. Bilateral anterior uveitis: a feature of streptokinase-induced serum sickness. N Engl J Med 1994; 330: 576–7
3. Birnbaum Y, et al. Acute iritis and transient renal impairment following thrombolytic therapy for acute myocardial infarction. Ann Pharmacother 1993; 27: 1539–40
4. Gray MY, Lazarus JH. Iritis after treatment with streptokinase. BMJ 1994; 309: 97.

Effects on the kidneys.

Transient proteinuria has been reported after use of streptokinase. In some patients proteinuria and renal impairment have developed about 7 days after thrombolytic therapy and have been associated with a syndrome resembling serum sickness,1,2 suggesting a delayed hypersensitivity reaction; a similar case in a patient receiving anistreplase was associated with Henoch-Schönlein-like vasculitis.3 These delayed reactions should be distinguished from the transient and apparently self-limiting proteinuria that has been reported in some patients in the first 24 to 72 hours after beginning streptokinase.4,5 Proteinuria within the first 24 hours has been attributed to deposition of an immune complex in the glomeruli,6 although haemodynamic and neurohormonal changes associated with acute myocardial infarction may be responsible since proteinuria has occurred in patients not receiving thrombolytic therapy.7,8 Streptokinase infusion has also been associated with acute oliguric renal failure due to acute tubular necrosis, apparently as a result of hypotension during the infusion, in a patient with existing renovascular narrowing.9 Interestingly, it has been pointed out that a variant streptokinase may be the pathogenic agent in glomerulonephritis occurring after Streptococcus pyogenes infection.10 Renal failure has developed as a consequence of streptokinaseinduced cholesterol embolism, see under Embolism, below.
1. Payne ST, et al. Transient impairment of renal function after streptokinase therapy. Lancet 1989; ii: 1398
2. Callan MFC, et al. Proteinuria and thrombolytic agents. Lancet 1990; 335: 106
3. Ali A, et al. Proteinuria and thrombolytic agents. Lancet 1990; 335: 106–7
4. Argent N, Adams PC. Proteinuria and thrombolytic agents. Lancet 1990; 335: 106
5. More RS, Peacock F. Haematuria and proteinuria after thrombolytic therapy. Lancet 1990; 336: 1454
6. Lynch M, et al. Proteinuria with streptokinase. Lancet 1993; 341: 1024
7. Pickett TM, Hilton PJ. Proteinuria and streptokinase. Lancet 1993; 341: 1538
8. von Eyben FE, et al. Albuminuria with or without streptokinase. Lancet 1993; 342: 365–6
9. Kalra PA, et al. Acute tubular necrosis induced by coronary thrombolytic therapy. Postgrad Med J 1991; 67: 212
10. Barnham M. Hypersensitivity and streptokinase. Lancet 1990; 335: 535.

Effects on the liver.

Raised serum-alanine aminotransferase values, and in some cases raised aspartate aminotransferase activity, were seen more frequently in 95 patients who received streptokinase than in 94 given placebo as part of a study in patients with myocardial infarction.1 The mechanism for the raised aminotransferase activity was not clear; a concomitant rise in γglutamyltransferase activity and bilirubin concentration suggested an hepatic source. For references to rupture of the liver occurring during treatment with streptokinase, see Haemorrhage, below.
1. Maclennan AC, et al. Activities of aminotransferases after treatment with streptokinase for acute myocardial infarction. BMJ 1990; 301: 321–2.

Effects on the nervous system.

There have been a few reports of Guillain-Barré syndrome after treatment with streptokinase.1-4 Whether streptokinase was the cause is not certain although its antigenic properties do suggest that induction of an immunological reaction might be responsible.3 For discussion of cerebrovascular effects of streptokinase, see Haemorrhage, below.
1. Eden KV. Possible association of Guillain-Barré syndrome with thrombolytic therapy. JAMA 1983; 249: 2020–1
2. Leaf DA, et al. Streptokinase and the Guillain-Barré syndrome. Ann Intern Med 1984; 100: 617
3. Barnes D, Hughes RAC. Guillain-Barré syndrome after treatment with streptokinase. BMJ 1992; 304: 1225
4. Taylor BV, et al. Guillain-Barré syndrome complicating treatment with streptokinase. Med J Aust 1995; 162: 214–15.

Effects on the respiratory system.

Fatal acute respiratory distress syndrome occurred in a patient given streptokinase for pulmonary embolism.1 It was suggested that streptokinase may have caused the pulmonary injury by altering vascular permeability due to generation of fibrinolytic products or via reperfusion oedema.
1. Martin TR, et al. Adult respiratory distress syndrome following thrombolytic therapy for pulmonary embolism. Chest 1983; 83: 151–3.

Effects on the skin.

Rashes may occur as an allergic reaction to streptokinase. For a report of skin necrosis possibly associated with cholesterol embolisation, see Embolism, below.


Thrombolytic therapy has occasionally and paradoxically been associated with further embolism. This may be due to clots that break away from the treated thrombus, or to cholesterol crystals released after removal of fibrin from atheromatous plaques by thrombolysis. Fatal pulmonary embolism has been reported,1 apparently due to breakaway from a deep-vein thrombus under treatment. However, comparative studies have suggested that there is no evidence of a higher rate of such complications with streptokinase than with heparin.2 When they do occur a good clinical response is usually seen to continued streptokinase.2 Complications due to multiple microemboli were reported3 in 7 of 475 consecutive patients treated with streptokinase or anistreplase for acute myocardial infarction. The sites of embolism were the legs (in 4) and brain (in 3); one patient apparently had systemic effects with skin infarction and renal impairment. Five of the 7 patients died. There has also been a report4 of acute peripheral arterial thromboembolism in a patient given alteplase for ischaemic stroke. Cholesterol embolisation can have many clinical manifestations depending on the location of the emboli. A classic presentation is livedo reticularis, gangrenous lower extremities, and acute renal failure.5,6 Symptoms may appear within a few hours of starting thrombolytic treatment,7 although in some cases they may not become evident for several days.8-11
1. Hill LN. Streptokinase therapy and breakaway pulmonary emboli. Am J Med 1991; 90: 411–12
2. Rogers LQ, Lutcher CL. Streptokinase therapy and breakaway pulmonary emboli. Am J Med 1991; 90: 412–13
3. Stafford PJ, et al. Multiple microemboli after disintegration of clot during thrombolysis for acute myocardial infarction. BMJ 1989; 299: 1310–12
4. Gomez-Beldarrain M, et al. Peripheral arterial embolism during thrombolysis for stroke. Neurology 2006; 67: 1096–7
5. Blankenship JC. Cholesterol embolisation after thrombolytic therapy. Drug Safety 1996; 14: 78–84
6. Wong FKM, et al. Acute renal failure after streptokinase therapy in a patient with acute myocardial infarction. Am J Kidney Dis 1995; 26: 508–10
7. Pochmalicki G, et al. Cholesterol embolisation syndrome after thrombolytic therapy for myocardial infarction. Lancet 1992; 339: 58–9
8. Ridker PM, Michel T. Streptokinase therapy and cholesterol embolization. Am J Med 1989; 87: 357–8
9. Pirson Y, et al. Cholesterol embolism in a renal graft after treatment with streptokinase. BMJ 1988; 296: 394–5
10. Dass H, Fescharek R. Skin necrosis induced by streptokinase. BMJ 1994; 309: 1513–14
11. Penswick J, Wright AL. Skin necrosis induced by streptokinase. BMJ 1994; 309: 378.


Haemorrhage is a common adverse effect of thrombolytic therapy, and the problem and its management have been reviewed.1 Thrombolytics are used to lyse pathological thrombi, but can also produce a ‘lytic state’ due to depletion of the natural plasmin inhibitor α2-antiplasmin by excess plasmin production; they may also cause lysis of thrombi required for haemostasis. Haemorrhage is a particular risk where there is existing or concomitant trauma. More than 70% of bleeding episodes occur at vascular puncture sites,1 so invasive procedures should be avoided if possible; if catheterisation is considered essential meticulous care of the vascular puncture site is necessary. Bleeding or severe bruising in patients receiving thrombolytic therapy have also been associated with intramuscular injection of analgesics,2the use of an automatic blood-pressure measuring machine,3 a pre-existing prosthetic abdominal aortic graft,4 and recent dental extraction.5 Other disease states may also contribute: haemospermia has been reported after thrombolysis in a patient with mild prostatic symptoms,6 haemorrhagic bullae have been reported in a patient with lichen sclerosus et atrophicus,7 and diabetic patients are at risk of retinal haemorrhage if they have diabetic retinopathy,8 although any increase in risk seems to be small.9 A review of the GUSTO-I Study10 (40 903 patients) identified older age, low body-weight, female sex, and African ancestry as other factors that increased the risk of haemorrhage. Intracranial haemorrhage leading to stroke is the most serious bleeding complication with thrombolytics, and has a high mortality. Assessment of data from national registries and large-scale trials has identified a number of risk factors for intracranial haemorrhage, including those mentioned above for overall haemorrhage, hypertension on admission, a history of stroke, and thrombolysis with current alteplase regimens.11-14 The benefits and risks must be assessed for each patient and thrombolytic therapy should still be given to the elderly and to those with hypertension if the expected benefits are great. Intracranial haemorrhage is a particular concern with the use of thrombolytics for the treatment of ischaemic stroke. In the NINDS study, using alteplase, clinical outcome appeared to be improved despite an increased incidence of symptomatic intracerebral haemorrhage. Subgroup analysis15 suggested that severe neurological deficit, brain oedema, and mass effect, before treatment, were risks associated with the increased incidence of haemorrhage. Fibrin-specific thrombolytics such as alteplase were developed in the hope that they would have less systemic effect than fibrinnonspecific thrombolytics such as streptokinase and therefore cause less bleeding. However, studies that have assessed comparative bleeding rates have failed to confirm this, although the use of adjunctive antithrombotics and different dose regimens makes comparison difficult. In GUSTO-I,10 the bleeding rate with alteplase plus intravenous heparin was lower than with streptokinase plus intravenous heparin, but was similar to that with streptokinase plus subcutaneous heparin. However, the rate of intracranial haemorrhage was higher with alteplase.16 In ASSENT-2,17 which compared bolus doses of the highly fibrinspecific thrombolytic tenecteplase with front-loaded alteplase, tenecteplase produced fewer major non-cerebral bleeds than alteplase but the rates of intracranial haemorrhage were nearly identical. Although a meta-analysis18 suggested that rates of intracranial haemorrhage may be higher with bolus thrombolytics, others have suggested that this may not be a problem with newer bolus regimens.19 Other bleeding complications reported with thrombolytics include rupture of the spleen20,21 and liver,22 and rupture of a follicle has been reported in a menstruating woman.23 Rupture of the heart with fatal consequences has been reported, although thrombolytics do not appear to increase the overall risk of cardiac rupture following myocardial infarction,24 except possibly for early rupture in women.25 Diffuse alveolar haemorrhage has been reported26 in a patient treated with streptokinase after myocardial infarction. Intrapleural use was associated with life-threatening haemorrhage in empyema following cardiac surgery,27 and with fatal haemorrhage in a case of aortic dissection misdiagnosed as empyema.28
1. Sane DC, et al. Bleeding during thrombolytic therapy for acute myocardial infarction: mechanisms and management. Ann Intern Med 1989; 111: 1010–22
2. Morris GC, Sterry MJG. [case report]. BMJ 1991; 302: 246
3. Gibson P. [case report]. BMJ 1991; 302: 1412
4. London NJM, et al. Systemic thrombolysis causing haemorrhage around a prosthetic abdominal aortic graft. BMJ 1993; 306: 1530–1
5. Lustig JP, et al. Thrombolytic therapy for acute myocardial infarction after oral surgery. Oral Surg Oral Med Oral Pathol 1993; 75: 547–8
6. Keeling PJ, Lawson CS. Haemospermia: a complication of thrombolytic therapy. Br J Hosp Med 1990; 44: 244
7. Dunn HM, Fulton RA. Haemorrhagic bullae in a patient with lichen sclerosus et atrophicus treated with streptokinase. Heart 1996; 76: 448
8. Caramelli B, et al. Retinal haemorrhage after thrombolytic therapy. Lancet 1991; 337: 1356–7
9. Ward H, Yudkin JS. Thrombolysis in patients with diabetes. BMJ 1995; 310: 3–4
10. Berkowitz SD, et al. Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. Circulation 1997; 95: 2508–16
11. Simoons ML, et al. Individual risk assessment for intracranial haemorrhage during thrombolytic therapy. Lancet 1993; 342: 1523–8
12. Aylward PE, et al. Relation of increased arterial blood pressure to mortality and stroke in the context of contemporary thrombolytic therapy for acute myocardial infarction: a randomized trial. Ann Intern Med 1996; 125: 891–900
13. Bovill EG, et al. Hemorrhagic events during therapy with recombinant tissue plasminogen activator, heparin, and aspirin for unstable angina (Thrombolysis in Myocardial Ischemia, Phase IIIB trial). Am J Cardiol 1997; 79: 391–6
14. Gurwitz JH, et al. Risk for intracranial hemorrhage after tissue plasminogen activator treatment for acute myocardial infarction. Ann Intern Med 1998; 129: 597–604
15. The NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke 1997; 28: 2109–18
16. Gore JM, et al. Stroke after thrombolysis: mortality and functional outcomes in the GUSTO-I trial. Circulation 1995; 92: 2811–18
17. Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet 1999; 354: 716–22
18. Mehta SR, et al. Risk of intracranial haemorrhage with bolus versus infusion thrombolytic therapy: a meta-analysis. Lancet 2000; 356: 449–54
19. Armstrong PW, et al. Bolus fibrinolysis: risk, benefit, and opportunities. Circulation 2001; 103: 1171–3
20. Wiener RS, Ong LS. Streptokinase and splenic rupture. Am J Med 1989; 86: 249
21. Blankenship JC, Indeck M. Spontaneous splenic rupture complicating anticoagulant or thrombolytic therapy. Am J Med 1993; 94: 433–7
22. Eklöf B, et al. Spontaneous rupture of liver and spleen with severe intra-abdominal bleeding during streptokinase treatment of deep venous thrombosis. Va sa 1977; 6: 369–71.
23. Müller C-H, et al. Near-fatal intra-abdominal bleeding from a ruptured follicle during thrombolytic therapy. Lancet 1996; 347: 1697
24. Massel DR. How sound is the evidence that thrombolysis increases the risk of cardiac rupture? Br Heart J 1993; 69: 284–7
25. Becker RC, et al. Fatal cardiac rupture among patients treated with thrombolytic agents and adjunctive thrombin antagonists: observations from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction 9 Study. J Am Coll Cardiol 1999; 33: 479–87
26. Yigla M, et al. Diffuse alveolar hemorrhage following thrombolytic therapy for acute myocardial infarction. Respiration 2000; 67: 445–8
27. Porter J, Banning AP. Intrapleural streptokinase. Thorax 1998; 53: 720
28. Srivastava P, et al. Fatal haemorrhage from aortic dissection following instillation of intrapleural streptokinase. Scott Med J 2000; 45: 86–7.


Streptokinase is a bacterial protein and has antigenic activity. The formation of streptokinase-neutralising antibodies may reduce the efficacy of subsequent doses and increase the risk of hypersensitivity reactions. In a series of 25 patients given intravenous streptokinase for myocardial infarction, titres of streptokinase-neutralising antibodies rose from a mean neutralisation capacity of 0.16 million units before treatment to a mean of 25.54 million units 2 weeks after treatment, the highest individual titre being 93 million units. After 12 weeks the neutralisation capacity was still sufficient in 24 patients to have neutralised a standard 1.5-million unit dose of streptokinase. After 17 to 34 weeks titres were still high enough in 18 of 20 patients examined to neutralise at least half a standard dose.1 As these results indicate, giving standard doses of streptokinase within up to a year of a previous course may lead to reduced effect. Thus, the period in which it should not be repeated is usually between 5 days and 12 months post infarction (see Precautions, below). However, high titres of neutralising antibodies persisting for up to 7.5 years after use of streptokinase have been reported.2-4 Since readministration also increases the risk of hypersensitivity reactions, it has been suggested2,5 that repeat courses should not be given within 4 or more years, and that if a repeat course is needed a non-antigenic thrombolytic such as alteplase or urokinase should be used until it is known whether or not high in-vitro titres affect efficacy. Increased titres of streptokinase-neutralising antibodies have also been measured in patients given topical streptokinase for wounds.6 Anistreplase also appears susceptible to neutralisation by streptokinase antibodies.7 Plasmacytosis,8,9 serum-sickness,8,10,11 rhabdomyolysis,12 renal impairment (see Effects on the Kidneys, above), uveitis and iritis (see Effects on the Eyes, above), arthritis,13 and anaphylaxis14-17have been reported in patients receiving streptokinase and are thought to represent hypersensitivity reactions, in some cases perhaps due to previous exposure to streptococcal antigens during infection. Back pain (see above) may also represent a hypersensitivity reaction. In some patients there may be a delay of between 1 and 10 days before appearance of the reaction.18 The incidence of severe hypersensitivity reactions is probably fairly low, however; in the GISSI study anaphylaxis was reported in only 7 of 5860 patients although other hypersensitivity reactions leading to withdrawal of streptokinase were reported in 99 patients, with a further 42 such reactions after completion of the infusion.15 Some episodes of apparent anaphylaxis seen with streptokinase may be fibrinolysin-mediated rather than antibodyantigen reactions. Alteplase, which is considered non-antigenic, produced an anaphylactoid reaction in a patient who had a history of atopy.19 Fibrinolysin, which activates complement cascade and the kinin system, is formed in quantity after the use of a thrombolytic. In most patients these effects are clinically insignificant, but in those who are strongly atopic there is the possibility of precipitating an anaphylactoid reaction.
1. Jalihal S, Morris GK. Antistreptokinase titres after intravenous streptokinase. Lancet 1990; 335: 184–5
2. Elliott JM, et al. Neutralizing antibodies to streptokinase four years after intravenous thrombolytic therapy. Am J Cardiol 1993; 71: 640–5
3. Lee HS, et al. Raised levels of antistreptokinase antibody and neutralization titres from 4 days to 54 months after administration of streptokinase or anistreplase. Eur Heart J 1993; 14: 84–9
4. Squire IB, et al. Humoral and cellular immune responses up to 7.5 years after administration of streptokinase for acute myocardial infarction. Eur Heart J 1999; 20: 1245–52
5. Jennings K. Antibodies to streptokinase. BMJ 1996; 312: 393–4
6. Green C. Antistreptokinase titres after topical streptokinase. Lancet 1993; 341: 1602–3
7. Binette MJ, Agnone FA. Failure of APSAC thrombolysis. Ann Intern Med 1993; 119: 637
8. Straub PW, et al. Plasmozytose nach thrombolytischer Therapie mit Streptokinase. Schweiz Med Wochenschr 1974; 104: 1891–2
9. Chan NS, et al. Plasmacytosis and renal failure after readministration of streptokinase for threatened myocardial reinfarction. BMJ 1988; 297: 717–18
10. Payne ST, et al. Transient impairment of renal function after streptokinase therapy. Lancet 1989; ii: 1398
11. Callan MFC, et al. Proteinuria and thrombolytic agents. Lancet 1990; 335: 106
12. Montgomery HE, et al. Rhabdomyolysis and multiple system organ failure with streptokinase. BMJ 1995; 311: 1472
13. Kelly MP, Bielawska C. Recurrence of a reactive arthritis following streptokinase therapy. Postgrad Med J 1991; 67: 402
14. McGrath KG, Patterson R. Anaphylactic reactivity to streptokinase. JAMA 1984; 252: 1314–17
15. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; i: 397–401
16. Bednarczyk EM, et al. Anaphylactic reaction to streptokinase with first exposure: case report and review of the literature. DICP Ann Pharmacother 1989; 23: 869–72
17. Tisdale JE, et al. Streptokinase-induced anaphylaxis. DICP Ann Pharmacother 1989; 23: 984–7
18. Seibert WJ, et al. Streptokinase morbidity—more common than previously recognised. Aust N Z J Med 1992; 22: 129–33
19. Purvis JA, et al. Anaphylactoid reaction after injection of alteplase. Lancet 1993; 341: 966–7.

💊 Treatment of Adverse Effects

Allergic reactions may require treatment with antihistamines and corticosteroids, which have sometimes been given prophylactically. Anaphylaxis requires the use of adrenaline. Severe haemorrhage not controlled by local pressure requires the streptokinase infusion to be stopped. Tranexamic acid, aminocaproic acid, or aprotinin may be of benefit. Packed red blood cells may be preferable to whole blood for replacement therapy; factor VIII preparations may also be given. Volume expansion may be necessary, but the use of dextrans should be avoided because of their platelet-inhibiting properties.

💊 Precautions

Streptokinase should be used with great care, if at all, in patients at increased risk of bleeding, or those in whom haemorrhage is likely to prove particularly dangerous. It should thus be avoided in patients with active internal bleeding or a recent history of peptic ulcer disease, oesophageal varices, ulcerative colitis or other bleeding gastrointestinal lesions, in patients with pancreatitis, in patients with subacute bacterial endocarditis, in patients with coagulation defects including those due to liver or kidney disease, or after recent surgery, childbirth, or trauma. It should not be given to patients at increased risk of cerebral bleeding including those with severe hypertension, haemorrhage or recent stroke, or to patients with cerebral neoplasm. It should not be given in pregnancy, particularly in the first 18 weeks because of the risk of placental separation and it has been suggested that it should not be used during heavy vaginal bleeding. Invasive procedures, including intramuscular injections, should be avoided during, and immediately before and after, streptokinase therapy as they may increase the risk of bleeding; care should be taken when physically handling patients. Streptokinase should also be used with care in elderly patients. Patients with mitral stenosis associated with atrial fibrillation are more likely to have left heart thrombus which may lead to cerebral embolism after thrombolytic therapy. Although there is a theoretical risk of retinal bleeding in patients with diabetic retinopathy the benefits of treatment generally outweigh the risk. Anti-streptokinase antibodies are formed after streptokinase use, with antibody titres rising abruptly after about 5 days. These antibodies may cause resistance or hypersensitivity to subsequent doses of streptokinase. Therefore, further doses of streptokinase should not be given in the period between 5 days and 12 months after the initial dose (even longer periods have been suggested, see Hypersensitivity, under Adverse Effects, above); if thrombolytic therapy is required in this period an alternative non-antigenic drug should be used. High titres of anti-streptokinase antibodies may also occur in patients after some streptococcal infections such as streptococcal pharyngitis or acute rheumatic fever or in those with acute glomerulonephritis secondary to streptococcal infections; in such patients there may be resistance to streptokinase or a reduced effect.


Overinfusion of streptokinase may occur if a drop-counting infusion pump is employed.1 This arises as a result of flocculation of the streptokinase solution producing translucent fibres that affect the drop-forming mechanism so increasing the drop size. For a comment on the incidence of flocculation in streptokinase solutions, see Stability, above.
1. Schad RF, Jennings RH. Overinfusions of streptokinase. Am J Hosp Pharm 1982; 39: 1850.

Aortic dissection.

A report of 4 cases of the inappropriate use of streptokinase in patients with aortic dissection misdiagnosed as myocardial infarction.1 Thrombolytics are likely to extend aortic dissection and adversely affect the outcome. Of the 2 patients who died, one, who would have been suitable for early operation, died through the delay caused by impaired clotting. Although early intervention with thrombolytics may be of major benefit in acute myocardial infarction it is important that accurate differential diagnosis takes place to exclude conditions such as aortic dissection and prevent avoidable deaths. For a report of fatal haemorrhage with streptokinase used in aortic dissection misdiagnosed as empyema, see Haemorrhage under Adverse Effects, above.
1. Butler J, et al. Streptokinase in acute aortic dissection. BMJ 1990; 300: 517–19.

Cardiopulmonary resuscitation.

Thrombolytics are not recommended after prolonged or traumatic cardiopulmonary resuscitation because of the risk of haemorrhage. However, studies1,2in patients given cardiopulmonary resuscitation for cardiac arrest associated with acute myocardial infarction have suggested that thrombolytics are generally safe and that any increase in bleeding complications is outweighed by the benefits of thrombolysis.
1. Cross SJ, et al. Safety of thrombolysis in association with cardiopulmonary resuscitation. BMJ 1991; 303: 1242
2. Kurkciyan I, et al. Major bleeding complications after cardiopulmonary resuscitation: impact of thrombolytic treatment. J Intern Med 2003; 253: 128–35.


Thrombolytics are generally contra-indicated in pregnancy. However there are a few reports of their use and these have been briefly reviewed.1 In most cases, thrombolytics were given at 28 weeks of pregnancy or later to patients with deepvein thrombosis, pulmonary embolism, or prosthetic valve thrombosis. There were some reports of favourable maternal and fetal outcomes although therapy was associated with maternal haemorrhage, including spontaneous abortion and minor vaginal bleeding, especially when given near the time of delivery. There was one report of placental abruption with fetal death.
1. Roth A, Elkayam U. Acute myocardial infarction associated with pregnancy. Ann Intern Med 1996; 125: 751–62.

💊 Interactions

Oral anticoagulants, heparin, and antiplatelet drugs such as aspirin are often used with streptokinase, but may increase the risk of haemorrhage. The risk may also be increased with dextrans, and with other drugs that affect coagulation or platelet function.
1. Harder S, Klinkhardt U. Thrombolytics: drug interactions of clinical significance. Drug Safety 2000; 23: 391–9.

💊 Pharmacokinetics

Streptokinase is rapidly cleared from the circulation after intravenous use. Clearance is biphasic with the initial and more rapid phase being due to specific antibodies. A half-life of 23 minutes has been reported for the streptokinase-activator complex.
1. Grierson DS, Bjornsson TD. Pharmacokinetics of streptokinase in patients based on amidolytic activator complex activity. Clin Pharmacol Ther 1987; 41: 304–13
2. Gemmill JD, et al. A comparison of the pharmacokinetic properties of streptokinase and anistreplase in acute myocardial infarction. Br J Clin Pharmacol 1991; 31: 143–7.

💊 Uses and Administration

Streptokinase is a thrombolytic drug derived from various streptococci. It rapidly activates endogenous plasminogen, indirectly by means of a streptokinase-plasminogen complex, to plasmin, which has fibrinolytic effects and can dissolve intravascular blood clots. Streptokinase affects circulating, unbound plasminogen as well as fibrin-bound plasminogen and thus may be termed a fibrin-nonspecific thrombolytic. Streptokinase is given by intravenous or sometimes intra-arterial infusion in the treatment of thromboembolic disorders such as myocardial infarction, peripheral arterial thromboembolism (below), and venous thromboembolism (deep-vein thrombosis and pulmonary embolism). It has also been tried in ischaemic stroke (below), although alteplase is generally preferred. Streptokinase may be used to clear cannulas and shunts and is used topically with streptodornase to clear clots and purulent matter. In acute myocardial infarction streptokinase is usually given intravenously as a single dose of 1.5 million units infused over 1 hour as soon as possible after the onset of symptoms. Streptokinase has also been given in a suitable dose by intracoronary infusion but coronary catheterisation with the aid of angiography is required, thus restricting use to suitably equipped centres. In the treatment of pulmonary embolism and other arteriovenous occlusions an initial loading dose of streptokinase, normally 250 000 units infused intravenously over 30 minutes, is given to overcome any resistance due to circulating antibodies. This is followed by infusion of a maintenance dose of 100 000 units/hour for 24 to 72 hours, depending on the condition to be treated; for central retinal thrombosis, 12 hours may be adequate. Treatment should be controlled by monitoring the thrombin clotting time, which should be maintained at 2 to 4 times normal values. Since thrombolytic activity rapidly fades when the infusion stops, streptokinase treatment is generally followed after 3 to 4 hours by intravenous heparin infusion, and then oral anticoagulation, to prevent re-occlusion. Streptokinase, as a solution containing 250 000 units in 2 mL is used to clear occluded cannulas; 1000 units/mL has been used to clear shunts of occluding thrombi.
1. Fears R. Biochemical pharmacology and therapeutic aspects of thrombolytic agents. Pharmacol Rev 1990; 42: 201–21
2. Stringer KA. Beyond thrombolysis: other effects of thrombolytic drugs. Ann Pharmacother 1994; 28: 752–6
3. Ludlam CA, et al. Guidelines for the use of thrombolytic therapy. Blood Coag Fibrinol 1995; 6: 273–85.

Administration in children.

There are limited data on the use of systemic thrombolytic therapy for arterial or venous thromboembolism in children and various dosage regimens have been used, based on case studies. The most widely used drugs are streptokinase and alteplase. For streptokinase, the Eighth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy1 suggests a loading dose of 2000 units/kg to be given intravenously, followed by continuous infusion of 2000 units/kg per hour for 6 to 12 hours. In the UK, the BNFC suggests a loading dose of 2500 to 4000 units/kg over 30 minutes, followed by infusion of 500 to 1000 units/kg per hour, continued until reperfusion occurs, up to a maximum of 3 days. Alteplase may be preferred because of its fibrin specificity and low immunogenicity. The dose of alteplase suggested by the ACCP is 100 to 600 micrograms/kg per hour by continuous intravenous infusion over 6 hours, while the dose recommended by the BNFC is 100 to 500 micrograms/kg per hour for 3 to 6 hours.
1. Monagle P, et al. Antithrombotic therapy in neonates and children: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008; 133 (suppl): 454S–545S.

Empyema and pleural effusion.

Thoracic empyema is treated with antibacterials and pleural drainage. Efficient removal of fluid may be impaired by fibrinous clots within the pleural cavity. Intrapleural instillation of streptokinase (100 000 to 750 000 units in up to 100 mL of sodium chloride 0.9%) has been reported to be effective in small series of patients1-4 and there have been reports of the successful use of alteplase5-7 and urokinase.4,8 However, a double-blind trial9 involving 454 patients found no benefit with streptokinase, and the role of thrombolytics remains unclear. A meta-analysis10 found no evidence of benefit, although a systematic review11 suggested that thrombolytics may reduce the need for surgical intervention. Intrapleural streptokinase has also been used successfully in a few patients with malignant multiloculated pleural effusion resistant to standard pleural drainage.12 Intrapericardial instillation of thrombolytics has been tried in a few patients with pericardial empyema to prevent the development of constrictive pericarditis.13,14 For reports of haemorrhage associated with intrapleural use of streptokinase, see Haemorrhage, under Adverse Effects, above.
1. Temes RT, et al. Intrapleural fibrinolytics in management of empyema thoracis. Chest 1996; 110: 102–6
2. Bouros D, et al. Role of streptokinase in the treatment of acute loculated parapneumonic pleural effusions and empyema. Thorax 1994; 49: 852–5
3. Davies RJO, et al. Randomised controlled trial of intrapleural streptokinase in community acquired pleural infection. Thorax 1997; 52: 416–21
4. Bouros D, et al. Intrapleural streptokinase versus urokinase in the treatment of complicated parapneumonic effusions: a prospective, double-blind study. Am J Respir Crit Care Med 1997; 155: 291–5
5. Bishop NB, et al. Alteplase in the treatment of complicated parapneumonic effusion: a case report. Abstract: Pediatrics 2003; 111: 423. Full version: reprint/111/2/e188 (accessed 16/06/04
6. Walker CA, et al. Intrapleural alteplase in a patient with complicated pleural effusion. Ann Pharmacother 2003; 37: 376–9
7. Weinstein M, et al. Effectiveness and safety of tissue plasminogen activator in the management of complicated parapneumonic effusions. Abstract: Pediatrics 2004; 113: 610. Full version: (accessed 30/04/08
8. Thomson AH, et al. Randomised trial of intrapleural urokinase in the treatment of childhood empyema. Thorax 2002; 57: 343–7
9. Maskell NA, et al. U.K. controlled trial of intrapleural streptokinase for pleural infection. N Engl J Med 2005; 352: 865–74. Correction. ibid.; 2146
10. Tokuda Y, et al. Intrapleural fibrinolytic agents for empyema and complicated parapneumonic effusions: a meta-analysis. Chest 2006; 129: 783–90
11. Cameron R, Davies HR. Intra-pleural fibrinolytic therapy versus conservative management in the treatment of adult parapneumonic effusions and empyema. Available in The Cochrane Database of Systematic Reviews; Issu
2. Chichester: John Wiley; 2008 (accessed 30/04/08)
12. Davies CWH, et al. Intrapleural streptokinase in the management of malignant multiloculated pleural effusions. Chest 1999; 115: 729–33
13. Winkler W-B, et al. Treatment of exudative fibrinous pericarditis with intrapericardial urokinase. Lancet 1994; 344: 1541–2
14. Juneja R, et al. Intrapericardial streptokinase in purulent pericarditis. Arch Dis Child 1999; 80: 275–7.

Intracardiac thrombosis.

Thrombosis of prosthetic heart valves is usually treated surgically, but thrombolytics have also been used. In a study1 of patients with left-sided prosthetic valve thrombosis, thrombolytic therapy was found to be more successful than surgery, especially in those who were critically ill; most patients were given streptokinase. Another retrospective study2 in which patients were given streptokinase, urokinase, or alteplase, concluded that thrombolytics were effective but embolic and haemorrhagic complications might limit their use.
1. Lengyel M, Vándor L. The role of thrombolysis in the management of left-sided prosthetic valve thrombosis: a study of 85 cases diagnosed by transesophageal echocardiography. J Heart Valve Dis 2001; 10: 636–49
2. Roudaut R, et al. Fibrinolysis of mechanical prosthetic valve thrombosis: a single-center study of 127 cases. J Am Coll Cardiol 2003; 41: 653–8.

Ischaemic heart disease.

Thrombolytics such as alteplase, streptokinase, and urokinase have an established role in the early management of acute myocardial infarction. Myocardial infarction is caused by coronary artery occlusion, usually due to thrombosis, and thrombolytics are given intravenously to break up the thrombus or clot and restore the patency of the coronary artery, thereby limiting infarct size and irreversible damage to the myocardium. Reduction of ECG abnormalities and modification of ventricular remodelling may also contribute to their effect. Other antithrombotics, in particular aspirin and heparin, are given as adjunctive therapy. Several large studies have established that thrombolytics can preserve left ventricular function and improve short-term and 1-year mortality figures;1,2 benefit has been maintained in 5-year3 and 10-year4,5 follow-up studies. Benefit is greatest with early treatment. Trials such as the GISSI-1 study6 and the ISIS-2 study7helped to establish that mortality is reduced if thrombolytics are given within 6 hours of the onset of symptoms8 and further studies provided evidence9,10 that patients presenting within 12 hours should receive a thrombolytic. Use after 12 hours has been associated with an increase in adverse effects,8 and is usually reserved for patients with evidence of ongoing ischaemia. Prehospital thrombolysis is feasible and reduces the time to thrombolysis and short-term mortality.11 Five-year follow-up of one study12 has suggested that there is also a beneficial effect on long-term mortality. Choice of thrombolytic depends on factors such as cost, method of administration, and contra-indications. Although streptokinase has been the most widely used, several large studies have compared clinical benefit in terms of improved left ventricular function and mortality and have shown no difference between streptokinase and other thrombolytics, including saruplase,13 the tissue plasminogen activator alteplase,14 anistreplase,15 and reteplase16 in overall efficacy. In the GUSTO-I study,17 accelerated or ‘front loaded’ alteplase (that is, rapid intravenous dosage over 1 ⁄ hours rather than the conventional 3 hours) was more effective than streptokinase, although the study was criticised for not comparing like with like. On the other hand, alteplase might be associated with a greater risk of stroke than streptokinase.18Studies comparing bolus injections of reteplase with accelerated alteplase (GUSTO-III)19 and tenecteplase with alteplase (ASSENT-2)20 have also found no difference in mortality rate. The overall effectiveness of thrombolytics is limited by persistent coronary occlusion, re-occlusion, and bleeding complications. Different thrombolytic regimens, such as bolus injections of reteplase, and combinations of thrombolytics, for example alteplase with streptokinase and alteplase with saruplase, have been investigated in attempts to improve patency rates. However, there has been concern that adverse effects may be higher with bolus injection. A study21 comparing double-bolus alteplase with accelerated alteplase was terminated early when excess deaths were found in the group receiving bolus injections, and a subsequent meta-analysis22 found a higher incidence of intracranial haemorrhage associated with bolus doses of various thrombolytics. Although use of thrombolytics before percutaneous coronary intervention (PCI) does not appear to be beneficial, a small study23 has suggested that intracoronary streptokinase given immediately after PCI may improve microvascular reperfusion; however, there was no effect on clinical outcomes. Thrombolytics have also been tried in other acute coronary syndromes, including unstable angina and non-ST elevation myocardial infarction. Although small-scale studies reported some benefit the results were variable, and an overview8 of trials in patients with suspected myocardial infarction, which included some patients with unstable angina, found that there was no mortality benefit in patients without ST elevation. In 2 studies that investigated alteplase (the TIMI-IIIB study24 with 1473 patients) and anistreplase (the UNASEM study25 involving 159 patients), thrombolysis failed to improve outcome and was associated with an excess of bleeding complications. Thrombolytic therapy is therefore not recommended for patients with unstable angina or non-ST elevation myocardial infarction.
1. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Long-term effects of intravenous thrombolysis in acute myocardial infarction: final report of the GISSI study. Lancet 1987; ii: 871–4
2. Wilcox RG, et al. Effects of alteplase in acute myocardial infarction: 6-month results from the ASSET study. Lancet 1990; 335: 1175–8
3. Simoons ML, et al. Long-term benefit of early thrombolytic therapy in patients with acute myocardial infarction: 5 year follow-up of a trial conducted by the Interuniversity Cardiology Institute of the Netherlands. J Am Coll Cardiol 1989; 14: 1609–15
4. Baigent C, et al. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. BMJ 1998; 316: 1337–43
5. Franzosi MG, et al. Ten-year follow-up of the first megatrial testing thrombolytic therapy in patients with acute myocardial infarction: results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto-1 Study. Circulation 1998; 98: 2659–65
6. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; i: 397–402
7. Second International Study of Infarct Survival Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; ii: 349–60
8. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet 1994; 343: 311–22
9. LATE Study Group. Late assessment of thrombolytic efficacy (LATE) study with alteplase 6–24 hours after onset of acute myocardial infarction. Lancet 1993; 342: 759–66
10. EMERAS (Estudio Multicéntrico Estreptoquinasa Repúblicas de América del Sur) Collaborative Group. Randomised trial of late thrombolysis in patients with suspected acute myocardial infarction. Lancet 1993; 342: 767–72
11. Morrison LJ, et al. Mortality and prehospital thrombolysis for acute myocardial infarction: a meta-analysis. JAMA 2000; 283: 2686–92
12. Rawles JM. Quantification of the benefit of earlier thrombolytic therapy: five-year results of the Grampian Region Early Anistreplase Trial (GREAT). J Am Coll Cardiol 1997; 30: 1181–6
13. PRIMI Trial Study Group. Randomised double-blind trial of recombinant pro-urokinase against streptokinase in acute myocardial infarction. Lancet 1989; i: 863–8
14. GISSI-2 and International Study Group. Six-month survival in 20 891 patients with acute myocardial infarction randomized between alteplase and streptokinase with or without heparin. Eur Heart J 1992; 13: 1692–7
15. Third International Study of Infarct Survival Collaborative Group. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41 299 cases of suspected acute myocardial infarction. Lancet 1992; 339: 753–70
16. International Joint Efficacy Comparison of Thrombolytics. Randomised, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT): trial to investigate equivalence. Lancet 1995; 346: 329–36
17. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673–82
18. Vaitkus PT, et al. Stroke complicating acute myocardial infarction: a meta-analysis of risk modification by anticoagulation and thrombolytic therapy. Arch Intern Med 1992; 152: 2020–4
19. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 1997; 337: 1118–23
20. Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet 1999; 354: 716–22
21. The Continuous Infusion versus Double-Bolus Administration of Alteplase (COBALT) Investigators. A comparison of continuous infusion of alteplase with double-bolus administration for acute myocardial infarction. N Engl J Med 1997; 337: 1124–30
22. Mehta SR, et al. Risk of intracranial haemorrhage with bolus versus infusion thrombolytic therapy: a meta-analysis. Lancet 2000; 356: 449–54
23. Sezer M, et al. Intracoronary streptokinase after primary percutaneous coronary intervention. N Engl J Med 2007; 356: 1823–34.
24. The TIMI IIIB Investigators. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction: results of the TIMI IIIB trial. Circulation 1994; 89: 1545–56
25. Bär FW, et al. Thrombolysis in patients with unstable angina improves the angiographic but not the clinical outcome: results of UNASEM, a multicenter, randomized, placebo-controlled, clinical trial with anistreplase. Circulation 1992; 86: 131–7.

Peripheral arterial

thromboembolism. Thrombolytics including streptokinase may be used in the management of peripheral arterial thromboembolism. Streptokinase has been injected intravenously or intra-arterially directly into the clot as an alternative to surgical treatment of the occlusion. It has also been infused intra-arterially to remove distal clots during surgery. The intravenous dose generally used is 250 000 units over 30 minutes followed by 100 000 units/hour. A lower dose of 5000 units/hour has been used intra-arterially directly into the clot1 and for removal of distal clots during surgery streptokinase has been given intra-arterially in a dose of 100 000 units over 30 minutes or as five bolus doses of 20 000 units at 5-minute intervals.2
1. Anonymous. Non-coronary thrombolysis. Lancet 1990; 335: 691–3
2. Earnshaw JJ, Beard JD. Intraoperative use of thrombolytic agents. BMJ 1993; 307: 638–9.


Stroke is normally considered a contra-indication to the use of thrombolytics, and clearly they would be inappropriate in acute haemorrhagic stroke. However, when stroke is associated with thrombotic occlusion there is evidence, as with myocardial infarction, that a degree of neuronal recovery is possible if the occlusion is reversed sufficiently quickly, and thrombolytics may therefore have a role in some patients with acute ischaemic stroke. Early studies with intravenous thrombolytics in acute ischaemic stroke suggested a reduction in early death, although subsequent randomised trials produced disappointing results, with the exception of one with alteplase given within 3 hours of the onset of stroke (NINDS—National Institute of Neurological Disorders and Stroke rt-PA Stroke Trial).1 The studies using streptokinase—MAST-E (Multicentre Acute Stroke Trial-Europe),2 ASK (Australian Streptokinase Trial),3 and MAST-I (Multicentre Acute Stroke Trial-Italy)4,5—were terminated before completion because of adverse outcomes (intracranial bleeding and increased mortality) in the treatment groups, particularly in those receiving therapy more than 3 hours after stroke onset.3 The study investigating alteplase given within 6 hours of the onset of symptoms (ECASS I—European Cooperative Acute Stroke Study)6 reported that, although some patients might benefit, overall alteplase was associated with higher mortality rates and an increase in some intracranial bleeding (parenchymal haemorrhage). In the NINDS randomised study,1 alteplase given within 3 hours of the onset of ischaemic stroke appeared to improve clinical outcome despite an increased incidence of symptomatic intracerebral haemorrhage. Patients treated with alteplase were more likely to have minimal or no disability 3 months after stroke,1 and this benefit was maintained at 12 months.7 However, there was no difference in mortality or rate of recurrence of stroke. A second ECASS study (ECASS II)8 that hoped to confirm the early findings of the NINDS study failed to confirm a statistical benefit for alteplase over placebo and found no significant differences between patients who received alteplase within 3 hours or between 3 and 6 hours. A review9 of several studies confirmed that alteplase needed to be given early, and preferably within 90 minutes, if it was to be effective. On the basis of the NINDS study, alteplase given within 3 hours of the onset of ischaemic stroke is now recommended for selected patients in most guidelines on stroke management.10-14 Despite their own disappointing results, the ECASS II investigators reached a similar conclusion. However, these recommendations have been criticised.15,16 It has been pointed out17,18 that very few patients will be eligible for treatment with alteplase, since the time of onset of symptoms is often uncertain and in many patients more than 3 hours elapses before a definite diagnosis of ischaemic stroke is made. In addition, the NINDS study1 excluded patients with severe stroke and those taking anticoagulants. The rationale for exclusion of patients with severe stroke is that haemorrhagic transformation is more likely to occur with large areas of infarction.17 However, size of infarct is difficult to identify by CT scanning.17 Anticoagulants or antiplatelets are also contra-indicated in the first 24 hours after use of alteplase. The poor results obtained in studies using streptokinase have led to recommendations that streptokinase should be avoided in ischaemic stroke,13 although an overview of thrombolytic studies18suggested that it may not be worse than alteplase and that the apparent hazards of streptokinase may be accounted for by differences in trial design (for example use with anticoagulants) and in patient population. Thus, while alteplase can be considered for those few patients meeting the entry criteria for the NINDS study, a systematic review19 concluded that further large studies are required to establish more clearly the overall role of thrombolytics in acute ischaemic stroke. Studies of the use of alteplase outside the setting of a clinical trial have had mixed results.20-22However, an observational study23 found that alteplase was safe and effective when used in accordance with guidelines, while another study24 found that it could be used in elderly patients (80 years-of-age and older), a group normally excluded from clinical trials. Intra-arterial thrombolytics may have advantages over intravenous use and may be used in selected patients.12-14 Studies with nasaruplase25 and urokinase26 have suggested benefit up to 6 hours after stroke due to middle cerebral artery occlusion, and use of intra-arterial thrombolytics may therefore be considered in such patients.12-14 Intra-arterial thrombolytics are also used in basilar artery occlusion, although evidence to support this is limited;12,13,27 intravenous alteplase may be an alternative.28 Combined use of intravenous and intra-arterial alteplase,29 as well as use of adjunctive therapies such as therapeutic ultrasound30 or antithrombotics, are under investigation but do not yet have an established role.13 Intravenous thrombolytics have no role in the management of acute haemorrhagic stroke, but they have been given locally to facilitate the aspiration of haematomas in both intracerebral31and subarachnoid haemorrhage. Small studies with urokinase have shown benefit in patients with intraventricular haemorrhage.
1. The National Institute of Neurological Disorders and Stroke rtPA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333: 1581–7
2. The Multicenter Acute Stroke Trial—Europe Study Group. Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med 1996; 335: 145–50
3. Donnan GA, et al. Streptokinase for acute ischemic stroke with relationship to time of administration. JAMA 1996; 276: 961–6
4. Multicentre Acute Stroke Trial - Italy (MAST-I) Group. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet 1995; 346: 1509–14
5. Tognoni G, Roncaglioni MC. Dissent: an alternative interpretation of MAST-I. Lancet 1995; 346: 1515
6. Hacke W, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA 1995; 274: 1017–25
7. Kwiatowski TG, et al. Effects of tissue plasminogen activator for acute ischemic stroke at one year. N Engl J Med 1999; 340: 1781–7
8. Hacke W, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet 1998; 352: 1245–51
9. The ATLANTIS, ECASS, and NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004; 363: 768–74
10. The International Liaison Committee on Resuscitation (ILCOR). 2005 International consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Section 2: Stroke and first aid. Part 9: Stroke. Circulation 2005; 112 (suppl I): III110–III114. Also available at: 22_suppl/III-110 (accessed 01/03/06
11. NICE. Alteplase for the treatment of acute ischaemic stroke: Technology Appraisal Guidance 122 (issued June 2007). Available at: TA122guidance.pdf (accessed 30/04/08
12. European Stroke Organisation (ESO) Executive Committee. ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008; 25: 457–507. Also available at: (accessed 11/07/08
13. Adams HP, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. Stroke 2007; 38: 1655
Published May 08, 2019.