Streptokinase
Drug Nomenclature
Pharmacopoeias. Europe includes a concentrated solution.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 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 properly of combining with human plasmino-gen 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.
Stability. 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.
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-Barre syndrome.
Streptokinase infusion may be associated with hypotension, both direct or as a result of reperflision; 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. 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. Alternatively, immediate substitution with a different thrombolytic has been suggested.
There have also been a few reports of low back pain associated with anistreplase infusion.
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. 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.
Effects on the eyes. Acute uveitis and iritis, associated with transient renal impairment in one patient, have followed treatment of myocardial infarction with intravenous streptokinase. In one case uveitis was associated with serum sickness and in all of them hypersensitivity to streptokinase was suspected.
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, suggesting a delayed hypersensitivity reaction; a similar case in a patient receiving anistreplase was associated with Henoch-Schonle in-like vasculitis. 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. Proteinuria within the first 24 hours has been attributed to deposition of an immune complex in the glomeruli, although haemodynamic and neurohormonal changes associated with acute myocardial infarction may be responsible since proteinuria has occurred in patients not receiving thrombolytic therapy.
Streptokinase infusion has also been associated with acute oligu-ric renal failure due to acute tubular necrosis, apparently as a result of hypotension during the infusion, in a patient with existing renovascular narrowing. Interestingly, it has been pointed out that a variant streptokinase may be the pathogenic agent in glomerulonephritis occurring after Streptococcus pyogenes infection.
Renal failure has developed as a consequence of streptokinase-induced cholesterol embolism, see under Embolism, below.
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. The mechanism for the raised aminotransferase activity was not clear; a concomitant rise in y-glutamyltransferase activity and bilirubin concentration suggested an hepatic source.
For references to rupture of the liver occurring during treatment with streptokinase, see Haemorrhage, below.
Effects on the nervous system. There have been a few reports of Guillain-Barre syndrome after treatment with streptokinase. Whether streptokinase was the cause is not certain although its antigenic properties do suggest that induction of an rmmunological reaction might be responsible.
For discussion of cerebrovascular effects of streptokinase, see Haemorrhage, below.
Effects on the respiratory system. Fatal acute respiratory distress syndrome occurred in a patient given streptokinase for pulmonary embolism. 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.
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.
Embolism. 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, 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. When they do occur a good clinical response is usually seen to continued streptokinase. Complications due to multiple microemboli were reported 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 report of acute peripheral arterial throm-boembolism 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. Symptoms may appear within a few hours of starting thrombolytic treatment, although in some cases they may not become evident for several days.
Haemorrhage. Haemorrhage is a common adverse effect of thrombolytic therapy, and the problem and its management have been reviewed. Thrombolytics are used to lyse pathological thrombi, but can also produce a ‘lytic state’ due to depletion of the natural plasmin inhibitor a2-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, 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, the use of an automatic blood-pressure measuring machine, a pre-existing prosthetic abdominal aortic graft, and recent dental extraction. Other disease states may also contribute: haemosper-mia has been reported after thrombolysis in a patient with mild prostatic symptoms, haemorrhagic bullae have been reported in a patient with lichen sclerosus et atrophicus, and diabetic patients are at risk of retinal haemorrhage if they have diabetic retinopathy, although any increase in risk seems to be small. A review of the GUSTO-I Study (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. 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 analysis 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 fibrin-nonspecific 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, 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. In ASSENT-2, which compared bolus doses of the highly fibrin-specific 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-analysis 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.
Other bleeding complications reported with thrombolytics include rupture of the spleen and liver, and rupture of a follicle has been reported in a menstruating woman. 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, except possibly for early rupture in women.
Diffuse alveolar haemorrhage has been reported in a patient treated with streptokinase after myocardial infarction. Intrapleural use was associated with life-threatening haemorrhage in empyema following cardiac surgery, and with fatal haemorrhage in a case of aortic dissection misdiagnosed as empyema.
Hypersensitivity. 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-millionunit 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. 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. Since readministration also increases the risk of hypersensitivity reactions, it has been suggested 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.
Anistreplase also appears susceptible to neutralisation by streptokinase antibodies.
Plasmacytosis, serum-sickness, rhabdomyolysis, renal impairment (see Effects on the Kidneys, above), uveitis and iritis (see Effects on the Eyes, above), arthritis, and anaphylaxis have 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. 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. Some episodes of apparent anaphylaxis seen with streptokinase may be fibrinolysin-mediated rather than antibody-antigen reactions. Alteplase, which is considered non-antigenic, produced an anaphylactoid reaction in a patient who had a history of atopy. 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.
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 (for further details).
Severe haemorrhage not controlled by local pressure requires the streptokinase infusion to be stopped. Tran-examic 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.
Administration. Overinfusion of streptokinase may occur if a drop-counting infusion pump is employed. 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.
Aortic dissection. A report of 4 cases of the inappropriate use of streptokinase in patients with aortic dissection misdiagnosed as myocardial infarction. 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.
Cardiopulmonary resuscitation. Thrombolytics are not recommended after prolonged or traumatic cardiopulmonary resuscitation because of the risk of haemorrhage. However, studies in 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.
Pregnancy. Thrombolytics are generally contra-indicated in pregnancy. However there are a few reports of their use and these have been briefly reviewed. 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.
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.
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.
Streptokinase: Uses. Preparations
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