a) Dose - 16 to 20 mL (4 to 5 g) of Amicar(R) Injection in 250 mL of diluent, administered by infusion during the first hour of treatment; then a continuing infusion at a rate of 4 mL (1 g) per hour in 50 mL of diluent; usually continued for about 8 hours or until the bleeding situation has been controlled.

a) Reperfusion dysrhythmias are common after the use of thrombolytics in the setting of acute myocardial infarction. A wide variety of atrial and ventricular dysrhythmias have been documented, including bradycardia, idioventricular rhythm, premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation (Collen et al, 1984; Prod Info Activase(R) alteplase, recombinant, 1996; Meinertz et al, 1988; Vallance et al, 1985; Been et al, 1985; Ikram et al, 1986; Kasper et al, 1986; Boissel et al, 1996; Bossaert et al, 1988; Jackson, 1987; Monnier et al, 1987).
b) These are related to the reperfusion of ischemic myocardium, rather than a direct dysrhythmogenic effect of thrombolytic therapies per se. Reperfusion dysrhythmias should be anticipated in patients receiving thrombolytic therapy for acute myocardial infarction. Dysrhythmias generally respond to conventional ACLS protocols.

a) CASE REPORT - Cholesterol crystal embolization occurred after alteplase thrombolysis procedure (Bhardwaj et al, 1989). The patient had a history of hypertension and hypercholesterolemia. The authors suggested that in this case, since no mechanical disturbances occurred, that the thrombolytic therapy may have destabilized a protective thrombus leading to the release of atheromatous debris into the arterial circulation.

a) CASE SERIES - The onset of fresh arterial occlusions was described in 11 patients receiving streptokinase infusions for chronic arterial occlusive diseases (Martin et al, 1969). Coagulation studies revealed decrease of whole blood calcification time and thromboplastin time. Mechanisms for onset of fresh arterial occlusions were not elucidated.

a) Hypotension has been reported in small numbers of patients receiving intravenous anistreplase (Meinertz et al, 1988; Anderson et al, 1988; Castaigne et al, 1987; Lenhoff et al, 1987; Timmis et al, 1987; Brochier et al, 1987; Kasper et al, 1986).
b) Bradycardia with hypotension have also been reported with intracoronary anistreplase (Bossaert et al, 1988; Jackson, 1987; Monnier et al, 1987).

a) Hypotension, thought to be a manifestation of a hypersensitivity reaction to reteplase, occurred in 2 of 3004 patients in one large trial (Anon, 1995).

a) In a study involving 98 patients with acute myocardial infarction, rapid IV infusion of streptokinase via peripheral vein over 30 minutes was associated with significant decreases in systolic and diastolic pressures. Hypotension was generally transient (9 minutes, range 2 to 30 minutes); however, in some patients, hypotension was severe and persisted for more than 1 hour (Markenvard et al, 1997; Herlitz et al, 1993; Lew et al, 1985).

a) Single case reports of subsequent complications occurring after intracoronary and intravenous infusion of streptokinase include hemorrhagic myocardial infarction (Little & Rogers, 1983; Mathey et al, 1982; Twidale et al, 1989), cardiac rupture (Vasilomanolakis et al, 1983), and mediastinal hemorrhage (Singh et al, 1983), and coronary artery aneurysm (Chen et al, 1990).
b) Myocardial rupture has been reported following the use of streptokinase for myocardial infarction (Van Doorn et al, 1992; Stiegel et al, 1987; Kao et al, 1984; Hollander et al, 1984). It is not clear whether the rupture is due to the myocardial infarction or the use of streptokinase.
c) CASE REPORT - Myocardial rupture occurred in a patient 12 hours after successful streptokinase recanalization (Hollander et al, 1984). It is postulated that streptokinase may cause reperfusion injury and convert a bland infarct to a hemorrhagic infarct. Ischemia may then extend beyond the initial area of necrosis resulting in possible cardiac rupture.
d) CASE REPORT - Ventricular rupture occurred after intravenous streptokinase and 10 hours after balloon angioplasty (Stiegel et al, 1987). A 2-centimeter long perforation was found in the infarcted area which was repaired with Teflon patching and saphenous vein grafting.
e) CASE REPORT - A patient had a hemorrhage in the area of myocardial necrosis after successful streptokinase recanalization (Kao et al, 1984). Hemorrhage was confined to muscle that was already necrotic.
f) CASE REPORT - Myocardial rupture occurred one hour after intravenous streptokinase was given for an acute anterior myocardial infarction (Van Doorn et al, 1992). Surgical repair was accomplished, with blood loss possibly reduced by administration of aprotinin, a protease inhibitor.

a) CASE REPORT - A case of hemorrhage into the myocardium in a patient with acute myocardial infarction who received urokinase is reported (Yasuno et al, 1984a). Urokinase was given through the infarct-related artery at 24,000 units/min for 10 minutes. During angiography, contrast medium extravasated from the right coronary artery, and at autopsy, marked hemorrhage in the posterior wall of the left ventricle was observed.
b) CASE SERIES - Hemorrhage in 30 patients who died after intracoronary perfusion of urokinase for acute myocardial infarction, was localized to the infarct area, and was due to the effects of reperfusion and large doses of urokinase (Fujiwara et al, 1986). Hemorrhage into the infarct area occurred in 15 patients all of whom received urokinase from 15 hours to 11 days after infarction.

a) Hemopericardium causing CARDIAC TAMPONADE has been observed following intravenous streptokinase for the treatment of pulmonary embolism (Giles et al, 1988). It is suggested that the possibility of hemopericardium causing tamponade should be considered when unexplained worsening of cardiac status occurs in a patient who has been treated recently with streptokinase for pulmonary embolism or myocardial infarction. The prevalence of this complication is about 0.3% (Renkin et al, 1991). Use of lytic therapy late in the course of myocardial infarction may increase this risk (Proli & Laufer, 1993).
b) Two patients who received intracoronary streptokinase for acute myocardial infarction and who subsequently developed hemopericardium with tamponade are reported (Walker et al, 1985). These patients began to experience symptoms of tamponade 8 and 10 days after streptokinase infusion, and in both cases a subxiphoid pericardial window resulted in release of 400 to 450 mL of grossly bloody fluid. The authors propose that the hemopericardium may have resulted from hemorrhage into coronary infarcts that were not salvaged by streptokinase. In these two cases, diffuse pericarditis was not found.
c) Two patients who were mistakenly believed to have acute myocardial infarction and given intravenous streptokinase subsequently developed hemopericardium. The first patient actually had thoracic and abdominal aortic dissection; he subsequently died after aortic repair was unsuccessful with massive bleeding. The second patient had pericardial disease; he survived after drainage of 1 liter hemorrhagic pericardial fluid (Blankenship & Almquist, 1989).

a) CASE SERIES - Bronchospasm has been reported in 3 of 50 patients receiving intravenous anistreplase as a 30 mg bolus (Kasper et al, 1986). Bronchospasm was also reported in anistreplase patients, but not heparin patients in another study (Meinertz et al, 1988).
b) CASE SERIES - Two patients experienced mild diaphoresis and dyspnea after treatment with anistreplase which resolved spontaneously within 10 minutes (Timmis et al, 1987).

a) Reversible bronchospasm has been reported (Brogden et al, 1973), as has a case of fatal bronchospasm possibly related to streptokinase (Shaw & Easthope, 1993).

a) Adult respiratory distress syndrome has been reported in one patient who received streptokinase intravenously for acute massive pulmonary embolism. Streptokinase may cause reperfusion edema which could contribute to the syndrome (Martin et al, 1983).
b) CASE REPORT - A case report describes a patient who received intra-arterial streptokinase for acute femoral artery occlusion and died from adult respiratory distress syndrome 96 hours after the initiation of streptokinase (Kerstein & Adinolfi, 1986). The authors speculate that elevated levels of fibrinogen degradation product D may be responsible for the pulmonary complications. In experimental animals, this fibrinogen degradation product causes pulmonary dysfunction and vascular leak.

a) In a total of 385 patients receiving intracoronary or intravenous anistreplase, adverse effects occurred in 21.5% (83 patients). Bleeding complications included hemoptysis and nasopharyngeal bleeding (Anderson et al, 1988; Jackson, 1987; Buchalter et al, 1987; Meinertz et al, 1988; Monnier et al, 1987; Brochier et al, 1987).

a) CASE REPORT - A subfascial thoracic hemorrhage developed in a 70-year-old woman after treatment with alteplase and heparin (Khanlou et al, 1999).

a) CASE REPORT - Hemothorax occurred 30 minutes after the intrapleural administration of urokinase in an 8-month-old boy with empyema and pneumonia. When the insertion of the chest tube produced only 5 mL of blood and no exudate, urokinase was administered. Thirty minutes after urokinase administration, the patient developed signs of circulatory insufficiency, a chest x-ray showed hemothorax, and 200 mL of blood was drained from the chest tube. Blood transfusion, administration of tranexamic acid, and resuscitation were successful (Blom et al, 2000).
b) CASE REPORT - Spontaneous pulmonary hemorrhage was reported in one patient who had received urokinase, alteplase, heparin, and aspirin during the course of treatment of an acute myocardial infarction (Nathan et al, 1992).

a) Fragmentation of arterial or venous thromboembolic occlusions during thrombolysis could result in embolism in other parts of the body, including the lung (Brogden et al, 1973). There are several cases of possibly associated pulmonary embolism during streptokinase therapy (Eklund et al, 1975; Gajewski, 1971; Robertson et al, 1970; Amery et al, 1970) Arnesen et al, 1978; (Goldsmith et al, 1981; Sugarman & Solomon, 1983; Jones et al, 1987; Holmstrom et al, 1990).
b) CASE REPORT - A massive, fatal pulmonary embolus occurred in a 52-year-old woman following 73 hours of continuous intravenous infusion of streptokinase (Gajewski, 1971).

a) CASE REPORT - A single case report implicating urokinase as contributing to a pulmonary embolus after lysing a right atrial thrombosis is presented (Hassall et al, 1983). The urokinase was administered to remove a thrombus from a central venous catheter in a 3-year-old boy receiving home total parenteral nutrition. A mass attached to the catheter, moving freely in the atrium, may have lysed secondary to the urokinase.

a) The GUSTO trial reported a total incidence of stroke of 1.5% in patients (n=10,268) treated with alteplase 100 mg. However, in patients older than 75 years of age, the incidence of stroke was increased to 3.9% (Anon, 1993a).
b) CASE SERIES - Intracranial hemorrhage occurred after treatment with alteplase for acute myocardial infarction in 6 patients (Kase et al, 1990).

a) Cerebrovascular accidents (CVA) following the use of intravenous anistreplase have been reported. These occurred more than 6 hours after the administered dose (Meinertz et al, 1988; Jackson, 1987; Bett et al, 1987; Brochier et al, 1987).

a) Intracranial bleeding occurs to a similar degree with reteplase and streptokinase. In a large trial (n=6010), stroke occurred in 36 patients receiving reteplase (n=3004) and in 30 receiving streptokinase (n=3006) (Anon, 1995).

a) Cerebral hemorrhage has occurred following streptokinase therapy (Eleff et al, 1990; Orr, 1970).
b) Risk factors for cerebral hemorrhage were evaluated in patients given thrombolytic therapy for acute myocardial infarction (De Jaegere et al, 1992). Over a period of 18 months, 24 of 2,469 patients experienced an intracerebral hemorrhage (1%), 16 of whom (66%) died as a result of bleeding. Risk factors associated with cerebral bleeding were the use of an oral anticoagulant prior to hospital admission, patient weight less than 70 kg, or patient age over 65 years.

a) Intracranial hemorrhage has been reported following urokinase use (Eleff et al, 1990; Hanaway et al, 1976).
b) CASE SERIES - Four patients receiving urokinase treatment for acute occlusive cerebral vascular disease developed intracerebral hemorrhage in the ischemic hemisphere within 24 hours of starting urokinase infusion (Hanaway et al, 1976). Three of the patients died.

a) Two cases of generalized tonic-clonic seizures occurring during combination therapy with alteplase and saruplase for acute myocardial infarction have been reported (Caramelli et al, 1992). Neither patient had a seizure disorder prior to this event; however, an ischemic etiology due to thromboembolic causes could not be ruled out.

a) Several cases of hallucinations, agitation, confusion, decreases in consciousness, and depression occurring during streptokinase therapy have been reported (Brogden et al, 1973).

a) The possible association of streptokinase therapy and Guillain-Barre Syndrome has been reported in several patients (Barnes & Hughes, 1992; Cicale, 1987; Leaf et al, 1984; Eden, 1983).

a) CASE REPORT - Neuralgic amyotrophy with severe pain and pareses in the upper extremities (Parsonage-Turner syndrome) occurred ten days after thrombolytic treatment with streptokinase 1.5 million IU in a 61-year-old man (Fink & Haupt, 1995). Other possible causes for the symptoms such as operative procedure, trauma, vaccination, infection, hypothermia and overuse could be ruled out, and a causal connection between streptokinase and the instance of neuralgic amyotrophy was judged to be probable. After three months of physical therapy and analgesic administration, the patient had improved.

a) Nausea and vomiting have been reported. These reactions are frequent sequelae of myocardial infarction and may or may not be attributable to alteplase therapy (Prod Info Activase(R) alteplase, recombinant, 1996).

a) Nausea and vomiting have been reported with intravenous anistreplase (Castaigne et al, 1987; Leizorovicz et al, 1987; Brochier et al, 1987; Kasper et al, 1986).
b) Eight of 83 patients receiving intracoronary anistreplase were described as having a syndrome of hyperthermia, shivering/rigors, back and abdominal pain, and nausea and vomiting (Jackson, 1987).

a) CASE REPORT - An 82-year-old man experienced odynophagia and complete dysphagia caused by hemorrhagic esophagitis a few hours after receiving alteplase (dose not specified) for an acute inferior- posterior myocardial infarction. Medical history included a long history of minor dyspeptic symptoms, a small diaphragmatic hernia, and pre-hospitalization treatment with aspirin (100 milligrams daily). Endoscopy 6 days after alteplase administration revealed total obstruction of the esophageal lumen by necrotic debris and bleeding tissue; biopsy specimens showed severe esophagitis with no malignant or dysplastic cells. Parenteral feeding was started 4 days after onset of symptoms; dysphagia improved during the 3-week hospitalization and endoscopy prior to discharge showed grade 4 esophagitis (Mosimann et al, 2000).

a) In a total of 385 patients receiving intracoronary or intravenous anistreplase, adverse effects occurred in 21.5% (83 patients). Bleeding complications were reported during 30 courses of the drug and included mild hematemesis (11 reports), slight gum bleeding (3 patients), and gastrointestinal bleeding (4 patients). Slight bleeding from the lips and face, mucosal bleeding, hemoptysis, retroperitoneal bleeding, hemorrhoidal bleeding, and thigh hematoma were reported by one patient each. Hematuria has also been reported in small numbers of patients in several studies (Jackson, 1987; Buchalter et al, 1987; Meinertz et al, 1988; Monnier et al, 1987; Brochier et al, 1987). Other studies have reported gum bleeding, mild upper gastrointestinal bleeding, and nasopharyngeal bleeding in small numbers of patients (Anderson et al, 1988; Kasper et al, 1986; Meinertz et al, 1988; Ikram et al, 1986).
b) Two deaths secondary to bleeding reactions were reported in a study comparing intravenous streptokinase and anistreplase. One death occurred in each treatment group. The deaths were attributed to retroperitoneal hematoma formation in one patient and intestinal occlusion by a small hematoma in the second (Brochier et al, 1987).

a) SPLENIC RUPTURE - Splenic rupture has been reported in 2 patients following the use of streptokinase for acute myocardial infarction (Weiner & Ong, 1989; Gardner-Medwin et al, 1989).

a) Massive retroperitoneal hemorrhage occurred in one patient who received intra-arterial urokinase for occlusion of the left limb of an aortoiliac Dacron graft (Perler et al, 1986).

a) Four healthy volunteers receiving anistreplase in doses of 2.5 to 7.5 units had increases in AST and ALT concentrations at 24 hours. Four patients had an increase in LDH and 3 had an increase in CPK 7 days after therapy (Marder et al, 1987).

a) A hepatitis-like reaction has been reported in one patient (Shepherd, 1976).
b) CASE REPORT - Elevated liver enzymes (AST, alkaline phosphatase) occurred in a patient who received intravenous streptokinase for left deep venous thrombosis (Rudolf et al, 1983). Hyperthermia also occurred with the liver function changes; AST remained elevated for 5 days. Upon rechallenge, temperature, AST, and alkaline phosphatase were again elevated within 24 hours. Three days after discontinuation, liver enzymes returned to normal.
c) CASE SERIES - Jaundice has occurred rarely following streptokinase administration (Gilutz et al, 1996; Mager et al, 1991). In two of the reported cases, the patients had G6PD deficiency; in another case, jaundice developed 48 hours after a hypersensitivity reaction. The symptoms resolved over three days to two weeks. A fourth case of streptokinase-induced jaundice was characterized by G6PD deficiency with hemolysis, elevated total (primarily unconjugated) serum bilirubin of 7.3 milligrams and normal aminotransferase and alkaline phosphatase concentrations (Sood & Midha, 2000).

a) Retroperitoneal hemorrhage from a renal angiomyolipoma has been reported immediately following administration of alteplase in a single patient (Kaplan et al, 1992).

a) Hematuria has been reported in small numbers of patients in several studies (Jackson, 1987; Buchalter et al, 1987; Meinertz et al, 1988; Monnier et al, 1987; Brochier et al, 1987).

a) CASE REPORT - Hematuria and glycosuria occurred in a 50-year-old man following 67 hours of streptokinase infusion for venous thrombosis in the right calf and thigh (Spangen et al, 1976).

a) CASE REPORT - Eight days after receiving thrombolytic therapy for acute myocardial infarction with streptokinase, a 53-year-old man developed acute tubular necrosis and serum sickness. Past relevant history in this patient included a previous cellulitis suggestive of a streptococcal infection, which may have produced the cross reactivity to streptokinase due to the antigenic similarity between the group A streptococcus (most likely responsible for the cellulitis) and the group C streptococcus used to produce the streptokinase. Development of serum sickness and renal failure in this patient is unique among the documented cases in that IgG anti-streptokinase antibodies were detectable in his serum before initiation of therapy and then rose sharply after treatment (Davies et al, 1990).
b) CASE REPORT - A 38-year-old man developed a hypersensitivity-induced interstitial nephritis after receiving streptokinase for recurrent pulmonary embolism (Pick et al, 1983).
c) CASE REPORT - Crescentic glomerulonephritis occurred 4 to 5 weeks after intravenous infusion of streptokinase (Murray et al, 1986). The patient also had a group G streptococcal throat infection 13 days prior to the appearance of purpura, swelling of hands and feet, proteinuria, hematuria, and elevated BUN and creatinine. The possibility that these findings were secondary to a hypersensitivity reaction to streptokinase is proposed.

a) The bleeding associated with thrombolytic therapy can be categorized into 2 groups. The first category is superficial or surface bleeding (primarily observed at disturbed sites including venous cutdowns, and arterial punctures). The second category is the internal bleeding involving the gastrointestinal tract, genitourinary tract, retroperitoneal sites, or intracranial sites. Systemic fibrinolysis has been less than that produced by streptokinase; however, bleeding incidences are similar (Khanlou et al, 1999; Van Schaeybroeck et al, 1998; Anon, 1993; Anon, 1990; Califf et al, 1988; Mueller et al, 1987; Topol et al, 1987).
b) Although use of thrombolytic therapy in premenopausal women is relatively uncommon, active menstrual bleeding might be considered a relative contraindication to the use of alteplase due to the risk of uterine hemorrhage. However, intravenous infusion of alteplase 100 mg was used successfully in a 29-year-old actively menstruating woman with an acute myocardial infarction (Chop et al, 1991).

a) Clinical trials using intravenous anistreplase have demonstrated significant reductions in hemoglobin concentrations (Lenhoff et al, 1987; Bett et al, 1987; Bassand et al, 1989), euglobin lysis time (Marder et al, 1987; Bonnier et al, 1988), plasminogen levels (Marder et al, 1986; Marder et al, 1987; Kasper et al, 1984), and fibrinogen levels (Marder et al, 1986; Marder et al, 1987; Kasper et al, 1986; Seabra-Gomes et al, 1987; Anderson et al, 1988; Bonnier et al, 1988; Bassand et al, 1989; Meinertz et al, 1988; Bett et al, 1987). Some of these changes appeared to be dose-related.
b) Significant increases in activated partial thromboplastin time (APTT) (Bett et al, 1987), reptilase time (Kasper et al, 1984; Been et al, 1985) and thrombin time (Been et al, 1985) have been reported for patients who received intravenous anistreplase. The elevation in reptilase time persisted for more than 10 hours, thus indicating prolonged fibrinolytic efficacy (Kasper et al, 1984).

a) Minor bleeding often occurs at invaded or disturbed sites. Severe internal bleeding (gastrointestinal, genitourinary, retroperitoneal, intracerebral) may occur. Several fatalities due to serious internal bleeding have occurred (Prod Info Streptase(R), streptokinase, 1998; Eriksen et al, 1992; Ness et al, 1974).
b) CASE SERIES - Bleeding and extravasation of contrast material has been reported in 4 patients who received local administration of streptokinase for thrombosed dacron grafts. Graft material was surgically placed 1 month to 6 years before streptokinase infusion at 5000 to 10,000 units/hour. Streptokinase may be responsible for lysis of fibrin in the graft interstices allowing leakage of contrast material (Rabe et al, 1982).
c) CASE REPORT - Major hemorrhage occurred following intrapleural streptokinase administration in a 36-year-old man. The total dose was 500,000 units administered via chest tube, resulting in hematuria, GI bleeding, oozing from puncture sites and epistaxis (Godley & Bell, 1984).
d) CASE REPORT - Retroperitoneal hemorrhage from an undiagnosed renal adenocarcinoma occurred 6 hours after streptokinase infusion for suspected myocardial infarction (Johnston et al, 1991).
e) CASE REPORT - Femoral neuropathy, thought to be due to bleeding in the iliac and psoas muscle sheaths, has been reported in a patient given streptokinase for ergotism (Ganel et al, 1979). Bleeding into the mediastinum with subsequent phrenic nerve hemorrhagic compression was reported (Seaberg & Generalovich, 1989).
f) CASE REPORT - In a 62-year-old man, trigeminal nerve root hemorrhage with resultant neuropathy was attributed to the combined effects of a head injury and streptokinase administration for acute myocardial infarction. Brain imaging revealed left trigeminal nerve root hemorrhage. The authors ruled out other potential etiologies including trigeminal neuroma and vascular malformation. Sensory symptoms persisted through 18 months of follow-up despite hemorrhage resolution (Almeida et al, 1999).
g) CASE REPORT - Intravenous streptokinase for acute myocardial infarction was associated with uvula hematoma in a mechanically-ventilated 72-year-old man. The hematoma went unnoticed until an unsuccessful attempt at extubation revealed an enlarged and bruised uvula obstructing the airway, necessitating uvulectomy. The authors recommended laryngoscopy prior to extubation in patients exposed to thrombolysis while intubated (Gill & Sadler, 1999).
h) CASE REPORT - Within hours of receiving topical streptokinase 100,000 international units to clear an endotracheal tube blood clot, a patient died of exsanguination. Mechanical ventilation was initially required for lung carcinoma-related hemoptysis and hypoxemia. The authors recommended lower, diluted topical streptokinase doses with careful monitoring because of the possibility of inducing a systemic lytic state (Bansal & Brandstetter, 1999).
i) Streptokinase caused platelet aggregation in 14 of 100 normal volunteers. Aggregation was associated with the presence of an anti-streptokinase antibody that binds to the streptokinase-plasminogen complex on the platelet surface. The therapeutic effectiveness of streptokinase may be limited in those patients who develop anti-streptokinase antibody and platelet aggregation (Vaughan et al, 1991).
j) Several cases of plasmocytosis were reported in patients receiving streptokinase for chronic arterial occlusion (Straub et al, 1974). Blood plasma cells were noted to increase from 0% to to 37% (average 2600/mm cu). Leukocytosis was present and lymphocytes and eosinophils tended to decrease. Proteinuria and increases of serum creatinine were noted on several occasions. The authors suggest that an immune mechanism is responsible for plasmocytosis secondary to streptokinase.

a) The most common complication observed with urokinase is overt bleeding or an unexplained fall in the hematocrit (Genton & Wolf, 1968; Kamitani & Ban, 1972; Litman et al, 1971; Sasahara et al, 1972; Stengle, 1970; Tow et al, 1967).
b) Eighty-two patients were treated with urokinase (normal dose) for pulmonary embolism (Sasahara et al, 1972). Thirty-six of the 82 patients demonstrated hemorrhagic complications and 20 of the 82 patients experienced bleeding at cut down or arterial puncture sites.

a) Bleeding is a potential complication of reteplase therapy; in clinical trials, the incidence of hemorrhage has been similar to that of alteplase and streptokinase (Anon, 1995; Smalling et al, 1995). In one large trial (n=6010), the incidence of bleeding with reteplase and streptokinase was 15.4% and 15.5%, respectively; almost all patients received both aspirin and heparin concurrently with the thrombolytic (Anon, 1995).

a) Hemorrhage is the major complication of therapy. Some studies suggest this may be reduced by not exceeding single bolus doses of 40 mg and reducing the dose of concomitant heparin (Anon, 1997).
b) In a large phase II trial (ASSENT-1, n=3235), intracranial hemorrhage occurred in 25 patients (0.77%); 16 patients (0.94%) were receiving tenecteplase (TNK) 30 mg and 9 patients (0.62%) were receiving TNK 40 mg. Severe bleeding episodes occurred in 1.6% of patients receiving doses of either 30 mg, 40 mg, or 50 mg (Van de Werf et al, 1999).

a) ANISTREPLASE

a) One patient was reported to have a severe but reversible ischemia of the leg after administration of anistreplase 30 mg as an intravenous bolus, possibly due to emboli (Timmis et al, 1987). A second patient was described as having had a shower of emboli to the lower trunk and legs 18 hours after treatment with anistreplase. This resulted in gangrene of the toes, with patches of skin and muscle necrosis. However, this phenomenon was also reported in one control patient (Ikram et al, 1986).

a) Embolism during thrombolysis and myocardial infarction during or within 24 hours after treatment has been reported occasionally, although there is no clear evidence that the use of streptokinase is associated with an increased risk as compared with anticoagulant therapy (Singh & Ruttley, 1986).
b) In one patient, on angiography, fragments of material occluding the left main coronary artery were dislodged and embolized distally after streptokinase infusion (Menke et al, 1986). At autopsy, multiple intramyocardial vessels were occluded with thrombi.
c) Cholesterol embolism is a rare but notable complication of thrombolytic therapy that is associated with a high mortality rate (Rivera-Manrique et al, 1998). Cholesterol embolization occurs from atherosclerotic plaques as fibrinolysis destroys the adherent platelet-fibrin thrombi normally covering ulcerated plaques (Schwartz & McDonald, 1987). In both cases reported here, evidence for distal arterial embolization occurred after intravenous streptokinase given for myocardial infarction. Skin biopsy from both patients revealed cholesterol microvascular embolization. Systemic streptokinase may increase the risk for developing this syndrome of cholesterol embolization.
d) CASE REPORT - A fatal case of cholesterol embolization occurred in a 67-year-old man being treated for acute myocardial infarction with intravenous streptokinase; he developed an abrupt pain in his first left toe, followed immediately by livedo reticularis over his lower extremities and lower hemiabdomen, within 10 hours of hospitalization (Rivera-Manrique et al, 1998).
e) CASE REPORT - A similar case of cholesterol embolization is described in which intravenous streptokinase was given for deep venous thrombosis (Ridker & Michel, 1989). Lower extremity arterial occlusion occurred, which, upon biopsy of the leg, revealed cholesterol deposition in small arteries. Necrosis of several toes required amputation.
f) CASE REPORT - A case of cholesterol embolization to the kidney in a renal transplant patient is reported (Pirson et al, 1988). Streptokinase was given intravenously for acute myocardial infarction. Subsequently, renal function deteriorated. Renal biopsy was consistent with cholesterol embolism. Ultrasonography revealed extensive aortic atherosclerosis. Fibrinolysis with consequent embolization secondary to streptokinase is proposed as the mechanism for this transient episode of renal dysfunction. A similar case where cholesterol embolization to the kidneys, adrenal glands, gastrointestinal tract, psoas muscle, and ovary was documented at autopsy was reported (Queen et al, 1990).

a) Platelet aggregation as measured in vitro with a turbidimetric method has been shown to be enhanced by urokinase therapy (Griguer et al, 1980). Patients with myocardial infarction and pulmonary emboli had increased platelet aggregation compared to control patients which was enhanced even further if the patients were treated with urokinase. Dipyridamole could inhibit the increased platelet aggregation. No explanation for these findings was presented. Spinal hematoma formation associated with spinal epidural anesthesia is reported in one case (Dickman et al, 1990).
b) The use of intra-arterial urokinase could possibly be responsible for thrombolysis within occluded vessels proximally, but with distal embolic occlusion secondary to the effects of fibrin fragments lysed from the original thrombus. Five such distal emboli occurred in five of thirty-five patients given urokinase for arterial ischemia of the lower extremities. Five other patients also experienced groin hematomas secondary to the arterial administration of urokinase (Fiessinger et al, 1986).
c) Arterial embolization to the iliac bifurcation from a left ventricular mural thrombus is reported (Paulson & Miller, 1988). Urokinase was given by local intra-arterial infusion to treat femoral artery thrombosis. Thrombolysis was unsuccessful; however, enough systemic thrombolytic effect was present to probably account for embolization of the mural thrombus.

a) Facial flushing immediately following the administration of anistreplase has been commonly reported (Kasper et al, 1986; Lenhoff et al, 1987; Leizorovicz et al, 1987; Ikram et al, 1986; Monnier et al, 1987; Brochier et al, 1987; Prod Info Eminase(R), anistreplase, 1996).

a) Hematomas and oozing from intravenous access sites is reported commonly with anistreplase (Jackson, 1987; Marder et al, 1986; Lenhoff et al, 1987; Timmis et al, 1987; Leizorovicz et al, 1987; Buchalter et al, 1987; Ikram et al, 1986; Kasper et al, 1986; Been et al, 1985; Monnier et al, 1987; Brochier et al, 1987; Bett et al, 1987).
b) Two patients defined as having peripheral hyperplasminemia (fibrinogen of less than 100 mg% and Factors V and VIII of less than 75% of baseline) after receiving intracoronary anistreplase had oozing from their puncture sites, however none required transfusion (Kasper et al, 1984).

a) Rash/dermatitis has been reported in patients who have received anistreplase (Buchalter et al, 1987; Meinertz et al, 1988; Prod Info Eminase(R), anistreplase, 1996).

a) Dermatologic reactions, morbilliform, erysipelas-like rash occur rarely (Dukes, 1975; Prod Info Streptase(R), streptokinase, 1994).

a) Hemorrhagic bursitis of the knee was reported in a single patient in association with the use of alteplase plus intravenous heparin for acute myocardial infarction (Perazella & Buller, 1991). Pain and swelling of the knee occurred 36 hours after the alteplase was given, and approximately 60 mL of blood was aspirated from the prepatellar bursa and the lateral extraarticular subcutaneous space. Recurrent bursal swelling, decreased hematocrit, and postinfarction angina further complicated the hospital course.

a) In healthy volunteers receiving 2.5 to 7.5 units of anistreplase, 5 of 10 patients complained of muscle pain 12 to 24 hours after administration of the drug (Marder et al, 1987).

a) Two cases of hemarthrosis occurred in previously damaged joints (Oldroyd et al, 1990). Both patients received streptokinase 1.5 million units intravenously over one hour for acute myocardial infarction. Six to 12 hours after the infusion, increased pain in the right knee in one patient and the right elbow in the other occurred. Aspiration of both joints revealed heavily blood-stained fluid without crystals. In patients with active joint disease, hemarthrosis is an uncommon complication of intravenous streptokinase.

a) CASE REPORT - Neuralgic amyotrophy with severe pain and pareses in the upper extremities (Parsonage-Turner syndrome) occurred ten days after thrombolytic treatment with streptokinase 1.5 million IU in a 61-year-old man (Fink & Haupt, 1995). Other possible causes for the symptoms such as operative procedure, trauma, vaccination, infection, hypothermia and overuse could be ruled out, and a causal connection between streptokinase and the instance of neuralgic amyotrophy was judged to be probable. After three months of physical therapy and analgesic administration, the patient had improved.

a) CASE REPORT - Streptokinase therapy of acute myocardial infarction might have precipitated severe rhabdomyolysis with extensive skin necrosis and acute renal failure necessitating dialysis in a 76-year-old man. The peak serum creatine kinase level was 85,000 units/liter. Scintigraphy indicated acute myocyte injury in the lower limbs (Emmett et al, 1999).

a) CASE REPORT - A report of anaphylaxis developed 30 minutes after alteplase infusion was initiated in a 70-year-old woman with no history of allergies. Her symptoms included acute severe sinus tachycardia and hypotension, followed by cyanosis and loss of consciousness. Serum samples analyzed with radioimmunoprecipitation assay were negative for antibodies to alteplase, but results in a subsequent assay (enzyme-linked immunoabsorbent assay) were positive for IgE antibodies to alteplase (Rudolf et al, 1999).
b) Two cases of alteplase-induced anaphylactoid reaction with angioedema occurred in elderly women being treated for acute ischemic stroke (Hill et al, 2000).
c) In one case of allergic reaction, the authors speculated that the patient with a history of several angioedema episodes might have had an undiagnosed complement C1 esterase inhibitor deficiency (Hill et al, 2000).
d) Another patient experienced unilateral tongue and lip swelling 30 minutes after completion of the alteplase infusion. She recovered uneventfully with supportive care. A possible predisposing factor was angiotensin-converting enzyme inhibitor (ACEI) therapy, which inhibits plasma kininases (Hill et al, 2000).

a) Eight of 83 patients receiving intracoronary anistreplase were described as having a syndrome of hyperthermia, shivering/rigors, back and abdominal pains, and nausea and vomiting (Jackson, 1987). Rigors have also been reported in one patient with anistreplase (Buchalter et al, 1987).

a) Anaphylactic reactions attributable to streptokinase have been observed rarely. The reactions have ranged in severity from minor breathing difficulties to bronchospasm, periorbital swelling, or angioedema (Gilutz et al, 1996) Prod Info Streptase(R), 1996; (Bednarczyk et al, 1989; Tisdale et al, 1989; McGrath et al, 1985; McGrath & Patterson, 1984; Baumgartner & Davis, 1982; Thayer, 1981). Milder allergic effects such as urticaria, itching, flushing, nausea, headache and musculoskeletal pain occur in about 12% of patients (Prod Info Streptase(R), 1996; (Thayer, 1981).
b) During a case of anaphylaxis to streptokinase in a 49-year-old man, elevated concentrations of specific IgE and IgG concentrations were demonstrated in vitro, and in vivo testing revealed cutaneous immediate-hypersensitivity with atypical wheal and flare reaction. The authors suggested the use of a skin test prior to treatment, as in vitro testing is impractical since rapid institution of thrombolytic therapy is required in post-MI patients. The authors currently use a skin test of 100 IU intradermal streptokinase, given 15 minutes prior to infusion. This reportedly allows an immediate reaction to occur without a large delayed reaction. If a positive immediate skin test develops, urokinase is recommended (Dykewicz et al, 1986).

a) Allergic phenomena (including anaphylaxis) have been reported rarely. Anaphylaxis was reported in less than 0.1% of patients treated with tenecteplase, and causality was not established (Prod Info TNKase(TM), tenecteplase, 2000).

a) CASE REPORT - An 11-year-old boy experienced hypotension, tachycardia, hyperthermia, decreased oxygen saturation, rigors, chills, dyspnea, and restlessness within 15 minutes after completion of an intravenous bolus of urokinase (Franco et al, 1998).
b) CASE REPORT - A 48-year-old woman developed chest pain, nausea, and ventricular fibrillation after receiving 15 mL of a urokinase 100,000 units in 50 mL saline solution intrapleurally. She had a previous allergic reaction (rash) to streptokinase. The woman recovered from the anaphylactic reaction without sequelae (Alfageme & Vazquez, 1997).

a) Serum sickness, with arthralgias, hyperthermia, purpura and decreased renal function, probably due to streptokinase, has been reported in one patient given low doses of streptokinase intraarterially, 5000 units/hour, for left leg claudication (Totty et al, 1982a). Similar findings, with documentation of IgA antibody to streptokinase, has been reported in a patient given streptokinase as thrombolysis after myocardial infarction (Zilliox et al, 1993).
b) A case of possible serum sickness with vasculitis is reported in one patient treated for pulmonary embolism with streptokinase. Six days after streptokinase was discontinued, abdominal pain, malaise, and bilateral wrist pain appeared. A rash that was nonpruritic, palpable, and purpuric was noted the next day. The rash improved rapidly over the next four days, but weakness and fatigability continued for about 6 weeks. This may have been a systemic hypersensitivity vasculitis secondary to streptokinase (Thompson et al, 1985). Similar incidences occurred in three patients; two had skin biopsies consistent with leukocytoclastic vasculitis (Noel et al, 1987).
c) Other authors have described serum sickness reactions to streptokinase (Ong et al, 1988; Davies et al, 1990; Patel et al, 1991; Schweitzer et al, 1991; Clesham et al, 1992).
d) CASE REPORT - A 53-year-old man developed acute tubular necrosis and serum sickness 8 days after receiving streptokinase for acute myocardial infarction. Past relevant history in this patient included a previous cellulitis suggestive of a streptococcal infection, which may have produced the cross reactivity to streptokinase due to the antigenic similarity between the group A streptococcus most likely responsible for the cellulitis and the group C streptococcus used to produce the streptokinase. Development of serum sickness and renal failure in this patient is unique among the documented cases in that IgG anti-streptokinase antibodies were detectable in his serum before initiation of therapy and then rose sharply after treatment (Davies et al, 1990). A similar case occurred in a 62-year-old man, except that anti-streptokinase antibodies were not detected (Birnbaum et al, 1993).

a) The manufacturer cautions that streptokinase effectiveness may be decreased if given within 5 days to 12 months after prior use of streptokinase or anistreplase, or after streptococcal infection (Prod Info Streptase(R), streptokinase, 1994). This is due to the formation of antistreptokinase antibodies which may result in resistance to thrombolysis. Patients with high antibody titers who are nevertheless given streptokinase are more prone to experience adverse reactions (hypotension; serum sickness).

a) RATS: There was no evidence of fetal anomalies when rats were administered reteplase at doses up to 15 times the human dose (4.31 units/kg) (Prod Info RETAVASE(R) IV injection, 2006).

a) RABBITS: No fetal anomalies were observed when rabbits were given tenecteplase (Prod Info TNKASE(R) IV injection, 2006).

a) MICE, RABBITS: There was no evidence of harm to the fetus when mice and rats were exposed to urokinase at doses up to 1000 times the human dose (Prod Info KINLYTIC(TM) IV injection, 2008).

a) CASE REPORTS: In a series of two case reports, urokinase was given as an intravenous infusion at a rate of 5000 units/hour for 36 hours for deep vein thrombosis. One woman was treated at 33 weeks' gestation and the second woman was treated at 11 weeks' gestation; in both cases the clots resolved and normal infants were delivered without complications (La Valleur et al, 1996). The safe and effective use of urokinase, using standard doses, in one pregnant patient with pulmonary embolism has been reported (Delclos & Davila, 1986).

a) RABBITS: Alteplase was embryocidal in rabbits when administered in doses of approximately 2 times (3 mg/kg) the human dose for acute myocardial infarction (Prod Info Activase(R) intravenous injection, 2015).
b) RATS, RABBITS: No maternal or fetal toxicity was evident at 0.65 times (1 mg/kg) the human dose in pregnant rats and rabbits given alteplase during the period of organogenesis (Prod Info Activase(R) intravenous injection, 2015).

a) RABBITS - An abortifacient effect has been demonstrated in rabbits when given reteplase in doses 3 times the human dose (0.86 units/kg). Hemorrhaging in the genital tract, leading to abortions in mid-gestation, has been reported when reteplase was administered to pregnant rabbits (Prod Info RETAVASE(R) IV injection, 2006).

a) RABBITS - Maternal and embryo toxicity has been observed in rabbits when given multiple tenecteplase IV administrations, but not with single IV administration. In rabbits given tenecteplase 0.5, 1.5, and 5 mg/kg/day, vaginal hemorrhage resulted in maternal deaths. Subsequent embryonic deaths were secondary to maternal hemorrhage and no fetal anomalies were observed. In rabbit studies, the no observable effect level of a single IV administration of tenecteplase on maternal or developmental toxicity was 5 mg/kg (approximately 8 to 10 times the human dose) (Prod Info TNKASE(R) IV injection, 2006).

a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to alteplase, streptokinase, and tenecteplase (Prod Info Activase(R) intravenous injection, 2015; Prod Info STREPTASE(R) injection, 2002; Prod Info TNKASE(R) IV injection, 2006).

a) RATS: There were no effects on fertility when rats were exposed to reteplase at doses up to 15 times the human dose (4.31 units/kg) (Prod Info RETAVASE(R) IV injection, 2006).

a) MICE, RATS: There was no evidence of impaired fertility in mice and rats when given urokinase at doses up to 1000 times the human dose (Prod Info KINLYTIC(TM) IV injection, 2008).

a) ACUTE ISCHEMIC STROKE
b) ACUTE MYOCARDIAL INFARCTION
c) PULMONARY EMBOLISM
d) RESTORATION OF FUNCTION TO OCCLUDED CENTRAL VENOUS ACCESS

a) THROMBOSIS, CORONARY ARTERIAL, ACUTE: 10 unit bolus IV, over 2 minutes; the second 10-unit dose is given 30 minutes after the first dose. Reteplase is incompatible with heparin; therefore, if the drug is to be administered through an IV line containing heparin, the line should be flushed before and after reteplase administration with either 0.9% sodium chloride or 5% dextrose solution (Prod Info Retavase(R), reteplase recombinant, 2001).

a) EMBOLISM: An intravenous loading dose of 250,000 International Units (IU) is given over 30 minutes; maintenance infusions of 100,000 Internationa Units/hour are given over 24 to 72 hours (Prod Info Streptase(R), streptokinase, 1998).
b) MYOCARDIAL INFARCTION: Intravenous streptokinase, given in a total dose of 1.5 million International Units over 60 minutes; for intracoronary infusion, a bolus dose of 20,000 International Units is followed by an infusion of 2000 International Units per minute for 60 minutes (Prod Info Streptase(R), streptokinase, 1998).

a) MYOCARDIAL INFARCTION: For thrombolysis in myocardial infarction, the manufacturer recommends basing dosage on patient weight according to the following table (Prod Info TNKase(TM), tenecteplase, 2000). The dose should be administered as a bolus over 5 seconds (Prod Info TNKase(TM), tenecteplase, 2000).
b) MAXIMUM DOSE: A total dose should not exceed 50 mg (Prod Info TNKase(TM), tenecteplase, 2000).

a) PULMONARY EMBOLISM: An intravenous priming dose of urokinase 4400 International Units/kg over 10 minutes; then a continuous infusion of 4400 International Units/kg/hour for 12 hours at a rate of 15 mL/hour (Prod Info KINLYTIC(TM) IV injection, 2008).

a) THROMBOLYSIS OF INTRAVASCULAR THROMBOSIS
b) TREATMENT OF CATHETER OCCLUSION

a) Safety and efficacy have not been established.

a) ARTERIAL THROMBOSIS: Loading Dose: Streptokinase 2000 units/kg and a maintenance dose of 2000 units/kg/hour for 6 to 12 hours were recommended in the Seventh American College of Chest Physicians (ACCP) guidelines for the treatment of thrombosis (Monagle et al, 2004).
b) In a case series, IV streptokinase (3000 units/kg bolus, then 1000 units/kg/hour) infusion administered 48 hours after catheterization, and continued for a means of 11.5 hours (range: 4 to 20 hours) has been shown to be effective in restoring distal pulses in pediatric patients aged 1 to 9 months (mean: 4 months) (Kothari et al, 1996).

a) Safety and efficacy have not been established.

a) ARTERIAL THROMBOSIS/DUCTUS ARTERIOUS: Intraarterial route: Loading dose: 4000 units/kg give IV over 10 minutes, followed by a maintenance dose of 4000 units/kg/hour infusion for 6 hours has been shown to be successful in restoring arterial pulse with no sequelae (Butera et al, 2004).

a) >58000 ku/kg (RTECS, 2002)

a) 34800 ku/kg (RTECS, 2002)

a) 4200 mg/kg (RTECS, 2002)

a) >10 gm/kg (RTECS, 2002)

a) >2727 ug/kg (RTECS, 2002)

a) >2727 ug/kg (RTECS, 2002)

a) >2727 ug/kg (RTECS, 2002)