Brief Review Thrombolytic Ann Bailey MD, J.C

385

Brief Review Thrombolytic Ann Bailey MD, J.C. Lydon MO, Fred J. Spielman MD therapy

Thrombolytic therapy represents a new medical ing allergic reactions in susceptible patients. It is approach to the treatment of patients with thrombo- isolated from the broth of group C streptococci. embolic disease. 1 Streptokinase and urokinase are Streptokinase is more widely used than urokinase, presently the only two thrombolytic drugs in use. being approved for use in pulmonary embolism, The advantage of thrombolytic agents is that they deep venous thrombosis, maintenance of patency of can dissolve thromboemboli, unlike the more con- vascular access devices and shunts and transmural ventional anticoagulant therapy with heparin and myocardial infarction.6 coumarin which is capable only of prevention of Urokinase was isolated from human urine by future clots. 2 Thrombolytic drugs, therefore, are Macfarlane and Pilling in 1946. 7 Urokinase is able to permit the return of blood flow through the non-allergenic, being derived from human protein. affected vessels, reducing pain and possibly the However, its cost is more than that of streptokinase morbidity and mortality associated with vascular and is approved only for pulmonary embolism. 6 occlusion, l Anaesthetists are likely to encounter patients who Mechanism of action are receiving thrombolytic therapy either in the These drugs have the ability to activate the body's operating room or in the intensive care unit. It is natural fibrinolytic system. When plasminogen is imperative, therefore, to have an understanding of converted to plasmin, it becomes a proteolytic agent the basic physiology and pharmacology of throm- capable of digesting fibrin, fibrinogen, prothrombin bolytic drugs as well as some practical insight into and Factors V & VIII. Fresh fibrin clots are lysed their clinical usage. with the generation of fibrin degradation products We will review the pharmacology, mechanisms (Figure). Urokinase activates plasminogen directly of action, indication for use, complications and by peptide bond cleavage at two different sites on contraindications to therapy with streptokinase and the plasminogen molecule. Streptokinase is an in- urokinase. direct activator. Initially it combines with plasminogen to form an activator complex. This com- Streptokinase and urokinase plex then converts free plasminogen to plasmin. 2 Streptokinase and urokinase are compared in Table Coagulation abnormalities should return to nor- I. Although discovered in 19333 the first intrave- mal within several hours of discontinuing treat- nous injection of streptokinase was not reported ment. Urokinase has a half-life of 16 minutes, while until 1955. 4 In 1959 it was shown to successfully streptokinase has two half-lives. The first is 18 lyse thrombi that had been experimentally induced minutes and represents clearance after binding with in forearm veins of volunteers. 5 Streptokinase is a antistreptokinase antibodies. The second involves foreign protein and therefore is capable of stimulat- the metabolism and excretion of the unbound drug and is not well understood. Sta'eptokinase has a half-life of 83 minutes by this mechanism, s From the Department of Anesthesiology, University of North Carolina at Chapel Hill, School of Medicine, Laboratory monitoring Chapel Hill, North Carolina 27514. Laboratory monitoring of flbrinogen, plasminogen Address correspondence to: Dr. Spielman. and partial thromboplastin time (PTT) does not

CAN ANAESTH SOC J L985 / 32:4 / pp385-9 386 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL

TABLE I Comparison of the features of strcptokinase and urokinase

Feature Streptokinase Urokinase

Source Group C streptococci Human kidney tissue culture; human urine Molecular weight 47,000 daltons 32,000-54,000 daitons Half-life 18 minutes 16 minutes Stability Room temperature 4~ Antigenicity Yes No Pyrogenicity Moderate Minimal Indications Pulmonmy embolism, deep-venous thrombosis, Pulmonaryembolism, occluded access shunts vascular access shunts, transmural myocardial infarction, arterial thrombosis Retail price ($US) per 250,000 IU (1985) $35 $135

Modified with permission of authors. 2

nase or heparin might be more effective. Patients STREPTOKINASE (SK) who show no evidence of fibrinolysis with uroki- ] PkASMINOGEN nase probably lack sufficient plasminogen sub- '1 strates. Heparin therapy should be initiated in these PLASMINOG EN patients. SK-PLASMINOGEN ...... ~'4 ( ...... UROKINASE COMPLEX PLASMIN

BLOOD I THROMBUS Clinical indications Thrombolytic agents have been investigated in LYRIC STATE DISSOLUTION numerous clinical situations. Many of these trials, however, have been criticized because of a lack of FIGURE Action of streptokinase and urokinase in achieving adequate data. 8 The United States Federal Drug thrombolysis. Reprinted with permission.' Administration has defined the clinical indications for these drugs (Table II). Streptokinase has been prove reliable in adjusting dosage. Monitoring is approved for treatment of acute pulmonary embo- useful, however, to determine whether systemic lism, deep venous thrombosis, acute myocardial fibrinolysis has been established. The most sensi- infarction and occlusion of access shunts and tive test for fibrinolysis is the whole blood euglo- intravascular or cavity catheters. Although under bulin lysis time, followed by the thrombin time. If investigation it is presently not approved for retinal these tests are unavailable, then PTT, prothrombin vein thrombosis, heart valve obstruction or haemo- time (PT) or fibrin degradation products should be thorax. Urokinase is approved for use in acute used. It is important that these tests are performed pulmonary embolism, occlusion of access shunts prior to initiating therapy in order to establish a and intravascular and cavity catheters. Presently it baseline or control and also to rule out a coagulation is not yet approved for vitreous haemorrhage or defect. A second set of tests should be performed renal-cortical necrosis. after 3-4 hours of therapy. A prolonged PT, PTT or decreased fibrinogen concentration will ensure that Pulmonary embolus systemic lysis has been established. 2 It is particular- One of the earliest uses of thrombolytic agents was ly important to perform coagulation studies early in the treatment of pulmonary embolism. Clinical after initiating streptokinase therapy because the trials conducted by the National Heart, Lung, and dosage regimen varies considerably due to dif- Blood Institute in 1973 and 1974 clearly docu- ferences in the titre of streptococcal antibodies. For mented the superiority of streptokinase and uroki- patients with very high levels of antibodies, urokinase as compared with heparin in resolving existing Bailey et al.: THROMBOLYTIC THERAPY 387

TABLE II Summary of clinical results in thrombolytic therapy extremities with streptokinase tended to preserve the anatomy and function of the venous valves more Condition Status often than did heparin. This observation may even- Pulmonary embolism Accelerated resolution of fresh tually prove important in attempts to prevent or emboli, improvement in reduce the occurrence of chronic venous insuffi- angiographic and ciency. haemodynamic parameters, possible lower mortality Deep vein thrombosis Lyses deep vein thrombosis more Acute myocardial infarction often and more completely than Angiographic studies have shown that coronary heparin, preserves venous artery thrombosis is present in about 85 per cent of valvular function and therefore patients with acute transmural infarction. Selective reduces frequency and severity intraeoronary infusion of streptokinase early in the of postphlebitic syndrome evolution of an acute myocardial infarction has Peripheral arterial Used for lysis of acute arterial resulted in successful recanalization in about 80 per occlusion thrombi and lysis of arterial cent of patients.~2 Patients with a recent (less than emboli, should not be used for arterial emboli originating from four to six hours) onset of typical chest pain with ST the left side of the heart segment elevation that persists after sublingual Myocardial infarction Does not decrease mortality nitroglycerin are excellent candidates for this treat- Occluded arteriovenous No controlled studies, should be ment. Reperfusion-associated arrhythmias may oc- shunts considered an altemative1o cur in as many as 80 per cent of patients given surgery intracoronary streptokinase. The most common are Retinal vessel occlusion Further studies required before accelerated idioventricular arrhythmias. 13 determining efficiency

Modified with permission. Peripheral arterial thrombosis M'arder VJ. Ann Intern Med 1979; 90: 802. Although the use of a balloon catheter has sim- plified the treatment of this vascular emergency, the technique is best suited for the removal of emboli pulmonary emboli. In addition, there was greater from large calibre arteries and is less effective when improvement in haemodynamic variables (right the distal arterial tree is involved, t4 The use of heart and pulmonary artery pressures) with lyric thrombolytic treatment in acute arterial thrombosis therapy than with heparin. Unfortunately, at the has been shown to be effective with marked present time there has been no demonstrable differ- improvement in the vast majority of patients, t2 The ence in mortality between patients given heparin advantages of infusing small amounts of thrombo- and those treated with thrombolytics for pulmonary lytic drugs directly into the affected area through the embolism. Many investigators believe, however, arterial catheter positioned adjacent to the thrombus that the use of thrombolytics (particularly in cases overcomes the limitations and complications of of recurrent thromboemboli) may prevent or mini- systemic administration. mize the development of pulmonary hypertension. Regardless of the drug employed, method of Deep-venous thrombosis infusion or pathology treated, the following factors will influence the success of thrombolytic therapy: The treatment of deep-venous thrombosis has in the (1) thrombi in small or totally occluded vessels are past been restricted to the use of heparin. Heparin difficult to lyse; (2) lesions greater than seven days exerts its anticoagulant effect by enhancing the old do not usually revolve; (3) massive clots are activity of antithrombin III, an a-globulin that difficult to lyse; (4) extremes in body temperatures inhibits the activated clotting factors XlIc~, Xlct, reduce the effectiveness of the fibrinolytie system. 8 Xcx, IXot and thrombin via binding or their serine residues. Recently, however, streptokinase has been found to be an equally effective and in some Complications ways superior mode of therapy. Kakkar et al.ll The use of these agents is associated with a high noted that lysis of deep-venous thrombi in the lower incidence of complications (Table III). The most 388 CANADIAN ANAESTHETISTS ~ SOCIETY JOURNAL

TABLE III Complicationsof thrombolytic therapy Distal embolization secondary to lysis of arterial thrombi has been reported. 17 It is speculated that Condition Status this complication occurs when a combination of Haemorrhage Overall incidence 30-50% fresh and old thrombus is present. Rapid lysis of the Chance of bleeding increased with fresh clot, along with arterial pulsations, may systemic administration. Usually liberate older and more resistant clot fragments. at site of venipunctures and arterial When peripheral embolizalion occurs, fibrinolytic cannulation Rarely will produce life-threatening GU, GI or CNS therapy can be continued as long as the patient is haemorrhage clinically stable and there is no danger of loss of Allergic reactions Nausea, vomiting, muscle and skeletal viability of the limb. However, significant occlu- pain, skin rash, headache, itching sion may require surgical intervention. (incidence 10-15%) Other complications include fever and allergic Anaphylaxis rare reactions. Up to 25 per cent of patients may have Consider steroid prophylaxis mild temperature elevations with streptokinase Fever Incidence 15-25% while less than 15 per cent of patients receiving Distal embolization Due to lysis of arterial thrombi urokinase demonstrate temperature elevations. I~ Acetaminophen has been an effective treatment for mild fever. Mild allergic reactions such as urticaria, common complication of fibrinolytic therapy is flushing, nausea, headache and muscle and skeletal haemorrhage. Bleeding following fibrinolytic treat- pain can occur in patients receiving streptokinase. 2 ment is due to depletion of clotting factors and lysis Severe allergic reactions with bronchospasm, an- of recently formed haemostatic plugs. 6 The inci- gioneurotic oedema and hypotension are rare. dence of bleeding has been reported to be as high as Minor reactions can be treated with antihistamines 30-50 per cent. t5 When administered systemically, at the time of detection. [t is not necessary to haemorrhage requiring transfusion occurs as often discontinue use of the agent. The administration of as 16 per cent of the time. If given regionally in 100 mg hydrocortisone prior to the institution of and smaller doses, the bleeding rate is the same as when every 12-24 hours during streptokinase therapy is systemically administered, but is of a minor degree useful in preventing these minor reactions. 2'6 and easily controlled. 16 The risk of haemorrhage Extremely rare reactions to streptokinase include increases with the length of infusion and is not diarrhoea, abdominal pain, hepatitis-like reaction, related to the degree of systemic fibrinolysis. 2 phlebitis and CNS effects such as delirium, depres- Bleeding most often occurs where invasive proce- sion and psychotic reaction. Cardiovascular com- dures are performed, such as surgical vascular ac- plications have included arrhythmias, dyspnoea and cess, arterial punctures and multiple venipunctures; tachycardia, a however, bleeding may also occur in the gastrointes- tinal and genitourinary systems and intracerebrally. Contraindications to therapy Mild bleeding, especially from vessel puncture The major complication associated with thrombo- sites in extremities, can often be controlled with lytic therapy is haemorrhage. Awareness of the mechanical compression. Occasionally, gauze profound alterations in the body's coagulation soaked with aminocaproic acid will aid in control- cascade caused by the use of these agents should ling stubborn oozing. Severe bleeding requires dis- lead to selection of patients in whom the risk of continuation of the fibrinolytic therapy. The short bleeding is minimal. 2 half-life allows rapid reversal of the drug effects. Absolute contraindications (Table IV) include a Fresh frozen plasma, fresh whole blood or several cerebrovascular procedure or process within the units of cryoprecipitate should be administered to preceding two months and an active internal bleed- more rapidly reverse the haemostatic alteration. ing state. Relative contraindications include those Although there are no studies documenting its conditions requiring fibrin plugs and strands for efficiency in this situation, parenteral aminocaproic normal haemostatis of healing, such as surgery or acid has been recommended to help control bleed- organ biopsy. The administration of thrombolytic ing in desperate situations. 2 drugs in the postpartum period or following lumbar Bailey el al.: THROMBOLYTIC THERAPY 389

TABLE IV Contraindicationsto fibrinolytictherapy pulmonary embolism trial: a national cooperative study. Circulation 1973; 47: Suppl 2: II 1-108. Condition Status 10 A Cooperative Study. Streptokinase-urokinase em- Absolute Active internal bleeding bolism trial: phase 2 results. JAMA 1974; 229: Recent cerebrovaseular accident or active 1606-13. neurovascular disease 11 Kakkar VV, Howe CC, Laws JW, Flane C. Late Relative Recent lumbar puncture, thoracentesis, major results of treatment of deep venous thrombosis. surgery Br Med J 1969; 1: 810-1. Patients already taking anticoagulantor 12 Anderson JL, Marshall HW, Bray BE et al. A ran- antiplatelet drugs Patients with active peptic ulcer disease, severe domized trial of intraeoronary streptokinase in hypertension, malignancy the treatment of acute myocardial infarction. N Engl Chronic hepatic or renal disease J Med 1983; 308: 1312-18. Heart disease likely to cause cerebral emboli, 13 Laffel GL, Braunwald E. Thrombolytic therapy. A such as atrial fibrillation new strategy for the treatment of acute myocardial infarction. N Engl J Med 1984; 311: 770-6. 14 Berni GA, Bandyk DF, Zierler RE, Thiele BL, puncture or thoracentesis is contraindicated. No Strandness DE Jr. Streptokinase treatment of acute anticoagulant or antiplatelet drugs should be admin- arterial occlusion. Ann Surg 1983; 198: 185-91. istered while the patient is receiving fibrinolytic 15 Genton E. Thrombolytic therapy of pulmonary therapy. Finally, streptokinase and urokinase thromboembolism. Prog Cardiovasc Dis 1979; 21: should not be given to patients prone to bleeding 333-41. complications which include those with hyperten- 16 Bookstein JJ. Selective fibrinolysis for peripheral sion or active peptic ulcer disease, is arterial disease. J Cardiovasc Med 1984; 9: 361-9. References 17 Wood WA, Tisnado J, Cho S-R. Visceral emboliza- 1 Jacobs J. Thrombolytic therapy. NC Med J tion during low-dose fibrinolysis of aortic graft 1984; 45: 297-301. occlusion. Am J Roentgenol 1983; 141: 1055-6. 2 Sharma GVRK, Celia G, Parisi AF, Sasahara AA. Thrombolytie therapy. N Engl J Med 1982; 406: 1268-76. 3 TiUett WS, Garner RL. The fibrinolytic activity of hemolytic streptococci. J Exp Med 1933; 58: 485- 502. 4 Sherry C. The fibrinolytic activity of sueptokinase activated human plasmin. J Clin Invest 1954; 33: 1054-63. 5 Johnson AF, McCarty WF. The lysis of artificially induced intravazcular clots in man by intravenous infusions of streptokinase. J Clin Invest 1959; 38: 1627-43. 6 Sasahara AA, Wall RT, Harbury CB. The use of fibrolytic agents. West J Med 1981; 134: 128- 33. 7 Mcfarlane RG, Pilling J. Observation of fibdn- olysis: plasminogen, plasmin, and antiplasmin con- tent of human blood. Lancet 1946; 2: 562-5. 8 Bell WR, MeekAF. Guidelines for the use ofthrom- bolytic agents. N Engl J Med 1979; 301: 1266- 70. 9 Sa~'aharaAA, Hyers TM, Cole CM. The urokinase