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Thrombolytic therapy in the treatment of peripheral arterial occlusions
SPECIAL CONTRIBUTION occlusion, peripheral arterial, tPA; tPA, arterial occlusion
Thrombolytic Therapy in the Treatment of Peripheral Arterial Occlusions Intra-arterial infusions of thrombo]ytic agents are useful adjuncts to surgery and percutaneous translumina] angioplasty The best results occur when the thrombus is Iysed within 30 days; however, successful thrombolysis has occurred up to four months after an arterial occlusion. Thrombolysis allows dissolution of thrombus in the small distal runoff vessels, decreasing outflow resistance and enabling the native artery or bypass graft to remain open longer. When native arteries are Iysed successfully, an underlying area of stenosis is usually identified and thus able to be corrected with either surgery or percutaneous transluminal angioplasty. When bypass grafts thrombose, thromboIytic agents are usually successful in Iysing the thrombus and identifying the cause for the thrombosis. With local intra-arterial infusions, side effects and complications may be kept to a minimum. [Olin JW, Graor RA: Thrombolytic therapy in the treatment of peripheral arterial occlusions. Ann Emerg Med November 1988;17:1210-1215.]
Jeffrey W OLin, DO, FACP Robert A Graor, MD Cleveland, Ohio From the Department of Peripheral Vascular Disease, Division of Internal Medicine, Cleveland Clinic Foundation, Cleveland, Ohio. Received for publication February 8, 1988. Accepted for publication July 22, 1988. Address for reprints: Jeffrey W Olin, DO, FACP, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44106.
INTRODUCTION Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality in the United States. Myocardial infarction and stroke are the two most common manifestations of atherosclerosis. More effective measures to prevent and treat stroke and myocardial infarction have become available, and therefore, patients are living longer, leading to a higher incidence of lower extremity occlusive disease. However, its diagnosis and management are often delayed and suboptimal. The most common causes of acute arterial insufficiency are thrombosis of native atherosclerotic arteries, thrombosis of bypass grafts, and emboli. Other causes include trauma, aortic dissection, drug abuse (IV injection of drags and ergot intoxication), trauma , and iliofemoral deep vein thrombosis (phlegmasia cerulea dolens and venous gangrene). A patient may present with a history of intermittent claudication that suddenly worsens, leading to rest pain (ie, progressive arteriosclerosis oblitera'ns with thrombosis in situ), or with a sudden onset of pain, pallor, pulselessness, paresthesias, or paralysis (acute arterial emboli or thrombosed b y p a s s graft). The classic teaching has been that thrombectomy, embolectomy, or surgical revascularization are the treatments of choice for acute arterial ischemia. In the last six years, there have been many studies that support the use of intra-arterial thromboiytic therapy in the management of patients with peripheral arterial occlusions. Tillett and Garner I discovered the fibrinolytic activity of hemolytic streptococci in 1933. Additional studies were performed in the late 1950s that further characterized the fibrinolytic activity of streptokinase.2, 3 During the next 20 years, several different thrombolytic agents were developed, and experience with them in the treatment of acute myocardial infarction, deep venous thrombosis, pulmonary emboli, and peripheral arterial occlusions grew. PRINCIPLES OF CLOT LYSIS Streptokinase, urokinase, and tissue-type plasminogen activator (tPA) are all commercially available and capable of acting as exogenous plasminogen activators. Streptokinase combines with the zymogen plasminogen to form an intermediate complex that further combines with additional plasminogen 17:11 November 1988
Annals of Emergency Medicine
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PERIPHERAL ARTERIAL OCCLUSIONS Olin & Graor
FIGURE 1. Administration of throm-
bolytic agent. FIGURE 2. Embolus of left common femoral artery. to form the active enzyme plasmin. Plasmin directly digests fibrin and fibrinogen. Streptokinase has been in use longer than urokinase or tPA, and more patients have been treated with it than with any of the other plasminogen activators. However, the drug is antigenic and has the potential for allergic reactions consisting of fever, chills, nausea, vomiting, hypotension, and anaphylaxis. If a patient has been previously exposed to streptococcal infections or has previously received streptokinase, there is a possibility of developing a n t i s t r e p t o c o c c a l antibodies that may limit the effectiveness of st reptokinase. Therefore, ret r e a t m e n t with the drug is often difficult within a four- to six-month period. Urokinase was originally discovered by MacFarlane and Pilling in 1947.4 It is produced from renal tubular cells by tissue culture techniques, s Urokinasc directly combines with plasminogen to form plasmin, which digests fibrin and, to a lesser extent, fibrinogen. Urokinase is nonantigenic, and allergic reactions are extremely uncommon. Retreatment with urokinase can be undertaken as often as necessary. Its main disadvantage is its cost, ap126/1211
proximately seven to ten times as expensive as streptokinase. tPA recently has been released by the Food and Drug Administration for the treatment of acute myocardial infarction. It is an endogenously produced plasminogen activator that has been s y n t h e s i z e d by r e c o m b i n a n t DNA technology. The major advantage of tPA is its relative clot selectivity and short duration of action. Many investigators hope this will lead to fewer bleeding complications and more rapid fibrinolysis. Fibrinolysis with tPA more closely resembles physiologically induced fibrinolysis than does fibrino!ysis produced -by streptokinase or urokinase, tPA selectively binds more to p!asminogen bound to fibrin (ie, clot-selective}, than to free circulating plasminogen. It is important to remember that clot selectivity is relative. It is unrealistic to expect any thrombolytic agent, when given in great excess, to be entirely clot-selective. Despite its clot selectivity, plasminogen and fibrinogen depletion occur. Like urokinase, the cost of tPA is much greater than that of streptokinase.
METHODS OF. ADMINISTRATION AND RESULTS OF R E C E N T TRIALS As early as 1959, Fletcher 6 administered IV streptokinase to patients with peripheral arterial occlusions and demonstrated thrombolysis. Durin.g the next 15 years, there were many Annals of Emergency Medicine
more reports describing the use of IV streptokinase in arterial disease. Some investigators used loading doses as high as 1,250,000 units followed by 100,000 units/hr7 Most investigators used at least 100,000 units/hr streptokinase and continued the infusions for 72 hours. However, infusions have been continued for as long as six days. 7-9 Successful thrombolysis occurred in approximately 55% of these early studies. Bleeding complications were extraordinarily high, and death occurred in 7% of one series, r These early results were not encouraging; in a review article in 1975, Fratantoni lo noted that there was some effect in the treatment of arterial occlusions; however, the results were generally unsatisfactory. It was suggested that thrombolytic therapy be reserved for patients who were poor surgical candidates. In the 1960s, several reports described intra-aTCerial administration of streptokinase for acute occlusions of the popliteal and superficial femoral arteries.U 14 In 1974, Dotter modified the intra-arterial technique in that "the tip of the perfusion catheter was placed just above or thrust into the substance of the offending clot."t5 He used from 1,000 to 10,000 units/hr streptokinase. The infusion duration was from one day to two weeks. Ten of 17 patients (59%) had total or partial clot lysis. Major bleeding complications occurred in two (12%) patients, including one death ('Fable). 17:11 November1988
This intra-arterial technique led to a rapid proliferation in the medical literature of intra-arterial streptokinase for peripheral arterial occlusions. T h e t e c h n i q u e of a d m i n i s t r a t i o n that we have adopted is t a k e n from M c N a m a r a et al. ~6 A 5-F e n d - h o l e catheter is inserted retrograde in the contralateral femoral artery for iliac or c o m m o n f e m o r a l disease and a n t e grade in the ipsilateral artery for more distal disease. T h e g u i d e w i r e is advanced as far into the clot as possible, a n d a 5-F catheter is advanced over the guidewire several centimeters into the clot. T h e guidewire is then removed. T h e thrombolytic agent is infused dir e c t l y into the clot (Figure 1). The usual dose of s t r e p t o k i n a s e is 5,000 to 10,000 u n i t s / h r and of u r o k i n a s e is 4,000 u n i t s / m i n u n t i l i n i t i a l rec a n a l i z a t i o n occurs and t h e n 1,000 u n i t s / m i n u n t i l complete lysis occurs. The dose of tPA in experimental protocols has been 0.05 to 0.1 mg/kg/hr. Some investigators infuse concomitant heparin at a rate of 3,000 units/hr in an a t t e m p t to decrease pericatheter t h r o m b u s f o r m a t i o n . We are c o n cerned that concomitant heparin administration with thrombolytic agents w i l l i n c r e a s e b l e e d i n g c o m plications; therefore, we do not use heparin. Instead, we use a high-flow rate through the intra-arterial catheter 17:11 November t988
to produce reflux of the lytic agent preventing pericatheter thrombus formation. Summarized are the most recent rep o r t s of t h e v a r i o u s t h r o m b o l y t i c agents in the treatment of peripheral arterial occlusions (Xhble). The duration of administration of streptokinase was variable w i t h infusions ranging f r o m one to 322 h o u r s (mean, 40 hours). A compilation of these data reveals t h a t of 474 p a t i e n t s w h o received streptokinase, successftfl thrombolysis occurred in 316 (67%). Major c o m p l i c a t i o n s were defined as complications that required either d i s c o n t i n u a t i o n of the t h r o m b o l y t i c agent, t r a n s f u s i o n of one or m o r e units of packed red blood cells, fresh frozen plasma, or cryoprecipitate, or as death. A m o n g the group of 474 patients, there .were 88 major complications (mean, 19%; range, 8% to 41%). In our experience, ~6 42% of patients receiving streptokinase had low-grade fever and 14% had other m i n o r reactions, including nausea, vomiting, or mild decreases in systolic blood pressure. This is similar to a group of patients treated for deep venous thrombosis in which 16 of 30 patients (53%) experienced fever and other m i n o r allergic reactions while receiving streptokinase, while no patients receiving urokinase had allergic reactions, go Annals of Emergency Medicine
FIGURE 3A. Cutoff in the rnid-caff of the anterior tibial, posterior tibial, and peroneal arteries by an arterial embolus. FIGURE 3B. After 12 hours of intraarterial urokinase infusion, the anterior tibial and peroneal arteries are widely patent. Note residual thrombus in the mid-portion of the posterior tibiaI artery. F I G U R E 3C. T h r o m b u s has corn pletely resolved in all three arteries. M c N a m a r a 16 has performed thrombolysis with urokinase in 85 patients (93 occlusions). The dose of urokinase was from 1 to 4,000 u n i t s / m i n and of heparin was 1,000 units/hr. The m e a n duration of infusion was 18 _+ 5 hours. In 61 patients who recanalized w i t h i n two hours, there was 100% complete clot lysis (P < .01) as compared with 23 infusions not recanalized w i t h i n two h o u r s in w h i c h o n l y 39% had complete clot lysis (P < .025). A n o t h e r predictor of whether clot lysis would occur was the ability to advance the guidewire through the entire length of the occlusion. This usually indicates soft thrombus, w h i c h is m o r e easily lysed. In the 52 patients in w h o m the g u i d e w i r e was p a s s e d t h r o u g h t h e clot, 100% were l y s e d successfully. 1212/127
PERIPHERAL ARTERIAL OCCLUSIONS Olin & Graor
Two patients who were resistant to high-dose streptokinase infusions for 62 and 140 hours had successful lysis with urokinase. Percutaneous transluminal angioplasty was required in 50 (78%} of the completed urokinase infusions. Six of the 93 infusions (6.5%} had major complications. In a follow-up study, 45 of 77 patients (59%) who were lysed successf u l l y h a d a p a t e n t a r t e r y at six months. 3~ Factors affecting long-term pateney include the size of the vessel (ie, the larger the vessel, the higher t h e l o n g - t e r m p a t e n c y rate) and whether a critical stenosis was present after the thrombus was successfully lysed. In three series 27-2~) comparing s t r e p t o k i n a s e w i t h urokinase, successful clot lysis occurred in 80% of patients receiving urokinase versus in 52% r e c e i v i n g s t r e p t o k i n a s e . T h e complication rate was 21% for urokinase and 35% for streptokinase. The clinical course of patients receiving intra-arterial urokinase seems to be much smoother than that of patients receiving streptokinase. Bleeding complications are probably less and allergic reactions are almost never present with urokinase. We have r e c e n t l y studied 55 patients with native peripheral arterial o c c l u s i o n s or bypass graft t h r o m bosis. 32 All patients received h u m a n tPA in a dose of 0.05 or 0.1 mg/kg/hr. The m e t h o d of a d m i n i s t r a t i o n was identical to that of streptokinase and urokinase. Infusion times ranged from one to eight hours (mean, 4.7 hours). F i f t y - o n e (93%) p a t i e n t s had successful thrombolysis. Major complications occurred in four (7.2%). One patient succumbed from an intracranial bleed 48 hours after receiving tPA while on heparin anticoagulation. Secondary procedures (surgery or p e r c u t a n e o u s t r a n s l u m i n a l angioplasty) w e r e p e r f o r m e d after successful t h r o m b o l y s i s in 29 patients (57%). Sixteen patients (31%) required long-term anticoagulation after successful thrombolysis. As can be seen, thrombolysis often uncovers anatomic lesion (severe stenosis) that will lead to rethrombosis of the native artery or by-pass graft if not properly treated. A group of 22 patients receiving tPA for t h r o m b o s e d i n f r a i n g u i n a l ext r e m i t y bypass grafts was m a t c h e d with a group of 38 patients who primarily underwent surgical thrombectomy. 33 Patients were matched for age, the presence or absence of diabetes, 128/1213
smoking, and the type of graft (ie, reverse s a p h e n o u s vein graft, i n s i t u saphenous vein graft, or PTFE graft). tPA was successful in lysing thrombus in all 22 patients. The mean time for graft patency was 136 _+ 254 days in patients primarily receiving surgery versus 231 + 211 days in patients receiving tPA (P 2= .01). Secondary procedures s u c h as surgery or percutaneous transluminal angioplasty were required in 20 (91%) of 22 patients receiving tPA. Logistic regression analysis determ i n e s t h a t those p a t i e n t s w h o received primarily surgical repair had a 2.97 times higher chance of amputation than those receiving tPA. At 30 days, the graft patency was 86% in those receiving tPA versus 42% in those receiving surgery (P = .001). The beneficial effects that occurred in the tPA group were only present during the first year; after that there was no difference in graft patency It is our impression that intra-arterial thrombolytic agents are useful adjuncts to surgical repair or percutaneous t r a n s l u m i n a l angioplasty. They help identify the a n a t o m y in cases in which the native arteries are thrombosed and allow the surgeon to better visualize the distal runoff and, therefore, chances for successful :surgical r e v a s c u l a r i z a t i o n . In cases of thrombosed bypass grafts, thrombolysis allows identification of the reason for the thrombosed graft and, therefore, choosing of a more rational treatment plan. In some instances, the distal anastomosis is stenotic and can be successfully dilated, while in others it must be surgically revised. Without thrombolysis, the best mode of therapy would never be known. Avoidance of catheter embolectomy or thrombectomy, which may disrupt the intima of the vessel wall and accelerate the atherosclerotic process, may be beneficial. There are clearly two situations in which thrombolytic agents should not be used. The first is if there are any c o n t r a i n d i c a t i o n s to the drug. T h e second is if the patient has sensory or m o t o r i m p a i r m e n t of the i s c h e m i c limb, indicating that the ischemia is limb t h r e a t e n i n g and the p a t i e n t could not tolerate even several more hours of ischemia without the chance of limb loss. An example of a large embolus of the left c o m m o n femoral artery in w h i c h the patient had no motion in the foot and no sensation is Annals of Emergency Medicine
shown (Figure 2}. This type of lesion is best treated surgically. On the other hand, emboli to the smaller vessels (Figures 3A, 3B, and 3C) are best treated with thrombolytic agents because catheter embolectomy may not result in as complete a resolution of emboli as may the use of thrombolytic agents and can further damage the fragile intima. The usual reasons for failure of clot lysis are that the clot is old (more than 30 days), firm, and organized. It is possible to s u c c e s s f u l l y lyse clots more than 30 days old, but as a general role, the older the clot, the less likely is achievement of complete lysis. Other reasons for failure are if there is a calcified obstructing atherosclerotic lesion in the middle of the occlusion, if the catheter tip cannot be directly positioned into the clot, or if there are high-titer antistreptococcal antibodies in a patient receiving streptokinase. CONTRAINDICATIONS
TO
THROMBOLYTIC THERAPY Absolute contraindications to the use of thrombolytic agents include active i n t e r n a l bleeding, r e c e n t (less than two months) stroke, or any intracranial or intraspinal process. Relative contraindications include major surgery within the last ten days, recent organ biopsy {less t h a n ten days), puncture of noncompressible vessels, recent gastrointestinal bleeding, severe 'and uncontrolled arterial hypertension, recent trauma including CPR, pregnancy, and u n c o r r e c t e d h e m o static defects. It is interesting to note that patients who have .undergone recent lower extremity revascularization can be lysed successfully even within the fi~st few days after surgery. External compression at the incision site will prevent any significant blood loss. Careful p a t i e n t selection is of the utmost importance. Unlike m o s t series in which patients are treated in the intensive care unit, m o s t of the patients in our series are treated on the general v a s c u l a r n u r s i n g floor. Physical handling of the patient is m i n i m i z e d , and i n t r a m u s c u l a r and s u b c u t a n e o u s injections are discontinued. Itwasive procedures are avoided if at all possible. Accessible invaded v e s s e l s are c o m p r e s s e d before initiation of thrombolytic therapy. Most complications that occur do so at sites of previously invaded vessels. Therefore, if patients are carefully selected, t h e r e s h o u l d be no 17:11 November 1988
TABLE. Pooled data on the use of streptokinase, urokinase, a n d tPA in the t r e a t m e n t of peripheral arterial occlusions
Drug Streptokinase
No. of Infusions
Duration of Infusion (hr)
Successful Thrombolysis
Major Complications
474
40
316 (67%)
88 (19%)
162
30
130 (81%)
19 (12%)
Dotter, 197418 Katzen, 198117 Totty, 198218 Berni, 198319 Mori, 198320 Becker, 198321 Katzen, 198422 Wolfson, 198423 van Breda, 198424 Kakkasseril, 198525 Graor, 198526 Belkin, 198627 van Breda, 198728 Koltun, 198729
Urokinase McNamara, 1985 ~6 Belkin, 198627 van Breda, 198728 Koltun, 198729
tPA Graor, 19863o bleeding at noncompressible sites. If m i n o r b l e e d i n g occurs, s i m p l e mec h a n i c a l c o m p r e s s i o n is applied to that vessel. In the presence of moderate or severe b l e e d i n g , the t h r o m bolytic agent is d i s c o n t i n u e d and a t r a n s f u s i o n is a d m i n i s t e r e d w i t h packed red blood cells and either fresh frozen plasma or cryoprecipitate. It is a matter of debate as to the exact cause of bleeding after the admini s t r a t i o n of t h r o m b o l y t i c a g e n t s . There are some data to suggest that the .longer the infusion time and the 'lower the plasma fibrinogen, the greater t h e l i k e l i h o o d of bleeding. T h i s , however, is controversial. In a series by T e n n a n t et al, 34 p a t i e n t s w i t h acute myocardial infarctions received either 2,000 u n i t s / m i n streptokinase or 6,000 u n i t s / m i n urokinase. Nineteen (66%) of those receiving Streptokinase demonstrated a fibrinogen level of less t h a n 100 mg/dL as compared w i t h t w o (6%) of t h o s e r e c e i v i n g urokinase (P < .001). Major bleeding c o m p l i c a t i o n s o c c u r r e d i n 20% of those receiving streptokinase versus 2% of those receiving urokinase. Seventy-five percent of all patients who exhibited major bleeding had fibrinogen levels of less t h a n 100 mg/dL. These are data similar to that we have published.26,3o,al
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55
4.7
SUMMARY There has been m u c h interest in the use of thrombolytic agents in the last 20 years. We have progressed from IV i n f u s i o n s of h i g h doses of s t r e p t o kinase to direct intra-arterial infusions of streptokinase, urokinase, and tPA. Urokinase and tPA appear to lyse the clot in a shorter period and may cause fewer bleeding complications. Thrombolytic agents are useful adj u n c t s to surgery a n d p e r c u t a n e o u s t r a n s l u m i n a l angioplasty. They allow lysis of the small distal runoff vessels, decreasing outflow resistance and enabling the native artery or bypass graft to remain open longer. They also further define the a n a t o m y so the angiographer, internist, and surgeon can predict a rational form of therapy after thrombolysisl However, to date, there have been no prospective randomized double-blind controlled trials comparing streptokinase, urokinase, tPA, and surgery i n the treatment of peripheral arterial occlusions. These are clearly needed to enable us to use the safest, most effective, and most cost-efficient therapeutic regimen.
The authors thank Micheline Watt for her help in the preparation of this manuscript.
Annals of Emergency Medicine
51 (93%)
4 (7.2%)
REFERENCES
1. Tillett WS, Garner RL: The fibrmolytic activity of hemolytic streptococci. J Exp Med 1933;58:485-502. 2. Johnson AJ, McCarty WR: The lysis of artificially induced intravascularclots in man by intravenous infusions of streptokinase. J Clin Invest 1959;38:1627-1643. 3. Sherry S, LindemeyerRI, Fletcher AP, et al: Studies on enhanced fibrinolytic activity in man. J Clin Invest 1959;38:810-822. 4. MacFarlane RG, Pilling J: Fibrinolytic activity of normal urine. Nature 1947;159:779. 5. Aoki N, Vonkaukla KN: Dissimilarity of human vascular plasminogen activator and human urokinase. J Lab Clin Med 1971; 78:354-362. 6. Fletcher AP, AlkjaersigN, Sherry S: Maintenance of a sustained fibrinolytic state in man. Induction and effects. J Clin Invest 1959;38: 1096-1110. 7. Amery A, Deloof W, Vermylen J, et al: Outcome of recent thromboembolic occlusions of limb arteries treated with streptokinase. Br Med J 1970;4:639-644. 8. Poliwoda H, Alexander K, Buhl V, et al: Treatment of chronic arterial occlusions with streptokinase. N Engl J Med 1969;280:689-692. 9. Martin M: Thrombolytic therapy in arterial thromboembolism. Prog Cardiovasc Dis 1979;21:351-374. 10. Fratantoni JC, Ness P, Simon TL: Thrombolytic therapy. N Engl J Med 1975;293: 1073-1075. 11. Cotton LT, Flute PT, Tsapogas MJC: Popliteal artery thrombosis treated with streptokinase. Lancet 1962;2:1081-1083.
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PERIPHERAL ARTERIAL OCCLUSIONS Olin & Graor
12. Clark MC, Howell M, Hawkey C, et al: Arterial occlusions treated with streptokinase. Postgrad Med ] 1965;4h96-100. 13. Hirsh I, O'Sullivan EF, Gallos AS, et al: Thrombosis in a patient with chronic thrombocytopenia: Successful treatment with intraarterial infusion of streptokinase. Med J Aust 1969;2:1304-1306. 14. McNicol GP, Douglas AS: Treatment of peripheral vascular occlusion by streptokinase perfusion. Scand J Clin Lab Invest 1964;16 (Suppl 78):23-29. 15. Dotter CT, Rosch J, Seaman AJ: Selective clot lysis with low dose streptokinase. Radiology 1974;111:31-37. 16. McNamara TO, Fischer JR: Thrombolysis of peripheral, arterial and graft occlusions: Improved results using high dose urokinase. AIR 1985~144:769-775. 17. Katzen BT, van Breda A: Low dose streptokinase in the treatment of arterial occlusions. AJR 1981;36:1171d178. 18. Totty WG, Gilula LA, McClennan BL, et al: Low dose intravascular fibrinolytic therapy. Radiology 1982; 143:59-69.
lective streptokinase infusion: Clinical and laboratory correlates. Radiology 1983;148:677-682.
Urokinase vs streptokinase in local thrombolysis. Radiology 1987;165:109-1ll.
2l. Becker GJ, Rabe FE, Richmond BD, et al: Low dose fibrinolytic therapy. Results and new concepts. Radiology 1983;148:663-670.
29. Koltun WA, Gardiner GA, Harrington DP, et ah Thrombolysis in the treatment of peripheral arterial vascular occlusions. Arch Surg 1987; 122:901-905.
22. Katzen BT, Edwards KC, Albert AS, et ah Low dose fibrinolysis in peripheral vascular disease. J ¼~sc Surg 1984;1:718-722. 23. Wolfson RH, Kumpe DA, Rutherford RB: Role of intra-artcrial streptokinase in the treatment of arterial thromboembolism. Arch Surg 1984;119:697-702. 24. van Breda A, Robison JC, Feldman L, et al: Local thrombolysis in the treatment of arterial graft occlusions. J Vase Surg 1984;1:103-112.
31. McNamara TO, Bomberger RA: Factors affecting initial and 6 month patency rates after intra-arterial thrombolysis with high dose urokinase. A m J Surg 1986;152:709-712.
25. Kakkasseril J8, Cranley JJ, Arbaugh JJ, et al: Efficacy of low dose streptokinase in acute arterial occlusion and graft thrombosis. Arch Surg 1985;120:427-429.
32. Graor RA, Risius B, Lucas FV, et ah Thrombolysis with recombinant human tissue type plasminogen activators in patients with pe ripheral artery and bypass graft thrombosis. Circulation 1986;74(Suppl I):I-15-I-20.
26. Graor RA, Risius B, Denny KM, et al: Local thrombolysis in the treatment of thrombosed arteries, bypass grafts and a r t e r i o v e n o u s fistulas. J Vase Surg 1985;2:406-414.
33. Graor RA, Risius B, Young JR, et ah Thrombolysis of peripheral arterial bypass grafts: Surgical thrombectomy compared with thrombolysis. A preliminary report. J Vasc Surg 1988; 7:347-355.
19. Bcrni GA, Bandyk DE Zierler E, et ah Streptokinase treatment of acute arterial occlusion. Ann Surg 1983;198:185d91.
27. Belkin M, Belkin B, Bucknam CA, et ah Intra-arterial fibrinolytic therapy. Efficacy of streptokinase vs. urokinase. Arch Surg 1986; 121:769-773.
20. Mori KW, Bookstein JJ, Heeney DJ, et ah Se-
28. van Breda A, Katzen BT, D e u t s c h AF:
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30. Graor RA, Young JR, Risius B, et ah Comparison of cost effectiveness of streptokinase and urokinase in the treatment of deep vein thrombosis. Ann Vase Surg 1987;I:524-528.
Annals of Emergency Medicine
34. Tennant SN, Dixon J, Venable TC, et al: Intra-coronary thrombolysis in patients with acute myocardial infarction: Comparison of efficacy of urokinase with streptokinase. Circulation 1984;69:756-760.
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Thrombolytic Therapy in the Treatment of Peripheral Arterial Occlusions Intra-arterial infusions of thrombo]ytic agents are useful adjuncts to surgery and percutaneous translumina] angioplasty The best results occur when the thrombus is Iysed within 30 days; however, successful thrombolysis has occurred up to four months after an arterial occlusion. Thrombolysis allows dissolution of thrombus in the small distal runoff vessels, decreasing outflow resistance and enabling the native artery or bypass graft to remain open longer. When native arteries are Iysed successfully, an underlying area of stenosis is usually identified and thus able to be corrected with either surgery or percutaneous transluminal angioplasty. When bypass grafts thrombose, thromboIytic agents are usually successful in Iysing the thrombus and identifying the cause for the thrombosis. With local intra-arterial infusions, side effects and complications may be kept to a minimum. [Olin JW, Graor RA: Thrombolytic therapy in the treatment of peripheral arterial occlusions. Ann Emerg Med November 1988;17:1210-1215.]
Jeffrey W OLin, DO, FACP Robert A Graor, MD Cleveland, Ohio From the Department of Peripheral Vascular Disease, Division of Internal Medicine, Cleveland Clinic Foundation, Cleveland, Ohio. Received for publication February 8, 1988. Accepted for publication July 22, 1988. Address for reprints: Jeffrey W Olin, DO, FACP, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44106.
INTRODUCTION Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality in the United States. Myocardial infarction and stroke are the two most common manifestations of atherosclerosis. More effective measures to prevent and treat stroke and myocardial infarction have become available, and therefore, patients are living longer, leading to a higher incidence of lower extremity occlusive disease. However, its diagnosis and management are often delayed and suboptimal. The most common causes of acute arterial insufficiency are thrombosis of native atherosclerotic arteries, thrombosis of bypass grafts, and emboli. Other causes include trauma, aortic dissection, drug abuse (IV injection of drags and ergot intoxication), trauma , and iliofemoral deep vein thrombosis (phlegmasia cerulea dolens and venous gangrene). A patient may present with a history of intermittent claudication that suddenly worsens, leading to rest pain (ie, progressive arteriosclerosis oblitera'ns with thrombosis in situ), or with a sudden onset of pain, pallor, pulselessness, paresthesias, or paralysis (acute arterial emboli or thrombosed b y p a s s graft). The classic teaching has been that thrombectomy, embolectomy, or surgical revascularization are the treatments of choice for acute arterial ischemia. In the last six years, there have been many studies that support the use of intra-arterial thromboiytic therapy in the management of patients with peripheral arterial occlusions. Tillett and Garner I discovered the fibrinolytic activity of hemolytic streptococci in 1933. Additional studies were performed in the late 1950s that further characterized the fibrinolytic activity of streptokinase.2, 3 During the next 20 years, several different thrombolytic agents were developed, and experience with them in the treatment of acute myocardial infarction, deep venous thrombosis, pulmonary emboli, and peripheral arterial occlusions grew. PRINCIPLES OF CLOT LYSIS Streptokinase, urokinase, and tissue-type plasminogen activator (tPA) are all commercially available and capable of acting as exogenous plasminogen activators. Streptokinase combines with the zymogen plasminogen to form an intermediate complex that further combines with additional plasminogen 17:11 November 1988
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PERIPHERAL ARTERIAL OCCLUSIONS Olin & Graor
FIGURE 1. Administration of throm-
bolytic agent. FIGURE 2. Embolus of left common femoral artery. to form the active enzyme plasmin. Plasmin directly digests fibrin and fibrinogen. Streptokinase has been in use longer than urokinase or tPA, and more patients have been treated with it than with any of the other plasminogen activators. However, the drug is antigenic and has the potential for allergic reactions consisting of fever, chills, nausea, vomiting, hypotension, and anaphylaxis. If a patient has been previously exposed to streptococcal infections or has previously received streptokinase, there is a possibility of developing a n t i s t r e p t o c o c c a l antibodies that may limit the effectiveness of st reptokinase. Therefore, ret r e a t m e n t with the drug is often difficult within a four- to six-month period. Urokinase was originally discovered by MacFarlane and Pilling in 1947.4 It is produced from renal tubular cells by tissue culture techniques, s Urokinasc directly combines with plasminogen to form plasmin, which digests fibrin and, to a lesser extent, fibrinogen. Urokinase is nonantigenic, and allergic reactions are extremely uncommon. Retreatment with urokinase can be undertaken as often as necessary. Its main disadvantage is its cost, ap126/1211
proximately seven to ten times as expensive as streptokinase. tPA recently has been released by the Food and Drug Administration for the treatment of acute myocardial infarction. It is an endogenously produced plasminogen activator that has been s y n t h e s i z e d by r e c o m b i n a n t DNA technology. The major advantage of tPA is its relative clot selectivity and short duration of action. Many investigators hope this will lead to fewer bleeding complications and more rapid fibrinolysis. Fibrinolysis with tPA more closely resembles physiologically induced fibrinolysis than does fibrino!ysis produced -by streptokinase or urokinase, tPA selectively binds more to p!asminogen bound to fibrin (ie, clot-selective}, than to free circulating plasminogen. It is important to remember that clot selectivity is relative. It is unrealistic to expect any thrombolytic agent, when given in great excess, to be entirely clot-selective. Despite its clot selectivity, plasminogen and fibrinogen depletion occur. Like urokinase, the cost of tPA is much greater than that of streptokinase.
METHODS OF. ADMINISTRATION AND RESULTS OF R E C E N T TRIALS As early as 1959, Fletcher 6 administered IV streptokinase to patients with peripheral arterial occlusions and demonstrated thrombolysis. Durin.g the next 15 years, there were many Annals of Emergency Medicine
more reports describing the use of IV streptokinase in arterial disease. Some investigators used loading doses as high as 1,250,000 units followed by 100,000 units/hr7 Most investigators used at least 100,000 units/hr streptokinase and continued the infusions for 72 hours. However, infusions have been continued for as long as six days. 7-9 Successful thrombolysis occurred in approximately 55% of these early studies. Bleeding complications were extraordinarily high, and death occurred in 7% of one series, r These early results were not encouraging; in a review article in 1975, Fratantoni lo noted that there was some effect in the treatment of arterial occlusions; however, the results were generally unsatisfactory. It was suggested that thrombolytic therapy be reserved for patients who were poor surgical candidates. In the 1960s, several reports described intra-aTCerial administration of streptokinase for acute occlusions of the popliteal and superficial femoral arteries.U 14 In 1974, Dotter modified the intra-arterial technique in that "the tip of the perfusion catheter was placed just above or thrust into the substance of the offending clot."t5 He used from 1,000 to 10,000 units/hr streptokinase. The infusion duration was from one day to two weeks. Ten of 17 patients (59%) had total or partial clot lysis. Major bleeding complications occurred in two (12%) patients, including one death ('Fable). 17:11 November1988
This intra-arterial technique led to a rapid proliferation in the medical literature of intra-arterial streptokinase for peripheral arterial occlusions. T h e t e c h n i q u e of a d m i n i s t r a t i o n that we have adopted is t a k e n from M c N a m a r a et al. ~6 A 5-F e n d - h o l e catheter is inserted retrograde in the contralateral femoral artery for iliac or c o m m o n f e m o r a l disease and a n t e grade in the ipsilateral artery for more distal disease. T h e g u i d e w i r e is advanced as far into the clot as possible, a n d a 5-F catheter is advanced over the guidewire several centimeters into the clot. T h e guidewire is then removed. T h e thrombolytic agent is infused dir e c t l y into the clot (Figure 1). The usual dose of s t r e p t o k i n a s e is 5,000 to 10,000 u n i t s / h r and of u r o k i n a s e is 4,000 u n i t s / m i n u n t i l i n i t i a l rec a n a l i z a t i o n occurs and t h e n 1,000 u n i t s / m i n u n t i l complete lysis occurs. The dose of tPA in experimental protocols has been 0.05 to 0.1 mg/kg/hr. Some investigators infuse concomitant heparin at a rate of 3,000 units/hr in an a t t e m p t to decrease pericatheter t h r o m b u s f o r m a t i o n . We are c o n cerned that concomitant heparin administration with thrombolytic agents w i l l i n c r e a s e b l e e d i n g c o m plications; therefore, we do not use heparin. Instead, we use a high-flow rate through the intra-arterial catheter 17:11 November t988
to produce reflux of the lytic agent preventing pericatheter thrombus formation. Summarized are the most recent rep o r t s of t h e v a r i o u s t h r o m b o l y t i c agents in the treatment of peripheral arterial occlusions (Xhble). The duration of administration of streptokinase was variable w i t h infusions ranging f r o m one to 322 h o u r s (mean, 40 hours). A compilation of these data reveals t h a t of 474 p a t i e n t s w h o received streptokinase, successftfl thrombolysis occurred in 316 (67%). Major c o m p l i c a t i o n s were defined as complications that required either d i s c o n t i n u a t i o n of the t h r o m b o l y t i c agent, t r a n s f u s i o n of one or m o r e units of packed red blood cells, fresh frozen plasma, or cryoprecipitate, or as death. A m o n g the group of 474 patients, there .were 88 major complications (mean, 19%; range, 8% to 41%). In our experience, ~6 42% of patients receiving streptokinase had low-grade fever and 14% had other m i n o r reactions, including nausea, vomiting, or mild decreases in systolic blood pressure. This is similar to a group of patients treated for deep venous thrombosis in which 16 of 30 patients (53%) experienced fever and other m i n o r allergic reactions while receiving streptokinase, while no patients receiving urokinase had allergic reactions, go Annals of Emergency Medicine
FIGURE 3A. Cutoff in the rnid-caff of the anterior tibial, posterior tibial, and peroneal arteries by an arterial embolus. FIGURE 3B. After 12 hours of intraarterial urokinase infusion, the anterior tibial and peroneal arteries are widely patent. Note residual thrombus in the mid-portion of the posterior tibiaI artery. F I G U R E 3C. T h r o m b u s has corn pletely resolved in all three arteries. M c N a m a r a 16 has performed thrombolysis with urokinase in 85 patients (93 occlusions). The dose of urokinase was from 1 to 4,000 u n i t s / m i n and of heparin was 1,000 units/hr. The m e a n duration of infusion was 18 _+ 5 hours. In 61 patients who recanalized w i t h i n two hours, there was 100% complete clot lysis (P < .01) as compared with 23 infusions not recanalized w i t h i n two h o u r s in w h i c h o n l y 39% had complete clot lysis (P < .025). A n o t h e r predictor of whether clot lysis would occur was the ability to advance the guidewire through the entire length of the occlusion. This usually indicates soft thrombus, w h i c h is m o r e easily lysed. In the 52 patients in w h o m the g u i d e w i r e was p a s s e d t h r o u g h t h e clot, 100% were l y s e d successfully. 1212/127
PERIPHERAL ARTERIAL OCCLUSIONS Olin & Graor
Two patients who were resistant to high-dose streptokinase infusions for 62 and 140 hours had successful lysis with urokinase. Percutaneous transluminal angioplasty was required in 50 (78%} of the completed urokinase infusions. Six of the 93 infusions (6.5%} had major complications. In a follow-up study, 45 of 77 patients (59%) who were lysed successf u l l y h a d a p a t e n t a r t e r y at six months. 3~ Factors affecting long-term pateney include the size of the vessel (ie, the larger the vessel, the higher t h e l o n g - t e r m p a t e n c y rate) and whether a critical stenosis was present after the thrombus was successfully lysed. In three series 27-2~) comparing s t r e p t o k i n a s e w i t h urokinase, successful clot lysis occurred in 80% of patients receiving urokinase versus in 52% r e c e i v i n g s t r e p t o k i n a s e . T h e complication rate was 21% for urokinase and 35% for streptokinase. The clinical course of patients receiving intra-arterial urokinase seems to be much smoother than that of patients receiving streptokinase. Bleeding complications are probably less and allergic reactions are almost never present with urokinase. We have r e c e n t l y studied 55 patients with native peripheral arterial o c c l u s i o n s or bypass graft t h r o m bosis. 32 All patients received h u m a n tPA in a dose of 0.05 or 0.1 mg/kg/hr. The m e t h o d of a d m i n i s t r a t i o n was identical to that of streptokinase and urokinase. Infusion times ranged from one to eight hours (mean, 4.7 hours). F i f t y - o n e (93%) p a t i e n t s had successful thrombolysis. Major complications occurred in four (7.2%). One patient succumbed from an intracranial bleed 48 hours after receiving tPA while on heparin anticoagulation. Secondary procedures (surgery or p e r c u t a n e o u s t r a n s l u m i n a l angioplasty) w e r e p e r f o r m e d after successful t h r o m b o l y s i s in 29 patients (57%). Sixteen patients (31%) required long-term anticoagulation after successful thrombolysis. As can be seen, thrombolysis often uncovers anatomic lesion (severe stenosis) that will lead to rethrombosis of the native artery or by-pass graft if not properly treated. A group of 22 patients receiving tPA for t h r o m b o s e d i n f r a i n g u i n a l ext r e m i t y bypass grafts was m a t c h e d with a group of 38 patients who primarily underwent surgical thrombectomy. 33 Patients were matched for age, the presence or absence of diabetes, 128/1213
smoking, and the type of graft (ie, reverse s a p h e n o u s vein graft, i n s i t u saphenous vein graft, or PTFE graft). tPA was successful in lysing thrombus in all 22 patients. The mean time for graft patency was 136 _+ 254 days in patients primarily receiving surgery versus 231 + 211 days in patients receiving tPA (P 2= .01). Secondary procedures s u c h as surgery or percutaneous transluminal angioplasty were required in 20 (91%) of 22 patients receiving tPA. Logistic regression analysis determ i n e s t h a t those p a t i e n t s w h o received primarily surgical repair had a 2.97 times higher chance of amputation than those receiving tPA. At 30 days, the graft patency was 86% in those receiving tPA versus 42% in those receiving surgery (P = .001). The beneficial effects that occurred in the tPA group were only present during the first year; after that there was no difference in graft patency It is our impression that intra-arterial thrombolytic agents are useful adjuncts to surgical repair or percutaneous t r a n s l u m i n a l angioplasty. They help identify the a n a t o m y in cases in which the native arteries are thrombosed and allow the surgeon to better visualize the distal runoff and, therefore, chances for successful :surgical r e v a s c u l a r i z a t i o n . In cases of thrombosed bypass grafts, thrombolysis allows identification of the reason for the thrombosed graft and, therefore, choosing of a more rational treatment plan. In some instances, the distal anastomosis is stenotic and can be successfully dilated, while in others it must be surgically revised. Without thrombolysis, the best mode of therapy would never be known. Avoidance of catheter embolectomy or thrombectomy, which may disrupt the intima of the vessel wall and accelerate the atherosclerotic process, may be beneficial. There are clearly two situations in which thrombolytic agents should not be used. The first is if there are any c o n t r a i n d i c a t i o n s to the drug. T h e second is if the patient has sensory or m o t o r i m p a i r m e n t of the i s c h e m i c limb, indicating that the ischemia is limb t h r e a t e n i n g and the p a t i e n t could not tolerate even several more hours of ischemia without the chance of limb loss. An example of a large embolus of the left c o m m o n femoral artery in w h i c h the patient had no motion in the foot and no sensation is Annals of Emergency Medicine
shown (Figure 2}. This type of lesion is best treated surgically. On the other hand, emboli to the smaller vessels (Figures 3A, 3B, and 3C) are best treated with thrombolytic agents because catheter embolectomy may not result in as complete a resolution of emboli as may the use of thrombolytic agents and can further damage the fragile intima. The usual reasons for failure of clot lysis are that the clot is old (more than 30 days), firm, and organized. It is possible to s u c c e s s f u l l y lyse clots more than 30 days old, but as a general role, the older the clot, the less likely is achievement of complete lysis. Other reasons for failure are if there is a calcified obstructing atherosclerotic lesion in the middle of the occlusion, if the catheter tip cannot be directly positioned into the clot, or if there are high-titer antistreptococcal antibodies in a patient receiving streptokinase. CONTRAINDICATIONS
TO
THROMBOLYTIC THERAPY Absolute contraindications to the use of thrombolytic agents include active i n t e r n a l bleeding, r e c e n t (less than two months) stroke, or any intracranial or intraspinal process. Relative contraindications include major surgery within the last ten days, recent organ biopsy {less t h a n ten days), puncture of noncompressible vessels, recent gastrointestinal bleeding, severe 'and uncontrolled arterial hypertension, recent trauma including CPR, pregnancy, and u n c o r r e c t e d h e m o static defects. It is interesting to note that patients who have .undergone recent lower extremity revascularization can be lysed successfully even within the fi~st few days after surgery. External compression at the incision site will prevent any significant blood loss. Careful p a t i e n t selection is of the utmost importance. Unlike m o s t series in which patients are treated in the intensive care unit, m o s t of the patients in our series are treated on the general v a s c u l a r n u r s i n g floor. Physical handling of the patient is m i n i m i z e d , and i n t r a m u s c u l a r and s u b c u t a n e o u s injections are discontinued. Itwasive procedures are avoided if at all possible. Accessible invaded v e s s e l s are c o m p r e s s e d before initiation of thrombolytic therapy. Most complications that occur do so at sites of previously invaded vessels. Therefore, if patients are carefully selected, t h e r e s h o u l d be no 17:11 November 1988
TABLE. Pooled data on the use of streptokinase, urokinase, a n d tPA in the t r e a t m e n t of peripheral arterial occlusions
Drug Streptokinase
No. of Infusions
Duration of Infusion (hr)
Successful Thrombolysis
Major Complications
474
40
316 (67%)
88 (19%)
162
30
130 (81%)
19 (12%)
Dotter, 197418 Katzen, 198117 Totty, 198218 Berni, 198319 Mori, 198320 Becker, 198321 Katzen, 198422 Wolfson, 198423 van Breda, 198424 Kakkasseril, 198525 Graor, 198526 Belkin, 198627 van Breda, 198728 Koltun, 198729
Urokinase McNamara, 1985 ~6 Belkin, 198627 van Breda, 198728 Koltun, 198729
tPA Graor, 19863o bleeding at noncompressible sites. If m i n o r b l e e d i n g occurs, s i m p l e mec h a n i c a l c o m p r e s s i o n is applied to that vessel. In the presence of moderate or severe b l e e d i n g , the t h r o m bolytic agent is d i s c o n t i n u e d and a t r a n s f u s i o n is a d m i n i s t e r e d w i t h packed red blood cells and either fresh frozen plasma or cryoprecipitate. It is a matter of debate as to the exact cause of bleeding after the admini s t r a t i o n of t h r o m b o l y t i c a g e n t s . There are some data to suggest that the .longer the infusion time and the 'lower the plasma fibrinogen, the greater t h e l i k e l i h o o d of bleeding. T h i s , however, is controversial. In a series by T e n n a n t et al, 34 p a t i e n t s w i t h acute myocardial infarctions received either 2,000 u n i t s / m i n streptokinase or 6,000 u n i t s / m i n urokinase. Nineteen (66%) of those receiving Streptokinase demonstrated a fibrinogen level of less t h a n 100 mg/dL as compared w i t h t w o (6%) of t h o s e r e c e i v i n g urokinase (P < .001). Major bleeding c o m p l i c a t i o n s o c c u r r e d i n 20% of those receiving streptokinase versus 2% of those receiving urokinase. Seventy-five percent of all patients who exhibited major bleeding had fibrinogen levels of less t h a n 100 mg/dL. These are data similar to that we have published.26,3o,al
17:11 November 1988
55
4.7
SUMMARY There has been m u c h interest in the use of thrombolytic agents in the last 20 years. We have progressed from IV i n f u s i o n s of h i g h doses of s t r e p t o kinase to direct intra-arterial infusions of streptokinase, urokinase, and tPA. Urokinase and tPA appear to lyse the clot in a shorter period and may cause fewer bleeding complications. Thrombolytic agents are useful adj u n c t s to surgery a n d p e r c u t a n e o u s t r a n s l u m i n a l angioplasty. They allow lysis of the small distal runoff vessels, decreasing outflow resistance and enabling the native artery or bypass graft to remain open longer. They also further define the a n a t o m y so the angiographer, internist, and surgeon can predict a rational form of therapy after thrombolysisl However, to date, there have been no prospective randomized double-blind controlled trials comparing streptokinase, urokinase, tPA, and surgery i n the treatment of peripheral arterial occlusions. These are clearly needed to enable us to use the safest, most effective, and most cost-efficient therapeutic regimen.
The authors thank Micheline Watt for her help in the preparation of this manuscript.
Annals of Emergency Medicine
51 (93%)
4 (7.2%)
REFERENCES
1. Tillett WS, Garner RL: The fibrmolytic activity of hemolytic streptococci. J Exp Med 1933;58:485-502. 2. Johnson AJ, McCarty WR: The lysis of artificially induced intravascularclots in man by intravenous infusions of streptokinase. J Clin Invest 1959;38:1627-1643. 3. Sherry S, LindemeyerRI, Fletcher AP, et al: Studies on enhanced fibrinolytic activity in man. J Clin Invest 1959;38:810-822. 4. MacFarlane RG, Pilling J: Fibrinolytic activity of normal urine. Nature 1947;159:779. 5. Aoki N, Vonkaukla KN: Dissimilarity of human vascular plasminogen activator and human urokinase. J Lab Clin Med 1971; 78:354-362. 6. Fletcher AP, AlkjaersigN, Sherry S: Maintenance of a sustained fibrinolytic state in man. Induction and effects. J Clin Invest 1959;38: 1096-1110. 7. Amery A, Deloof W, Vermylen J, et al: Outcome of recent thromboembolic occlusions of limb arteries treated with streptokinase. Br Med J 1970;4:639-644. 8. Poliwoda H, Alexander K, Buhl V, et al: Treatment of chronic arterial occlusions with streptokinase. N Engl J Med 1969;280:689-692. 9. Martin M: Thrombolytic therapy in arterial thromboembolism. Prog Cardiovasc Dis 1979;21:351-374. 10. Fratantoni JC, Ness P, Simon TL: Thrombolytic therapy. N Engl J Med 1975;293: 1073-1075. 11. Cotton LT, Flute PT, Tsapogas MJC: Popliteal artery thrombosis treated with streptokinase. Lancet 1962;2:1081-1083.
1214/129
PERIPHERAL ARTERIAL OCCLUSIONS Olin & Graor
12. Clark MC, Howell M, Hawkey C, et al: Arterial occlusions treated with streptokinase. Postgrad Med ] 1965;4h96-100. 13. Hirsh I, O'Sullivan EF, Gallos AS, et al: Thrombosis in a patient with chronic thrombocytopenia: Successful treatment with intraarterial infusion of streptokinase. Med J Aust 1969;2:1304-1306. 14. McNicol GP, Douglas AS: Treatment of peripheral vascular occlusion by streptokinase perfusion. Scand J Clin Lab Invest 1964;16 (Suppl 78):23-29. 15. Dotter CT, Rosch J, Seaman AJ: Selective clot lysis with low dose streptokinase. Radiology 1974;111:31-37. 16. McNamara TO, Fischer JR: Thrombolysis of peripheral, arterial and graft occlusions: Improved results using high dose urokinase. AIR 1985~144:769-775. 17. Katzen BT, van Breda A: Low dose streptokinase in the treatment of arterial occlusions. AJR 1981;36:1171d178. 18. Totty WG, Gilula LA, McClennan BL, et al: Low dose intravascular fibrinolytic therapy. Radiology 1982; 143:59-69.
lective streptokinase infusion: Clinical and laboratory correlates. Radiology 1983;148:677-682.
Urokinase vs streptokinase in local thrombolysis. Radiology 1987;165:109-1ll.
2l. Becker GJ, Rabe FE, Richmond BD, et al: Low dose fibrinolytic therapy. Results and new concepts. Radiology 1983;148:663-670.
29. Koltun WA, Gardiner GA, Harrington DP, et ah Thrombolysis in the treatment of peripheral arterial vascular occlusions. Arch Surg 1987; 122:901-905.
22. Katzen BT, Edwards KC, Albert AS, et ah Low dose fibrinolysis in peripheral vascular disease. J ¼~sc Surg 1984;1:718-722. 23. Wolfson RH, Kumpe DA, Rutherford RB: Role of intra-artcrial streptokinase in the treatment of arterial thromboembolism. Arch Surg 1984;119:697-702. 24. van Breda A, Robison JC, Feldman L, et al: Local thrombolysis in the treatment of arterial graft occlusions. J Vase Surg 1984;1:103-112.
31. McNamara TO, Bomberger RA: Factors affecting initial and 6 month patency rates after intra-arterial thrombolysis with high dose urokinase. A m J Surg 1986;152:709-712.
25. Kakkasseril J8, Cranley JJ, Arbaugh JJ, et al: Efficacy of low dose streptokinase in acute arterial occlusion and graft thrombosis. Arch Surg 1985;120:427-429.
32. Graor RA, Risius B, Lucas FV, et ah Thrombolysis with recombinant human tissue type plasminogen activators in patients with pe ripheral artery and bypass graft thrombosis. Circulation 1986;74(Suppl I):I-15-I-20.
26. Graor RA, Risius B, Denny KM, et al: Local thrombolysis in the treatment of thrombosed arteries, bypass grafts and a r t e r i o v e n o u s fistulas. J Vase Surg 1985;2:406-414.
33. Graor RA, Risius B, Young JR, et ah Thrombolysis of peripheral arterial bypass grafts: Surgical thrombectomy compared with thrombolysis. A preliminary report. J Vasc Surg 1988; 7:347-355.
19. Bcrni GA, Bandyk DE Zierler E, et ah Streptokinase treatment of acute arterial occlusion. Ann Surg 1983;198:185d91.
27. Belkin M, Belkin B, Bucknam CA, et ah Intra-arterial fibrinolytic therapy. Efficacy of streptokinase vs. urokinase. Arch Surg 1986; 121:769-773.
20. Mori KW, Bookstein JJ, Heeney DJ, et ah Se-
28. van Breda A, Katzen BT, D e u t s c h AF:
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30. Graor RA, Young JR, Risius B, et ah Comparison of cost effectiveness of streptokinase and urokinase in the treatment of deep vein thrombosis. Ann Vase Surg 1987;I:524-528.
Annals of Emergency Medicine
34. Tennant SN, Dixon J, Venable TC, et al: Intra-coronary thrombolysis in patients with acute myocardial infarction: Comparison of efficacy of urokinase with streptokinase. Circulation 1984;69:756-760.
17:11 November 1988