SPECIAL CONTRIBUTION deep-vein thrombophlebitis; embolism, arterial; pulmonary embolism; thrombolytic therapy

Thrombolytic Therapy for Noncoronary Diseases Thrombolytic therapy has been used fairly extensively in the management of acute proximal deep-vein thrombophlebitis of the extremities, acute pulmonary embolism, and acute peripheral arterial thrombosis and embolism in addition to acute thrombotic coronary events. In the presence of acceptable indications and a favorable benefit to risk ratio, this form of therapy, when successful, has served as a useful adjunct in the management of these disorders. In deep-vein thrombophlebitis, lysis of the thrombus before permanent pathological changes (eg, organization, scarring) have occurred can prevent venous valvular dysfunction and postural venous hypertension and its complications, especially the postphlebitic syndrome. In the more severe forms of acute pulmonary embolism, thrombolytic therapy, when applied early after symptom onset, decreases morbidity and is likely to prevent a chronic increase in pulmonary vascular resistance and persistent pulmonary hypertension. In peripheral arterial thrombo-occJusive events, early restoration of flow through thrombolysis has been shown to limit ischemic damage and serve as a useful supplement to angioplasty or surgery, Thrombolytic therapy has been used less extensively in acute strokes. Here the danger of reperfusion causing bleeding into a softened area of brain undergoing infarction has slowed its evaluation for this disorder; its application to stroke remains experimental. [Sherry S: Thrombolytic therapy for noncoronary diseases. Ann Emerg Med April 1991;20:396-404.]

Sol Sherry, MD, DSc (Hon) Philadelphia, Pennsylvania From the School of Medicine, Temple University, Philadelphia, Pennsylvania. Received for publication March 12, 1990. Revision received August 23, 1990. Accepted for publication August 29, 1990. Presented at the ACEP Winter Symposium in Tucson, Arizona, March 1990. Address for reprints: Sol Sherry, MD, DSc, School of Medicine, Temple University, 3400 North Broad Street, Philadelphia, Pennsylvania 19140-9999.

INTRODUCTION Besides its established role in the management of acute transmural myocardial infarction and its present evaluation in the treatment of unstable angina, thrombolytic therapy has been used to restore blood flow through various vessels occluded by thrombi or emboli. Most of the clinical experience has been in the management of major areas such as proximal deepvein thrombophlebitis, acute pulmonary embolism, peripheral arterial thrombosis and embolism, and, to a more limited extent, acute cerebrovascular occlusions. The current state of the application of thrombolytic therapy to these major areas is the subject of this review.

PROXIMAL DEEP-VEIN THROMBOPHLEBITIS OF THE EXTREMITIES Rationale Ideal management of the patient with proximal deep-vein thrombophlebitis of the extremities (involvement of the popliteal, femoral, or ileofemoral veins of the lower extremity and of the brachial and axillary veins of the upper extremity) should involve symptomatic support and prevention of extension or embolization, and subsequent venous valvular dysfunction. The latter leads to venous hypertension when the extremity is in a dependent position and is often the cause of chronic symptoms and signs that may be confused with recurrent episodes of thrombophlebitis. When the venous hypertension is severe, a more disabling postphlebitic syndrome may occur. 1,2 Although anticoagulation may prevent extension and embolization, and surgical procedures directed at the inferior vena cava may prevent emboli-

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THROMBOLYTIC THERAPY Sherry

I zation, neither has much influence in preventing subsequent venous valvular dysfunction. For example, review of the literature on t r e a t m e n t of proximal deep-vein thrombophlebitis of the lower extremity with heparin has revealed, on the basis of serial venographic examinations conducted during a ten-day period, that no lysis or actual extension of the thrombus occurred in approximately 80% of cases; 3 in only 6% of cases had there been s u f f i c i e n t r e s o l u t i o n of the thrombus (90% or more) in the first ten days (by that time organization is taking place) to prevent permanent venous valvular damage. This finding is consistent with the natural history of this disorder in pat i e n t s t r e a t e d by a n t i c o a g u l a t i o n alone; the vast majority will develop chronic symptoms of venous hypertension, and about 15% or more will develop a full-blown postphlebitic syndrome.2, 4 Consequently, to avoid this chronic and potentially disabling a f t e r m a t h , e a r l y r e m o v a l of the t h r o m b u s is n e c e s s a r y . B e c a u s e thrombectomy has not proven to be a viable alternative because of the high rate of rethrombosis, t h r o m b o l y t i c therapy is the current approach of choice.

Results Achieved Acute

In r a n d o m i z e d trials, t r e a t m e n t with a t h r o m b o l y t i c agent has res u i t e d in c o m p l e t e l y s i s of t h e t h r o m b u s in approximately half of the patients and in partial lysis in an additional 20%.~,3, 5 The rapid restoration of flow has been associated with faster clinical improvement (ie, subsidence of edema, induration). 6 (Clinical i m p r o v e m e n t , but at a slower rate, also takes place with heparin therapy; this is primarily a result of in-hospital leg elevation and the availability of collateral flow.) Success in dissolving the thrombus has been related to 1) the timing of the onset of thrombolytic therapy after the appearance of symptoms (the highest and most rapid success rate has been observed when treatment was initiated within the first day after symptom onset, and the success rate progressively decreases with further delays in therapy); 2) the nature and extent of the thrombotic event (totally occluding thrombi w i t h o u t any p e r f u s i o n around t h e m h a v e been more difficult to dissolve than 98/397

those with a larger surface area exposed to the circulating blood); 3) the d u r a t i o n of t h e r a p y ( w h e n t h e amount of clot is extensive, several days of therapy may be necessary the longer the treatment period, the greater the success rate, but with an increased incidence of bleeding complications); and 4) evidence that the thrombolytic agent is active in vivo (if no evidence of induced activity is found, little lysis is likely to be present - however, the level of activity induced has little relation to the success of the therapy). Thrombolytic therapy has not been associated w i t h an increased incidence of pulmonary embolism. The thrombus lyses from the surface progressively from the outside, but in a low-pressure, slow-flow environment, this is not conducive to embolization. In contrast, in the high-pressure, rapid-flow environment of the arterial circulation, the risk of embolization is increased as the size of the thrombus or embolus shrinks. Long-term

T h e l o n g - t e r m e v a l u a t i o n of thrombolytic therapy for deep-vein thrombophlebitis has been difficult because there have been no large, randomized trials, and m a n y years may pass before the disabling consequences of a postphlebitic insufficiency s y n d r o m e b e c o m e evident. However, there are three studies in which patients have been followed over long periods of time 7~9 and several studies with shorter follow-up periods. 1o-1s All except one of the studies have demonstrated that patients who had undergone thrombolytic therapy compared with conventional anticoagulation alone exhibited a more normal venous system by v e n o g r a p h y and, m o r e i m p o r t a n t , had a lower incidence of swelling, pain, and stasis ulceration. Nevertheless, in one trial with a long followup period, there was little difference between the two groups on the basis of venous valvular function studies. 9 Although additional studies m a y be indicated, it can be concluded that anticoagulation alone in the vast majority of cases does not p r e v e n t venous valvular dysfunction and its consequences and that thrombolytic therapy administered within the first few days after s y m p t o m onset and continued until there is good evidence of restoration of flow (preferaAnnals of Emergency Medicine

bly by noninvasive techniques such, as duplex uhrasonography) is muchi more likely to prevent venous valvular dysfunction and its consequences.

Indications and Contraindications Present indications for thrombolyric therapy for this condition are adequately documented (usually by v e n o g r a p h y ) p r o x i m a l deep-vein thrombosis of the upper and lower extremities within seven days of the onset of symptoms, although preferably m u c h earlier, provided that the benefit-to-risk ratio favors its use. Because there is the risk of a significant bleed, even ill the absence of invasive procedures (5% total with 1% intracerebra18), patient selection is most important. Absolute contraindications include actively bleeding lesion or the presence of intracranial vascular disorders, such as a recent cerebrovascular accident or ischemic episode within the past two months, cerebral t u m o r , or cerebral arter i o v e n o u s m a l f o r m a t i o n . Relative c o n t r a i n d i c a t i o n s i n c l u d e age of more than 70 years; large abraided wounds, fractures, major surgery or deep closed biopsies within the previous ten days; severe hypertension (diastolic blood pressure of more than 110 m m Hg); and any known increased bleeding risk, such as constitutional or acquired coagulation or platelet defect, severe liver failure, or advanced uremia. Insufficiently stressed in the literature is the increased risk of bleeding when heparin therapy is given simultaneously with thrombolytic agents. In one study, the incidence of bleeding w i t h low-dose (approximately 10% of the n o r m a l dose) streptokinase plus full-dose heparin therapy was as great as that observed with high-dose streptokinase alone; 16 in another study, the combination of low-dose streptokinase and low-dose heparin produced poorer results than high-dose streptokinase alone. 17

Approved Agents Thrombolytic therapy for proximal , deep-vein thrombophlebitis has been carried out with streptokinase, urokinase, recombinant tissue-type plasminogen activator (rtPA), and anisoylated plasminogen-streptokinase activator complex (APSAC). is Most of the studies have been conducted in countries other than the United 20:4 April 1991

7HROMBOLYTIC THERAPY Sherry

States, where streptokinase is the 0nly approved agent for this indication. None of the studies has established superiority for one agent over another, and the m a i n interest at present is to determine the most effective and safest regimen for each of the agents.

Complications A l t h o u g h t h e r e is an a p p r o x i mately 2% incidence of allergic reactions with streptokinase and APSAC, with 0.2% being of an anaphylactoid type, none has been fatal, and most can be managed readily with antihistamines and hydrocortisone. The somewhat more frequent febrile reaction can be controlled w i t h acetaminophen. Occasionally, an acute hypotensive episode has been encountered. These also can be managed (with fluids, Trendelenburg position, and dopamine, if necessary) without interrupting the therapy. The major concerns, however, are with bleeding complications and rethrombosis; it is surprising that the latter has received little attention in the literature, but it is not an infrequent occurrence. Bleeding is the most serious complication; consequently, a t t e n t i o n to proper technique and patient selection are critical factors in reducing its incidence. Surface bleeding can be either prevented or c o n t r o l l e d by p r e s s u r e dressings. Severe i n t e r n a l h e m o r rhages require s u p p o r t i v e therapy and, if necessary, the re-establishment of a normal hemostatic mechanism; this may require cryoprecipitate, fresh frozen plasma, or whole blood. The roles of platelet packs and desmopressin (DDAVP), if any, remain to be established. When severe bleeding occurs during active therapy, particularly if intracerebral, serious consideration should be given to the use of an antifibrinolytic agent (eg, epsilon aminocaproic or tranexamic acid}. To reduce the likelihood of rethrombosis, meticulous anticoagulation should be applied after the termination of t h r o m b o l y t i c therapy and beginning when the activated partial thromboplastin time (APTT) is within the therapeutic range for heparin (1.5-fold to twofold that of normal). Now that we have learned that thrombolytic therapy accelerates platelet activation as well as coagula20:4 April 1991

tion, there may be a role for antiplatelet agents in rethrombosis prevention.

Recommended Protocol Before initiation of therapy, baseline h e m o g l o b i n and c o a g u l a t i o n studies should be obtained. Our preference is plasma fibrinogen to monitor the lytic state and the APTT for eventual changeover to heparin. If streptokinase is used, hydrocortisone s o d i u m s u c c i n a t e 100 m g or its equivalent is given intravenously, which reduces the incidence of febrile and allergic reactions to less than 5%. A loading dose of 250,000 units t h e n is a d m i n i s t e r e d intravenously by infusion pump during a 30-minute period, followed by a sustaining infusion of 100,000 units/hr. After the sustaining infusion has been in place for two to four hours, the plasma fibrinogen level is again checked as an indirect indicator of the presence of a plasma thrombolytic state. With streptokinase, the plasma fibrinogen should be lowered significantly, often to far less than 50% of pretreatment levels. Lesser degrees of hypofibrinogenemia, on the order of a 25% lowering, are seen with urokinase and tPA. Once the presence of a p l a s m a thrombolytic state is demonstrated, therapy should continue at standard doses for the previously noted treatm e n t period (ie, for as long as 72 hours but earlier if adequate reperfusion is established by noninvasive techniques). No titration of dosage is required because in contrast to the situation with heparin, studies have shown that neither efficacy nor toxicity is determined by a t t e m p t s to target specific levels of change in coagulation parameters. After completion of the thrombolytic infusion and a waiting period of three to four hours, coagulation tests are repeated. If the APTT remains elevated but within heparin's therapeutic range (1.5-fold to twofold that of baseline}, a sustaining infusion of heparin w i t h o u t a loading dose is started and maintained. If the APTT is more than twofold that of control, the physician should wait another two to three hours; repeat the APTT, and once it is in the t h e r a p e u t i c range for heparin, start heparin as above. If the APTT is less than 1.5fold that of control, a small bolus of heparin is given, followed by a susAnnals of Emergency Medicine

taining infusion. Heparin and oral anticoagulants then should be administered as usually recommended. Although not yet approved by the Food and Drug Administration bec a u s e of i n s u f f i c i e n t l o n g - t e r m studies of clinical benefit, urokinase has been used successfully in many short-term studies and m a y be administered as an alternative or when the patient is streptokinase resistant (no decrease in fibrinogen or prolongation of the APTT). 18 The protocol is the same, except that no hydrocortisone is given; the loading dose of u r o k i n a s e is 2,000 IU/lb body weight given intravenously, followed by a sustaining infusion of 2,000 IU/ lb body weight per hour until blood flow has b e e n restored. Because urokinase is not antigenic, the therapy may be continued as long as necessary, providing there is evidence of progress in restoring the circulation.

New Developments As noted, studies are under way to develop more effective regimens for streptokinase, urokinase, rtPA, and APSAC, and they may be followed by studies of c o m b i n a t i o n s of t h e s e drugs. Ultimately, studies also will be undertaken on the usefulness of newer antiplatelet agents (eg, thromboxane synthetase inhibitors, thromboxane receptor inhibitors, fibrinogen receptor inhibitors} and potent i a l l y s a f e r or m o r e e f f e c t i v e anticoagulants (eg, low-molecularweight heparin fractions, synthetic thrombin inhibitors, and hirudin). Pharmaceutical firms are heavily engaged in the development of a host of potentially more effective or safer agents. Prourokinase is only one of many new thrombolytic agents whose usefulness for the treatment of deep-vein thrombosis will be explored. Although systemic infusions for this indication have been the usual mode of therapy, local perfusion by catheter, as is frequently used for peripheral arterial thrombo-occlusive events, has not undergone sufficient study; however, in the author's experience, it has been the more desirable approach for the treatment of proximal upper-extremity deep-vein. t h r o m b o p h l e b i t i s . Because of the a c h i e v e m e n t of higher concentrations of the t h r o m b o l y t i c agent in the i m m e d i a t e p r o x i m i t y of the thrombus, local therapy does not re398/99

THROMBOLYTIC THERAPY Sherry

quire a loading dose or as high a sustaining dosage as systemic therapy.

ACUTE P U L M O N A R Y EMBOLISM Rationale Although generally not recognized, conventional anticoagulant therapy ( h e p a r i n f o l l o w e d by oral a n t i coagulants) for acute pulmonary embolism is directed at the source of the embolism, not at the embolism itself. Thus, its aim is to prevent recurrent pulmonary embolism; in this respect, it is considered prophylactic therapy. That most patients survive the insult and recover from the major hemodynamic disturbances that occur is because of the body's ability to make physiological adjustments and ultimately recanalize the embolic occlusion. However, when the embolism is large and occludes a major pulmonary artery, when a shower of emboli occlude a number of vessels simultaneously, or when physiological adjustments cannot be made because of advanced cardiac or pulmonary disease, the risk of death is m u c h higher and, even among survivors, there m a y be a p r o t r a c t e d morbid state. There are also long-term effects of large emboli or recurrent embolism; chronic pulmonary hypertension resulting f r o m increased p u l m o n a r y vascular resistance is not an infreq u e n t a f t e r m a t h . 19-~1 This results from residual abnormalities in the pulmonary vascular bed, even though lung scan defects may disappear.19, 2~ Thus, in the more severe cases of acute pulmonary embolism, thrombolytic therapy can, by lysing the embolus, bring about rapid acute relief from the occlusive event and avoid long-term consequences. Theoretically, it should also improve the survival rate. z3 In addition, it may have a salutary effect on the thrombotic source of the embolus. Results Achieved Acute Short-term improvement has been well documented in the Urokinase and Urokinase-Streptokinase Pulmonary E m b o l i s m Trials (UPET and USPET) ~4 and in several smaller, carefully conducted studies.26, 2z In all of these studies, patients who received a thrombolytic agent followed by heparin had greater reperfusion of the o b s t r u c t e d p u l m o n a r y a r t e r y 100/399

with reduction in the elevated pulmonary artery pressure than patients treated w i t h heparin alone. Also, there was a more rapid improvement in the perfusion defect as determined by perfusion lung scanning. Similar observations have been made on the acute effects of thrombolytic agents in uncontrolled studies. Although there have been suggestions that acute mortality may be reduced, especially in patients w i t h massive embolism where the immediate results are m o s t impressive, proof has not been obtained. The problem in demonstrating a mortality reduction is trial size. In the largest study (UPET), z4 only 160 patients were entered (78 heparin, 82 urokinase); it was recognized in the planning of the study that a trial size at least tenfold larger would be necessary to show a projected and statistically significant reduction in mortality of 25%. (By the time proof of the presence of an embolism by pulmonary angiography is obtained and a patient is placed on heparin, in-hospital mortality is only about 8%. Furthermore, many of the deaths result from underlying complicating diseases rather than the pulmonary embolism itself. Accordingly, a mortality study would require a very large number of patients.) Although trial size could be reduced by only entering patients with a higher mortality rate (ie, those with massive p u l m o n a r y e m b o l i s m and persistent shock), such selection of patients would require an inordinate number of collaborating institutions to fulfill the requirements for patient accession. Despite this lack of proof of mortality reduction, it can be implied because the need for pulmonary e m b o l e c t o m y has v i r t u a l l y disappeared since the advent of thrombolytic therapy. As w i t h t h e l y s i s of v e n o u s thrombi, thrombolytic agents work best on fresh clots, and their ability to lyse a pulmonary embolism with current regimens progressively decreases with time; emboli that are more than five to seven days old are quite resistant to lysis. Because the onset of the disorder is usually sudden and symptomatic and involves t h e f r e s h e n d of an u n d e r l y i n g thrombus, the opportunity exists, in the absence of unnecessary delays, to obtain more rapid and better results than with thrombolytic therapy for Annals of Emergency Medicine

deep-vein thrombosis. In the latte~ instance, the onset of the disease is much more subtle, and patients often delay seeking medical help. The large, centrally located pulmonary emboli (ie, those involving the main pulmonary and lobar arteriesl are m u c h more susceptible to lysis than emboli in the segmental or sub. segmental vessels. The former usu. ally h a v e s o m e p e r f u s i o n around them, so a large surface area is exposed to the a c t i o n of the plas. minogen activator, whereas the latte~ totally obstruct the smaller vessels, thus exposing only a limited surface with a stagnant zone of blood in its proximity. This is why the most dra. matic and impressive results are obtained in patients seriously ill with a massive pulmonary embolism. Studies have also been conducted comparing the results achieved with IV and intrapulmonary therapy; the latter mode of therapy has been used in some studies. 28,29 No significant differences have been o b s e r v e d Y Consequently, local perfusion offers no advantage but is convenient if a catheter has been placed in the pul-~ monary artery for angiography or serial measurements of pulmonary artery pressure. Measurements of the latter, however, will allow therapy to be discontinued once an acceptable benefit has been achieved.

Long-term Long-term physiological benefits were shown in a study in which the total pulmonary capillary blood volume of patients treated with throm-, bolytic therapy and measured at two and 52 weeks after treatment were, on average, in the normal range. In contrast, patients treated with heparin had a 25% reduction in their total pulmonary capillary blood volu m e at two weeks; this reduction was still present at the 52-week follow-up. 31 In another study, sustained i m p r o v e m e n t of p u l m o n a r y hemod y n a m i c s in p a t i e n t s at rest and during exercise after thrombolytic treatment of massive pulmonary embolism was d e m o n s t r a t e d at a 15m o n t h follow-up; 32 this is in contrast to o b s e r v a t i o n s made in patients treated with heparin alone in w h o m persistent pulmonary hypertension and its aggravation by exercise was still evident in most cases three to five years laterA 9 A recently reported comparative 20:4 April 1991

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study involving a seven-year followup of patients randomized to either thrombolytic therapy or heparin confirmed that unlike heparin-treated patients, p a t i e n t s t r e a t e d w i t h thrombolytic therapy have a normal long-term vascular response to exercise.2o

artery is recommended because hemostasis can be accomplished more readily with pressure dressings. Also, w h e n i n t r a v a s c u l a r lines are required, it would be best to place them through a cutdown to minimize trauma to the invaded vessel.

Approved Agents Indications The classic indication for thrombolytic therapy is massive pulmonary embolism with or without shock, massive being defined as 40% or greater obstruction of the pulmonary vascular bed (ie, a perfusion defect equal to two or more lobes or obstruction of one of the main pulmonary arteries); in European studies, massive embolism is defined as 50% or more obstruction of the pulmonary vascular bed. However, on the basis of a Consensus Development Conferenceg3 and subsequent reports, it was recommended that thrombolytic therapy be considered in any patient who has a perfusion defect involving the equivalent of one lobe or more. It was also recommended that it be considered seriously for any patient who is in protracted shock regardless of the size of the embolism (patients with underlying advanced cardiac or cardiopulmonary disease cannot tolerate or adjust to a small decrease in cardiac output; mortality in this group, even in the presence of heparin therapy, approaches 100%). Were it possible to measure pulmonary artery pressure routinely in patients with an acute pulmonary embolism, the a u t h o r believes that thrombolytic therapy should be considered seriously for any patient with acute pulmonary hypertension. In its absence, there would be little need for thrombolytic therapy unless there was an indication to treat the underlying deep-vein thrombosis, g4

Contraindications Contraindications are similar to those described for proximal deepvein thrombophlebitis. Also with pulmonary embolism, it is wise to keep in mind that procedures such as multiple blood gas analyses and placement of various lines that involve invasive procedures should be avoided, if possible, because there will be b l e e d i n g f r o m t h e s e iatrogenic wounds. For the initial blood gas analysis, puncture of the radial artery rather than the femoral 20:4 April 1991

The only approved agents for the treatment of acute pulmonary embolism are streptokinase and urokinase. However, in recent years there have been a n u m b e r of studies using rtPA.30 35,36 With the regimens that have been used in studies with rtPA, no striking difference in efficacy or safety has been achieved over that previously reported with streptokinase or urokinase. However, in the study directly comparing a short course of rtPA with 12-hour and 24hour infusions of urokinase, 36 the speed of lysis was initially faster with rtPA, but there was no difference at 24 hours in the extent of lysis of the embolism between the two regimens. However, the initial rate of lysis of the embolism by urokinase can be accelerated by using a regimen for urokinase similar to that used for rtPA (ie, administering a large dose over a shorter period of time).g7, 38

Complications The incidence of serious bleeding c o m p l i c a t i o n s is at an acceptable level when the treatment is carried out w i t h m i n i m a l i n v a s i v e procedures, careful technique, and attention to contraindications. Because the therapeutic regimen used in the treatment of pulmonary embolism is usually shorter than that for the m a n a g e m e n t of deep-vein thrombosis, the incidence of bleeding complications is somewhat less than for the latter indication. However, considering that the incidence of serious bleeding complications approaches twice that observed with heparin therapy, 33 patients without pulmonary hypertension or large perfusion defects (single or multiple smaller ones) need n o t be t r e a t e d w i t h thrombolytic agents.

Recommended Protocols In general, a protocol similar to that used for the treatment of deepvein thrombosis (vide supra) is recommended for the treatment of acute p u l m o n a r y e m b o l i s m except that with streptokinase, the therapy is Annals of Emergency Medicine

carried out for a 24-hour period; with urokinase, for a 12-hour period; and with rtPA, 100 mg has been recommended to be administered over a seven-hour period, g°

New Developments Current interest centers around the best regimen for each of the agents. Because most of the thrombolytic effect is observed early (begins in approximately 30 minutes and is essentially complete by six hours), more recent studies have involved the use of bolus therapy or larger doses over a shorter period of infusion. The initial results with such an approach have been encouraging.ah 39 It is likely that high-dose, brief-duration therapy similar to that used in the treatment of acute myocardial infarction will replace the longer-treatment schedules.

PERIPHERAL ARTERIAL THROMBOSIS AND EMBOLISM Rationale When occlusive thrombi or emboli occur in limb vessels involving arterial blood (arteries and bypass grafts either venous or artificial), several options, including surgical or mechanical thrombectomy or embolect o m y , b a l l o o n a n g i o p l a s t y , and thrombolytic therapy are available. The rationale behind all of these procedures is similar: Rapid removal of the obstructing occlusion with early restoration of the circulation prevents the occurrence of irreversible tissue damage or c h r o n i c symptomatology. The role of thrombolytic therapy, in this regard, should not be considered independent of other procedures; it is currently viewed as being useful under certain indications and not others, as an adjunct to surgery or percutaneous transluminal angioplasty, and for intraoperative use. T h r o m b o l y t i c t h e r a p y is being used increasingly by vascular surgeons, interventional radiologists, and angiologists because of its demonstrated efficacy when directly injected or infused into the occlusion and its general usefulness under a variety of conditions. The procedure of local injection or infusion of the agent into the interstices of the thrombus or embolus with the advancement of the catheter as lysis is progressing has replaced 400/I 01

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systemic administration as the most desirable form of thrombolytic therapy for arterial thrombo-occlusive events, although proof of greater efficacy has not been established. However, the use of lower doses during regional therapy avoids excessive systemic hematological effects and may reduce the incidence of bleeding complications. Serial angiograms allow monitoring of the results of the procedure and repositioning of the catheter; the results of the procedure more clearly clarify the need for and timing of adjunctive procedures. In the case of an embolic episode, local therapy is less likely than systemic therapy to result in an increased risk of a new embolic event arising from the intracardiac source of the original embolism. Studies with regional therapy have shown that reperfusion can be accomplished in 50% to 90% of attempts; the best results are obtained when t h e thrombolytic therapy is initiated within several hours after the onset of the acute event. As with all forms of thrombosis and embolism, the success rate diminishes with each passing day; is less with clots f o r m e d on u n d e r l y i n g atherostenotic lesions than with embolic occlusions, probably a result, in part, of continuing clotting and a higher incidence of rethrombosis; is increased by guide-wire placement, especially when it can pass through the clot; and is more difficult to achieve with lengthy graft occlusions, which require much longer periods of therapy than shorter ones. In addition, the increased incidence of bleeding complications during extended periods of therapy significantly reduces the benefit-to-risk ratio.

The presence of a significant residual stenosis after r e p e r f u s i o n by thrombolytic therapy has resulted in follow-up angioplasty or surgical correction. Thus, the excellent longterm effects c u r r e n t l y being described (75% or more) may not be the result of the thrombolytic therapy alone, especially as t h r o m b o l y t i c therapy is best viewed as an adjunct to the surgical or mechanical treatment of peripheral thrombotic occlusions of the limb vessels, s2-s7 In the absence of surgical or mechanical follow-up, approximately 50% of the recanalized vessels have remained open for one year. Better results are achieved with therapy for embolic occlusions.S2, s8 The longterm clinical benefits when thrombolytic therapy is used alone, or preferably as an adjunct to other forms of treatment, are now well accepted.

RESULTS

Indications

Acute

Comerota lists the following indications for thrombolytic therapy: 1) to convert an urgent surgical procedure to an elective one; 2) to identify the underlying cause of thrombosis so that it can be easily cor N rected with ultimate salvage of the native vessel or primary graft; 3) to convert a major vascular reconstruc~ tion to a limited, less extensive procedure; 4) to prevent arterial intimal injury from balloon catheter thrombectomy; 5) to restore the patency of branch vessels (or any vessels) that are i n a c c e s s i b l e to m e c h a n i c a l

With proper selection of patients and initiation of therapy by local perfusion within the first few hours after symptom onset, reperfusion can be expected to take place in 75% or more of vessels (similar to results obtained by the intracoronary perfusion of thrombolytic agents within the first three hours after the onset of an acute m y o c a r d i a l infarction). Although pooling of data or retrospective analysis of an institutional experience suggests that urokinase and rtPA may be more effective than 102/401

streptokinase in reperfusing vessels and providing safety from bleeding complications, 40-48 one cannot exclude that better patient selection, earlier onset of treatment, type of regimen used, and more experience in the use of thrombolytic therapy make the newer agents appear better than the agent originally used in most studies. Consequently, there is a need for a direct comparative study of the various agents in terms of efficacy, safety, and long-term effects but with optimal regimens for each of the agents. The ability to reperfuse acutely occluded vessels appears to be associated with significant clinical benefits, both symptomatically and in reducing the need for or limiting the extent of surgical procedures, including amputation.47, 49-sl

Long-term

Annals of Emergency Medicine

thrombectomy; and 6) to reduce the extent of amputation when complete success cannot be obtained, s4 Comerota considers patients who should be evaluated for thrombolytic t h e r a p y as t h o s e w i t h an a c u t e thrombosis of a popliteal aneurysm (especially when there is trifurcation involvement), saphenous vein bypass, femorotibial bypass, any bypass in which runoff vessels are involved, or any bypass with multiple previous procedures and those with an embolic occlusion of vessels inaccessible to mechanical thrombectomy or vessels in patients in whom mechan~ ical thrombectomy carries a high potential for morbidity or mortality.

Contraindications Other than the usual contraindicat i o n s for t h r o m b o l y t i c therapy, which can be considered as less stringent when the agent is instilled directly into the thrombus or embolus, certain types of lesions in patients are not suitable for t h r o m b o l y t i c therapy. Comerota lists these as patients with ischemia so severe as to threaten viability if perfusion is not restored immediately (these individuals must be taken to the operating room as soon as possible); acute postoperative thrombosis of a bypass graft (these patients should be operated on immediately because most thromboses result from a technical error); acute embolic occlusion of the femoral artery or another vessel easily accessed through a limited incision under local or regional anesthesia; t h r o m b o s e d k n i t t e d Dacron ® grafts w i t h o u t an external velour covering (this type of Dacron ® graft carries a high risk of transgraft hemorrhage); s9,6° and patients with mildto-moderate ischemia (tolerable claudication) who would not ordinarily be offered arteriography and/or operative intervention, s4

Approved Agents Despite the availability of strept o k i n a s e , u r o k i n a s e , rtPA, and APSAC for local perfusion of an obstructed vessel, this specific method of administration has not been approved by the Food and Drug Administration for any agent. The only agent approved for the treatment of acute thrombosis and embolism is streptokinase, but only by the intravenous route. Nevertheless, as noted, local administration has become the 20:4 April 1991

THROMBOLYTIC THERAPY Sherry

method of choice, and all of the agents are currently being used for the treatment of arterial thrombosis and embolism.

Complications Despite the use of doses lower than those used systemically, complication rates with local perfusion have been high. However, the incidence of complications varies among studies, depending on how they are reported and defined {eg, concerning bleeding, some studies report total bleeds, others report major bleeds, and still others report only those requiring transfusions). Also, it is unclear how m u c h of the bleeding results from the simultaneous administration of heparin. Besides bleeding complications, there is the risk of distal embolization; during lysis of a thrombus or embolism in the highpressure, rapid-flow arterial system, embolization may occur. In addition, there is the problem of rethrombosis and, for streptokinase and APSAC, allergic reactions. Because the experience of individual investigators has been relatively small, it is difficult to assign an incidence rate of complications, but on the basis of pooled data, the incidence of m a j o r c o m p l i c a t i o n s has ranged between 6% and 22%. 18 Although it is claimed that the highest rates of complications are observed with streptokinase and the least with urokinase and rtPA, no prospective, randomized trials with these agents have been undertaken.

Recommended Protocol It is difficult to r e c o m m e n d any specific protocol because each vascular surgeon, angiologist, or interventional r a d i o l o g i s t u s e s his o w n schema, and these vary in the technique used, the agent used, and the dosage regimen.

New Developments A major new development in the treatment of arterial thrombosis and embolism is its use intraoperatively as an adjunct to a surgical procedure.S4,61, 62 Preliminary observations by several vascular surgeons have shown that this is an encouraging and significant i m p r o v e m e n t in the management of surgically indicated acute vascular problems. The use of angioplasty in c o n j u n c t i o n with thrombolytic therapy has also 20:4 April 1991

been an advance in therapy, 52,s3,ss,56 and new, and perhaps more effective, forms of angioplasty are under development. Another development is the application of thrombolytic therapy to the management either by IV administration or local perfusion for thrombi in the systemic or venous circulation other than the limbs or coronary arteries. Case reports or more extensive studies document its application for t h r o m b o t i c problems in vessels in virtually all organs and for the reopening of clotted central venous catheters or arteriovenous shunts. For example, it has been used successfully by local perfusion for the treatment of acute thrombosis of the superior mesenteric, 63 hepatic, 64 and renal arteries;6S, 66 for various venous thromboses; 67-76 for vitreous hemorrhage 77 by local injection for clotted shunts and indwelling catheters; 76-82 by IV administration for native83, 84 and prosthetic valve thrombosis; 85 and, although risky, even for left ventricular mural thrombi, s6-s8 It is also clear that there is a need to establish which of the agents and regimens, if any, is the most effective and safest for regional perfusion. Also, we need to know the best antit h r o m b o t i c regimen to be used to prevent reclotting during the therapy and to minimize the problem of rethrombosis. There may be a need for platelet inhibitors (platelets play a major role in initiating clotting in the arterial system) and for improved forms of anticoagulation (low-molecular-weight fractions of heparin, hirudin, and so on).

CEREBRAL INFARCTION Rationale Cerebral vascular occlusions remain the greatest challenge for the successful application of thrombolytic therapy. Theoretically, lysis of the occluding thrombus or embolus within the first 20 minutes or so of the acute ischemic event could prevent irreversible damage from taking place, and s u c c e s s f u l r e p e r f u s i o n within the first few hours could limit the size of the cerebral infarct and its neurological sequelae.

Problems Encountered There are two basic problems with thrombolytic therapy for stroke, and they are interrelated: the time from onset of the event to the initiation of Annals of Emergency Medicine

therapy, and the risk of intracranial hemorrhage. It is well known that an ischemic cerebral infarct may transform into a hemorrhagic infarct consequent to the leakage of blood through damaged capillaries and venules into a softening brain. The incidence of this transformation varies and appears to be greatest after cerebral embolism and among hypertensive patients. Reperfusion through such leaky vessels will speed up the process of bleeding into the parenchyma, expanding the infarct and increasing the mortality rate. Also, if there are h e m o s t a t i c plugs already present in some of these vessels, they will also be lysed, increasing the danger of intracerebral bleeding. Furthermore, in contrast to the heart, the structure of which can withstand bleeding into the cardiac musculature, the brain's structure is not equipped to limit the progression of intracerebral bleeding, especially when it is undergoing necrosis and softening. C o n s e q u e n t l y , if t h r o m b o l y t i c therapy is to be successful, it must be administered very soon after the onset of the acute event (ie, before the ischemic area is undergoing softening), and it would be contraindicated in patients with a hemorrhagic infarct. The latter requires evidence by sophisticated imaging techniques that bleeding into the brain is not occurring, and this significantly delays the initiation of thrombolytic therapy. The availability of newer thrombolytic agents stimulates reinvestigation of this subject, 89-95 but it is beneficial to note that because of older studies and clinical experience with the use of thrombolytic therapy as a cause of cerebral hemorrhage, a history of a recent stroke is considered an absolute contraindication when considering its use for any indication.

Current Status The availability of rtPA and, more recently, APSAC has resulted in new interest in the application of these agents for the treatment of strokes of very recent onset. There are already a number of reports in the literature, but whether they are more encouraging than a review of older studies 96 remains to be established. At present, this application would be best c o n s i d e r e d as e n t i r e l y i n v e s t i g a 402/103

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tional, especially as initial enthusiasm usually tends to be tempered with time and experience. SUMMARY Thrombolytic therapy has an established role to play in the management of proximal deep-vein thrombophlebitis, acute pulmonary embolism, and acute peripheral arterial occlusive disease. With proper case selection, successful use of this therapy in proximal deep-vein thrombosis can avoid subsequent venous valve dysfunction, venous hypertension, and the development of a postphlebitic syndrome in the affected extremity. In the more severe cases of acute pulmonary embolism, the treatment can rapidly alleviate the acute pulmonary hypertension and avoid a chronic increase in pulmonary v a s c u l a r r e s i s t a n c e and decreased pulmonary vascular volume. The application of thrombolytic therapy to acute peripheral arterial occlusive disease n o w adds significantly to the armamentariurn of the interventional radiologist and vascular surgeon for dealing w i t h this problem. Because of the potential hazards involved, the application of thrombolytic therapy to the treatment of acute stroke remains in an experimental state. REFERENCES 1. Hailer JA: Deep Thrornbophlebitis: Pathophysiology and Treatment. Philadelphia, WB 8aunders, 1968. 2. Imrnelman El, Jeffery PC: The postphlebitic syndrome: Pathophysiology, prevention and management. Clin Chest Med 1984;5:537-550. 3. Sherry S: Thrombolytic therapy for deep vein thrombosis. Semin Intervent Radioi 1985;2:331-337. 4. Browse NL, Clemenson G, Lea Thomas M: Is the postphlebitic leg always postphlebitic? Relation between phlebographic appearances of deep-vein thrombosis and late sequelae. Br Med J 1980;28I:1167-1170. 5. Rogers LQ, Lutcher CL: Streptokinase therapy for deep vein thrombosis: A comprehensive review of the English literature. Arn J Med i990;88:389-395. 6. Robertson BR, Nilsson IM, Nylander G: Value of streptokinase and heparin in treatment of acute deep vein thrombosis. Acta Chir Scand I968;i34:203-208. 7. Arnesen H, Hello A, Jakobsen E, et al: A prospective study of streptokinase and heparin in the treatment of v e n o u s t h r o m b o s i s . A c t a M e d S c a n d 1978;203: 457-463. 8. Johansson L, Nylander G, Hedner U, et al: Comparison of streptokinase with heparin: Late results in the treatment of deep vein thrombosis. Acta Med Scand 1979;206:93-98. 9. Kakkar VV, Howe CT, Laws JW, et al: Late results of treatment of deep vein thrombosis. Br Med J 1969;

rive randomized trial of heparin versus streptokinase in the treatment of acute proximal venous thrombosis: An interim report of a prospective trial. Br J Surg 1979; 66:838-843. 12. Norgren L, Gjores JE: Venous function in previously thrombosed legs. Acta Chir Scand 1977;I43:421-424. 13. Olow B, Johanson C, Andersson J, et al: Deep venous thrombosis treated with a standard dosage of streptokinase. Acta Chir Scand 1970;136:181-189. 14. Rosch J, Dotter LCT, Seaman AJ, et al: Healing of deep venous thrombosis: Venographic findings in a randomized study comparing streptokinase and heparin. A m J Roentgeno] 1976~127:553-558. 15. Watz R, Savidge GF: Rapid thrornbolysis and preservation of venous valvular function in high deep vein thrombosis. Acta Med Scand 1979;205:293-298. 16. Hirsh J: The use of anticoagulants in patients treated with streptokinase, in Martin M, Schoop W, Hirsh J (eds): N e w Concepts in Streptokinase Dosimetr~z Bern, Switzerland, Han Huber Publishers, 1978, p 142. 17. Schulrnan S, Lockner D, Granqvist S, et al: A comparative randomized trial of low-dose versus high-dose streptokinase in deep vein thrombosis of the thigh. Thrornb Haemost 1984;51:261-265. 18. Verstraete M: Use of thrombolytic drugs in non-coronary disorders. Drags 1989;38:801-821. 19. deSoyza NDB, Murphy ML: Persistent post-embolic pulmonary hypertension. Chest 1972;62:665-668. 20. Sharma GVRK, Folland ED, McIntyre KM, et al: Long-term hernodynarnic benefit of thrombolytic therapy in pulmonary embolic disease (abstract). J A m Coil Cardio] 1990;15(snppl A):65A. 21. Shuck JW, Walder JS, Kam TH, et al: Chronic persistent pulmonary embolism. A m f Med 1980;69:790-794. 22. Freiman DG: Venous thromboembolie disease in medical and malignant states, in Sherry S, Brinkhous KM, Genton G, et al (eds): Thrombosis. Washington, DC, National Academy of Sciences, 1969, p 5-18. 23. Riedel M, Stanek V, Widensky J, et al: Longterm follow-up of patients with pulmonary thromboembolism. Chest 1982;81:151-158. 24. U r o k i n a s e P u l m o n a r y E m b o l i s m Trial Study Group: Urokinase Pulmonary Embolism Trial: A national cooperative study. Circulation 1973;47(suppl II): lI- i -II- 108.

25. Urokinase-Streptokinase Pulmonary Embolism Trial Study Group: Urokinase-Streptokinase Pulmonary Embolism Trial: Phase II results: A national cooperative study, lAMA 1974;229:1606-1613. 26. Miller GAH, Hall RJC, Paneth M: Pulmonary embolectomy, heparin and streptokinase: Their place in the treatment of acute massive pulmonary embolism. A m Heart ] 1977;93:568-574. 27. Ly B, Arnesen H, Eie H, et al: A controlled trial of streptokinase and heparin in the treatment of major pulmonary embolism. Acta M e d Scand 1978;203: 465-470. 28. Demeter SL, Fuenning CH: Intra-pulmonary artery streptokinase. Angiology 1983;34:70-77. 29. Gran E, Fontcuberta J, Pages MA, et al: Massive pulmonary embolism: Short-term effects of thrornbolytic treatment. Angiology 1986;37:832-839. 30. Verstraete M, Miller GAH, Bounarneaux H, et al: Intravenous and intrapulmonary recombinant tissuetype plasrninogen activator in the treatment of acute massive pulmonary embolism. Circulation 1988;77: 353-360. 31. Sharma GVRK, Burleson VA, Sasabara AA: Effect of thrombolytic therapy on pulmonary-capillary blood volume in patients with pulmonary embolism. N Engl f Med 1980;303:842-845.

10. Bieger R, Boekhout-Mussert RJ, Hohmann F, et al: Is streptokinase useful in the treatment of deep vein thrombosis? Acta Med 8cand 1976~199:81-88.

32. Schwarz F, Stehr H, Zimmerrnan R, et al: Sustained improvement of pulmonary hernodynarnics in patients at rest and during exercise after thrombolytic treatment of massive pulmonary embolism. Circulation 1985;71: 117-123.

11. Elliot MS, Immelman El, Jeffery P, et al: A compara-

33. National Institutes of Health Consensus Panel:

1:810-811.

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Thrombolytic therapy in thrombosis: A National Institutes of Health Consensus Development Conference. Ann Intern Med 1980;93:141-144. 34. Sharrna GURK, O'Connell DJ, Belko JS, et al: Thrombolytic therapy in deep vein thrombosis, in Paoletti R, Sherry S (eds}: Thrombosis and Urokinas¢ New York, Academic Press, 1977, p 181-189. 35. Goldhaber SZ, Vaughan DE, Markis JE, et al: Acute pulmonary embolism treated with tissue plasminogen activator. Lancet 1986;1:886-889. 36. Goldhaber SZ, Kessler CM, Heft J, et al: Randomized controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment 0I acute pulmonary embolism. Lancet 1988;2:293-298. 37. Petitpretz P, Simmoneau G, Cerrina J, et al: Effect of a single bolus of urokinase in patients with lifethreatening pulmonary emboli: A descriptive trial. Cir. culation 1984;70:861-866. 38. Sasahara AA, H e n k i n J, Janicki RS: Urokinase versus tissue plasminogen activator in pulmonary embolism. Lancet 1988;2:691. 39. Ozbek C, Sen S, Frank S, et al: Rapid high dose streptokinase in severe pulmonary embolism. Lancet 1989;2: 229-230. 40. McNamara TO, Fischer JR: Thrombolysis of peripheral arterial and graft occlusions: Improved results using high-dose u r o k i n a s e . A m J Roentgeno] 1988;144: 769-775. 41. Katzen BT: Technique and results of "low dose" infusion. Cardiovasc Intervent Radio] 1988;11(suppl}: 541-547. 42. Groar RA, Olin JW: Regional thrombolysis in peripheral arterial occlusions, in Julian D, et al (edsl: Thrombolysis in CardiovasctzJar Disease. N e w York, Marcel Dekker, 1989, p 381-395. 43. Groar RA, Risius B, Lucas FV, et al: Thrombolysis with recombinant human tissue-type plasminogen activator in patients with peripheral artery and bypass graft occlusions. Circulation 1986;74(suppl I):I-l-I-15. 44. Groar RA, Risius B, Young JR, et al: Peripheral artery and bypass graft thrombolysis with recombinant tissue-type plasminogen activator, f Vasc Surg 1986; 3:115-124. 45. Verstraete M, Hess H, Mahler F, et al: Femoro-popliteal artery thrombolysis with intra-arterial infusion ot recombinant tissue-type plasminogen activator: Report of a pilot trial. Eur J Vasc &trg 1988;2:155-159. 46. Belkin M, Belkin B, Buckman CA, et a]: Intra-arterial fibrinolytic therapy: Efficacy of streptokinase versus urokinase. Arch Surg 1986;121:769-773. 47. Gardiner GA, Koltun W, Kandarpak, et al: Thrornbolysis of occluded f e m o r o p o p l i t e a l grafts. A m J Roentgenol 1986;147:621-626. 48. vanBreda A, Katzen BT, Deutsch AS: Urokinase versus streptokinase in local thrombolysis. Radiology 1987;165:109-111. 49. Cornerota AJ, Rubin RN, Tyson RR, et al: Intra-arterial thrombolytic therapy in peripheral vascular disease. Surg Gynecol Obstet 1987;165:1-8. 50. Hargrove WC, Barker CF, Berkowitz HD, et al: Treatment of acute peripheral arterial and graft thromboses with low-dose streptokinase. Surgery 1982;92: 981-993. 51. Long D: Thrombolytic therapy in severe arterial ins u f f i c i e n c y w i t h absent distal pulses. Vasc Surg i982;16:219-237. 52. McNamara TO, Bowberger RA: Factors affecting initial and 6-rnonth patency rates after intraarterial thrornbolysis w i t h high dose urokinase. A m J Surg 1986;152:709-712. 53. Poredos P, Keber I9, Videcnik V: Late results of local thrombolytic treatment of peripheral arterial occlusions. Angdo]ogy 1989;40:941-947. 54. Comerota AJ: Intra-arterial thrombolytic therapy, in Comerota AJ (ed): Thrombolytic Therapy. Orlando, Florida, Grune & Stratton, 1988, p 125-152. 55. Rubin JR, Pond GD, Bernhard VM: Combined thrombolytic therapy and percutaneous translurninal

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angioplasty for t r e a t m e n t of complex arterial graft thrombosis - A case report. Angiology 1988;39:169-173. 56. Totty WG r Gilula LA, McClennan BL, et al: Lowdose intravaseular fibrinolytic therapy. Radiology 1982;143:59-69. 57. vanBreda A, Robison JC, Iaeldman L, et al: Local thrombolysis in the treatment of arterial graft occlusions. J Vasc Surg 1984;1:103-112. 58. Verstraete M: Biochemical and clinical aspects of thrombolysis. Semin HematoI 1978;15:35-54. 59. Rabe FE, Becker G, Richmond BD, et al: Contrast extravasation through dacron grafts: A sequela of lowdose streptokinase therapy. A m J RoentgenoI 1982; 138:917-920. 60. Goldberg L, Ricci M, Sanvage LR, et al: Thrombolyric therapy for delayed occlusion of knitted dacron bypass grafts in the axillofemoral, femoropoplital and femoral tibiaI position. Surg Gynecol Obstet 1985;160: 491-498.

69. Sholar PW, Bell WR: Thrombolytic therapy of inferior vena cava thrombosis in paroxysmal nocturnal hemoglobinuria. Ann Intern Med 1985;103:539-541. 70. Rowe JM, Rasmussen RL, Mader SL~ et al: Successful thrombolytic therapy in two patients with renal vein thrombosis. A m J Med 1984;77:1111-1114. 7L Farrer JF, Goodwin WE: Treatment of priapism: Comparison of methods in fifteen cases. J UroI 1961; 86:768-775. 72. Druy EM~ Trout HH III, Giordano JM, et al: Lytic therapy in the treatment of axillary and subclavian vein thrombosis. J Vasc Surg 1988;2:821-827. 73. Smith NL, Ravo B, Soroff HS, et ah Successful fibrinolytic therapy for superior vena cava thrombosis secondary to long-term total parentera] nutrition. ]PEN 1985~9:55-57. 74. Kohner EM, Pettit JE, Hamilton AM, et ah Streptokinase in central retinal vein occlusion: A controlled clinical trial. Br Med J 1976;1:550-553.

61. Quinones-Baldrich WJ, Baker JD, Busutte] RW, et al: Intraoperative infusion of lytic drugs for thrombotic complications of revascularization. J Vasc Surg 1989~ 10:408-417.

75. Elliot MS, Immelman EJ, Jeffery P, et al: The role of thrombolytic therapy in the management of phlegmasia caerulea dolens. Br J Surg 1979~66:422-424.

62. Cohen LH, Kaplan M, Bernhard VM: Intraoperative streptokinase, an adjunct to mechanical thrombectomy in the m a n a g e m e n t of acute ischemia. Arch Surg 1986;121:708 715.

76. Ruhinstein M, Creger WP: Successful streptokinase therapy for catheter-induced subclavian vein throm~ bosis. Arch Intern Med 1980;140:1370-1371.

63. Flickinger EG, Johnsrude I8, Ogburn NL, et al: Local streptokinase infusion for superior mesenteric artery thromboembolism. A m J Roentgenol 1983;140:771-772. 64. Andrews JC, Griggs TJ, Ensminger WD, et al: Local thrombolytic therapy for hepatic artery thrombosis following chemotherapy infusion catheter placement. Invest Radio] 1987;22:467-471. 65. Fischer CP, Konnak JW, Cho KJ, et ah Renal artery embolism: Therapy with intra-arterial streptokinase infusion. ]~ Urol 1981~125:402-404. 66. Steckel A, Johnston J, Fraley DS, et aI: The use of streptokinase to treat renal arterial thromboembolism. Am J Kidney Dis 1984;4:166-170.

77. 8ellors pJ, Kanski JJ, Watson DM: Intravitreal urokinase in the management of vitreous haemorrhage. Trans Ophthalmol Soc UK 1974;94:591-598. 78. Hurtubise MR, Bottino JC, Lawson M, et al: Restoring patency of occluded central venous catheters. JAMA 1980;115:212-213. 79. Lawson M, Bottino JC, Hurtubise MR, et al: The use of urokinase to restore patency of occluded central venous catheters. A m [ Intravent Ther Ciin N u t r 1982;2:29-32. 80. Glynn MF, Langer B, Jeejeebhoy KN: Therapy for thrombotic occlusion of Iong-term intravenous alimentation catheters. ]PEN 1980;4:387-390.

83. Gagnon RM, Beaudet R, Lemire J, et al: Streptokinase thrombolysis of a chronically thrombosed mitral prosthetic valve. Cathet Cardiovasc Diagn 1984;

10:5-10. 84. Lnluaga IT, Carrera D, d'Oliveira J, et al: Successful thrombolytic therapy after acute tricuspid-valve obstruction. Lancet 1971;1:1067-1068. 85. Roudaut M-FL, Ledain L, Roudaut R, et al: Throm~ bolytic treatment of acute thrombotic obstruction with disk valve protheses: Experience with 26 cases. Semin Thromb Hemost 1987;13:201-205. 86. Krewmer P, Piebig R, Tilsner V, et al: Lysis of left v e n t r i c u l a r t h r o m b i w i t h u r o k i n a s e . Circulation 1985;72:112-118. 87. Keren A, Median A, Gottlieb S, et al: Lysis of mobile left ventricular thrombi during acute myocardial infarction w i t h urokinase. A m J Cardiol 1987;60: 1180-1181. 88. Shenoy MM, Friedman 8A, Dhar S, et al: Streptokinase lysis of intraventricular thrombus and pulmonary emboli with resolution of acquired intracardiac shunt. Ann Intern Med 1985;103:65-66. 89. Barsan WG, Brott TG, Olinger CP, et al: Early treatment for acute ischemic stroke. Ann Intern Med 1989; 111:449-451. 90. Brott TG, Haley EC, Levy DE, et al: Tissue plasminogen activator {tPA} as very early therapy for cerebral infarction (abstract). Stroke 1988;19:133. 91. Del Zoppo GJ, Zeumer H, Harker LA: Thrombolytic . therapy in acute stroke: Possibilities and hazards. Stroke 1986;17:595-607. 92. Sloan MA: Thrombolysis and stroke: Past and fu ture. Arch Neurol 1987;44:748-768. 93. Zivin JA, Fisher M, DeGirolami V, et ah Tissue plasminogen activator reduced neurological damage after cerebral embolism. Science 1985;230:1289-1292. 94. Shiva A, Pnlsinelli W: Hemorrhagic complications of thrombolytic therapy in experimental stroke. Stroke 1987;18:1148-1156.

67. Pritchard SL, Culham JAG, Rogers PC]: Low-dose fibrinolytic therapy in infants. J Pediatr 1985;106: 594-598.

81. Cocke TB, Burgos-Calderon RA, Gonzalez FM: The use of streptokinase infusions for arteriovenous shunt declotting. Trans A m Soc Artif Intern Organs 1970; 16:292-299.

95. del Zoppo GJ, Copeland BR, Watz TA, et al: The beneficial effect of intracarotid urokinase on acute stroke in a baboon model. Stroke 1986~17:638-643.

68. Greenwood LH, Yrizarry JM, Hallatt GW Jr, et al: Urokinase treatment of Budd-Chiari syndrome. A m J goentgenoI 1983~141:1057-1059.

82. Kudo S, Chuang VP, Wallace S, et al: Transcatheter thrombolysis in cancer patients. Cardiovasc Intervent Radio] 1985;8:1-7.

96. Nenci GG, Gresele P, Taramelli M, et al: Thrombolytic therapy for thromboembolism of vertebro-basilar artery. Angiology 1983;34:561-571.

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