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Thrombolysis in the Treatment of Lower Extremity Occlusive Disease
LOWER EXTREMITY ARTERIAL OCCLUSIVE DISEASE
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THROMBOLYSIS IN THE TREATMENT OF LOWER EXTREMITY OCCLUSIVE DISEASE Patrick Riggs, MD, and Kenneth Ouriel, MD
Thrombolytic agents comprise a group of proteins that can dissolve fibrin thrombi. Some of the agents are found endogenously, such as urokinase and tissue plasminogen activator (t-PA). Others, specifically streptokinase, are collected as bacterial exoproducts. Still others, including recombinant t-PA (rt-PA) and recombinant urokinase (r-UK), are produced through genetic engineering techniques. It is important to note that thrombolytic agents are inactive alone, and the addition of a thrombolytic agent to a pure (plasminogen-free) fibrin clot is not associated with any degree of clot dissolution. 3o All thrombolytic agents achieve fibrin dissolution indirectly, through a conversion of the plasminogen to the active agent plasmin. Plasmin is the active protein that produces cleavage of insoluble fibrin to soluble degradation products; thus, all thrombolytic agents require plasminogen as a substrate. The goal of this article is to examine the role of thrombolytic therapy in the treatment of lower extremity occlusive disease, including patient selection and therapeutic technique. A review of the available data serves to illustrate the caveat that thrombolytic therapy cannot be viewed as an absolute alternative to operative intervention. Rather, the two modalities must be used in conjunction with one another, through a coordinated angiographic and surgical team approach. HISTORY OF THROMBOLYSIS
Tillet and Garner32 first characterized the mechanism of action of thrombolytic agents in the 1930s and 1940s. Streptokinase was the agent of interest
From the Department of Surgery, The University of Rochester, Rochester, New York
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during those early years. Impurities in the early preparations confined the use of thrombolytic agents to the laboratory setting. In the late 1940s, however, streptokinase was employed in the setting of a loculated hemothorax, instilling the agent into the pleural space to dissolve the fibrinous pleural cap.33 Nevertheless, the inability to produce a pure product continued to limit clinical applications, and the desired route of intravascular administration awaited further purification of the product in order to limit significant systemic reactions. Therapeutic intravascular administration of thrombolytic agents was pioneered by Cliffton4 and Cliffton and Grossi5 in the mid-1950s, when they successfully administered a mixture of streptokinase and plasminogen directly into the veins and arteries of patients with vascular occlusions. Cliffton believed that the lysis he observed was due to the exogenous plasmin generated by the actions of streptokinase on plasminogen. Subsequent work, however, would show that purified preparations of plasmin are inactive in a red cell-rich rnilieu,26,30 thus implicating the excess streptokinase as the active agent. In the years that followed, sporadic anecdotal reports defined only modest efficacy with the use of streptokinase, achieved at the cost of a wide variety of complications. These findings discouraged the widespread acceptance of thrombolytic therapy in peripheral arterial occlusion. It was not until the report of catheter-directed, intra-arterial streptokinase by Dotter and associates9 in 1974 that interest in thrombolytic therapy was renewed. Dotter, through innovative endovascular technique$, was able to deliver streptokinase directly into the substance of the occluding arterial thrombus. Intrathrombus administration provided the theoretical advantage of increasing surface contact between the agent and the thrombus while minimizing the risk of systemic bleeding complications. The decade of the 1980s was characterized by a wide variety of retrospective reports comprising large groups of patients treated with streptokinase, urokinase, and rt-PA. 10--12, 15 Acceptance of thrombolytic agents in the treatment of lower extremity occlusive disease was expanded during these years with the publication of impressive rates of success in the treatment of acute and chronic occlusions of the lower extremity arterial tree. The reports of innovative investigators such as McNamara, Graor, and Katzen documented excellent therapeutic results with newer thrombolytic agents and methods of delivery. Improved lytic efficacy was achieved in concert with a virtual elimination of the allergic complications prevalent with streptokinase. The results of these retrospective series broadened the use of thrombolytic therapy for acute arterial occlusion. Surgical methods, however, had been used since the late 1940s,8,17 and their success in restoring limb viability was well documented. 35 Nevertheless, the highly effective operative techniques were associated with a significant risk of mortality, presumably from the performance of a highly invasive intervention in a medically compromised patient.1 Clinicians now began to separate into two distinct camps with respect to the most appropriate initial therapy for peripheral arterial thrombotic occlusion-operation or thrombolytic therapy. The retrospective decade of the 1980s was replaced by the prospective decade of the 1990s, as investigators chose to settle their differences through the perfqrmance of well-controlled clinical trials. The large studies of thrombolytic therapy in acute coronary artery occlusion served as an additional impetus to the development of well designed trials of peripheral thrombolysis, comparing thrombolytic therapy with standard operative techniques in the treatment of acute arterial occlusion. The ill-defined and subjective endpoints of "arteriographic lysis" and "clinical success" were superseded by more objective and relevant endpoints, such as limb salvage, patient survival, and a documented
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decrease in the magnitude of operative interventions. For the first time in over four decades of clinical use, thrombolytic therapy was about to undergo a critical comparison with standard operative techniques in the treatment of limb ischemia. BIOLOGY OF THROMBOLYTle AGENTS
Under normal conditions, there exists a tenuous balance between intravascular thrombosis and thrombolysis, maintaining hemostasis and preserving tissue perfusion in response to constantly occurring minor endothelial trauma. 3D, 31 Physiologic thrombolysis requires the conversion of plasminogen to plasmin, which in tum cleaves cross-linked fibrin at an arginyl-Iysyl amino acid bond. The conversion of plasminogen is catalyzed by endogenous plasminogen activators released from endothelial cells. All of the currently available exogenously administered thrombolytic agents are plasminogen activators, used at supraphysiologic doses to stimulate the fibrinolytic system (Fig. 1). Although the development of new thrombolytic agents is a very active area of current research, with a host of novel agents undergoing laboratory and clinical trials, only four agents are commercially available at the this time (Table 1).21 Streptokinase, a proteolytic enzyme produced by J3-hemolytic streptococci, has the advantage of being the least expensive plasminogen activator. It has several disadvantages, however; most importantly its antigenicity. Streptokinase may be bound by circulating antibodies formed after recent streptococcal infection or previous administration of the agent. Pre-existent antibodies to streptokinase greatly reduce the bioavailability of circulating activator and are responsible for allergic reactions. Further, streptokinase appears to be less efficient at lysing thrombus than the other available agents. 13
IFree plasmin I + -. - , , . . . - -
Figure 1. Biochemical interactions in the plasma and the thrombus during thrombolytic therapy. (From Ouriel K: Thrombolytic therapy for acute arterial occlusion. In Daly JM (ed): Current Opinion in General Surgery, vol 2. Philadelphia, Current Science, 1994, p 258; with permission.)
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Table 1. PROPERTIES OF COMPONENTS OF THE THROMBOLYTIC SYSTEM Component
Streptokinase Urokinase rt-PA APSAC Pro-urokinase
Molecular Weight
46 54 70 131 53
kD kD kD kD kD
Structure
Single chain Two chains One or two chains Lys-plas + SK Single chain
Half-life
11 10 5 70 6
minutes minutes minutes minutes minutes
Adapted from Ouriel K: Thrombolytic therapy for acute arterial occlusion. In Daly JM (ed): Current Opinion in General Surgery, vol 2. Philadelphia, Current Science, 1994, p 258; with permission. Data originally from Marder VJ: The use of thrombolyfic agents: Choice of patient, drug administration, laboratory monitoring. Ann Intern Med 90:802-a12, 1979.
Urokinase was the second thrombolytic agent to be evaluated.3,18 Initially purified from human urine, urokinase is now produced by fetal kidney cell cultures. It is nonantigenic and more efficient at lysing thrombus than streptokinaseY Urokinase is currently the agent most widely used in peripheral arterial occlusion, despite the lack of acknowledgment of this indication by the US Food and Drug Administration. The plasminogen activator associated with the most rapid lysis of fibrin thrombus may be rt-PAY This agent was initially touted as a superior agent with regard to fibrin specificity.29 rt-PA was thought to activate only plasminogen bound to fibrin, thus sparing systemic fibrinogen and avoiding a systemic proteolytic state. In fact, none of the agents is truly fibrin specific, and rt-PA causes fibrinogen breakdown to a degree similar to the other available agents. 24 Additionally, clinical bleeding appears more closely linked to the dissolution of small hemostatic plugs at the site of local trauma, plugs that are structurally identical to the target thrombus causing vascular compromise. In large clinical trials, rt-PA has been associated with more bleeding complications than other agents. 19 Further, concern has been generated by the development of Significant thrombocytopenia in some patients receiving systemic rt_PA.14 A final approved thrombolytic agent, acylated plasminogen-streptokinase complex (APSAC), is actually a mixture of two components, streptokinase and plasminogen. APSAC was developed in the hope of improving fibrin specificity and increasing fibrinolytic efficacy. APSAC retains the antigenicity of streptokinase, and investigation has revealed that APSAC is no more specific or efficient than streptokinase alone. 16 The half-life of streptokinase is lengthened when complexed to plasminogen, however, providing a theoretical advantage in the setting of systemic administration for acute coronary occlusion. CLINICAL USE OF THROMBOLYTIC AGENTS
Thrombolytic agents have been used in a variety of clinical settings, including deep venous thrombosis, acute coronary occlusion, peripheral arterial occlusion, and stroke. Several caveats should be remembered in each of these applications. First, thrombolytic therapy is in a state of evolution, and the indications for its use are not completely defined. One should avoid unstructured experimentation in novel clinical settings and indications heretofore undescribed. Second, the effectiveness and safety of these agents are operator dependent. One should not expect to duplicate the results achieved by experienced investigators without the equipment and trained personnel to support the proven protocols. Third, the availability of less invasive treatment modalities such as thrombolytic therapy should not alter the historically proven indications for intervention.
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Thus, the indications for the use of intra-arterial thrombolysis for peripheral arterial occlusion parallel those for lower extremity operative revascularization. It is important to consider the factors that determine the success or failure of thrombolytic therapy when deciding how best to treat a particular patient. Biophysical factors playa prominent role in achieving a successful thrombolytic result. For example, effective thrombolysis requires contact of the thrombolytic agent with the fibrin within the thrombus. In vitro studies have demonstrated that thrombolytic agents permeate thrombus very slowly by simple diffusion, requiring hundreds of hours for lysis to proceed a single centimeter.7 In a flowing system, however, thrombolysis is greatly accelerated by the formation of small channels through the thrombus, permitting plasminogen activator and plasminogen to come in contact with cross-linked fibrin at multiple sites. Laboratory studies using magnetic resonance imaging to visualize flow through thrombi have confirmed the clinical observation that high-flow systems lyse faster than low-flow systems. 2 Additionally, adequate outflow is necessary for the efficient formation of channels within the thrombus. Vessels with numerous side branches have multiple outflow sites, providing pathways for the elimination of the byproducts of upstream thrombolysis and maximizing the contact between fresh thrombolytic agent and plasminogen (Fig. 2). Applying these principles to clinical thrombolysis, it was predictable that intravenous therapy would be far more effective in treating small coronary thrombi than in lysing large peripheral arterial clots. Coronary thrombi are situated in a high-flow arterial segment with many side branches, whereas infrainguinal thrombi are usually present in long, branchless conduits. Thus, the relatively small amounts of thrombolytic agent presented to the thrombus in the intravenous treatment of coronary occlusion are not likely to be sufficient to dissolve thrombi within the peripheral arterial tree. Catheter placement into peripheral arterial thrombi, with direct administration of the agent into the substance of the thrombus, appears to be of critical importance in the treatment . of large lower extremity occlusive clots.25 The progression of thrombolysis must be serially assessed for therapy to be effective, repositioning the delivery catheter as necessary. Multi-side hole catheters allow activator to contact thrombus at numerous sites along the length of the thrombus. A multihole catheter with a few side holes or the end hole positioned outside the thrombus is potentially detrimental to thrombolytic success. The lytic agent traverses the path of least resistance and flows preferentially through the holes outside of the substance of the thrombus, avoiding contact with the fibrin clot (Fig. 3). "Pulse-spray" delivery of thrombolytic agent is a method whereby the lytic drug is administered in multiple short boluses into the thrombus. Some have argued that pulse-spray administration is more effective in augmenting thrombolysis than are continuous infusions, possibly by enhancing channel formation and contact of the agent with the thrombus. 34 This delivery mode has been avoided by some clinicians on the basis of fears of increasing the chance of distal embolization of partially dissolved clot into the distal arterial circulation. CONTRAINDICATIONS TO THE USE OF THROMBOLYTIC THERAPY
Almost all major complications of thrombolytic therapy are related to local or distant hemorrhage. Thus, contraindications to the use of thrombolytic agents are generally related to situations that are associated with a bleeding tendency. Patients with sites of recent internal or noncompressible hemorrhage are not appropriate candidates for thrombolysis (Table 2). Patients with a history of
Systemic Activator ---~
Systemlc _ _ _- I.. ~ Activator Byproducts In Boundary Meniscus
A
Systemic Activator - - .
Systemlc _ _ _ _ _ _ _ _ _ _ _ _ _ _ _~ Activator ~
B
~~
Figure 2. Intravenous, systemic thrombolytic therapy is more successful when the involved arterial segment has numerous, closely spaced side branches. A, Schematic representation of a large, branchless vessel such as the superficial femoral artery. Thrombolysis proceeds only a few millimeters before progress is blocked by a "meniscus" of byproducts. B, By contrast, a coronary artery has numerous side branches that allow the wash-out of the byproducts and contact between the clot and fresh plasma with activator agent and plasminogen. (From Ouriel K, Comerota AJ: Thrombolytic therapy in the management of peripheral arterial occlusion. In Ouriel K (ed): Lower Extremity Vascular Disease. Philadelphia, WB Saunders, 1995, p 301.)
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No Lysis
Some Lysis
639
Lysis
Figure 3. The position of the catheter infusion ports is important in providing for effective distribution of lytic agent into the substance of the thrombus. (From Ouriel K, Comerota AJ: Thrombolytic therapy in the management of peripheral arterial occlusion. In Ouriel K (ed): Lower Extremity Vascular Disease. Philadelphia, WB Saunders, 1995, p 303.)
major gastrointestinal hemorrhage within the recent past or patients who have undergone major surgical procedures should not be subjected to the challenges of even locally administered thrombolysis. Patients with intracranial lesions, including recent cerebrovascular accidents, neoplasms, or recent craniotomies, are at increased risk of intracranial hemorrhage, and thrombolytic therapy should be .avoided. The one setting in which thrombolysis may be used in a patient with specific contraindications relating to a hemorrhagic tendency is the intraoperative administration of lytic agents distal to an occluding tourniquet. The protection of a tourniquet is only partial, however, as a bolus of agent may be released into the systemic circulation when the tourniquet is released. The use of thrombolytic agents in attempting to treat irreversibly ischemic limbs is probably not warranted. The severely ischemic limb is not likely to achieve function; even if much of the muscle and skin is salvaged, the nervous tissue rarely regains function. Thus, the presence of marked motor and sensory loss represents a relative contraindication to thrombolysis. Operation, frequently in the form of major amputation, is usually more appropriate. Table 2. SUGGESTED CONTRAINDICATIONS TO THROMBOLYTIC THERAPY Major operative procedure Cerebrovascular accident Cerebrovascular neoplasm Major gastrOintestinal hemorrhage Renal insufficiency Nonambulatory patient
<14 days <6 months Absolute <3 months Creatinine >2.5 mg/dL Absolute
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SPECIFIC INDICATIONS
The use of thrombolytic agents for the acutely occluded artery has the potential to restore arterial flow using a modality that is frequently less invasive than open surgical revascularization. McNamara and Bomberger23 reported excellent results in the treatment of iliac and superficial femoral arterial occlusions. They obtained an overall immediate patency of 89%, with 92% of the opened vessels remaining patent at 6 months. Infrainguinal vessels remained patent when subsequent angiography demonstrated no residual stenosis, with a 6month patency of 77%. By contrast, only 10% of vessels were patent if a residual stenosis remained. We found a difference in the ability to open thrombosed prosthetic grafts and vein grafts, with initial success rates of 83% and 50%, respectively. Successfully thrombolysed prosthetic bypass grafts were unassociated with an underlying stenosis in a remarkable number of cases, comprising 59% in our experience. These patients were managed with long-term anticoagulation following thrombolysis, reasoning that the anatomic and physiologic parameters were unchanged from those present at the time of graft failure. By contrast, virtually all failed vein grafts manifested an underlying lesion following thrombolysis, suggesting that autogenous conduits rarely fail in the absence of a hemodynamically significant anatomic lesion. Popliteal artery aneurysms frequently present with distal thrombosis and present another potential indication for thrombolysis. Dissolution of tibial thrombus may provide a suitable outflow vessel for operative bypass, where before there had been none. When the initial diagnostic arteriogram reveals the presence of an open tibial or pedal vessel suitable for outflow, however, we do not use thrombolytic therapy. Operative revascularization is feasible as a sole intervention in these cases, and lysis of the popliteal clot merely places the limb at risk for embolization of partially lysed clot into the distal arterial tree. TECHNICAL ASPECTS OF THROMBOLYSIS
Once thrombolytic therapy has been elected, patients are taken expeditiously to the angiography suite. An appropriate diagnostic study is performed through a catheter insertion site remote from the occlusion, generally accomplishing access through the contralateral femoral artery. Antegrade approaches through the ipsilateral femoral artery have been useful only for occlusions of grafts originating from the superficial femoral artery and more distal vessels or for distal native artery occlusions. We have treated patients undergoing thrombolysis with aspirin and/or heparin to prevent pericatheter thrombus deposition during thrombolysis. Although we have been impressed by a subjectively higher incidence of bleeding with concurrent heparin anticoagulation, some investigators continue to tout its use. The most important determinant of thrombolytic success is the ability to place the catheter within the substance of the occlusive process. 25 Sophisticated angiographic techniques are often required to visualize the proximal stump of a failed bypass graft, utilizing oblique views or ultrasonic guidance techniques. An attempt is always made to pass a guide wire through the thrombus, both to ascertain the likelihood of thrombolysis and, occasionally, to create channels to improve the distribution of lytic agent within the clot. A multihole catheter is positioned so that all the infusion ports are within the thrombus. Coaxial systems are used when two separate thrombosed segments are encountered with open
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artery in between. When this situation is present, the catheter is positioned in the proximal clot and an infusion guide wire is threaded into the distal clot. Experience has shown that the choice of specific agent and dose appears to be less critical than the position of the infusion catheter. We repeat angiography at intervals and reposition the catheter as needed. Therapy is terminated when successful lysis is demonstrated angiographically, when clinical deterioration progresses during lytic therapy, or when major complications develop. We have found little benefit with continued lytic infusion if no lysis is achieved within 12 hours. 27 Others have observed a dramatic increase in the rate of complications when therapy is continued beyond 48 hours.1o An average reperfusion time of 4 to 8 hours should be expected, with some degree of improvement in the clinical status of the limb and some antegrade flow of contrast through the occlusive thrombus by that time.27 However, considerable variation exists between patients, and the time to reperfusion decreases with increasing experience in invasive angiographic techniques. If completion arteriography demonstrates a stenosis of the native artery, bypass graft, or outflow vessel, the unmasked lesion is aggressively corrected by operative or endovascular techniques. We have relied on open surgical techniques to repair neointimal fibrous lesions at graft anastomoses or for diffuse lesions running for a considerable distance along a native artery or bypass graft. Balloon angioplasty has been reserved for focal atherosclerotic lesions. Thus, the majority of our patients who have undergone successful thrombolysis are treated with an adjuvant operative procedure, frequently in the form of patch angioplasty of a stenotic lesion. In support of the above approach, we have completed a prospective randomized trial of surgery versus thrombolysis as the initial treatment for 114 eligible patients with limb-threatening ischemia secondary to embolic or thrombotic occlusion of native vessels or bypass grafts in the lower extremity.27 Patients failing thrombolytic therapy (30%) were treated with operative revascularization (26%) or primary amputation (4%). AnalysiS of the outcome data showed no significant difference in limb salvage (12-month amputation rate approximately 20% in each group), but a 62% reduction in I-year risk of mortality was observed in the thrombolytic group (84% versus 58%, respectively, Fig. 4). This finding was corroborated by Comerota et aI's6 observation of improved survival in patients receiving intraoperative thrombolytic agents during elective infra inguinal reconstructions. The reasons for this effect are unknown but may be related to the reduction in systemic fibrinogen levels incurred in thrombolytic therapy, which may reduce intracoronary thrombotic potential. Further, the magnitude of operation required is frequently reduced by the adjunctive use of thrombolytics, and a significant number of patients do not require an operation after successful therapy.27 INTRAOPERATIVE AND POSTOPERATIVE THROMBOLYSIS
Perioperative lytic agents have been avoided in many instances because of a fear of bleeding complications. Performance of arterial thrombectomy or bypass for acute arterial occlusions represents an ideal setting for the use of lytic agents because Fogarty catheter thrombectomy is associated with a high frequency of residual thrombus in both animal and clinical studies.28 Catheterdirected lytic agents infused into the distal arterial tree have been shown to increase the amount of thrombus removed. Comerota et al6 have collected a series of 53 patients treated with thrombolytic agents infused into the runoff
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1.00
.80
L 6 '~i---o---o,l··--·6---.. ,
Thrombolytic
r----- -----------. ----------Operative
.40
.20
Thromb. Operat.
46 41
40 33
4
8
0
37 24
29 20
21 11
18 8
20
24
I
0
12
16
Months Figure 4. The survival of patients presenting with acute limb-threatening ischemia treated with initial operative or thrombolytic intervention.
vessels at the time of operative revascularization. They achieved limb salvage in 70% of the cases and surmised that these results were directly attributable to lysis of the distal thrombus in 47% of the series. Currently, Comerota et al suggest that an effective method of re-establishing outflow is a combination of Fogarty thrombectomy and urokinase (250,000 to 500,000 IV in approximately 30 mL of normal saline), instilled as a bolus through a catheter placed into the distal outflow vessel. Repeat thrombectomy is performed prior to completion of the distal anastomosis. When distal thrombus remains, another option is to continue local thrombolytic infusion during the postoperative period. A catheter is passed from a remote site and advanced into the thrombus. The catheter must be well past the distal anastomosis to avoid anastomotic bleeding, but a moderate degree of oozing from the wound should be expected as long as the thrombolytic infusion is continued. The vessel is infused with urokinase (1000 to 2000 IV /min), and arteriography is serially repeated. The patients are monitored in the intensive care setting and closely followed for bleeding. Isolated limb perfusion is a relatively new technique under investigation as an adjunct to surgical revascularization. Candidates have severe limb-threatening ischemia and outflow vessel thrombosis, usually with extension of the process to the small distal vessels not amenable to catheter thrombectomy. One method we have found useful in occasional instances utilizes a pump oxygenator to perfuse the isolated limb. A low thigh tourniquet is inflated to suprasystolic pressure, and the popliteal artery and vein are cannulated. High-dose urokinase (frequently over 1 million IV) is circulated through the limb by a pump oxygenator primed with 500 mL of fresh frozen plasma to provide necessary plasminogen substrate. The perfusions are continued for 90 to 120 minutes, with intraoperative arteriography performed through the arterial cannula. We have salvaged
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an occasional limb using this technique, but our results have not been as encouraging as those observed by other investigators. CHRONIC OCCLUSIONS
The role of lytic agents is less defined in the setting of chronic arterial occlusion than acute occlusion. As an adjuvant to surgical revascularization, thrombolytic therapy may be of benefit in shortening the length of a chronic occlusion. This is particularly relevant when the superficial femoral artery is occluded and adequate saphenous vein is not available for a longer bypass graft. Dissolution of the thrombus propagated proximally and distally around the atherosclerotic lesion at the adductor hiatus may leave the patient with a much shorter length of occluded artery, suitable for a short bypass, endarterectomy, or balloon angioplasty. McNamara22 has reported a series of 24 patients with occlusions of greater than 3 months' duration treated with intra-arterial thrombolytic agents. He documented recanalization in 48% of the patients. Patients were treated for the underlying cause of occlusion by balloon angioplasty or placement of a stent. Patients failing therapy and those reoccluding the recanalized segment did not experience worsening of symptoms. The best results were achieved in iliac lesions and lesions that were traversable by a guide wire. MONITORING OF PATIENTS
Careful laboratory and clinical monitoring of patients receiving thrombolytics is essential to avoid unnecessary complications. The patients are monitored by nurses familiar with the use of thrombolytic agents, usually in the setting of an intensive care or "step-down" unit. Laboratory surveillance includes hemoglobin, hematocrit, platelet count, partial thromboplastin time, and fibrinogen level at 6-hour intervals or when clinically indicated by a change in the patient's examination. We do not heparinize patients at the initiation of lytic therapy, although many centers advocate heparin to avoid thrombus formation on the catheter. We routinely use heparin in the interval between thrombolysis and operative revascularization, as well as in cases of graft occlusion without an underlying stenosis. These patients are then anticoagulated with warfarin indefinitely. Fibrinogen levels correlate poody with hemorrhagic complications and are of questionable clinical benefit. Levels below 100 mg/ dL are indicative of a systemic lytic state, and empiric correction with a decrease in the dose of thrombolytic agent has been advocated by some. We have not altered therapy based on asymptomatic hypofibrinogenemia. The appearance of severe bleeding, however, mandates immediate discontinuation of therapy and aggressive correction of the coagulation and thrombotic abnormalities. Epsilon-aminocaproic acid, a competitive inhibitor of plasminogen activators, arrests ongoing fibrinolysis. Fresh frozen plasma or cryoprecipitate is administered to replete fibrinogen, and platelets may be required to replace losses. ADJUNCTS TO THE USE OF THROMBOL YTICS
Despite the advances in thrombolytic therapy, there remain a significant number of treatment failures. Techniques to improve the efficacy of these agents
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can be divided into two categories. First, investigators have attempted to increase the rate of thrombolysis through the development of novel agents such as bat plasminogen activator ("Bat PA"), single-chain urokinase ("pro-UK"), and chimeric alterations of current activators. A second research initiative is undertaking the development of new strategies for improving the efficacy of current agents. We have tested a technique that holds promise for augmenting thrombolysis using any of the currently available activator agents. We have found that clot lacing with plasminogen, the substrate for all thrombolytic agents, significantly improves the lytic efficacy of urokinase and rt-PA. The studies were conducted in a recirculating in vitro system that closely approximates the physiologic parameters of catheter-directed thrombolysis. A relative depletion of plasminogen appears to be present within the thrombus during infusion of activators, such that plasminogen availability becomes rate limiting for thrombolysis. Our work suggests that catheter-directed exogenous plasminogen administration may accelerate thrombolysis in the clinical setting, possibly without a parallel increase in the risk of distant bleeding complications.
References 1. Blaisdell FW, Steele M, Allen RE: Management of acute lower extremity arterial ischemia due to embolism and thrombosis. Surgery 84:822-834, 1978 2. Blinc A, Planinsic G, Keber D, et al: Dependence of blood clot lysis on the mode of transport of urokinase into the clot: A magnetic resonance imaging study in vitro. Thromb Haemost 65:549-552,1991 3. Bovel GW, Mohler SR, Jones NW, et al: Urokinase: An activator of plasma profibrinolysin extracted from urine. Am J Physiol 171:768-769, 1952 4. Cliffton EE: The use of plasmin in humans. Ann NY Acad Sci 68:209-229, 1957 5. Cliffton EE, Grossi CE: Investigations of intravenous plasmin (fibrinolysin) in humans: Physiologic and clinical effects. Circulation 14:919, 1956 6. Comerota AI, Rao AK, Throm RC, et al: A prospective, randomized, blinded, and placebo-controlled trial of intraoperative intra-arterial urokinase infusion during lower extremity revascularization: Regional and systemic effects. Ann Surg 218:534-543,1993 7. Diamond SL, Anand S: Inner clot diffusion and permeation during fibrinolysis. Biophys J 65:2622-2643, 1993 8. Dos Santos JC: Sur la desobstruction des thrombus arterielles anciennes. Mem Acad Chir 73:409, 1947 9. Dotter CT, Rosch I, Seaman AJ: Selective clot lysis with low-dose streptokinase. Radiology 111:31-37, 1974 10. Gardiner GA Jr, Harrington DP, Koltun W, et al: Salvage of occluded arterial bypass grafts by means of thrombolysis. J Vasc Surg 9:426--431, 1989 11. Graor RA, Risius B, Denny KM, et al: Local thrombolysis in the treatment of thrombosed arteries, bypass grafts, and arteriovenous fistulas. J Vasc Surg 2:406--414, 1985 12. Graor 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 74:1-15-1-20, 1986 13. Graor RA, Olin I, Bartholomew JR, et al: Efficacy and safety of intraarterial local infusion of streptokinase, urokinase, or tissue plasminogen activator for peripheral arterial occlusion: A retrospective review. J Vasc Med Bio 2:310-315, 1990 14. Harrington RA, Sane DC, Sigmon KN, et al: Clinical importance of thrombocytopenia occurring in the hospital phase after administration of thrombolytic therapy for acute myocardial infarction. The Thrombolysis and Angioplasty in Myocardial Infarction Study Group. J Am Coli Cardiol 23:891-898, 1994 15. Hess H, Ingrisch H, Mietaschk A, et al: Local low-dose thrombolytic therapy of peripheral arterial occlusions. N Engl J Med 307:1627-1630,1982
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16. ISIS-3 Study Group: ISIS-3: A randomized comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. Lancet 339:753-770,1992 17. Kunlin J: Le traitement de l'arterite obliterante par la greffe veineuse. Arch Mal Coeur 42:371, 1949 18. Macfarlane RG, Pilling J: Observations on fibrinolysis: Plasminogen, plasmin, and antiplasmin content of human blood. Lancet 2:562-565, 1946 19. Maggioni AP, Franzosi MG, Santoro E, et al: The risk of stroke in patients with acute myocardial infarction after thrombolytic and antithrombotic treatment. N Engl J Med 327:1-{), 1992 20. Marder VJ: The use of thrombolytic agents: Choice of patient, drug administration, laboratory monitoring. Ann Intern Med 90:802--812,1979 21. Marder VJ, Sherry S: Thrombolytic therapy: Current status-I. N Engl J Med 318:15121520, 1988 22. McNamara TO: Thrombolysis for chronic occlusions. Presented at "Thrombolytic Therapy in the Management of Vascular Disease" Symposium. Santa Monica, CA, October,I993 23. McNamara TO, Bomberger RA: Factors affecting initial and 6 month patency rates after intraarterial thrombolysis with high dose urokinase. Am J Surg 152:709-712, 1986 24. Meyerovitz MF, Goldhaber SZ, Regan K, et al: Recombinant tissue-type plasminogen activator versus urokinase in peripheral arterial and graft occlusions: A randomized trial. Radiology 175:75-78, 1990 25. Ouriel K, Shortell CK, Azodo MVU, et al: Predictors of success in catheter-directed thrombolytic therapy of acute peripheral arterial occlusion. Radiology 193:561-566, 1994 26. Ouriel K, Stoughton J: Plasminogen acceleration of urokinase thrombolysis. J Vase Surg 19:298--305, 1994 27. Ouriel K, Shortell CK, DeWeese JA, et al: A comparison of thrombolytic therapy with operative revaseularization in the initial treatment of acute peripheral arterial ischemia. J Vase Surg 12:1021-1026, 1994 28. Quinones-Baldrich WJ, Ziomek S, Henderson TC, et al: Intraoperative fibrinolytic therapy: Experimental evaluation. J Vasc Surg 4:229-236, 1986 29. Risius B, Graor RA, Geisinger MA, et al: Recombinant human tissue-type plasminogen activator for thrombolysis in peripheral arteries and bypass grafts. Radiology 160:183188,1986 30. Sherry S: History and development of thrombolytic therapy. In Comerota AJ (ed): Thrombolytic Therapy. Orlando, Grune & Stratton, 1988, pp 1-15 31. Sherry S, Fletcher AP, Alkjaersig N: Fibrinolysis and fibrinolytic activity in man. Physiol Rev 39:343, 1959 32. Tillett WS, Gamer Rl: The fibrinolytic activity of hemolytic streptococci. J Exp Med 58:485-502, 1933 33. Tillett WS, Sherry S: The effect in patients of streptococcal fibrinolysin (streptokinase) and streptococcal desoxyribonuclease on fibrinous, purulent, and sanguinous pleural exudations. J Clin Invest 28:173, 1949 34. Valji K, Roberts AC, Davis GB, et al: Pulsed-spray thrombolysis of arterial and bypass graft occlusions. AJR 156:617-{)21, 1991 35. Veith FJ, Gupta SK, Ascer E, et al: Six-year prospective multicenter randomized comparison of autologous saphenous vein and expanded polytetrafluoroethylene grafts in infrainguinal arterial reconstructions. J Vasc Surg 3:104-114, 1992
Address reprint requests to Patrick Riggs, MD Department of Surgery The University of Rochester Rochester, NY 14642
0039-6109/95 $0.00 + .20
THROMBOLYSIS IN THE TREATMENT OF LOWER EXTREMITY OCCLUSIVE DISEASE Patrick Riggs, MD, and Kenneth Ouriel, MD
Thrombolytic agents comprise a group of proteins that can dissolve fibrin thrombi. Some of the agents are found endogenously, such as urokinase and tissue plasminogen activator (t-PA). Others, specifically streptokinase, are collected as bacterial exoproducts. Still others, including recombinant t-PA (rt-PA) and recombinant urokinase (r-UK), are produced through genetic engineering techniques. It is important to note that thrombolytic agents are inactive alone, and the addition of a thrombolytic agent to a pure (plasminogen-free) fibrin clot is not associated with any degree of clot dissolution. 3o All thrombolytic agents achieve fibrin dissolution indirectly, through a conversion of the plasminogen to the active agent plasmin. Plasmin is the active protein that produces cleavage of insoluble fibrin to soluble degradation products; thus, all thrombolytic agents require plasminogen as a substrate. The goal of this article is to examine the role of thrombolytic therapy in the treatment of lower extremity occlusive disease, including patient selection and therapeutic technique. A review of the available data serves to illustrate the caveat that thrombolytic therapy cannot be viewed as an absolute alternative to operative intervention. Rather, the two modalities must be used in conjunction with one another, through a coordinated angiographic and surgical team approach. HISTORY OF THROMBOLYSIS
Tillet and Garner32 first characterized the mechanism of action of thrombolytic agents in the 1930s and 1940s. Streptokinase was the agent of interest
From the Department of Surgery, The University of Rochester, Rochester, New York
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during those early years. Impurities in the early preparations confined the use of thrombolytic agents to the laboratory setting. In the late 1940s, however, streptokinase was employed in the setting of a loculated hemothorax, instilling the agent into the pleural space to dissolve the fibrinous pleural cap.33 Nevertheless, the inability to produce a pure product continued to limit clinical applications, and the desired route of intravascular administration awaited further purification of the product in order to limit significant systemic reactions. Therapeutic intravascular administration of thrombolytic agents was pioneered by Cliffton4 and Cliffton and Grossi5 in the mid-1950s, when they successfully administered a mixture of streptokinase and plasminogen directly into the veins and arteries of patients with vascular occlusions. Cliffton believed that the lysis he observed was due to the exogenous plasmin generated by the actions of streptokinase on plasminogen. Subsequent work, however, would show that purified preparations of plasmin are inactive in a red cell-rich rnilieu,26,30 thus implicating the excess streptokinase as the active agent. In the years that followed, sporadic anecdotal reports defined only modest efficacy with the use of streptokinase, achieved at the cost of a wide variety of complications. These findings discouraged the widespread acceptance of thrombolytic therapy in peripheral arterial occlusion. It was not until the report of catheter-directed, intra-arterial streptokinase by Dotter and associates9 in 1974 that interest in thrombolytic therapy was renewed. Dotter, through innovative endovascular technique$, was able to deliver streptokinase directly into the substance of the occluding arterial thrombus. Intrathrombus administration provided the theoretical advantage of increasing surface contact between the agent and the thrombus while minimizing the risk of systemic bleeding complications. The decade of the 1980s was characterized by a wide variety of retrospective reports comprising large groups of patients treated with streptokinase, urokinase, and rt-PA. 10--12, 15 Acceptance of thrombolytic agents in the treatment of lower extremity occlusive disease was expanded during these years with the publication of impressive rates of success in the treatment of acute and chronic occlusions of the lower extremity arterial tree. The reports of innovative investigators such as McNamara, Graor, and Katzen documented excellent therapeutic results with newer thrombolytic agents and methods of delivery. Improved lytic efficacy was achieved in concert with a virtual elimination of the allergic complications prevalent with streptokinase. The results of these retrospective series broadened the use of thrombolytic therapy for acute arterial occlusion. Surgical methods, however, had been used since the late 1940s,8,17 and their success in restoring limb viability was well documented. 35 Nevertheless, the highly effective operative techniques were associated with a significant risk of mortality, presumably from the performance of a highly invasive intervention in a medically compromised patient.1 Clinicians now began to separate into two distinct camps with respect to the most appropriate initial therapy for peripheral arterial thrombotic occlusion-operation or thrombolytic therapy. The retrospective decade of the 1980s was replaced by the prospective decade of the 1990s, as investigators chose to settle their differences through the perfqrmance of well-controlled clinical trials. The large studies of thrombolytic therapy in acute coronary artery occlusion served as an additional impetus to the development of well designed trials of peripheral thrombolysis, comparing thrombolytic therapy with standard operative techniques in the treatment of acute arterial occlusion. The ill-defined and subjective endpoints of "arteriographic lysis" and "clinical success" were superseded by more objective and relevant endpoints, such as limb salvage, patient survival, and a documented
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decrease in the magnitude of operative interventions. For the first time in over four decades of clinical use, thrombolytic therapy was about to undergo a critical comparison with standard operative techniques in the treatment of limb ischemia. BIOLOGY OF THROMBOLYTle AGENTS
Under normal conditions, there exists a tenuous balance between intravascular thrombosis and thrombolysis, maintaining hemostasis and preserving tissue perfusion in response to constantly occurring minor endothelial trauma. 3D, 31 Physiologic thrombolysis requires the conversion of plasminogen to plasmin, which in tum cleaves cross-linked fibrin at an arginyl-Iysyl amino acid bond. The conversion of plasminogen is catalyzed by endogenous plasminogen activators released from endothelial cells. All of the currently available exogenously administered thrombolytic agents are plasminogen activators, used at supraphysiologic doses to stimulate the fibrinolytic system (Fig. 1). Although the development of new thrombolytic agents is a very active area of current research, with a host of novel agents undergoing laboratory and clinical trials, only four agents are commercially available at the this time (Table 1).21 Streptokinase, a proteolytic enzyme produced by J3-hemolytic streptococci, has the advantage of being the least expensive plasminogen activator. It has several disadvantages, however; most importantly its antigenicity. Streptokinase may be bound by circulating antibodies formed after recent streptococcal infection or previous administration of the agent. Pre-existent antibodies to streptokinase greatly reduce the bioavailability of circulating activator and are responsible for allergic reactions. Further, streptokinase appears to be less efficient at lysing thrombus than the other available agents. 13
IFree plasmin I + -. - , , . . . - -
Figure 1. Biochemical interactions in the plasma and the thrombus during thrombolytic therapy. (From Ouriel K: Thrombolytic therapy for acute arterial occlusion. In Daly JM (ed): Current Opinion in General Surgery, vol 2. Philadelphia, Current Science, 1994, p 258; with permission.)
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Table 1. PROPERTIES OF COMPONENTS OF THE THROMBOLYTIC SYSTEM Component
Streptokinase Urokinase rt-PA APSAC Pro-urokinase
Molecular Weight
46 54 70 131 53
kD kD kD kD kD
Structure
Single chain Two chains One or two chains Lys-plas + SK Single chain
Half-life
11 10 5 70 6
minutes minutes minutes minutes minutes
Adapted from Ouriel K: Thrombolytic therapy for acute arterial occlusion. In Daly JM (ed): Current Opinion in General Surgery, vol 2. Philadelphia, Current Science, 1994, p 258; with permission. Data originally from Marder VJ: The use of thrombolyfic agents: Choice of patient, drug administration, laboratory monitoring. Ann Intern Med 90:802-a12, 1979.
Urokinase was the second thrombolytic agent to be evaluated.3,18 Initially purified from human urine, urokinase is now produced by fetal kidney cell cultures. It is nonantigenic and more efficient at lysing thrombus than streptokinaseY Urokinase is currently the agent most widely used in peripheral arterial occlusion, despite the lack of acknowledgment of this indication by the US Food and Drug Administration. The plasminogen activator associated with the most rapid lysis of fibrin thrombus may be rt-PAY This agent was initially touted as a superior agent with regard to fibrin specificity.29 rt-PA was thought to activate only plasminogen bound to fibrin, thus sparing systemic fibrinogen and avoiding a systemic proteolytic state. In fact, none of the agents is truly fibrin specific, and rt-PA causes fibrinogen breakdown to a degree similar to the other available agents. 24 Additionally, clinical bleeding appears more closely linked to the dissolution of small hemostatic plugs at the site of local trauma, plugs that are structurally identical to the target thrombus causing vascular compromise. In large clinical trials, rt-PA has been associated with more bleeding complications than other agents. 19 Further, concern has been generated by the development of Significant thrombocytopenia in some patients receiving systemic rt_PA.14 A final approved thrombolytic agent, acylated plasminogen-streptokinase complex (APSAC), is actually a mixture of two components, streptokinase and plasminogen. APSAC was developed in the hope of improving fibrin specificity and increasing fibrinolytic efficacy. APSAC retains the antigenicity of streptokinase, and investigation has revealed that APSAC is no more specific or efficient than streptokinase alone. 16 The half-life of streptokinase is lengthened when complexed to plasminogen, however, providing a theoretical advantage in the setting of systemic administration for acute coronary occlusion. CLINICAL USE OF THROMBOLYTIC AGENTS
Thrombolytic agents have been used in a variety of clinical settings, including deep venous thrombosis, acute coronary occlusion, peripheral arterial occlusion, and stroke. Several caveats should be remembered in each of these applications. First, thrombolytic therapy is in a state of evolution, and the indications for its use are not completely defined. One should avoid unstructured experimentation in novel clinical settings and indications heretofore undescribed. Second, the effectiveness and safety of these agents are operator dependent. One should not expect to duplicate the results achieved by experienced investigators without the equipment and trained personnel to support the proven protocols. Third, the availability of less invasive treatment modalities such as thrombolytic therapy should not alter the historically proven indications for intervention.
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Thus, the indications for the use of intra-arterial thrombolysis for peripheral arterial occlusion parallel those for lower extremity operative revascularization. It is important to consider the factors that determine the success or failure of thrombolytic therapy when deciding how best to treat a particular patient. Biophysical factors playa prominent role in achieving a successful thrombolytic result. For example, effective thrombolysis requires contact of the thrombolytic agent with the fibrin within the thrombus. In vitro studies have demonstrated that thrombolytic agents permeate thrombus very slowly by simple diffusion, requiring hundreds of hours for lysis to proceed a single centimeter.7 In a flowing system, however, thrombolysis is greatly accelerated by the formation of small channels through the thrombus, permitting plasminogen activator and plasminogen to come in contact with cross-linked fibrin at multiple sites. Laboratory studies using magnetic resonance imaging to visualize flow through thrombi have confirmed the clinical observation that high-flow systems lyse faster than low-flow systems. 2 Additionally, adequate outflow is necessary for the efficient formation of channels within the thrombus. Vessels with numerous side branches have multiple outflow sites, providing pathways for the elimination of the byproducts of upstream thrombolysis and maximizing the contact between fresh thrombolytic agent and plasminogen (Fig. 2). Applying these principles to clinical thrombolysis, it was predictable that intravenous therapy would be far more effective in treating small coronary thrombi than in lysing large peripheral arterial clots. Coronary thrombi are situated in a high-flow arterial segment with many side branches, whereas infrainguinal thrombi are usually present in long, branchless conduits. Thus, the relatively small amounts of thrombolytic agent presented to the thrombus in the intravenous treatment of coronary occlusion are not likely to be sufficient to dissolve thrombi within the peripheral arterial tree. Catheter placement into peripheral arterial thrombi, with direct administration of the agent into the substance of the thrombus, appears to be of critical importance in the treatment . of large lower extremity occlusive clots.25 The progression of thrombolysis must be serially assessed for therapy to be effective, repositioning the delivery catheter as necessary. Multi-side hole catheters allow activator to contact thrombus at numerous sites along the length of the thrombus. A multihole catheter with a few side holes or the end hole positioned outside the thrombus is potentially detrimental to thrombolytic success. The lytic agent traverses the path of least resistance and flows preferentially through the holes outside of the substance of the thrombus, avoiding contact with the fibrin clot (Fig. 3). "Pulse-spray" delivery of thrombolytic agent is a method whereby the lytic drug is administered in multiple short boluses into the thrombus. Some have argued that pulse-spray administration is more effective in augmenting thrombolysis than are continuous infusions, possibly by enhancing channel formation and contact of the agent with the thrombus. 34 This delivery mode has been avoided by some clinicians on the basis of fears of increasing the chance of distal embolization of partially dissolved clot into the distal arterial circulation. CONTRAINDICATIONS TO THE USE OF THROMBOLYTIC THERAPY
Almost all major complications of thrombolytic therapy are related to local or distant hemorrhage. Thus, contraindications to the use of thrombolytic agents are generally related to situations that are associated with a bleeding tendency. Patients with sites of recent internal or noncompressible hemorrhage are not appropriate candidates for thrombolysis (Table 2). Patients with a history of
Systemic Activator ---~
Systemlc _ _ _- I.. ~ Activator Byproducts In Boundary Meniscus
A
Systemic Activator - - .
Systemlc _ _ _ _ _ _ _ _ _ _ _ _ _ _ _~ Activator ~
B
~~
Figure 2. Intravenous, systemic thrombolytic therapy is more successful when the involved arterial segment has numerous, closely spaced side branches. A, Schematic representation of a large, branchless vessel such as the superficial femoral artery. Thrombolysis proceeds only a few millimeters before progress is blocked by a "meniscus" of byproducts. B, By contrast, a coronary artery has numerous side branches that allow the wash-out of the byproducts and contact between the clot and fresh plasma with activator agent and plasminogen. (From Ouriel K, Comerota AJ: Thrombolytic therapy in the management of peripheral arterial occlusion. In Ouriel K (ed): Lower Extremity Vascular Disease. Philadelphia, WB Saunders, 1995, p 301.)
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No Lysis
Some Lysis
639
Lysis
Figure 3. The position of the catheter infusion ports is important in providing for effective distribution of lytic agent into the substance of the thrombus. (From Ouriel K, Comerota AJ: Thrombolytic therapy in the management of peripheral arterial occlusion. In Ouriel K (ed): Lower Extremity Vascular Disease. Philadelphia, WB Saunders, 1995, p 303.)
major gastrointestinal hemorrhage within the recent past or patients who have undergone major surgical procedures should not be subjected to the challenges of even locally administered thrombolysis. Patients with intracranial lesions, including recent cerebrovascular accidents, neoplasms, or recent craniotomies, are at increased risk of intracranial hemorrhage, and thrombolytic therapy should be .avoided. The one setting in which thrombolysis may be used in a patient with specific contraindications relating to a hemorrhagic tendency is the intraoperative administration of lytic agents distal to an occluding tourniquet. The protection of a tourniquet is only partial, however, as a bolus of agent may be released into the systemic circulation when the tourniquet is released. The use of thrombolytic agents in attempting to treat irreversibly ischemic limbs is probably not warranted. The severely ischemic limb is not likely to achieve function; even if much of the muscle and skin is salvaged, the nervous tissue rarely regains function. Thus, the presence of marked motor and sensory loss represents a relative contraindication to thrombolysis. Operation, frequently in the form of major amputation, is usually more appropriate. Table 2. SUGGESTED CONTRAINDICATIONS TO THROMBOLYTIC THERAPY Major operative procedure Cerebrovascular accident Cerebrovascular neoplasm Major gastrOintestinal hemorrhage Renal insufficiency Nonambulatory patient
<14 days <6 months Absolute <3 months Creatinine >2.5 mg/dL Absolute
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SPECIFIC INDICATIONS
The use of thrombolytic agents for the acutely occluded artery has the potential to restore arterial flow using a modality that is frequently less invasive than open surgical revascularization. McNamara and Bomberger23 reported excellent results in the treatment of iliac and superficial femoral arterial occlusions. They obtained an overall immediate patency of 89%, with 92% of the opened vessels remaining patent at 6 months. Infrainguinal vessels remained patent when subsequent angiography demonstrated no residual stenosis, with a 6month patency of 77%. By contrast, only 10% of vessels were patent if a residual stenosis remained. We found a difference in the ability to open thrombosed prosthetic grafts and vein grafts, with initial success rates of 83% and 50%, respectively. Successfully thrombolysed prosthetic bypass grafts were unassociated with an underlying stenosis in a remarkable number of cases, comprising 59% in our experience. These patients were managed with long-term anticoagulation following thrombolysis, reasoning that the anatomic and physiologic parameters were unchanged from those present at the time of graft failure. By contrast, virtually all failed vein grafts manifested an underlying lesion following thrombolysis, suggesting that autogenous conduits rarely fail in the absence of a hemodynamically significant anatomic lesion. Popliteal artery aneurysms frequently present with distal thrombosis and present another potential indication for thrombolysis. Dissolution of tibial thrombus may provide a suitable outflow vessel for operative bypass, where before there had been none. When the initial diagnostic arteriogram reveals the presence of an open tibial or pedal vessel suitable for outflow, however, we do not use thrombolytic therapy. Operative revascularization is feasible as a sole intervention in these cases, and lysis of the popliteal clot merely places the limb at risk for embolization of partially lysed clot into the distal arterial tree. TECHNICAL ASPECTS OF THROMBOLYSIS
Once thrombolytic therapy has been elected, patients are taken expeditiously to the angiography suite. An appropriate diagnostic study is performed through a catheter insertion site remote from the occlusion, generally accomplishing access through the contralateral femoral artery. Antegrade approaches through the ipsilateral femoral artery have been useful only for occlusions of grafts originating from the superficial femoral artery and more distal vessels or for distal native artery occlusions. We have treated patients undergoing thrombolysis with aspirin and/or heparin to prevent pericatheter thrombus deposition during thrombolysis. Although we have been impressed by a subjectively higher incidence of bleeding with concurrent heparin anticoagulation, some investigators continue to tout its use. The most important determinant of thrombolytic success is the ability to place the catheter within the substance of the occlusive process. 25 Sophisticated angiographic techniques are often required to visualize the proximal stump of a failed bypass graft, utilizing oblique views or ultrasonic guidance techniques. An attempt is always made to pass a guide wire through the thrombus, both to ascertain the likelihood of thrombolysis and, occasionally, to create channels to improve the distribution of lytic agent within the clot. A multihole catheter is positioned so that all the infusion ports are within the thrombus. Coaxial systems are used when two separate thrombosed segments are encountered with open
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artery in between. When this situation is present, the catheter is positioned in the proximal clot and an infusion guide wire is threaded into the distal clot. Experience has shown that the choice of specific agent and dose appears to be less critical than the position of the infusion catheter. We repeat angiography at intervals and reposition the catheter as needed. Therapy is terminated when successful lysis is demonstrated angiographically, when clinical deterioration progresses during lytic therapy, or when major complications develop. We have found little benefit with continued lytic infusion if no lysis is achieved within 12 hours. 27 Others have observed a dramatic increase in the rate of complications when therapy is continued beyond 48 hours.1o An average reperfusion time of 4 to 8 hours should be expected, with some degree of improvement in the clinical status of the limb and some antegrade flow of contrast through the occlusive thrombus by that time.27 However, considerable variation exists between patients, and the time to reperfusion decreases with increasing experience in invasive angiographic techniques. If completion arteriography demonstrates a stenosis of the native artery, bypass graft, or outflow vessel, the unmasked lesion is aggressively corrected by operative or endovascular techniques. We have relied on open surgical techniques to repair neointimal fibrous lesions at graft anastomoses or for diffuse lesions running for a considerable distance along a native artery or bypass graft. Balloon angioplasty has been reserved for focal atherosclerotic lesions. Thus, the majority of our patients who have undergone successful thrombolysis are treated with an adjuvant operative procedure, frequently in the form of patch angioplasty of a stenotic lesion. In support of the above approach, we have completed a prospective randomized trial of surgery versus thrombolysis as the initial treatment for 114 eligible patients with limb-threatening ischemia secondary to embolic or thrombotic occlusion of native vessels or bypass grafts in the lower extremity.27 Patients failing thrombolytic therapy (30%) were treated with operative revascularization (26%) or primary amputation (4%). AnalysiS of the outcome data showed no significant difference in limb salvage (12-month amputation rate approximately 20% in each group), but a 62% reduction in I-year risk of mortality was observed in the thrombolytic group (84% versus 58%, respectively, Fig. 4). This finding was corroborated by Comerota et aI's6 observation of improved survival in patients receiving intraoperative thrombolytic agents during elective infra inguinal reconstructions. The reasons for this effect are unknown but may be related to the reduction in systemic fibrinogen levels incurred in thrombolytic therapy, which may reduce intracoronary thrombotic potential. Further, the magnitude of operation required is frequently reduced by the adjunctive use of thrombolytics, and a significant number of patients do not require an operation after successful therapy.27 INTRAOPERATIVE AND POSTOPERATIVE THROMBOLYSIS
Perioperative lytic agents have been avoided in many instances because of a fear of bleeding complications. Performance of arterial thrombectomy or bypass for acute arterial occlusions represents an ideal setting for the use of lytic agents because Fogarty catheter thrombectomy is associated with a high frequency of residual thrombus in both animal and clinical studies.28 Catheterdirected lytic agents infused into the distal arterial tree have been shown to increase the amount of thrombus removed. Comerota et al6 have collected a series of 53 patients treated with thrombolytic agents infused into the runoff
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1.00
.80
L 6 '~i---o---o,l··--·6---.. ,
Thrombolytic
r----- -----------. ----------Operative
.40
.20
Thromb. Operat.
46 41
40 33
4
8
0
37 24
29 20
21 11
18 8
20
24
I
0
12
16
Months Figure 4. The survival of patients presenting with acute limb-threatening ischemia treated with initial operative or thrombolytic intervention.
vessels at the time of operative revascularization. They achieved limb salvage in 70% of the cases and surmised that these results were directly attributable to lysis of the distal thrombus in 47% of the series. Currently, Comerota et al suggest that an effective method of re-establishing outflow is a combination of Fogarty thrombectomy and urokinase (250,000 to 500,000 IV in approximately 30 mL of normal saline), instilled as a bolus through a catheter placed into the distal outflow vessel. Repeat thrombectomy is performed prior to completion of the distal anastomosis. When distal thrombus remains, another option is to continue local thrombolytic infusion during the postoperative period. A catheter is passed from a remote site and advanced into the thrombus. The catheter must be well past the distal anastomosis to avoid anastomotic bleeding, but a moderate degree of oozing from the wound should be expected as long as the thrombolytic infusion is continued. The vessel is infused with urokinase (1000 to 2000 IV /min), and arteriography is serially repeated. The patients are monitored in the intensive care setting and closely followed for bleeding. Isolated limb perfusion is a relatively new technique under investigation as an adjunct to surgical revascularization. Candidates have severe limb-threatening ischemia and outflow vessel thrombosis, usually with extension of the process to the small distal vessels not amenable to catheter thrombectomy. One method we have found useful in occasional instances utilizes a pump oxygenator to perfuse the isolated limb. A low thigh tourniquet is inflated to suprasystolic pressure, and the popliteal artery and vein are cannulated. High-dose urokinase (frequently over 1 million IV) is circulated through the limb by a pump oxygenator primed with 500 mL of fresh frozen plasma to provide necessary plasminogen substrate. The perfusions are continued for 90 to 120 minutes, with intraoperative arteriography performed through the arterial cannula. We have salvaged
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an occasional limb using this technique, but our results have not been as encouraging as those observed by other investigators. CHRONIC OCCLUSIONS
The role of lytic agents is less defined in the setting of chronic arterial occlusion than acute occlusion. As an adjuvant to surgical revascularization, thrombolytic therapy may be of benefit in shortening the length of a chronic occlusion. This is particularly relevant when the superficial femoral artery is occluded and adequate saphenous vein is not available for a longer bypass graft. Dissolution of the thrombus propagated proximally and distally around the atherosclerotic lesion at the adductor hiatus may leave the patient with a much shorter length of occluded artery, suitable for a short bypass, endarterectomy, or balloon angioplasty. McNamara22 has reported a series of 24 patients with occlusions of greater than 3 months' duration treated with intra-arterial thrombolytic agents. He documented recanalization in 48% of the patients. Patients were treated for the underlying cause of occlusion by balloon angioplasty or placement of a stent. Patients failing therapy and those reoccluding the recanalized segment did not experience worsening of symptoms. The best results were achieved in iliac lesions and lesions that were traversable by a guide wire. MONITORING OF PATIENTS
Careful laboratory and clinical monitoring of patients receiving thrombolytics is essential to avoid unnecessary complications. The patients are monitored by nurses familiar with the use of thrombolytic agents, usually in the setting of an intensive care or "step-down" unit. Laboratory surveillance includes hemoglobin, hematocrit, platelet count, partial thromboplastin time, and fibrinogen level at 6-hour intervals or when clinically indicated by a change in the patient's examination. We do not heparinize patients at the initiation of lytic therapy, although many centers advocate heparin to avoid thrombus formation on the catheter. We routinely use heparin in the interval between thrombolysis and operative revascularization, as well as in cases of graft occlusion without an underlying stenosis. These patients are then anticoagulated with warfarin indefinitely. Fibrinogen levels correlate poody with hemorrhagic complications and are of questionable clinical benefit. Levels below 100 mg/ dL are indicative of a systemic lytic state, and empiric correction with a decrease in the dose of thrombolytic agent has been advocated by some. We have not altered therapy based on asymptomatic hypofibrinogenemia. The appearance of severe bleeding, however, mandates immediate discontinuation of therapy and aggressive correction of the coagulation and thrombotic abnormalities. Epsilon-aminocaproic acid, a competitive inhibitor of plasminogen activators, arrests ongoing fibrinolysis. Fresh frozen plasma or cryoprecipitate is administered to replete fibrinogen, and platelets may be required to replace losses. ADJUNCTS TO THE USE OF THROMBOL YTICS
Despite the advances in thrombolytic therapy, there remain a significant number of treatment failures. Techniques to improve the efficacy of these agents
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can be divided into two categories. First, investigators have attempted to increase the rate of thrombolysis through the development of novel agents such as bat plasminogen activator ("Bat PA"), single-chain urokinase ("pro-UK"), and chimeric alterations of current activators. A second research initiative is undertaking the development of new strategies for improving the efficacy of current agents. We have tested a technique that holds promise for augmenting thrombolysis using any of the currently available activator agents. We have found that clot lacing with plasminogen, the substrate for all thrombolytic agents, significantly improves the lytic efficacy of urokinase and rt-PA. The studies were conducted in a recirculating in vitro system that closely approximates the physiologic parameters of catheter-directed thrombolysis. A relative depletion of plasminogen appears to be present within the thrombus during infusion of activators, such that plasminogen availability becomes rate limiting for thrombolysis. Our work suggests that catheter-directed exogenous plasminogen administration may accelerate thrombolysis in the clinical setting, possibly without a parallel increase in the risk of distant bleeding complications.
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Address reprint requests to Patrick Riggs, MD Department of Surgery The University of Rochester Rochester, NY 14642