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7.15 Thrombolytic therapy

GLENN M. LaMURAGLIA AND WILLIAM M. ABBOTT

Since heparin anticoagulation was found to have a beneficial effect in the treatment of thromboembolic disease there have been further efforts to improve the treatment of thrombotic disorders. Instead of using inhibitors of coagulation to shift the equilibrium of the clotting cascade, retarding the formation of thrombus with resulting slow absorption of clot, attempts were made to activate safely the endogenous serum fibrinolytic system. This goal can be achieved by the activation of the serum proteolytic precursor, plasminogen, to form plasmin  (Fig. 1) 375. In the presence of fibrin substrate, plasmin fragments fibrin and promotes active thrombus dissolution.

THROMBOLYTIC AGENTS

Streptokinase

Streptokinase is a non-enzymatic polypeptide isolated from &bgr;-haemolytic streptococci and is the least expensive of the thrombolytic drugs. To initiate thrombolysis it must first combine with plasminogen in equal proportions to form an activated streptokinase–plasminogen complex that activates another plasminogen molecule to form plasmin. Sensitized individuals bear anti-streptococcal antibodies which inactivate streptokinase; the drug therefore has to be administered following a 100000 to 250000 IU loading dose. Intravenous doses of streptokinase average 100000 IU/hour, while local intra-arterial administration usually requires 5000 to 10000 IU/hour. The half-life is short (23 min); however, the effects of plasmin activation may persist for longer.

Urokinase

Urokinase is an enzymatic two-chain polypeptide produced by endothelial and renal tubular cells. Originally isolated from urine, where it is found in a concentration of approximately 6 IU/ml, it is now obtained from tissue cultures of human kidney cells. Since urokinase is an endogenous human protein and is not antigenic, in contrast to streptokinase it does not cause allergic side-effects such as pyrexia, anaphylaxis, rash, and serum sickness. Since urokinase does not complex with antibodies or plasminogen present in the serum, its dose effects are more predictable than those of streptokinase. Intravenous administration is commonly started by a bolus of 4400 IU/kg followed by infusion of 4400 IU/kg.h. Local intra-arterial doses vary between 1000 and 6000 IU/min. Like streptokinase, the half-life of the drug is short (16 min).

Tissue plasminogen activator and pro-urokinase

To minimize the bleeding complications associated with the use of thrombolytic drugs, efforts have been undertaken to find plasminogen activators which are much more efficient in the presence of fibrin. This would mean that the activity of the thrombolytic drug could be limited to the thrombotic process, and little systemic fibrinolysis would occur. The benefits of the drug's clinical activity could thus be optimized, while haemorrhagic complications could be reduced.

Tissue plasminogen activator was the first ‘clot specific’ thrombolytic agent to be used clinically and is produced using recombinant genetic technology. This glycosylated protease is a poor activator of plasminogen to plasmin, except in the presence of fibrin, when this reaction is greatly enhanced, apparently due to specific molecular conformational changes noted in vitro. This results in the production of high concentrations of plasmin in thrombus. Despite high hopes of tissue plasminogen activator being a very specific drug for thrombus dissolution, initial clinical trials have been disappointing. In addition, plasma half-life of the drug is very short (approximately 5 min).

Pro-urokinase is an inactive precursor of urokinase which is converted to urokinase by plasmin. This activation is slow except in the presence of fibrin or its split products; it is therefore thought to have thrombus selectivity and, because of its rapid inactivation by thrombin, its use should theoretically be associated with fewer haemorrhagic complications. The half-life of pro-urokinase is 3 to 6 min, but clinical experience with it is limited.

CLINICAL USE

Indications

Thrombolytic therapy is indicated for the treatment of venous thrombosis, peripheral arterial occlusion, and myocardial infarction.  The clinical aim of thrombolytic therapy is to achieve a faster and more thorough dissolution of thrombus than can be achieved by anticoagulation alone. Most clinicians agree that anticoagulation is primarily of use in preventing thrombus propagation, not in thrombolysis.

Several important factors need to be considered in patients prior to thrombolytic therapy. First, there must be unequivocal evidence that a thrombus is causing the clinically important vascular occlusion. Clot lysis is most successful when the thrombus is fresh or only a few days old. When occlusions are arterial, the ischaemia must not be severe enough to require emergency surgical intervention. There must be no contraindications to the use of the thrombolytic drug  (Table 1) 204: even with judicious use of these agents complications occur and these risks need to be weighed against the potential benefits of thrombolytic therapy.

Cardiac indications

Thrombolytic drugs may be used to relieve acute coronary thrombosis during myocardial infarction. The clinical goal is for immediate clot lysis with reperfusion of the ischaemic cardiac muscle to limit the extent of infarction.

The optimal method by which this goal can be achieved is by the intravenous administration of thrombolytic drugs shortly after the onset of cardiac symptoms. Minimizing the delay between onset of symptoms and administration of the drug increases the likelihood of limiting the infarct: the thrombolytic drugs that hold the greatest appeal for this application are those with clot or fibrin ‘selectivity’. Tissue plasminogen activator has found its widest application in patients with acute myocardial infarction: it should be given within 4 h of onset of coronary symptoms, as a loading dose (10 mg intravenously), followed by 50 mg/h for the next 2 h. Streptokinase has been shown to be as effective as tissue plasminogen activator in recent trials.

Thrombolytic drugs have also been administered very successfully via the intracoronary route at the time of acute cardiac catheterization. In the 70 to 80 per cent of patients in whom coronary flow is successfully re-established anticoagulation diminishes the risk of reocclusion while the stenotic lesion that precipitated the original thrombosis is treated.

Venous indications

Venous thrombosis or thromboembolism is a common and potentially life threatening problem. In cases of deep venous thrombosis, the objectives of therapy are inhibition of clot propagation and embolism and minimizing the venous injury precipitated by the thrombus, thus reducing the morbidity associated with venous insufficiency and the postphlebitic syndrome. The standard therapy of anticoagulants, bedrest, and elevation of the extremities effectively achieves the former objectives. It does not, however, minimize the venous inflammation, scarring, and valve injury with subsequent venous hypertension.

The effectiveness of thrombolytic drugs and anticoagulation in patients with deep venous thrombosis of the lower extremity has been compared in several studies. The pooled results indicate that thrombolytic therapy lyses 47 per cent of clots compared with 6 per cent lysis achieved with anticoagulation alone. The mode of acute treatment did not affect the incidence of pulmonary emboli. The incidence of bleeding complications was four times higher in patients treated with thrombolytic therapy than in those treated with anticoagulation alone. Although it is clear that thrombolytic drugs are useful and effective for the acute removal of thrombus from veins, no published series has demonstrated a clinical advantage of this therapy to avoid the long-term complications of postphlebitic syndrome years after the illness. There is no long-term benefit in reducing venous valve incompetence with thrombolytic drugs in the treatment of deep venous thrombosis of the lower extremities. This makes justification for the use of thrombolytic drugs for this indication difficult, and we rarely use it in our practice.

The use of thrombolytic therapy in patients with a pulmonary embolus is controversial. The mainstay of therapy for acute minor pulmonary emboli remains heparin anticoagulation followed by several months of oral anticoagulation, and treatment of the precipitating cause of the venous thrombosis. In patients with acute massive pulmonary emboli, with significant haemodynamic compromise and pulmonary hypertension, thrombolytic therapy can cause a more rapid improvement in haemodynamics and in the angiographic appearance of the emboli. There is no evidence that its use improves mortality rates, and at 7 days there were no differences in lung scans of patients treated with heparin alone and those treated with thrombolytic drugs. Again, bleeding complications are more common in patients treated with thrombolytic drugs. In our practice we use thrombolytic therapy in those few patients without contraindications who have symptomatic pulmonary emboli with dyspnoea and hypoxia, but not in patients with severe right heart failure, who should have surgical embolectomy. Most patients are therefore treated with heparin, followed by coumadin anticoagulation as clinically indicated.

Subclavian or axillary vein thrombosis is a specific type of venous thrombosis that can be successfully treated with thrombolytic therapy; its use in this setting is less controversial  (Fig. 2) 376,377,378. These thromboses can be precipitated by local intimal injury or effort thrombosis, thoracic outlet obstruction with venous compression, and by chronic indwelling venous catheters. Thrombolytic therapy has been used more frequently and with a higher degree of success in proximal upper extremity thrombosis for several reasons. Firstly, the clot is usually localized to the axillary–subclavian distribution, without distal extension down the arm veins. There is not usually a large number of venous tributaries present, in contrast to the situation when thrombus is present in the lower extremities. Another important factor is that catheters can readily be inserted into the axillary–subclavian venous thrombus, allowing the use of high dose local infusions that yield a higher lysis rate with a lower incidence of complications. Once recanalization of the vein has been established, the precipitating factor for the venous thrombosis can be ascertained and appropriately treated.

Arterial indications

The use of thrombolytic therapy in patients with an acute peripheral arterial thrombosis or embolus is controversial. It can, however, be very useful in the properly selected patient with an acute presentation, in whom ischaemic symptoms are not severe, where thrombus diffusely affects run-off, and when the risks for surgical intervention are high.

Before describing the criteria by which patients should be selected for arterial thrombolytic therapy, it is important to discuss its mode of administration. Historically, the drug was given intravenously to achieve a systemic thrombolytic state. Because the initial results were promising only for localized and acute artery occlusions, and were uniformly poor for thrombosed grafts, regimens of administration were altered to permit recovery of endogenous plasma levels of plasminogen. One of these protocols was ‘burst’ therapy, which called for a high dose intravenous administration of the thrombolytic drug for several hours followed by a recovery time of 12 to 24 h and a repeat of the cycle several times.

These intravenous methods have been largely replaced by intra-arterial infusion of the thrombolytic drug directly into the thrombus. Local injection of the drug into the thrombus can activate intra-clot, or local plasminogen, increasing the rapidity of lysis without totally depleting systemic concentrations of plasminogen. Lower doses of thrombolytic agents can also be used with this route of administration. Technical success can also be predicted during such local administration by the ability to pass a guidewire through the occlusion in question. After thrombolysis, sheaths are already in place for balloon angioplasty, if the lesion is suitable for such treatment  (Fig. 3) 379.

Although the technique by which thrombolytic therapy is administered is important, the aspect crucial to success is proper selection of patients. As well as recognizing an appropriate indication, it is important to determine that there are no contraindications to lytic therapy. Only patients who would otherwise be candidates for surgery because of their clinical presentations should be considered. This includes patients with an occluding thrombus precipitating a significant clinical end-organ ischaemia and a clinical presentation that would have a high likelihood of benefiting from its use  (Table 2) 205.

Recent arterial occlusions are clearly more responsive to thrombolytic therapy than well-organized, older clot. Therefore, a new thrombus that forms during an interventional technique or manipulation is the most likely to lyse. Acute occlusions of bypass grafts can be recanalized with thrombolytic therapy, followed by identification and treatment of the precipitating cause of the thrombosis: preoperative identification of the precipitating factor facilitates the subsequent procedure. Long-standing prosthetic bypass occlusions can be recanalized since they do not scar down as do thrombosed vein grafts but retain organized thrombus at either anastomosis with resorbed thrombus in their midportion. Thrombolytic therapy is often useful in acute arterial or graft occlusion in the presence of loss of outflow vessels  (Fig. 4) 380. Surgical thrombectomy of small or partially diseased arteries that have occluded as part of a graft or arterial thrombosis is often unsuccessful, and thrombolytic therapy can re-establish outflow before correction of the precipitating problem is attempted. In deciding whether to use thrombolytic therapy, other considerations include general surgical risk, complex anatomy, and scarring secondary to multiple operations.

Besides the usual contraindications to thrombolytic therapy there are specific contraindications for patients with arterial occlusions. Since implementation of the procedure and infusion to achieve clinical success can take up to 48 h, patients in whom end-organ viability is seriously threatened should not undergo thrombolytic therapy, but should immediately be taken to the operating room. Patients with early postoperative occlusion of a bypass graft should not be treated with thrombolytic therapy because of the high likelihood of substantial bleeding from the surgical site. An embolus in a surgically accessible vessel is not a good indication, especially when the added potential risk of further fragmenting an intracardiac thrombus and precipitating further emboli is considered. The presence of knitted Dacron grafts is considered a relative contraindication because of the reported incidence of bleeding through the graft wall if thrombolysis is performed before the graft is incorporated by the surrounding tissue (2–4 weeks).

Results of thrombolytic therapy for arterial or bypass occlusion varies with the technique, drug, and route of administration, but probably depend most of all on selection of patients. Experience from several units suggested that intravenous administration of thrombolytic therapy resulted in successful lysis in 38 per cent of 340 patients, with an incidence of major complications of 8 per cent. Intra-arterial administration of thrombolytic drugs does not change the complication rate (13 per cent), but more than doubles the success rate, to 78 per cent in 478 patients reviewed. These studies and their methods differed significantly and they include many early studies, performed when the technique was still evolving.

We exclusively use intra-arterial thrombolytic drugs for recanalizing occluded peripheral arteries or bypass grafts. Attempts at recanalizing native arterial occlusions are undertaken in patients with recent onset of symptoms and minimal atherosclerotic disease in the adjacent vessels, suggesting focal disease. Attempts at intra-arterial thrombolysis are more frequently performed in patients with recent occlusions of infrainguinal bypass grafts. These distal reconstructions are more likely to benefit from thrombolysis which allows the precipitating cause of the thrombosis to be determined, distal run-off that may have been lost at the time of occlusion to be re-established, and balloon angioplasty for correction of the underlying problem to be used. Suprainguinal bypass grafts, such as thrombosed limbs of aortofemoral grafts, present a different problem. Invariably, the occlusion results from a problem with the distal anastomosis, revision of which can be performed at the time of surgical thrombectomy of the limb of the aortofemoral graft. Thrombolysis is therefore of little benefit in this setting.

Intraoperative indications

Intraoperative thrombolytic therapy has been used when residual thrombus has been identified on intraoperative arteriography or when there is evidence of distal run-off loss. The reported series are small and hard to interpret since they are anecdotal, with no control group. Success of thrombolytic therapy is also variably defined, from angiographic criteria to restoration of pedal pulses. Arterial flow in these patients was invariably restored after administration of the drug, and it is difficult to know how many of the ‘thrombotic blockages’ were thin thrombus films that would have opened in response to arterial pressure. Our indications for thrombolytic therapy are the angiographic presence of retained thrombus after thrombectomy or known loss of distal run-off. Reported success averages 69 per cent, with a 14 per cent incidence of bleeding complications, and an amputation rate of approximately 15 per cent. Both streptokinase and urokinase are effective, but we have used a regimen of two slow injections of 100000 U of urokinase into the clamped distal circulation separated by 10 to 15 min.

MONITORING THROMBOLYTIC THERAPY

Before thrombolytic therapy is instituted, a standard haematological screen, including a complete blood count, prothrombin time, partial thromboplastin time, platelet count, thrombin time, and fibrinogen level should be performed to exclude an underlying coagulopathy. Once thrombolytic therapy is begun, haematological monitoring has two purposes: to ensure a lytic state, and to minimize haemorrhagic complications. To ensure a lytic state is necessary only if the procedure is unsuccessful. It is especially important if streptokinase is used, since high levels of antibodies can inactivate the drug and make the therapy ineffective. There are no good laboratory tests which can predict lysis or haemorrhagic problems. The thrombin time, which measures the clotting time of plasma after the administration of thrombin, is an indirect measure of the fibrinogen and fibrin split products: these can now be measured directly.

Some evidence suggests that low fibrinogen levels are associated with a higher incidence of haemorrhagic complications and that the patients who have serious problems are those with fibrinogen levels below 0.05 g/dl. It is therefore recommended that fibrinogen levels are checked and maintained above 0.05 g/dl, either by slowing the infusion of thrombolytic agent or by the administration of cryoprecipitate. Despite these published data, we have not used clinical laboratory testing during thrombolytic therapy other than a routine haematological screen to exclude a coagulopathy. The results of these tests are difficult to obtain rapidly, and careful clinical evaluation in an ICU setting for evidence of bleeding has resulted in minimal complications.

Complications of thrombolytic therapy

Some complications of thrombolytic therapy are common to all of the drugs, while others are specific to an individual drug  (Table 3) 206. Immunological reactions such as pyrexia, anaphylaxis, serum sickness, or a rash are limited to streptokinase because of its antigenic source: such complications are treated by stopping the infusion, with supportive care to treat the symptoms.

The most common complication is haemorrhage. Because bleeding is unpredictable, its potential occurrence is the major criterion for exclusion of patients from thrombolytic therapy. Bleeding can occur at the site of drug administration, from other puncture sites, or from areas of recent surgery as well as spontaneously in other anatomical areas. Treatment consists of stopping the infusion of the thrombolytic drug, treating the haemorrhagic area as warranted, and, if necessary, transfusing blood products to replenish coagulation factors. If bleeding is serious, cryoprecipitate, the only source of fibrinogen, must be replenished along with fresh frozen plasma. Administration of &egr;-aminocaprionic acid is not usually needed since the half-life of the thrombolytic agents is very short.

The administration of heparin during thrombolytic therapy to inhibit the formation of thrombus around catheters, or keep the thrombus from propagating has been said to increase the incidence of haemorrhagic complications. However, with the use of intra-arterial catheters, heparin decreases catheter thrombosis and does not appear to increase the incidence of haemorrhagic complications.

Embolism is a potentially serious complication, which has been inconsistently reported, but may have an incidence as high as 50 per cent. It can occur as a result of thrombus formation around the catheters used in intra-arterial infusion, the partial dissolution of thrombus and distal embolization in the same vessel, or as a wash-over from the thrombus into a more proximal vessel secondary to the breakup of clot and infusion into an occluded artery. These emboli may be clinically silent; however, they can temporarily produce worsening of ischaemia during the procedure. If emboli are identified, they are treated with continued thrombolytic therapy to the embolus, but if there is no clinical improvement surgical intervention may be required.

FUTURE TRENDS OF THROMBOLYTIC THERAPY

As thrombolytic therapy has been used for over two decades, advances continue. New drugs may be more selective in activating clot specific plasminogen without causing a systemic activation of the thrombolytic system. New and better delivery methods are being developed: coaxial systems that inject the drug at high speeds through many small side holes improve delivery of the drug and diminish the time of administration. New mechanical devices are being developed that work along with the thrombolytic drugs to break up the clot and remove it by suction. There are also pulsed laser systems that can selectively ablate thrombus, thereby enhancing the efficiency of the thrombolytic drug. Continued research will make thrombolytic therapy more widespread and safer in its applications for the treatment of thrombotic disorders.

FURTHER READING

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