Which of the following is a significant complication associated with thrombolytic therapy?

General information

The major thrombolytic agents are:

streptokinase;

urokinase;

anistreplase (anisoylated plasminogen streptokinase activator complex or APSAC);

pro-urokinase (single-chain urokinase-type plasminogen activator or scu-PA);

alteplase (recombinant tissue plasminogen activator or rt-PA);

reteplase (r-PA: a deletion mutant of rt-PA);

tenecteplase (a triple combination mutant variant of alteplase).

Although their pharmacodynamic properties do not differ significantly, some characteristics, as a result of their origin or mode of action, explain specific differences in their adverse effects and pharmacokinetics.

The pharmacology of reteplase has been reviewed [1].

6.34.5.1 Streptokinase

The first large-scale thrombolytic trial was the GISSI-1 (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico), which evaluated the efficacy of a thrombolytic treatment with streptokinase on in-hospital mortality of patients with acute myocardial infarction (AMI). The GISSI demonstrated that overall in-hospital mortality was reduced in those who received streptokinase (10.7%) compared to controls (13%). The degree of benefit, which was sustained up to 1 year after the AMI episode, was related to the time between onset of symptoms and streptokinase treatment; the sooner thrombolytics were administered the greater the reduction in mortality. When thrombolytics were administered more than 6 h after AMI no difference was appreciated.53

Similar benefits were noted in the ISIS-2 trial (Second International Study of Infarct Survival), in which patients presenting to hospitals within 24 h (mean of 5 h) of onset of suspected AMI were randomly assigned to either: (1) 1 h i.v. infusion of streptokinase; (2) 1 month of 160 mg day−1 of enteric coated aspirin (with the first tablet crushed for a rapid antiplatelet effect); (3) both treatments; or (4) neither treatment Streptokinase alone and aspirin alone each produced a significant reduction in 5-week vascular mortality. A combination of streptokinase and aspirin was significantly better than either agent alone and displayed a synergistic effect in the reduction of mortality from 13.2% (placebo) to 8.0% (streptokinase+aspirin).54 As in the GISSI trial, the ISIS-2 demonstrated that early therapy (within 6–24 h) is essential if mortality benefit and long-term benefit is to be achieved.55

Thrombolysis

Thrombolytic therapy has dramatically improved the outcome of patients with STEMI. It is readily available, may be administered during the prehospital phase, does not require specialized staff, and has been reproducibly shown to reduce mortality by more than 25%. Front-loaded alteplase was shown to be superior to streptokinase in terms of vessel patency, left ventricular function, and mortality reduction in the large-scale GUSTO I trial. Subsequent development of bolus thrombolytics, such as tenecteplase and reteplase, allowed for easier administration than alteplase but failed to further improve survival. The combination of thrombolytic agents with GP IIb/IIIa receptor antagonists also failed to improve survival, resulted only in modest reductions of reinfarction, and was associated with considerable bleeding complications.

There are several shortcomings of thrombolytic therapy. Even the most modern thrombolytic agents achieve vessel patency in only 60% of patients. The most important adverse events related to thrombolytic therapy are bleeding complications, notably a 0.5% to 1.0% incidence of intracranial hemorrhage. Furthermore, a reocclusion rate of 20% to 30% is observed at 3 months, and the benefit of thrombolytic therapy in elderly patients remains undefined.

Thrombolytic and Fibrinolytic Therapy

Thrombolytic agents actively dissolve fibrin clots that have already formed. Exogenous plasminogen activators such as streptokinase and urokinase not only dissolve a thrombus but affect circulating plasminogen, leading to decreased levels of both plasminogen and fibrin. Recombinant tissue-type plasminogen activator (rt-PA), an endogenous agent, is more fibrin selective and has less effect on circulating plasminogen levels. Clot lysis leads to elevation of fibrin degradation products, which themselves have an anticoagulant effect by inhibiting platelet aggregation. Hemostasis remains altered for approximately a day after administration of a thrombolytic drug. Fibrinogen is the last factor to recover.

In addition to the fibrinolytic agent, these patients frequently receive intravenous heparin to maintain an APTT of 1.5 to 2 times normal and clopidogrel/aspirin. No controlled studies have examined the risk. Several cases of spinal hematoma in patients with indwelling epidural catheters who received thrombolytic agents have been reported in the literature and through the MedWatch system [18].

Guidelines detailing original contraindications for thrombolytic drugs suggest avoidance of these drugs within 10 days of puncture of noncompressible vessels. Data are not available to clearly outline the length of time neuraxial puncture should be avoided after discontinuation of these drugs.

Invasive management

Thrombolytic therapy is an invasive, site-directed approach in treating PVT and is useful in cases where systemic anticoagulation is contraindicated. This type of treatment involves the placement of a catheter within the thrombosed vein using portal venography and administration of thrombolytic agents to achieve lysis of the clot. Similar to the timing of anticoagulation, thrombolytic therapy is more effective with early initiation.62

Mechanical thrombectomy involves mechanical removal of the venous thrombus and can be achieved with either portal venography by an interventional radiologist or with surgery via laparotomy. When performed venographically, mechanical thrombectomy is often combined with direct infusion of lytic agents into thrombi that are less likely to clear with thrombolytics alone. In cases where thrombolysis therapy fails to dissolute a clot completely, mechanical thrombectomy can also be performed as an adjunct following thrombolysis for persistent, residual clots.

Surgery in the form of mechanical thrombectomy and/or bowel resection is the most aggressive treatment for PVT and should only be employed in cases where bowel ischemia is evident. However, operative thrombectomy is rarely needed for PVT related to islet cell transplantation and has only been reported in autologous cases where patients undergo open surgery for pancreatectomy.30 Nonetheless, it is an available, definitive treatment for severe cases of PVT that have failed medical management and thrombolytic interventions.

Embolus destruction

Fibrinolytics

Fibrinolytic agents cause decreased fibrinogen levels and increased fibrin degradation products (FDP). Increases in the concentration of fibrinopeptide A in the plasma suggests continuing thrombin activity in patients treated with thrombolytic agents. It has also been proposed that platelet activation occurs at the thrombus undergoing lysis by thrombin liberated from the dissolving clot or generated by activation of the coagulation system. Therefore, platelets from these patients may either have reduced or increased responsiveness to added agonists during platelet activation or aggregation testing. Both potent antithrombins and GPIIb–IIIa antagonists are being evaluated as conjunctive agents.

Thrombolytic Therapy

Thrombolytic agents cause the direct acceleration of clot lysis and a reduction in clot burden by activating plasminogen to form plasmin, which then results in fibrinolysis as well as fibrinogenolysis. Defining those patients in whom the benefit of a rapid reduction in clot burden outweighs the increased hemorrhagic risk of thrombolytic therapy may be difficult. The case for thrombolytic use is strongest in patients with massive PE complicated by shock, which occurs in approximately 10% of patients with a mortality rate as high as 25%. Thrombolysis in these patients results in a more rapid resolution of abnormal right ventricular function. Emerging data suggest that patients with acute submassive embolism (extensive clot burden without shock or severe hypoxemia) may also benefit from thrombolysis. A prospective randomized clinical trial suggested that patients with acute PE without hypotension but with right ventricular dysfunction on echocardiogram may have had an improved clinical course when given thrombolytic therapy plus heparin versus heparin alone in that thrombolysis seemed to prevent clinical deterioration and the need for escalation of care. The subjective nature of the end points studied in this trial limits the interpretation of the results.

No clear data indicate that any one thrombolytic agent is superior to another, although shorter regimens and even bolus dosing may be favored in the case of massive PE. Each of the approved regimens is administered at a fixed dose, making measurements of coagulation unnecessary during infusion (Table 26.1). The aPTT should be measured after the thrombolytic infusion is completed and repeated at 4-hour intervals until the aPTT is less than twice the upper limit of normal. At this point, continuous intravenous unfractionated heparin should be administered without a loading bolus dose.

Thrombolytic therapy is contraindicated in patients at high risk for hemorrhage because both the lysis of hemostatic fibrin plugs and fibrinogenolysis can lead to severe bleeding (Box 26.3). Intracranial hemorrhage is the most devastating (and often fatal) complication of thrombolytic therapy and is generally stated to occur in approximately 2% of patients. Invasive procedures should be minimized because bleeding commonly occurs at sites of catheter placement. Retroperitoneal hemorrhage may result from a vascular puncture above the inguinal ligament and is often initially silent but may be life-threatening. The decision to use thrombolysis should be made on a case-by-case basis because there should be a lower threshold to administer therapy in the setting of a contraindication when a patient is extremely unstable from life-threatening PE.

Thrombolysis

Thrombolytic treatment can be considered for specific subgroups of patients with PE or DVT. Data on thrombolytic therapy in cancer patients are limited, because most trials excluded cancer patients owing to a presumed higher risk of bleeding. Small retrospective studies examined the degree of clot lysis and safety of catheter-directed thrombolytic therapy between patients with and without cancer and found the procedure equally effective and safe for both patient groups.256,257

Thrombolysis accelerates clot lysis and leads to faster hemodynamic improvement in patients with PE. In patients with massive DVT, thrombolysis administered as catheter-directed thrombolysis can achieve more rapid symptom relief, restore limb perfusion, and reduce the incidence of postthrombotic syndrome. Special consideration should be paid to the use of thrombolysis in cancer patients because it is associated with a threefold higher risk of major bleeding, and whether it has a benefit on mortality or incidence of recurrent VTE in the general population remains uncertain.258 Because of its significant risks, the indications for thrombolytic therapy should be reviewed carefully in each patient. Only in patients with massive life-threatening PE with hemodynamic instability in the absence of an increased risk of bleeding is thrombolysis considered standard of care.259 The ACCP recommends against thrombolytic therapy in most hemodynamically stable patients but mentions that it can be considered in the situation of a patient deteriorating with severe right ventricular dysfunction, cardiopulmonary arrest due to PE, extensive clot burden, or a free-floating right atrial or ventricular thrombus.259 Further indications for thrombolysis according to NCCN and ESMO guidelines are limb-threatening or life-threatening acute proximal DVT or massive iliofemoral thrombosis, in which rapid venous decompression and flow restoration may be desirable.169,255

In all patients with cancer, imaging of the brain before thrombolysis should be considered in order to rule out an intracranial tumor or hemorrhage, which are absolute contraindications to thrombolysis. Other contraindications are history of hemorrhagic stroke, ischemic stroke in previous 3 months, history of major trauma, surgery or head injury in previous 3 weeks, platelet count below 100,000/m3, active bleeding or bleeding diathesis, refractory hypertension (i.e., systolic blood pressure >180 mm Hg and diastolic blood pressure >100 mm Hg), recent gastrointestinal bleeding, and advanced liver disease.255 At present, the use of catheter-directed thrombolytic therapy for acute PE may be considered for hemodynamically compromised patients or those with significant right ventricular dysfunction when systemic thrombolysis has failed or as an alternative to systemic thrombolytic therapy, if local expertise is available.259–261

Mechanism of action

Fibrinolytic drugs enhance fibrinolysis by substituting for the naturally occurring t-PA. They bind to and activate plasminogen to plasmin, which degrades fibrin thrombi. Alteplase is a genetically engineered copy of the naturally occurring t-PA that binds directly to fibrinogen and fibrin. It has a wide range of clinical uses. Tenecteplase is a genetically engineered modified form of t-PA with increased fibrin specificity, less sensitivity to plasminogen activator inhibitors and a longer duration of action than alteplase. Tenecteplase is only licensed for treatment of myocardial infarction.

Streptokinase is obtained from haemolytic streptococci and is inactive until it forms a complex with circulating plasminogen; the resultant streptokinase–plasminogen activator complex substitutes for t-PA in the fibrinolytic cascade, causing plasminogen activation. Streptokinase is used much less frequently than other fibrinolytic drugs.

The effectiveness of any fibrinolytic agent is greatest with fresh thrombus and if a large surface area of thrombus is exposed to the drug.