However, these agents also cause systemic plasminogen activation. By cleaving and inactivating fibrinogen and clotting factors II, V and VIII, they interfere with blood coagulation and produce a systemic hypocoagulable state. Furthermore, elevated serum fibrin and fibrinogen degradation products inhibit the conversion of fibrinogen to fibrin by negative feedback; and therefore interfere with fibrin polymerization. There is also a direct neurohormonal effect on pulmonary vasoconstriction and bronchoconstriction; substances such as serotonin and thromboxane A 2 are released in the presence of PE and promote local vasoconstriction and bronchoconstriction.
Finally, thrombolysis may cause platelet dysfunction by affecting platelet surface receptors GpIb and GpIIb. USET 5 was the first trial comparing two thrombolytic agents, and no difference in efficacy between urokinase and streptokinase was apparent. Further studies by Goldhaber and associates 10 and the European Cooperative study 11 compared rtPA and urokinase and found that, although rtPA initially produced a faster resolution of the clot, results were the same after 24 hours.
Thrombolytics are given according to regimens approved by the FDA Table 2. During administration, laboratory monitoring is unnecessary. However, after the infusion is given, partial thromboplastin time PTT should be measured. If it is less than 2. If the PTT initially is greater than 2.
In contrast to thrombolysis for myocardial infarction and stroke, thrombolysis for PE has a longer time window of opportunity. One group 12 compared data for patients from five PE thrombolysis trials and followed the improvement based on lung scans and angiograms up to 14 days after initial presentation with a PE.
These data showed a persistent but attenuated benefit from thrombolysis when given up to 14 days later: 86 percent of patients improved an average of 16 percent when thrombolytics were given within the first 24 hours, whereas 69 percent of patients improved an average of 8 percent when treated seven to 14 days after a PE.
Therefore, although benefit from thrombolysis for PE may be seen when given up to 14 days after the initial diagnosis of a PE, it is most beneficial when given as early as possible.
Finally, little evidence supports the concept of local administration or bolus dosing of thrombolytic therapy. More than 80 percent of patients with massive PE die within the first two hours after onset, mainly from right-sided heart failure.
Furthermore, the rate of recurrence of PE must be reduced. The first trial to look at the effect of thrombolysis on mortality was the USET study. Other studies Table 3 4 , 6 , 7 , 17 , 18 involving both clinically stable and unstable patients showed similar mortality rates, ranging from 3 to 11 percent.
Therefore, no evidence suggests that thrombolytic therapy reduces mortality. Levine, et al. Goldhaber Information from references 4 , 6 , 7 , 17 and The rate of recurrent PE in patients who develop an initial PE and are treated with heparin is 10 percent over two weeks.
The rate of recurrence in the UPET trial 4 was 15 percent in the thrombolytic group and 19 percent in the heparin group. Data from other recent randomized clinical trials Table 3 4 , 6 , 7 , 17 , 18 have shown similar results between groups treated with heparin and those treated with thrombolytic therapy. Therefore, no evidence exists to prove that thrombolysis decreases the rate of recurrent PE.
Approximately 40 to 50 percent of echocardiograms performed in patients with acute PE show evidence of right ventricular RV dysfunction. This leads to RV dilatation, dysfunction and ischemia, and possible interventricular septal shift. Decreased cardiac output ensues, reducing systemic and coronary perfusion and eventually causing hemodynamic collapse.
A study by Goldhaber and colleagues 17 provides the most evidence of benefit of thrombolytic therapy for RV dysfunction. Echocardiography performed in hemodynamically stable patients who were randomly assigned to treatment with heparin or thrombolysis showed 39 percent improvement in RV function in the thrombolytic therapy group versus 17 percent improvement in the heparin group. In addition, pulmonary perfusion improved 14 percent in the thrombolytic therapy group versus 1.
Two of the 55 patients in the heparin group died, while none of the 46 patients in the thrombolysis group died. Unfortunately, other studies failed to confirm these results or to show any benefit from thrombolysis of hemodynamically stable patients with evidence of RV dysfunction. Therefore, no evidence at this time supports the efficacy of thrombolysis in these patients. The major complication of thrombolytic therapy is bleeding. The rate of bleeding in earlier trials ranged from 22 to 45 percent, mainly because of the use of larger doses and an increased rate of venous cutdowns.
The most critical bleeding is intracranial bleeding, which occurs at the rate of 2. Risk factors for bleeding include invasive procedures, dose and length of time of thrombolytic therapy, increased body mass index, hypertension and age over 70 years. Several other contraindications preclude the use of thrombolytic therapy Table 4. Cerebrovascular accident, intracranial trauma or surgery within past two months. Very little data are available on the benefits of thrombolysis versus surgical therapy for pulmonary embolism.
The largest study to date to compare these therapies examined 37 patients with massive PE and shock who were randomized to receive one of the two interventions. However, the disadvantage of embolectomy is that it requires more hospital resources and may not always be available. Despite the theoretic advantages of thrombolysis over standard therapy, little data support its widespread use except in situations where it is truly indicated Table 1. Hemodynamic instability is the only absolute indication.
No firm evidence exists to show benefit over standard therapy for recurrent PE, mortality or chronic complications. Because most patients with hypotensive massive PE die within two hours of the onset of symptoms, the use of thrombolytic therapy may be more beneficial and practical in hospitalized patients who develop PE because diagnosis and therapy are able to proceed quicker.
This therapy may be used to save lives of patients who present with classic symptoms and risk factors for PE. However, little data currently exist to support this type of therapy. In most situations, reliable confirmation of the diagnosis of PE must be made before this therapy is utilized Table 5. Confirm the diagnosis of pulmonary embolism, preferably with noninvasive means; in unstable patients, diagnosis may be based on echocardiography or a right-sided heart catheterization in addition to clinical examination and the presence of risk factors.
Minimize invasive tests e. Infuse thrombolytic agent peripherally, using one of the three regimens approved by the U. Food and Drug Administration. Anticoagulate with heparin and eventually warfarin immediately after thrombolytic agent is completely infused; do not administer heparin concomitantly; check PTT every 6 hours until therapeutic 1. If bleeding occurs, stop thrombolytic infusion and give blood products as needed.
Patients should preferably be in a closely monitored setting i. Today, complications are fewer, the window of opportunity is longer, the route of administration is peripheral and laboratory tests are fewer. Nevertheless, more data based on larger prospective, randomized clinical trials are needed to clarify indications and clinical benefits of thrombolysis, its long-term effects and its advantages over surgical therapies. Already a member or subscriber? Log in. Interested in AAFP membership?
Learn more. He received his medical degree from the Royal College of Physicians and Surgeons, Ireland, and served a residency in internal medicine at the Medical College of Wisconsin, Milwaukee. Address correspondence to Khalid Almoosa, M. Reprints are not available from the author. The author indicates that he does not have any conflicts of interest. Sources of funding: none reported. Mortality from pulmonary embolism in the United States: to Lilienfeld DE. Decreasing mortality from pulmonary embolism in the United States, — Int J Epidemiol.
Goldhaber SZ. Pulmonary embolism. N Engl J Med. Urokinase pulmonary embolism trial: Phase I results A cooperative study. Urokinase-streptokinase embolism trial: Phase 2 results.. A cooperative study.
A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen activator in patients with acute pulmonary embolism. PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism.
J Am Coll Cardiol. Pulmonary embolism: diagnosis with spiral CT and ventilation-perfusion scanning-correlation with pulmonary angiographic results or clinical outcome. Diagnosis of pulmonary embolism. Curr Opin Hematol. Randomised controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism.
Effects of intravenous urokinase versus alteplase on total pulmonary resistance in acute massive pulmonary embolism. Relation of duration of symptoms with response to thrombolytic therapy in pulmonary embolism. Note that fibrinolytic therapy is always given simultaneously with anticoagulation using unfractionated heparin or low molecular weight heparin.
When the decision to treat a patient experiencing a STEMI with fibrinolytic therapy is made, because primary PCI is not available in a timely fashion, contraindications must be considered; suspected aortic dissection, active bleeding excluding menses or a bleeding diathesis are contraindications to fibrinolytic therapy.
Streptokinase is immunogenic; once exposed, a repeat exposure can cause severe allergic reactions including anaphylaxis, and thus is not recommended. Back to Healio. Topic Reviews A-Z Save. Fibrinolytic Therapy Thrombolytic Therapy Topic Review Introduction Fibrinolytic therapy, also known as thrombolytic therapy, is used to lyse acute blood clots by activating plasminogen, resulting in the formation of plasmin, which cleaves the fibrin cross-links causing thrombus breakdown.
Names tPA tissue plasminogen activator , alteplase, reteplase, streptokinase, tenecteplase, urokinase Indications Fibrinolytic therapy is used in the treatment of a ST segment elevation myocardial infarction STEMI , acute stroke and other less common indications such as pulmonary embolism and acute deep venous thrombosis. Contraindications When the decision to treat a patient experiencing a STEMI with fibrinolytic therapy is made, because primary PCI is not available in a timely fashion, contraindications must be considered; suspected aortic dissection, active bleeding excluding menses or a bleeding diathesis are contraindications to fibrinolytic therapy.
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