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eMedicine Specialties > Emergency Medicine > Cardiovascular

Thrombolytic Therapy

Wanda L Rivera-Bou, MD, FAAEM, FACEP, Assistant Professor and ACLS Training Center Director, Department of Emergency Medicine, University of Puerto Rico, School of Medicine
Jose G Cabanas, MD, Clinical Instructor, Department of Emergency Medicine, University of North Carolina at Chapel Hill School of Medicine; Assistant Medical Director, Orange County EMS; Salvador E Villanueva, MD, FACEP, Assistant Professor, Department of Emergency Medicine, University of Puerto Rico School of Medicine

Updated: Nov 20, 2008

Introduction

Clinical problems associated with thrombosis

Thrombosis is an important part of the normal hemostatic response that limits hemorrhage from microscopic or macroscopic vascular injury. Physiologic thrombosis is counterbalanced by intrinsic antithrombotic properties and fibrinolysis. Under normal conditions, a thrombus is confined to the immediate area of injury and does not obstruct flow to critical areas, unless the blood vessel lumen is diminished already as it is in atherosclerosis.

Under pathological conditions, a thrombus can propagate into otherwise normal vessels. A thrombus that has propagated where it is not needed can obstruct flow in critical vessels and can obliterate valves and other structures that are essential to normal hemodynamic function. The principal clinical syndromes that result are acute myocardial infarction (AMI), deep vein thrombosis, pulmonary embolism, acute ischemic stroke, acute peripheral arterial occlusion, and occlusion of indwelling catheters.

Pathophysiology of thrombosis

Both hemostasis and thrombosis depend on the coagulation cascade, vascular wall integrity, and platelet response. Several cellular factors are responsible for thrombus formation. When a vascular insult occurs, immediate local cellular response takes place. Platelets migrate to the area of injury where they secrete several cellular factors and mediators. These mediators promote the clot formation.

The 3 main components of a blood clot are platelets, thrombin, and fibrin, and each is a key therapeutic target. During thrombus formation, circulating prothrombin is activated to the active clotting factor, thrombin, by activated platelets. Fibrinogen is activated to fibrin by the newly activated thrombin. Fibrin is then formed into the fibrin matrix. All this takes place while platelets are being adhered and aggregated. Aspirin, glycoprotein (GP) IIb/IIIa inhibitors, and clopidogrel have an inhibitory effect on platelet activation and aggregation. Plasminogen gathers in the fibrin matrix. Fibrin-bound plasminogen will be converted by thrombolytic drugs to plasmin, the rate-limiting step in thrombolysis.

It is important to state that the thrombolysis process works best on recently formed thrombi. Older thrombi have an extensive fibrin polymerization that makes thrombi more resistant to thrombolysis; hence, the importance of time for thrombolytic therapy.

Pathological thrombosis can occur in any vessel at any location in the body. Several causes that predispose to thrombosis include the following:

  • Atherosclerosis (plaque rupture)
  • Blood flow changes
  • Metabolic disorders (diabetes mellitus, hyperlipidemia)
  • Hypercoagulable states
  • Smoking
  • Trauma/burns

For excellent patient education resources, visit eMedicine's Circulatory Problems Center. Also, see eMedicine's patient education article Blood Clot in the Legs.

Thrombolytic agents

Thrombolytic agents available today are serine proteases that work by converting plasminogen to the natural fibrinolytic agent plasmin. Plasmin lyses clot by breaking down the fibrinogen and fibrin contained in a clot.

The history of thrombolytic therapy began in 1933 when it was discovered that filtrates of broth cultures of certain strains of Streptococcus bacteria (beta-hemolytic streptococci) could dissolve a fibrin clot.1 Streptokinase found its initial clinical application in combating fibrinous pleural exudates, hemothorax, and tuberculous meningitis.2 In 1958, streptokinase was first used in patients with acute myocardial infarction, and this changed the focus of treatment.

At first, streptokinase infusion produced conflicting results until the Gruppo Italiano per la Sperimentazione della Streptochinasi nell'Infarto Miocardico (GISSI) trial in 1986, which validated streptokinase as an effective therapy and established a fixed protocol for its use in acute myocardial infarction.2

The fibrinolytic potential of human urine was first described in 1947. The active molecule was named urokinase.1 Unlike streptokinase, urokinase is not antigenic and directly activates plasminogen to form plasmin. Their ability to catalyze the conversion of plasminogen to plasmin is affected only slightly by the presence or absence of local fibrin clot.

Tissue plasminogen activator (tPA) is a naturally occurring fibrinolytic agent found in vascular endothelial cells and is involved in the balance between thrombolysis and thrombogenesis. It exhibits significant fibrin specificity and affinity. At the site of the thrombus, the binding of tPA and plasminogen to the fibrin surface induces a conformational change facilitating the conversion of plasminogen to plasmin and dissolving the clot.1

Fibrinolytics, sometimes referred to as plasminogen activators, are divided into two categories. Fibrin-specific agents such as alteplase, reteplase, and tenecteplase produce limited plasminogen conversion in the absence of fibrin, whereas non–fibrin-specific agents such as streptokinase catalyze systemic fibrinolysis. Streptokinase is indicated for the treatment of acute myocardial infarction, acute massive pulmonary embolism, deep vein thrombosis, arterial thrombosis, and occluded arteriovenous cannulae. Streptokinase is not widely used in the United States but continues to be used elsewhere because of its lower cost.

Alteplase is the only current lytic agent US Food and Drug Administration (FDA) approved for AMI, acute ischemic stroke, massive pulmonary embolism, and occluded central venous access devices. New agents and new dosing regimens are under constant investigation. A choice of lytic agents must be based upon the results of ongoing clinical trials and upon the clinician's experience. The most appropriate agent and regimen for each clinical situation will change over time and may differ from patient to patient.

The information presented here is based on clinical and investigational experience as reported in the current literature to the authors' best knowledge, without respect to FDA approval for a particular indication. Where the literature does not suggest an effective dose for a lytic agent in a particular clinical setting, no dose information is presented. Currently available agents today are alteplase (tPA), reteplase (r-PA), tenecteplase (TNKase), urokinase, prourokinase, anisoylated purified streptokinase activator complex (APSAC), and streptokinase.

 Alteplase

Alteplase (tPA, Activase) was the first recombinant tissue-type plasminogen activator and is identical to native tissue plasminogen activator. In vivo, tissue-type plasminogen activator is synthesized and made available by cells of the vascular endothelium. It is the physiologic thrombolytic agent responsible for most of the body's natural efforts to prevent excessive thrombus propagation.

Alteplase is fibrin specific with a plasma half-life of 4-6 minutes. It is the fibrinolytic agent most familiar to emergency departments and is the lytic agent most often used for the treatment of coronary artery thrombosis, pulmonary embolism, and acute ischemic stroke given as an infusion. Alteplase is FDA approved for treatment of ST-elevation myocardial infarction (STEMI), acute ischemic stroke (AIS), acute massive pulmonary embolism, and central venous access devices (CVAD).3,4

In theory, alteplase should be effective only at the surface of fibrin clot. In practice, however, a systemic lytic state is seen, with moderate amounts of circulating fibrin degradation products and a substantial risk of systemic bleeding.

Alteplase may be re-administered as necessary, as it is not antigenic and almost never is associated with any allergic manifestations.

Currently, alteplase is the only thrombolytic drug approved for acute ischemic stroke.

Reteplase

Reteplase (r-PA, Retavase) is a second-generation recombinant tissue-type plasminogen activator that seems to work more rapidly and to have a lower bleeding risk than the first-generation agent alteplase.

Reteplase is a synthetic nonglycosylated deletion mutein of tissue plasminogen activator containing 355 of the 527 amino acids of native tissue plasminogen activator. The drug is produced in Escherichia coli by recombinant techniques.5 Reteplase does not bind fibrin as tightly as native tissue plasminogen activator, allowing the drug to diffuse more freely through the clot rather than binding only to the surface the way tissue plasminogen activator does. In high concentrations, Reteplase does not compete with plasminogen for fibrin-binding sites, allowing plasminogen at the site of the clot to be transformed into clot-dissolving plasmin. These characteristics help explain the faster clot resolution seen in patients receiving reteplase than in those receiving alteplase.

The modifications also resulted in a molecule with a longer half-life (approximately 18 min) allowing for bolus administration. Reteplase is FDA approved for acute myocardial infarction, and it is administered as two 10 U boluses given 30 minutes apart, each bolus is given over 2 minutes.5 The result is more convenient administration and faster thrombolysis with reteplase than with alteplase, which is given by a bolus followed by an intravenous (IV) infusion.

Reteplase may be re-administered as necessary, as it is not antigenic and almost never is associated with any allergic manifestations.

 Tenecteplase (TNKase)

TNKase was approved by the FDA as a fibrinolytic agent in 2000. This drug has a similar mechanism of action as alteplase (tPA). It is the latest thrombolytic agent approved for use in clinical practice. TNKase is currently indicated for the management of acute myocardial infarction (AMI).

Tenecteplase is produced by recombinant DNA technology using Chinese hamster ovary cells. This drug is a 527 amino acid glycoprotein, which sustained several modifications in amino acids molecules. These modifications consist of a substitution of threonine 103 with asparagine, asparagine 117 with glutamine, and a tetra-alanine substitution at amino acids 296-299 in the protease domain. This change permits TNKase to have a longer plasma half-life and more fibrin specificity. Tenecteplase has a half-life ranging initially from 20-24 minutes up to 130 minutes final clearance, most of it by liver metabolism.6

Because of the amino acid modifications, TNKase has the advantage for a single bolus administration and decreased bleeding side effects due to high fibrin specificity. The ASSENT-2 trial evaluated the efficacy and safety of tenecteplase compared with alteplase in patients with AMI. Tenecteplase was found noninferior to alteplase in terms of 30-day mortality. Tenecteplase was associated with fewer bleeding complications, major bleeding events (4.66% vs 5.94%), and lower need for blood transfusion (4.25% vs 5.49%; p=.0002). Rates for intracranial hemorrhage were similar (tenecteplase 0.93%, alteplase 0.94%).7 Follow-up study showed that mortality rates between the two active therapy groups remained similar after one year.8

Several clinical trials are in progress seeking new indications for this drug such as in acute ischemic stroke.

Urokinase

Urokinase (Abbokinase) is the fibrinolytic agent most familiar to interventional radiologists and the one that has been used most often for peripheral intravascular thrombus and occluded catheters. Recently, urokinase was made available once again from the manufacturer. After some years hold from the market due to manufacturer issues with the FDA, it has been reintroduced. The package insert was revised and, since then, has an indication only for massive pulmonary embolism. During the time this drug was not available, the FDA encouraged the off-label use of reteplase and alteplase for local-regional lysis of venous and arterial thrombus at any location. Currently, this drug is readily used for this purpose in different clinical and interventional settings.

Urokinase is a physiologic thrombolytic agent that is produced in renal parenchymal cells. Unlike streptokinase, urokinase directly cleaves plasminogen to produce plasmin. When purified from human urine, approximately 1500 L of urine are needed to yield enough urokinase to treat a single patient. Urokinase is also commercially available in a form produced by tissue culture, and recombinant DNA techniques have been developed for urokinase production in E coli cultures.

In plasma, urokinase has a half-life of approximately 15 minutes. Allergic reactions are rare, and the agent can be administered repeatedly without antigenic problems.

Prourokinase

Prourokinase is a new fibrinolytic agent that is currently undergoing clinical trials for a variety of indications. It is a relatively inactive precursor that must be converted to urokinase before it becomes active in vivo. This has handicapped therapeutic exploitation of its fibrin-specific physiological properties.

Researches have developed a mutant of prourokinase (M5) with even greater plasma stability and which causes faster plasminogen activation and greater fibrin-specific clot lysis than wild-form prourokinase.9 As with tissue-type plasminogen activator, prourokinase is somewhat clot specific, since the presence of fibrin enhances the conversion of prourokinase to active urokinase by an unknown mechanism.

Streptokinase

Streptokinase is the least expensive fibrinolytic agent, but, unfortunately, it is antigenic and produces a high incidence of untoward reactions. This drawback limits the usefulness of streptokinase in the clinical setting. Although other fibrinolytic agents are more popular in developed nations like the United States, streptokinase continues to be widely used in developing nations.2

Streptokinase is produced by beta-hemolytic streptococci. Streptokinase by itself is not a plasminogen activator, but it binds with free circulating plasminogen (or with plasmin) to form a complex that can convert additional plasminogen to plasmin. Streptokinase activity is not enhanced in the presence of fibrin.

The principal plasma activity half-life of streptokinase is about 20 minutes, but an unbound fraction (about 15%) has a half-life of 80 minutes. Since it is produced from streptococcal bacteria, it often causes febrile reactions and other allergic problems. It can also cause hypotension that appears to be dose-related. Streptokinase usually cannot be administered safely a second time within 6 months, because it is highly antigenic and results in high levels of antistreptococcal antibodies.

Anisoylated purified streptokinase activator complex

APSAC is a complex of streptokinase and plasminogen that does not require free circulating plasminogen to be effective. It has many theoretical benefits over streptokinase but suffers antigenic problems similar to those of the parent compound.

The half-life of APSAC in plasma is somewhere between 40 and 90 minutes.

Thrombolytic Therapy for Acute Myocardial Infarction

Thrombolytic therapy is indicated in patients with evidence of ST-segment elevation myocardial infarction (STEMI) or presumably new left bundle branch block (LBBB) presenting within 12 hours of the onset of symptoms if there are no contraindications to fibrinolysis. Patients with STEMI usually have complete occlusion of an epicardial coronary vessel caused by an acute thrombotic obstruction.10

Coronary atherosclerosis is a diffuse process with segmental lesions called coronary plaques. The plaque ruptures, exposing the endothelial lining, and allowing prothrombotic enzymes and molecular triggers to mix with the blood. Platelets are activated, and the coagulation cascade is amplified resulting in a thrombus that occludes the vessel, preventing the circulation of oxygenated blood. Irreversible ischemia-induced myocardial necrosis may occur within 20-60 minutes of occlusion. The mainstay of treatment is reperfusion therapy through administration of fibrinolytics (pharmacologic reperfusion) or primary percutaneous coronary intervention (PCI) (mechanical reperfusion).

PCI when performed within 90 minutes of patient arrival has been shown to be superior to fibrinolysis in combined end points of death, stroke, and reinfarction in many studies. The reality is that PCI is not widely available at acute care hospitals. In the United States, of the nearly 5,000 acute care hospitals, 2,200 have catheterization laboratories. Among those, only 1,200 (<25%) are capable of performing PCI.11

Fibrinolytic therapy is a proven and effective treatment for the management of acute myocardial infarction (AMI). It is more universally available to patients without contraindications, can be administered by any properly trained health care provider, and can be given in the prehospital setting, reducing the time to treatment. The goal is a door-to-needle time of less than 30 minutes. Every effort must be made to minimize the time to therapy. The efficacy of fibrinolytic therapy declines as the duration of ischemia increases.

Fibrinolytic agents are given in conjunction with antithrombin and antiplatelet agents, which help to maintain vessel patency once the clot has been dissolved.

  • Aspirin inhibits platelets; the recommended dose is 162-325 mg of chewable aspirin.
  • Clopidogrel inhibits platelets. In patients younger than 75 years, administer an oral loading dose of 300 mg. The COMMIT-CCS-2 and CLARITY-TIMI 28 trials provided evidence for benefit of adding clopidogrel to aspirin in patients undergoing fibrinolytic therapy.12,13 No data are available to guide decision-making regarding an oral loading dose in patients aged 75 years or older. In this group of patients, administer 75 mg per day.14
  • Heparins (unfractionated heparin [UFH] or low molecular weight heparin [LMWH]) inhibit thrombin. For UFH, the recommended dose is an intravenous bolus of 60 U/kg (maximum 4,000 U) followed by an initial infusion of 12 U/kg/h (maximum 1000 U/h) adjusted to maintain aPTT at 1.5-2 times control.
  • LMWH (enoxaparin) is emerging as an alternative to UFH. Enoxaparin may be administered to patients younger than 75 years; the recommendation is 30 mg IV bolus followed by 1 mg/kg subcutaneous every 12 hours. For patients at least 75 years old, the intravenous bolus is eliminated and the subcutaneous dose is reduced to 0.75 mg/kg every 12 hours. Regardless of age, if the creatinine clearance is less than 30 mL/min, the subcutaneous dose is 1 mg/kg every 24 hours.14 Enoxaparin appears superior to UFH in the EXTRACT-TIMI 25 trial.15

Contraindications for fibrinolytic use in STEMI10

Absolute contraindications

  • Prior intracranial hemorrhage (ICH)
  • Known structural cerebral vascular lesion
  • Known malignant intracranial neoplasm
  • Ischemic stroke within 3 months
  • Suspected aortic dissection
  • Active bleeding or bleeding diathesis (excluding menses)
  • Significant closed-head trauma or facial trauma within 3 months

Relative contraindications

  • History of chronic, severe, poorly controlled hypertension
  • Severe uncontrolled hypertension on presentation (SBP >180 mm Hg or DBP >110 mm Hg)
  • Traumatic or prolonged (>10 min) CPR or major surgery less than 3 weeks
  • Recent (within 2-4 wk) internal bleeding
  • Noncompressible vascular punctures
  • For streptokinase/anistreplase - prior exposure (more than 5 d ago) or prior allergic reaction to these agents
  • Pregnancy
  • Active peptic ulcer
  • Current use of anticoagulant (eg, warfarin sodium) that has produced an elevated international normalized ratio (INR) >1.7 or prothrombin time (PT) >15 seconds

Alteplase

Alteplase (tPA) can be administered in an accelerated infusion (1.5 h), 50-mg and 100-mg vials reconstituted with sterile water to 1 mg/mL.

The accelerated infusion of alteplase (tPA) for acute MI is 15 mg IV bolus, followed by 0.75 mg/kg (up to 50 mg) IV over 30 minutes, then 0.5 mg/kg (up to 35 mg) IV over 60 minutes, with a maximum total dose of 100 mg. This is the most common alteplase infusion parameter used for acute myocardial infarction.

Reteplase

Must reconstitute two 10-U vials with sterile water (10 mL) to 1 U/mL. The adult dose of reteplase for acute MI is 2 IV boluses of 10 units each; there is no weight-adjustment. The first 10 U IV bolus is given over 2 minutes; 30 minutes later, the second 10 U IV bolus is given over 2 minutes. Administer normal saline (NS) flush before and after each bolus.

Tenecteplase (TNKase)

To reconstitute, mix the 50-mg vial in 10 mL sterile water (5 mg/mL).

TNKase is administered 30-50 mg IV bolus over 5 seconds. Dosage is calculated based on the patient's weight.

  • <60 kg - 30 mg (6 mL)
  • >60 kg to <70 kg - 35 mg (7 mL)
  • >70 kg to <80 kg - 40 mg (8 mL)
  • >80 kg to <90 kg - 45 mg (9 mL)
  • >90 kg - 50 mg (10 mL)

Streptokinase

The adult dose of streptokinase for AMI is 1.5 million U in 50 mL D5W given IV over 60 minutes. Allergic reactions force the termination of many infusions before a therapeutic dose can be administered.

APSAC

The adult dose of anisoylated purified streptokinase activator complex (APSAC) for AMI is 30 U given IV over 2-5 minutes.

Thrombolytic Therapy for Pulmonary Embolism

Pulmonary embolism (PE) is a common disorder and an important cause of morbidity and mortality. Pulmonary embolism occurs in approximately 650,000 patients annually in the United States. Among patients who are hemodynamically unstable at presentation, in-hospital mortality reaches 30%. 

Pulmonary emboli often arise from thrombi originating in the deep venous system of the lower extremities or pelvis. A blood clot dislodges and is swept into the pulmonary circulation and lodges in a pulmonary artery. If the clot is large enough to obstruct large vessels in the lung, it can cause hemodynamic instability, along with right ventricular failure, and possibly death. Currently, thrombolytic therapy in pulmonary embolism is still controversial.

Pulmonary embolism varies in severity from acute massive pulmonary embolism, acute pulmonary infarction, acute embolism without infarction to multiple emboli. Only patients with acute massive pulmonary embolism, those at the highest risk of immediate death, are eligible for fibrinolytic therapy if no contraindications are present. Other types are treated with anticoagulants or antithrombotic therapy.

Nevertheless, there is a subgroup of patients who present hemodynamically stable but with right ventricular (RV) dysfunction, who might benefit from fibrinolytic therapy due to increased risk of death. Fibrinolytic therapy in these patients (normotensive with RV dysfunction) remains controversial. In this regard, a large trial is needed using contemporary methods and criteria for the inclusion of high-risk normotensive patients.16

In addition to generalized, nonspecific symptoms, patients with acute massive pulmonary embolism also present with systemic hypotension, SBP <90 mm Hg or a decrease in systolic arterial pressure of at least 40 mm Hg for at least 15 minutes, and/or cardiogenic shock.17

Patients with pulmonary thromboembolism often decompensate suddenly, and, once hemodynamic compromise has developed, the mortality rate is extremely high. When the decision is made to use thrombolysis, the fastest-acting available thrombolytic agent with an acceptable safety and efficacy profile should be chosen. Many centers prefer off-label regimens to the slower on-label regimens that have been approved by the FDA.

UFH should not be given concomitantly with fibrinolytic therapy in acute massive pulmonary embolism. After fibrinolytic therapy, anticoagulation treatment is recommended to prevent recurrent thrombosis. Do not begin heparin until the aPTT has decreased to less than twice the normal control value.

In the worst clinical scenario, pulmonary embolism can cause cardiac arrest. The most common cardiac arrest initial rhythms documented include pulseless electrical activity and asystole. Cardiac arrest in the event of pulmonary embolism has a mortality of about 70%. Recently, numerous case reports state the use of thrombolytic boluses in cardiac arrest due to pulmonary embolism, with apparent heroic results. The clinician’s main goal should focus on avoiding the cardiac arrest and identifying patient candidates for thrombolytic therapy in the event of a pulmonary embolism.

Reteplase

Reteplase has not been labeled by the FDA for any indication except acute MI, but it is widely used for acute deep vein thrombosis and pulmonary embolism. The dosing used is the same as that approved for patients with acute MI: 2 IV boluses of 10 U each, administered 30 minutes apart.

Alteplase

The FDA-approved regimen for pulmonary thromboembolism is 100 mg as a continuous infusion over 2 hours.

First, administer 15-mg bolus followed by 85 mg over a 2-hour infusion. Heparin drip must be discontinued during alteplase infusion.

Some centers prefer to use an accelerated 90-minute regimen that appears to be faster acting, safer, and more efficacious than the 2-hour infusion. For patients weighing less than 67 kg, the drug is administered as 15 mg IV bolus, followed by 0.75 mg/kg infused over the next 30 minutes (maximum 50 mg) and then 0.50 mg/kg over the next 60 minutes (maximum 35 mg). For patients weighing more than 67 kg, 100 mg is administered as 15 mg IV bolus, followed by 50 mg infused over the next 30 minutes and then 35 mg infused over the next 60 minutes.

Urokinase

The FDA-approved regimen is 4,400 U/kg as a loading dose given at a rate of 90 mL/h over a period of 10 minutes, followed by a continuous infusion of 4,400 U/kg/h at a rate of 15 mL/h for 12-24 hours.

Streptokinase

The FDA-approved regimen for pulmonary embolism is 250,000 U as a loading dose over 30 minutes, followed by 100,000 U/h over 12-24 hours.

Thrombolytic Therapy for Deep Vein Thrombosis

Deep vein thrombosis (DVT) occurs when clots form in the extremities. If pieces of these clots break off and travel to the lungs, pulmonary embolism can occur. The annual incidence of venous thromboembolism (VTE) in the United States is 600,000 cases. Early diagnosis and treatment is crucial to prevent morbidity and mortality. Death from DVT is attributed to massive pulmonary embolism.

The mainstay of initial treatment for DVT is anticoagulation. In selected patients with extensive acute proximal DVT (eg, iliofemoral DVT, upper extremity DVT, symptoms <14 d, good functional status, life expectancy >1 y) with low risk of bleeding, catheter-directed thrombolysis (CDT) may be used to reduce symptoms and post thrombotic morbidity if appropriate resources are available.18

Catheter-directed thrombolysis is performed under imaging guidance; the procedure delivers thrombolytic directly to the clot through a catheter inserted in the vein. Intraclot injection of the thrombus with a fibrin-specific thrombolytic agent such as alteplase is an alternative to continuous-infusion and minimizes the duration of systemic exposure to thrombolytic agents.19

Systemic thrombolytic therapy is reserved for selected patients with extensive proximal DVT (eg, symptoms <14 d, good functional status, life expectancy >1 y) who have a low risk of bleeding, to reduce post thrombotic morbidity if catheter-directed thrombolysis is not available.18

Reteplase

Non–FDA-approved indication for DVT for lysis of venous thrombus, a catheter-directed infusion of 1 U/h is maintained for 18-36 hours.

Alteplase

For lysis of venous thrombus, a catheter-directed infusion of 1-1.5 mg/h for 12-24 hours has been used, it depends on local expertise.

Urokinase

The usual systemic dose for deep venous thrombosis is 4,400 U/kg as an IV bolus, followed by a maintenance drip of 4,400 U/kg/h. The drip is continued for 1-3 days, until clinical or laboratory investigations demonstrate thrombus resolution. When available, intrathrombus delivery of urokinase can avoid a systemic lytic state. The dose for this route of administration is a loading dose of 250,000 U IV, followed by an infusion of 500 U/kg/h. If clot lysis is inadequate, the infusion rate can be increased gradually up to 2,000 U/kg/h.

Streptokinase

The usual dose regimen for deep venous thrombosis is an IV bolus of 250,000 U followed by a maintenance drip at 100,000 U/h. The drip is continued for 1-3 days, until clinical or laboratory investigation shows thrombus resolution.

Thrombolytic Therapy for Blocked Catheters

Central venous access devices (CVADs) are an important component of chronic treatments that require ongoing venous access and regular maintenance. CVADs are subject to malfunctions, such as thrombotic occlusion with an incidence range from 2-40%. Risk factors include type of malignancy, chemotherapy, CVAD, insertion site, and catheter tip.20

Thrombolytic therapy has reopened occluded catheters in 85-90% of episodes, and removal of the catheter is not usually required. Alteplase (tPA), urokinase, and streptokinase have all been used.

Streptokinase is not commonly used because of its antigenic properties and allergic reactions. Urokinase was used until 1999 when the FDA reported the potential for viral contamination and it was removed from distribution. It is available again but does not have an approved FDA indication for clearance of occluded catheters. A randomized trial comparing urokinase (10,000 U) with tPA (2 mg) suggested marked superiority for tPA.21

Alteplase

FDA approved for thrombotically occluded CVADs. tPA is available in a 2 mg/2 mL vial, a volume sufficient to fill most catheter lumens. For patients ≥30 kg, 2 mg in 2 mL saline is used. Patients ≤30 kg, fill 100% of the internal lumen volume of the catheter, not to exceed 2 mg in 2 mL saline. It should dwell for 30 minutes to 2 hours and then be withdrawn. The dose may be repeated. If this is unsuccessful, an infusion of tPA 2 mg/50 mL infused over 4 hours may be used.

Urokinase

The dose of urokinase for catheter clearance is 5,000 U in each lumen over 1-2 minutes, leave in the lumen for 1-4 hours, then aspirate: may repeat with 10,000 U in each lumen if 5,000 U fails to clear the catheter. Volume to instill into catheter is equal to the volume of the catheter. For patients undergoing dialysis, 5,000 U is administered in each lumen over 1-2 minutes; leave in the lumen for 1-2 days, then aspirate.

Streptokinase

Slowly instill 250,000 U of streptokinase in 2 mL of solution into each occluded limb of the cannula. Clamp off the cannula limb(s) for 2 hours, and, after treatment, aspirate the contents of the cannula limb(s), flush with saline, and reconnect the cannula.

Thrombolytic Therapy for Acute Ischemic Stroke

Stroke is the leading cause of long-term disability and the third leading cause of death in the United States. Approximately 700,000 new cases occur annually in the United States, of which 85% are ischemic and the remainder are hemorrhagic. Among patients with ischemic strokes, 8-12% die within 30 days.22 Intravenous thrombolytic therapy for acute ischemic stroke is now generally accepted.

The US Food and Drug Administration (FDA) approved the use of intravenous tPA in 1996, partly on the basis of the results of the NINDS rtPA Stroke Study. The primary end point was neurological improvement at 24 hours. Favorable outcomes were achieved in 31-50% of patients treated with rtPA compared with 20-38% of patients given placebo. The major risk of treatment was symptomatic intracranial hemorrhage, which occurred in 6.4% of patients treated with rtPA and in 0.6% of patients given placebo.23

Other intravenously administered thrombolytics agents have been considered for treatment of patients with acute ischemic stroke. Clinical trials of streptokinase were halted prematurely because high rates of hemorrhage; therefore, this agent should not be used.24 Tenecteplase appears promising as an effective thrombolytic agent with fewer bleeding complications, but future trials are needed to compare the effect of tenecteplase on neurological outcome and safety compared with tPA.25 Desmoteplase has been tested in a pilot study but was stopped because of lack of efficacy in the desmoteplase-treated patients.26

Alteplase

Alteplase (tPA) is the only drug approved by the FDA for use in acute ischemic stroke with well-established time of symptom onset (<3 h). Currently, several clinical trials are running with third-generation thrombolytic drugs in order to evaluate their efficacy and safety in stroke.

Patients must arrive preferably to an institution with a stroke center. Time of symptom onset must be well established (<3 h), and the patient must be presenting with a measurable neurologic deficit. Stroke severity must be assessed with NIH stroke scale (maximum score 42). Patients with a score above 22 are considered high risk for hemorrhagic conversion due to the probability of a large infarcted area. Patients with a score less than 4 have only minor neurologic deficits, for which thrombolytic therapy is not indicated. High-risk patients often have early CT scan changes showing a large area of edema or mass effect.

Despite the increased risk of hemorrhage in patients with a massive stroke, fibrinolysis remains indicated whenever other exclusion criteria are absent, because the potential benefit is tremendous in this population of patients, who almost always have a dismal outcome if therapy is withheld. Inclusion and exclusion criteria must be reviewed before administration of thrombolytic. Be aware of subarachnoid hemorrhages that present early without CT scan findings.

Contraindications for alteplase

Absolute contraindications

  • History or evidence of intracranial hemorrhage
  • Clinical presentation suggestive of subarachnoid hemorrhage
  • Known arteriovenous malformation
  • Systolic blood pressure (SBP) >185 mm Hg or diastolic blood pressure (DBP) >110 mm Hg despite repeated measurements and treatment
  • Seizure with postictal residual neurologic impairment
  • Platelet count <100,000/mm3
  • Prothrombin time (PT) >15 or INR >1.7
  • Active internal bleeding or acute trauma (fracture)
  • Head trauma or stroke in the previous 3 months
  • Arterial puncture at a noncompressible site within 1 week

Relative contraindications

  • Suspected acute pericarditis
  • Rapidly improving stroke symptoms
  • Myocardial infarction in the previous 3 months
  • Glucose level <50 mg/dL or >400 mg/dL

If no contraindications, start 2 peripheral IV lines, one for alteplase infusion and the second one to manage any complication that may occur. The recommended dose of alteplase for acute ischemic stroke is 0.9 mg/kg (maximum of 90 mg) infused over 60 minutes, with 10% of the total dose administered as an initial IV bolus over 1 minute.3,27

The patient must be admitted to a critical care area in order to provide frequent neurologic assessments and blood pressure and cardiovascular monitoring. The clinician must be ready to recognize and manage possible complications mentioned below. The effectiveness of thrombolytic therapy in stroke is strictly associated to strict patient selection within the inclusion and exclusion criteria.

No adjunctive therapies should be given with alteplase for the management of acute ischemic stroke. Anticoagulants and antiplatelet agents may increase the risk of bleeding complications and are not recommended within 24 hours of alteplase administration.

Alteplase is a safe and effective treatment for carefully selected stroke patients presenting within 3 hours of symptoms onset.23,27,28,29 The benefit is higher if tPA is given earlier and is attributed to rescuing the area of ischemic penumbra. Although risks are associated with its use, these risks, in appropriate patients, do not outweigh the benefits.

A recent randomized study evaluated the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of an ischemic stroke in more than 800 patients. The primary end point was disability at 90 days, and the secondary end point was global outcome analysis of four neurologic and disability scores combined.30

In this study, intravenous alteplase given 3-4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke. The incidence of intracranial hemorrhage was higher in the alteplase group than in the placebo group, but mortality rates did not differ between the groups.30 Alteplase remains safe when given at 3-4.5 hours after ischemic stroke, offering an opportunity for patients who cannot be treated within the standard 3-hour time frame. Early treatment remains essential, and patients should be treated with tPA as soon as possible to maximize the benefit. The 3-hour time window for alteplase is based on findings from the NINDS trials, which reported that the benefits of tPA decrease as the duration of occlusion increases.23

An alternative regimen to systemic thrombolysis is to give a lower dose of local intra-arterial thrombolysis. No drugs currently are approved by the FDA for intra-arterial treatment of acute ischemic stroke, and such therapy is not standard. Intra-arterial thrombolysis is an option for treatment of selected patients who can be treated within 3-6 hours after symptoms onset due to occlusion of the middle cerebral artery (MCA) and who are not otherwise candidates for intravenous tPA.27,28

Thrombolytic Therapy for Peripheral Arterial Disease

Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis and may present as an obstruction of arterial blood flow to an extremity.

Low-dose intra-arterial thrombolytic therapy is being used for acute arterial occlusions. Primary fibrinolysis is the initial treatment of choice for many patients with acute peripheral arterial occlusions. The ability to perform catheter-directed thrombolysis with subsequent angioplasty and stenting has reduced the need for arterial surgery in many settings.

Patients with limb-threatening ischemia are not candidates for local fibrinolysis. Usually, it takes between 6 and 72 hours to achieve clot lysis. These patients require emergent embolectomy. Catheter-directed thrombolysis is reserved for patients with non–life-threatening limb ischemia due to in situ thrombosis of less than 14 days.31,32,33,34 Consider that patients with thrombosis for more than 30 days are not likely to respond to local fibrinolysis.

Initially, streptokinase was the most widely used agent but later was replaced by urokinase and alteplase (tPA). Other drugs that have been studied include prourokinase (not currently available), reteplase, and tenecteplase. The optimal dosage and concentration of reteplase, alteplase, and tenecteplase are still under investigation.34

Reteplase

0.5 U/h by intra-arterial infusion

Alteplase

Standard regimen: 0.05-0.1 mg/kg/h intra-arterially

High-dose regimen: 3 doses of 5 mg over 30 min, then 3.5 mg/h for up to 4 h

Urokinase

4,000 U/min until initial recanalization, then 1,000-2,000 U/min until complete lysis, all given intra-arterially

Streptokinase

5,000-10,000 U/h intra-arterially

Thrombolytic Therapy Complications

Complications of thrombolytic therapy include hemorrhage, allergic reactions, embolism, stroke, and reperfusion arrhythmias, among others. Clinicians must be prepared to handle such complications in a timely manner. The most feared complication of fibrinolysis is intracranial hemorrhage, but serious hemorrhagic complications can occur from bleeding at any site in the body.

Risk factors for hemorrhagic complications include increasing age, elevated pulse pressure, uncontrolled hypertension, recent stroke or surgery, the presence of a bleeding diathesis, and severe congestive heart failure.

Overdoses of fibrinolytic agents can cause severe hemorrhagic complications. Overdose most often occurs when a full dose of a fibrinolytic agent is given to a small patient with a low body weight.

In patients receiving fibrinolysis for AMI, the overall incidence of hemorrhagic complications is about 10%, and the incidence of intracranial hemorrhage is about 0.8%. In patients receiving fibrinolysis for acute ischemic stroke, the incidence of intracranial hemorrhage is higher, approximately 6%.

Patients receiving thrombolytic therapy for acute ischemic stroke must have constant neurologic and cardiovascular reevaluation. Blood pressure checks must be every 15 minutes for 2 hours, then every 30 minutes for 6 hours and finally every hour for 16 hours.10 Strict blood pressure monitoring is essential during and after thrombolytic treatment in order to prevent complications. If a patient has signs of neurologic deterioration, stop thrombolytic therapy and obtain an emergent CT scan. Consider immediate expert consultation.

If a patient who was treated with fibrinolytic medications develops serious bleeding complications, the first step is cessation of the fibrinolytic agent and of any anticoagulation therapy. Supportive therapy should be instituted. This often includes volume repletion and transfusion of blood factors. When possible, direct pressure should be used to control bleeding. If the patient has also been receiving heparin, protamine sulfate may be used to reverse the heparin effect.

Aminocaproic acid (Amicar) is a specific antidote to fibrinolytic agents. In adults, 4-5 g of aminocaproic acid in 250 mL of diluent is administered by infusion during the first hour of treatment, followed by a continuing infusion at the rate of 4 mL (1 g) per hour in 50 mL of diluent. The infusion would be continued for about 8 hours or until the bleeding situation has been controlled.35 Fresh frozen plasma and/or cryoprecipitate may be used to replenish fibrin and clotting factors.

Aminocaproic acid should not be given unless hemorrhage is life threatening, because it inhibits intrinsic fibrinolytic activity and can precipitate runaway thrombosis with end-organ damage at many sites. The drug worsens disseminated intravascular coagulation, including that associated with heparin-induced thrombocytopenia.

Thrombolytic Therapy in Cardiac Arrest

Several reports of adult patients have documented successful resuscitation after thrombolytic administration during cardiac arrest. In most case reports, acute pulmonary embolism or acute myocardial infarction were the suspected cause; these patients failed initially to standard CPR guidelines and ACLS protocols.36  Active CPR is clearly not a contraindication for thrombolytic therapy. Today, evidence to support the routine use of thrombolytic drugs during cardiac arrest is not sufficient. The clinician may consider it on a case-by-case basis.

Out-of-Hospital Thrombolytic Therapy

Currently, prehospital 12-lead ECG programs have been recommended for urban and rural EMS systems. Medical literature supports this recommendation because of its benefits in early diagnosis and earlier treatment. Several studies have documented the ability for trained prehospital professionals to adequately acquire STEMI with 12-lead ECGs.37

Paramedics can provide advance notification to the receiving facility when they encounter an acute coronary syndrome, being able to provide a 12-lead ECG of such patients allows the institution to prepare for reperfusion strategies. It is also recommended that EMS personnel start screening for possible thrombolytic therapy in patients who may be having a STEMI in order to further decrease the time for reperfusion.

For some years, controversy has existed regarding the administration of thrombolytic drugs in the prehospital setting. Previously, out-of-hospital fibrinolysis was only recommended when patient transport time was more than 1 hour. However, today several studies and clinical trails have demonstrated contrary. Out-of-hospital fibrinolysis is safe and reasonable. It can be performed by skilled, trained paramedics, nurses, or physicians under strict protocols. If emergency medical system (EMS) has fibrinolytic capability and the patient qualifies for therapy, prehospital fibrinolysis should be started within 30 minutes of arrival on the scene.14

For EMS systems to implement out-of-hospital thrombolytic programs, several quality standards are required. Protocols must include thrombolytic checklists, 12-lead ECG interpretation and transmission, ACLS-trained personnel, and medical direction must be available at all times. These programs should have an adequate quality evaluation process to evaluate efficacy and safety.

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Keywords

thrombolytic therapy, thrombus, thrombosis, tissue plasminogen activator, tPA, streptokinase, urokinase, alteplase, reteplase, pathophysiology of thrombosis, complications of thrombosis, thrombolytic agents, fibrinolytic agents

Contributor Information and Disclosures

Author

Wanda L Rivera-Bou, MD, FAAEM, FACEP, Assistant Professor and ACLS Training Center Director, Department of Emergency Medicine, University of Puerto Rico, School of Medicine
Wanda L Rivera-Bou, MD, FAAEM, FACEP is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American Heart Association, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Jose G Cabanas, MD, Clinical Instructor, Department of Emergency Medicine, University of North Carolina at Chapel Hill School of Medicine; Assistant Medical Director, Orange County EMS
Jose G Cabanas, MD is a member of the following medical societies: American College of Emergency Physicians, National Association of EMS Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Salvador E Villanueva, MD, FACEP, Assistant Professor, Department of Emergency Medicine, University of Puerto Rico School of Medicine
Salvador E Villanueva, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians and Puerto Rico Medical Association
Disclosure: Nothing to disclose.

Medical Editor

William G Gossman, MD, Associate Clinical Professor of Emergency Medicine, Creighton University School of Medicine; Consulting Staff, Department of Emergency Medicine, Creighton University Medical Center
William G Gossman, MD is a member of the following medical societies: American Academy of Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Gary Setnik, MD, Chair, Department of Emergency Medicine, Mount Auburn Hospital; Assistant Professor, Division of Emergency Medicine, Harvard Medical School
Gary Setnik, MD is a member of the following medical societies: American College of Emergency Physicians, National Association of EMS Physicians, and Society for Academic Emergency Medicine
Disclosure: SironaHealth Salary Management position; South Middlesex EMS Consortium Salary Management position

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

David FM Brown, MD, Assistant Professor, Division of Emergency Medicine, Harvard Medical School; Vice Chair, Department of Emergency Medicine, Massachusetts General Hospital
David FM Brown, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Acknowledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Craig F Feied, MD, and Jonathan A Handler, MD, to the development and writing of this article.

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