Continuing Education Activity

Alteplase (tPA) is a powerful thrombolytic agent used in the lysis of acute thromboembolism. FDA-approved indications for alteplase include pulmonary embolism, myocardial infarction with ST-segment elevation (STEMI), ischemic stroke when given within 3 hours of the start of symptoms, and re-establishment of patency in occluded intravenous (IV) catheters. There are also off-label indications. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, toxicity, and monitoring, of tPA therapy with agents like alteplase, so providers can direct patient therapy where they are indicated as part of the interprofessional team.

Objectives:

• Identify the indications for initiating therapy with a tPA agent such as alteplase.
• Review the mechanism of action of tissue plasminogen activators such as alteplase.
• Summarize the contraindications and adverse event profile of tPA medications such as alteplase.
• Describe interprofessional team strategies for improving care coordination and communication to properly use tPA agents like alteplase to improve patient outcomes in the varied scenarios where it can be effective.

Indications

Alteplase (tPA) is a powerful thrombolytic agent used in the lysis of acute thromboembolism.[1][2][3]

FDA-approved indications for alteplase include pulmonary embolism, myocardial infarction with ST-segment elevation (STEMI), ischemic stroke when given within 3 hours of the start of symptoms, and re-establishment of patency in occluded intravenous (IV) catheters.

Common off-label indications include:

• Treatment of deep venous thrombosis (DVT) and peripheral arterial thrombosis with local administration of a thrombolytic agent in catheter-directed thrombolysis
• Ischemic stroke when administered more than 3 hours, but no longer than 4.5 hours, after symptom onset
• Management of prosthetic valve thrombosis
• Adjunct treatment of a pediatric pleural effusion or empyema.

Mechanism of Action

Alteplase acts within the endogenous fibrinolytic cascade to convert plasminogen to plasmin by hydrolyzing the arginine-valine bond in plasminogen. The activated plasmin then degrades fibrin and fibrinogen, allowing for the dissolution of the clot and re-establishment of blood flow.[4][5]

Administration

The dosing and administration of tPA are specific to the indication.

FDA Approved Indications

Pulmonary Embolism

• 100 mg over 2 hours; may be administered as a 10 mg bolus followed by 90 mg over 2 hours

Ischemic Stroke: The only blood test that is necessary before tPA usage is the blood glucose level. If the patient is on anticoagulation like coumadin, then only we should do PT, PTT, and INR, etc. The benefit of tPA depends a lot on time. The sooner the patient receives tPA; the better are the outcomes. 

• Maximum recommended dose is 90mg 
• Patients less than or equal to 100 kg load with 0.09 mg/kg (10% of 0.9 mg/kg dose) as an IV bolus over 1 minute, followed by 0.81 mg/kg (90% of 0.9 mg/kg dose) as a continuous infusion over 60 minutes.
• Patients greater than100 kg load with 9 mg (10% of 90 mg) as an IV bolus over 1 minute, followed by 81 mg (90% of 90 mg) as a continuous infusion over 60 minutes.

STEMI

• Administer within 30 minutes of hospital arrival
• Adults greater than or equal to 67 kg get 100 mg total dosage administered as a 15 mg IV bolus, followed by 50 mg IV infused over 30 minutes, and then 35 mg IV infused over the next 60 minutes
• Adults less than 67 kg get 15 mg IV bolus, followed by 0.75 mg/kg IV (not to exceed 50 mg) infused over 30 minutes, and then 0.5 mg/kg IV (not to exceed 35 mg) over the next 60 minutes

IV Catheter Occlusion

• Instill 2 mg of alteplase in the occluded lumen and allow a 2-hour dwell time. This dose is repeatable one time if the first attempt is not successful, the use of greater than 4 mg of alteplase for this indication has not been a topic of research.

Off-Label Indications

Pediatric Pleural Effusions

• Four mg in 30 mL to 50 mL 0.9% intrapleural sodium chloride injection via chest tube and left to dwell for 1 hour as a single dose or as multiple doses 24 hours apart

Catheter-Directed Therapy

• 0.1 mg/kg/hr (maximum of 20 mg per 24 hours for up to 96 hours)

Prosthetic Valve Thrombosis

• Twenty-five mg intravenously over 25 hours repeated as needed until a total dose of 200 mg of alteplase administered or resolution is confirmable by TEE

Alteplase is administered intravenously as a bolus injection or infusion. In emergencies, it is reasonable to administer tPA through intraosseous access.

Adverse Effects

The most frequent serious adverse events associated with the administration of tPA are related to bleeding.[6][7][8]

Bleeding associated with alteplase therapy can be divided into two broad categories. Internal bleeding includes intracranial bleeding (0.4% to 15.4%), retroperitoneal bleeding (less than 1%), gastrointestinal (GI) bleeding (5%), genitourinary bleeding (4%), and respiratory bleeding. Superficial or surface bleeding is observed mainly at invaded or disturbed sites such as venous cutdowns, arterial punctures, and recent surgical intervention sites. Less serious spontaneous bleeding includes ecchymosis (1%), gingival bleeding (less than 1%), and epistaxis (less than 1%). In clinical studies of adult patients with acute ischemic stroke (n = 624), a higher incidence of intracranial bleeding, especially symptomatic intracranial bleeding, was seen in patients receiving alteplase compared to placebo (total intracranial bleeding 15.4% versus 6.4%, p < 0.01; symptomatic intracranial bleeding 8% versus 1.3%, p < 0.01). However, there was no increase in the incidence of 90-day mortality or severe disability in patients receiving alteplase. Studies indicate that the incidence of intracranial bleeding is dose-related, with the greatest percentage occurring at a dosage of 150 mg (1.3%) compared to 100 mg (0.4%). Rates of adverse events, including bleeding, correlate to the total exposure of tPA.

Cardiac dysrhythmias may occur when tPA is administered for NSTEMI and is related to the re-establishment of tissue perfusion rather than drug exposure.

Allergic reactions, including anaphylactic-type reactions, are possible following exposure to tPA. Various sources of tPA have varying levels of antigenicity. See “streptokinase” for further discussion. The rapid conversion of plasminogen to plasmin signals a complement cascade leading to mast cell degranulation and subsequent anaphylactic reaction.  

Contraindications

A 2016 update was published by the American Heart Association to guide tPA inclusion and exclusion criteria for the management of ischemic stroke. The following list includes the most recent absolute and relative contraindications for therapy as determined by the AHA.

Exclusion Criteria

• Significant head trauma or prior stroke in the previous 3 months
• Symptoms suggest subarachnoid hemorrhage
• Arterial puncture at a noncompressible site in previous 7 days
• History of previous intracranial hemorrhage
• Intracranial neoplasm, AVM, or an aneurysm
• Recent intracranial or intraspinal surgery
• Elevated blood pressure (systolic greater than 185 mmHg or diastolic greater than 110 mmHg)
• Active internal bleeding
• Acute bleeding diathesis, including but not limited to
• Platelet count less than 100 000/mm^3
• Heparin received within 48 hours resulting in abnormally elevated aPTT above the upper limit of normal
• Current use of anticoagulant with INR greater than 1.7 or PT greater than 15 seconds
• Current use of direct thrombin inhibitors or direct factor Xa inhibitors with elevated sensitive laboratory tests (e.g., aPTT, INR, platelet count, ECT, TT, or appropriate factor Xa activity assays)
• Blood glucose concentration less than 50 mg/dL (2.7 mmol/L)
• CT demonstrates multilobar infarction (hypodensity greater than a one-third cerebral hemisphere)

Relative Exclusion Criteria

Recent experience suggests that under some circumstances, with careful consideration and weighing of risk to benefit, patients may receive fibrinolytic therapy despite 1 or more relative contraindications. Consider the risk to the benefit of intravenous rtPA administration carefully if any of these relative contraindications are present:

• Only minor or quickly improving stroke symptoms (clearing automatically)
• Pregnancy
• Seizure at the onset with postictal residual neurological impairments
• Major surgery or serious trauma within prior 14 days
• Recent GI or urinary tract hemorrhage (within previous 21 days)
• Recent acute myocardial infarction (within preceding 3 months)

Monitoring

There are no therapeutic drug monitoring recommendations that pertain to the efficacy of tPA therapy. If prolonged off-label therapy is occurring in the event of catheter-directed treatment or repeated dosing in valve thrombosis, serial imaging of the thrombus is reasonable. The safety profile is best monitored by prothrombin time (PT), partial thromboplastin time (PTT), Hemoglobin, and hematocrit to assess ongoing bleeding. Of note, fibrinogen levels may be an indicator of increased bleed risk for values less than 150mg/dL.

Toxicity

There is no direct reversal agent for the potentially major bleeding that may occur during tPA therapy. Commonly employed strategies include anti-fibrinolytic therapy such as tranexamic acid or aminocaproic acid though there is no research on specific dosages. If fibrinogen levels are less than 150mg/dL, there may be added benefit from fresh frozen plasma or cryoprecipitate. Cryoprecipitate should be used without any delay and monitor the fibrinogen level closely.  

Enhancing Healthcare Team Outcomes

There is no longer any question about the effectiveness of thrombolytic agents for the treatment of several medical disorders, but nurses, pharmacists, and radiologists must be fully aware of their indications and contraindications. For these agents to be effective, not only do they require administration within a certain timeframe, but one also has to ensure that the patient has no condition that contraindicates the therapy. Also, the nurse should educate the patient about the procedure, the need to remain at bed rest for several hours after the procedure, and the need to constantly monitor for bleeding.  Plus, the pharmacist must be familiar with the recent novel anticoagulants and any possible interactions with the thrombolytic drugs. Only through close communication and constant vigilance between the various healthcare professionals can the serious complications of these drugs be prevented. [2][9] [Level V]

Outcomes

There have been many clinical trials undertaken to determine the effectiveness of thrombolytic agents in patients with acute myocardial infarction, pulmonary embolism, acutely ischemic limb, and an embolic stroke. When used to treat acute MI, embolic stroke, and pulmonary embolism, the outcomes are fair to good. The biggest drawback to this therapy is a patient delay in arriving at the emergency room or a delay in diagnosis. These drugs have saved many lives and are cost-effective and reduce hospital stays.[10][11][7] [Level II]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Grossberg JA, Rebello LC, Haussen DC, Bouslama M, Bowen M, Barreira CM, Belagaje SR, Frankel MR, Nogueira RG. Beyond Large Vessel Occlusion Strokes: Distal Occlusion Thrombectomy. Stroke. 2018 Jul;49(7):1662-1668. [PubMed: 29915125]

2.

Benoit JL, Khatri P, Adeoye OM, Broderick JP, McMullan JT, Scheitz JF, Vagal AS, Eckman MH. Prehospital Triage of Acute Ischemic Stroke Patients to an Intravenous tPA-Ready versus Endovascular-Ready Hospital: A Decision Analysis. Prehosp Emerg Care. 2018 Nov-Dec;22(6):722-733. [PubMed: 29847193]

3.

Mac Grory B, Yaghi S. Updates in Stroke Treatment. R I Med J (2013). 2018 Mar 01;101(2):30-33. [PubMed: 29490322]

4.

Imbarrato G, Bentley J, Gordhan A. Clinical Outcomes of Endovascular Thrombectomy in Tissue Plasminogen Activator versus Non-Tissue Plasminogen Activator Patients at Primary Stroke Care Centers. J Neurosci Rural Pract. 2018 Apr-Jun;9(2):240-244. [PMC free article: PMC5912031] [PubMed: 29725176]

5.

Knecht T, Story J, Liu J, Davis W, Borlongan CV, Dela Peña IC. Adjunctive Therapy Approaches for Ischemic Stroke: Innovations to Expand Time Window of Treatment. Int J Mol Sci. 2017 Dec 19;18(12) [PMC free article: PMC5751355] [PubMed: 29257093]

6.

Liu H, Zheng H, Cao Y, Pan Y, Wang D, Zhang R, You S, Zhang X, Li S, Tong X, Liu CF, Wang Y. Low- versus Standard-Dose Intravenous Tissue-Type Plasminogen Activator for Acute Ischemic Stroke: An Updated Meta-Analysis. J Stroke Cerebrovasc Dis. 2018 Apr;27(4):988-997. [PubMed: 29224744]

7.

Gilliland C, Shah J, Martin JG, Miller MJ. Acute Limb Ischemia. Tech Vasc Interv Radiol. 2017 Dec;20(4):274-280. [PubMed: 29224661]

8.

Vivien D. Can the benefits of rtPA treatment for stroke be improved? Rev Neurol (Paris). 2017 Nov;173(9):566-571. [PubMed: 28797689]

9.

Kepplinger J, Barlinn K, Deckert S, Scheibe M, Bodechtel U, Schmitt J. Safety and efficacy of thrombolysis in telestroke: A systematic review and meta-analysis. Neurology. 2016 Sep 27;87(13):1344-51. [PubMed: 27566746]

10.

Aoki J, Suzuki K, Suda S, Okubo S, Mishina M, Nishiyama Y, Sakamoto Y, Kimura K. In Hyperacute Recanalization Therapy, Early Hospital Arrival Improves Outcome in Patients with Large Artery Occlusion. Eur Neurol. 2018;79(5-6):335-341. [PubMed: 29986341]

11.

Man S, Zhao X, Uchino K, Hussain MS, Smith EE, Bhatt DL, Xian Y, Schwamm LH, Shah S, Khan Y, Fonarow GC. Comparison of Acute Ischemic Stroke Care and Outcomes Between Comprehensive Stroke Centers and Primary Stroke Centers in the United States. Circ Cardiovasc Qual Outcomes. 2018 Jun;11(6):e004512. [PMC free article: PMC5978771] [PubMed: 29794035]

Disclosure: Robert Hughes declares no relevant financial relationships with ineligible companies.

Disclosure: Prasanna Tadi declares no relevant financial relationships with ineligible companies.

Disclosure: Pradeep Bollu declares no relevant financial relationships with ineligible companies.