TPA Therapy


Article Author:
Robert Hughes
Prasanna Tadi


Article Editor:
Pradeep Bollu


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
3/22/2019 1:12:14 AM

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 should be done 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 tPA is given, 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 may be repeated one time if the first attempt is not successful, use of greater than 4 mg of alteplase for this indication has not been studied

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 confirmed by TEE

Alteplase is administered intravenously as a bolus injection or infusion. In emergency situations, 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 are related to the total exposure of tPA.

Cardiac dysrhythmias may be noted when tPA is administered for NSTEMI and is related to 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/mm3
  • 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 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 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 therapy 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 no specific dosages have been studied. 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 it is vital that nurses, pharmacists, and radiologists be fully aware of their indications and contraindications. For these agents to be effective not only do they have to be administered within a certain time period, but one also has to ensure that the patient has no condition that contraindicates the therapy. In addition, 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

Many clinical trials have been 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 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)


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TPA Therapy - Questions

Take a quiz of the questions on this article.

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A 65 year old male is admitted to the emergency department with left hemiparesis but is awake and alert. CT scan shows no intracranial hemorrhage or tumor and the infarct area is not well visualized at this time. The patient's symptoms developed approximately 2 hours ago. There is no past history of stroke. He had recent arthroscopic knee surgery. He is given tPA. Which of the following would NOT be a contraindication to this therapy?



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An elderly female with a prior history of type 2 diabetes mellitus and hypertension is brought promptly to the emergency department by her husband because he noticed her slurring her words. The probability is that she is having a stroke and quick action is needed. Which of the following would absolutely contraindicate thrombolytic therapy with tPA?



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What medication is demonstrated mortality reduction in GUSTO I trial?



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Which of the following did the Global Utilization of Streptokinase and TPA for Occluded Arteries-I trial conclude?



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Which of the following can be used to treat an overdose of tissue plasminogen activator (tPA)?



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Which of the following medications can break up a blood clot?



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Prior to administering tissue plasminogen activator,TPA, it is most important to obtain which blood test?



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TPA Therapy - References

References

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     [PubMed]
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. Prehospital emergency care : official journal of the National Association of EMS Physicians and the National Association of State EMS Directors. 2018 May 30     [PubMed]
Mac Grory B,Yaghi S, Updates in Stroke Treatment. Rhode Island medical journal (2013). 2018 Mar 1     [PubMed]
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. Journal of neurosciences in rural practice. 2018 Apr-Jun     [PubMed]
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. International journal of molecular sciences. 2017 Dec 19     [PubMed]
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. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2018 Apr     [PubMed]
Gilliland C,Shah J,Martin JG,Miller MJ Jr, Acute Limb Ischemia. Techniques in vascular and interventional radiology. 2017 Dec     [PubMed]
Vivien D, Can the benefits of rtPA treatment for stroke be improved? Revue neurologique. 2017 Nov     [PubMed]
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     [PubMed]
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. European neurology. 2018     [PubMed]
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. Circulation. Cardiovascular quality and outcomes. 2018 Jun     [PubMed]

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