Tissue Plasminogen Activator


Article Author:
Talha Jilani


Article Editor:
Abdul Siddiqui


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Dustin Constant
Donald Kushner


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Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
3/26/2019 11:42:22 PM

Indications

Tissue plasminogen activator (tPA) is classified as a serine protease (enzymes that cleave peptide bonds in proteins) and is thus one of the essential components of the dissolution of blood clots. Its primary function includes catalyzing the conversion of plasminogen to plasmin, the primary enzyme involved in dissolving blood clots.

Recombinant biotechnology has allowed tPA to be manufactured in labs, and these synthetic products are called recombinant tissue plasminogen activator (rtPA). Examples of these drugs include alteplase, reteplase, and tenecteplase. These drugs have undergone various modifications to amplify their pharmacokinetic and pharmacodynamic properties, especially to prolong their short half-life in the circulation and further increase their fibrin specificity, to prevent an unwanted fibrinolytic state.  

Indications for the use of tPA include the following:

  1. Ischemic stroke (most common) in patients presenting to treating facility within 3 hours (4.5 hours in certain, eligible people) after the onset of symptoms.[1][2]
  2. Myocardial Infarction if there would be a delay of more than 1 to 2 hours before percutaneous transluminal coronary angioplasty.[3] 
  3. Pulmonary embolism in massive pulmonary embolisms, causing severe instability due to high pressure on the heart.[4] 
  4. Thrombolysis (e.g., deep vein thrombosis).[5]

Definitions

  • Alteplase is the normal, human plasminogen activator and is FDA-approved for the management of patients with ischemic stroke, myocardial infarction with ST-elevation (STEMI), acute massive pulmonary embolism, and those with central venous access devices (CVAD).[6][7]  
  • Reteplase is a modified form of human tPA with similar effects but a faster onset and longer duration of action. It is currently FDA-approved for the management of acute myocardial infarction. Preferred over alteplase due to its longer half-life, which allows it to be given as a bolus injection rather than through an infusion like Alteplase.[8][9]
  • Tenecteplase is another modified version of tPA with a longer half-life. It is indicated for the management of acute myocardial infarction.[10]

Mechanism of Action

tPA is a thrombolytic (i.e., it breaks up blood clots) formed by aggregation of activated platelets into fibrin meshes by activating plasminogen. More specifically, it cleaves the zymogen plasminogen at its Arg561-Val562 peptide bond to form the serine protease, plasmin. Plasmin, an endogenous fibrinolytic enzyme, breaks the cross-links between fibrin molecules, which are the structural support of the blood clot, and its activity is extremely short-lived. This is because alpha 2-antiplasmin, an abundant inhibitor of plasmin, quickly inactivates it and restricts the action of plasmin to the vicinity of the clot.

The following sequence summarizes the action of tPA:

  1. tPA attaches to the fibrin on the clot surface.
  2. It activates the fibrin-bound plasminogen.
  3. Plasmin is subsequently cleaved from the plasminogen affiliated with the fibrin.
  4. The molecules of fibrin are broken up by the plasmin, and the clot dissolves.

Plasminogen activator inhibitor 1 (PAI 1) eventually terminates the catalytic activity of tPA by binding to it, and this inactive complex (PAI 1-bound tPA) is removed from the circulation by the liver, more specifically via the scavenger receptor, LDL receptor-related protein 1 (LRRP1). In the nervous system, a neuronal-specific inhibitor of tPA, neuroserpin, acts similarly to PAI 1, and the inactive tPA-neuroserpin complexes are internalized by the LRRP1 for removal from circulation.[11][12][13]

Administration

Alteplase

Alteplase is administered intravenously. However, for catheter clearance, it is administered directly into the catheter.

Acute myocardial infarction

For the management of acute myocardial infarction in adults, administer alteplase as soon as possible after the onset of symptoms. The patient's weight determines the dose to be administered, which is not to exceed 100 mg irrespective of the selected administration method (accelerated infusion preferred by the AHA/ACCA or slower, 3-hour infusion as per manufacturer's labeling). 

Accelerated infusion (1-1/2 hr):

  • For patients who weigh less than or equal to 67 kg: 15 mg IVP bolus is administered over 1 to 2 minutes, followed by 0.75 mg/kg intravenous (IV) infusion given over 30 minutes (not to exceed 50 mg), followed by 0.5 mg/kg IV over the following 60 minutes (not to exceed 35 mg over 1 hour).
  • For patients who weigh greater than 67 kg: (A total of 100 mg is infused over 1.5 hours) 15 mg intravenous pyelogram (IVP) bolus is administered over 1 to 2 minutes, followed by 50 mg IV infusion during the next 30 minutes, and then the remaining 35 mg over the following 60 minutes.  

 3-hour infusion:

  • For patients who weigh less than 65 kg: A dose of 0.075 mg/kg IVP bolus is administered over 1 to 2 minutes, followed by a 0.675 mg/kg infusion over the rest of the first hour, and, lastly, 0.25 mg/kg IV over the next 2 hours. 
  • For patients who weigh greater than or equal to 65 kg: A 100 mg total dose is infused over 3 hours. Six to 10 mg IVP bolus is given over 1 to 2 minutes, followed by 50 to 54 mg over the rest of the first hour (i.e., 60 mg in the first hour including 6 to 10 mg bolus), and then 20 mg/hr over the next 2 hours.

Pulmonary embolism

  • Infuse 100 mg IV over 2 hours. Institute parenteral anticoagulation towards the end of or immediately following the alteplase infusion when the thrombin time or PTT returns to less than two times the reference range.

Acute ischemic stroke

  • A dose of 0.9 mg/kg is given through IV infusion, not to exceed 90 mg total dose. Ten percent of the total dose is administered initially as an IV bolus over 1 minute, and the remaining is gradually infused over 60 minutes. 

  Dosing considerations for acute ischemic stroke:

  1. Intracranial hemorrhage should be excluded as the primary cause of stroke before initiation of treatment.
  2. Administer alteplase as soon as possible but ideally within 3 hours after onset of symptoms.
  3. Monitor and control the blood pressure during and after administration.
  4. In patients who have not recently used oral anticoagulants or heparin, treatment can be started before the availability of coagulation study test results.
  5. Discontinue if the pretreatment INR is greater than 1.7 or the aPTT is elevated.

Arterial thrombosis and embolism

  • 0.05-0.1 mg/kg/hr is given by transcatheter intra-arterial infusion for about 1 to 8 hours or until the lysis of the thrombus.

Central venous catheter occlusion 

  • 1 mg/mL, intracatheter
  • Adult patients who weigh less than 30 kg: Administer 110% of the lumen volume of the catheter (intracatheter), not exceeding 2 mg/2 mL; then retain in the catheter for around 0.5 to 2 hours; can instill a second dose if the catheter remains occluded.
  • Patients who weigh greater than or equal to 30 kg: Administer 2 mg/2 mL; retain in the catheter for around 0.5 to 2 hours; can instill a second dose if the catheter remains occluded.  
  • Pediatric patients who weigh less than 30 kg: Administer 110% of the measured internal lumen volume of the catheter with alteplase; not exceeding 2 mg/2 mL.
  • Pediatric patients who weigh greater than or equal to 30 kg: Instill 2 mg of alteplase into the occluded catheter.

After 30 minutes of dwell time, the function of the catheter is assessed by attempting to aspirate blood; if you cannot aspirate blood 120 minutes after dwell time, a second dose may be administered and the process is repeated.

If the catheter function is restored, aspirate around 4 to 5 mL of blood in patients who weigh 10 kg or more (aspirate around 3 mL if the patient weighs less than 10 kg) to remove the drug and the residual clot. Then gently irrigate with 0.9% NaCl. 

Pleural Catheter or Chest tube drainage

  • Concurrent TPA and human Deoxyribonuclease (DNAse) can be administered intrapleurally through the chest tube or pleural catheters. It has shown to assist with better drainage of thick loculated effusions like empyema. 

Reteplase

  • Reteplase is administered intravenously as soon as possible after the onset of symptoms.
  • Adults patients: Initially administer 10 units IV bolus (over 2 minutes) with the second dose given 30 minutes after first (for a total cumulative dose of 20 units). An IV line is used to administer the bolus injection, and no other medication should be simultaneously injected or infused through this IV line.
  • Pediatric patient safety and efficacy is not established.

Tenecteplase

  • Tenecteplase is administered intravenously as soon as possible after the onset of symptoms.
  • In adult patients, administer a 30 to 50 mg IV bolus over 5 seconds one time (based on weight): 30 mg for patients weighing less than 60 kg; 35 mg for patients weighing 60-70 kg; 40 mg for patients weighing 70-80 kg; 45 mg for patients weighing 80-90 kg; 50 mg for patients weighing more than 90 kg.
  • Pediatric patient safety and efficacy not established.

Adverse Effects

Alteplase: Adverse effects are seen in 1% to 10% of the people who are administered alteplase. The most common adverse effect is bleeding, and the most serious is a stroke. Other side effects include bruising, pulmonary edema, arterial embolism, deep vein thrombosis, orolingual angioedema, intracranial hemorrhage, shock, hypersensitivity, nausea/vomiting, seizure, ischemic stroke, thromboembolism, and sepsis.[14][15]

Tenecteplase: Adverse effects are seen in greater than 10% of the patients who are administered tenecteplase. The most common is minor bleeding. Other adverse effects include fever, myocardial infarction, reperfusion arrhythmias, nausea/vomiting, edema, allergic reaction, and cholesterol embolization.[14][15][16]

Reteplase: As with other tPAs, the most common adverse effect seen with reteplase is bleeding. Other observed adverse effects include reperfusion arrhythmias, hypotension, nausea/vomiting, cardiogenic shock, muscle pain, allergic reaction, a reaction at injection site, anemia, gastrointestinal/urogenital bleed, intracranial hemorrhage, cholesterol embolization.[15][17]

Contraindications

1. Do not administer tPA for the treatment of acute ischemic stroke in the following scenarios:

  • If the risk of bleeding and serious complications are greater than the potential benefit of tPA therapy. These include patients with current intracranial hemorrhage (ICH), subarachnoid hemorrhage, and those who have active internal bleeding. 
  • If the patient underwent recent (less than 3 months) intracranial or intraspinal surgery or suffered a serious head trauma. 
  • Evidence of intracranial conditions that may possibly increase the risk of bleeding. 
  • Bleeding diathesis (hemorrhagic diathesis).
  • Patients with severe uncontrolled hypertension.[18][19][20]

2. Do not administer tPA in the management of acute myocardial infarction or pulmonary embolism in the following:

  • If the risk of bleeding is greater than any potential benefit. This includes active internal bleeding; patients with a recent history of stroke. 
  • Recent (within three months) intracranial or intraspinal surgery or serious head trauma. 
  • Presence of intracranial pathologies that may increase the risk of bleeding. 
  • Bleeding diathesis (hemorrhagic diathesis).
  • Current severe uncontrolled hypertension.[18]

3. Do not administer tPA in any patient who had a hypersensitivity reaction to a previous dose of tPA (urticarial or anaphylactic reactions).[18][21]

Monitoring

Monitoring During Therapy with tPA

  • Perform regular neurologic assessment on the patient.
  • Check thoroughly for major or minor bleeding.
  • Continuously monitor the blood pressure of the patient.
  • Check for the signs and symptoms of ICH.
  • Check for the signs of orolingual angioedema.
  • Discontinue tPA infusion and order an emergency CT scan if the patient develops a severe headache, severe hypertension, nausea/vomiting, or has a worsening neurologic examination.
  • If a hypersensitivity reaction occurs in the patient, stop the tPA administration and immediately initiate supportive therapy with antihistamines and corticosteroids.[22][23]

Monitoring After Therapy with tPA

  • Follow up the patient to monitor for any neurologic deterioration.
  • Check for any major or minor bleeding.
  • Monitor and strictly control blood pressure.
  • Order a follow-up CT scan or MRI at least 24 hours before initiating anticoagulants or antiplatelet agents.
  • Continue to monitor for hypersensitivity and signs of orolingual angioedema.[22][23][24]

Toxicity

The drug used to reverse tPA toxicity is aminocaproic acid, an FDA-approved drug for the management of acute bleeding caused by increased fibrinolytic activity. It acts as an effective inhibitor for proteolytic enzymes like plasmin, which is the primary enzyme responsible for fibrinolysis.[25][26]  

Drug Interactions

Monitor closely with any drug that causes anticoagulation as there is an increased risk of bleeding.

  • Defibrotide: Through pharmacodynamic synergism, defibrotide increases the effects of tPA drugs and is thus contraindicated.
  • Prothrombin complex concentrate, human: This can cause pharmacodynamic antagonism of the tPA drugs.
  • Apixaban: Apixaban and tPA drugs increase anticoagulation and can lead to an increased bleeding risk.
  • Nitroglycerin: This could decrease the serum concentration of tPA drugs.
  • Salicylates: These could enhance the toxic effects of thrombolytic drugs. Monitor therapy as there is an increased risk of bleeding.

Enhancing Healthcare Team Outcomes

tPA as a significant risk of causing complications as well as helping the patient. An interprofessional team consisting of the nurses, pharmacist, and physicians should monitor patients received this drug to provide the safest care and best patient outcome. [Level V]


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Tissue Plasminogen Activator - Questions

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A 69-year-old comes into the hospital with chest pain and is started on tissue plasminogen activator. The patient does well and is discharged after two days. What is alteplase?



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What is the best medication to improve perfusion of the heart six hours after a myocardial infarction?



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A 66-year-old is admitted via the emergency department with chest pain. ECG confirms a lateral wall MI. It is decided to use a lytic agent in this patient. The most likely agent is:



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What medication should be used to perfuse the heart less than 12 hours after myocardial infarction?



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Which condition is not treated with fibrinolytic therapy?



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A 69 year old comes in to the hospital with chest pain and is started on tPA. The patient does well and is discharged after 2 days. How is tPA best described?



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When administering tissue plasminogen activator (TPA), which of the following is unlikely?



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In which disorder is tissue plasminogen activator contraindicated?



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The provider should monitor most closely for which of the following after a 59-year-old patient receives TPA for an acute myocardial infarction?



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Which of the following is a contraindication to administration of tPA to a 66-year-old patient with myocardial infarction?



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Tissue plasminogen activator (tPA) is recommended for many patients with an acute myocardial infarction (MI). After the onset of symptoms, when should It should be administered?



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Which medication is most commonly co-administered with tissue plasminogen activator (t-PA)?



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Which medication causes lysis of blood clots?



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What is recombinant alteplase?



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A 65-year-old obese female presents with sudden onset of right arm weakness, loss of vision, and slurred speech which started 60 minutes ago. An emergency CT scan reveals that she most likely has an ischemic infarct. How soon should tissue plasminogen activator be administered to be effective?



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A 75-year-old man presents with new onset right-sided facial weakness and slurring of his speech. He reports that he has been sick for the last several days with cold-like symptoms. His prior medical history is significant for poorly controlled diabetes mellitus type 2 and a remote history of alcohol use disorder. The patient is taken back for imaging. CT scan shows no acute bleeding abnormality. The patient is admitted and diagnosed with a cerebral vascular accident. He is admitted and administered recombinant tissue plasminogen activator (rtPA), leading to gradual resolution of his symptoms. Approximately 4 hours later the man begins to develop a rapidly progressing right sided weakness, neck stiffness, and progressive confusion. What is the most likely diagnosis?



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A 65-year-old man comes into the emergency department with recent onset left arm and facial weakness. The symptoms began abruptly approximately 45 minutes ago. The patient has a history of chronic uncontrolled hypertension and diabetes mellitus. He is not on any medications and has not seen a physician for over ten years and beyond today's complaint has been in a good state of health. The vitals are 148/91, temp: 37 C, heart rate: 85, and respirations: 14. The man is taken for head CT without contrast which when reviewed by the radiologist shows a bright intensity in the periventricular space. Which of the following are contraindications to tPA use in this patient?



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A 65-year-old woman presents to the emergency department within 5 hours of new onset right facial and arm weakness. Temp: 98.6 C, Pulse: 76 bpm, and BP: 150/95 mmHg, CT scan of the head is unrevealing. Lab values are within normal limits. The patient takes no medications. Which of the following is the best treatment for this patient at this time?



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Tissue Plasminogen Activator - References

References

Gravanis I,Tsirka SE, Tissue-type plasminogen activator as a therapeutic target in stroke. Expert opinion on therapeutic targets. 2008 Feb;     [PubMed]
Heiferman DM,Li DD,Pecoraro NC,Smolenski AM,Tsimpas A,Ashley WW Jr, Intra-Arterial Alteplase Thrombolysis during Mechanical Thrombectomy for Acute Ischemic Stroke. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2017 Dec     [PubMed]
Rogers SD,Riemersma LB,Clements SD, Tissue plasminogen activator: an evaluation of clinical efficacy in acute myocardial infarction. Pharmacotherapy. 1987     [PubMed]
Niedermeyer J,Meissner E,Fabel H, [Thrombolytic therapy in pulmonary embolism. Indications and therapeutic strategies]. Zeitschrift fur die gesamte innere Medizin und ihre Grenzgebiete. 1993 Jun-Jul     [PubMed]
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