What is the role of Alteplase (tissue plasminogen activator) in the management of acute ischemic stroke in adults?

Alteplase in Acute Ischemic Stroke

Primary Recommendation

Alteplase (0.9 mg/kg, maximum 90 mg) is the standard of care for acute ischemic stroke and should be administered within 4.5 hours of symptom onset to eligible patients, with 10% given as an IV bolus over 1 minute and 90% infused over 60 minutes. 1, 2

Time Windows and Eligibility

0-3 Hour Window

• All eligible patients should receive alteplase within 3 hours of symptom onset, regardless of age (including patients >80 years) or stroke severity. 1, 2
• This includes patients with severe stroke symptoms despite increased hemorrhagic transformation risk, as clinical benefit remains proven. 1
• Treatment should be initiated as rapidly as possible, with door-to-needle time <60 minutes in 90% of patients and optimal median of 30 minutes. 2

3-4.5 Hour Window

• Alteplase is recommended for patients ≤80 years without both diabetes AND prior stroke, NIHSS ≤25, not on oral anticoagulants, and without imaging showing >1/3 MCA territory involvement. 1, 2
• Patients >80 years presenting in this window can be treated safely and effectively. 1
• The benefit for very severe strokes (NIHSS >25) in this window remains uncertain. 1

Critical Dosing Protocol

The stroke dosing protocol differs critically from myocardial infarction dosing and using the wrong protocol is potentially harmful. 1, 2

• Total dose: 0.9 mg/kg (maximum 90 mg total) 1, 2
• Bolus: 10% of total dose (0.09 mg/kg) IV push over exactly 1 minute 1, 2
• Infusion: 90% of total dose (0.81 mg/kg) IV infusion over 60 minutes 1, 2

Pre-Treatment Requirements

Blood Pressure Management

• BP must be lowered safely to <185/110 mmHg before initiating alteplase. 1, 2
• Assess BP stability before starting treatment. 1

Laboratory Parameters

• Glucose >50 mg/dL is required; treatment may be reasonable if initially <50 or >400 mg/dL but subsequently normalized. 1
• Platelets must be ≥100,000/mm³ 2
• INR must be ≤1.7 and PT <15 seconds 1, 2
• aPTT must be ≤40 seconds 2

Imaging Requirements

• Non-contrast CT must exclude intracranial hemorrhage before administration. 1, 2
• Alteplase should be initiated immediately after CT confirms no hemorrhage rather than delaying for additional workup. 2
• Extensive regions of clear hypoattenuation (obvious hypodensity representing irreversible injury) contraindicate treatment. 1

Absolute Contraindications

Do not administer alteplase in the following situations: 1, 2

• Evidence of intracranial hemorrhage on CT 1, 2
• Ischemic stroke within 3 months 1, 2
• Severe head trauma within 3 months 1, 2
• History of intracranial hemorrhage 2
• Active internal bleeding 2
• GI or urinary tract hemorrhage within 21 days 2
• Infective endocarditis (increased intracranial hemorrhage risk) 1
• Known or suspected aortic arch dissection 1
• Intra-axial intracranial neoplasm 1

Antiplatelet and Anticoagulant Considerations

Prior Antiplatelet Use

• Patients on antiplatelet monotherapy (e.g., aspirin alone) should receive alteplase as benefits outweigh small increased sICH risk. 1
• Patients on dual antiplatelet therapy (e.g., aspirin + clopidogrel) should receive alteplase as benefits outweigh probable increased sICH risk. 1

Anticoagulation

• Patients on DOACs should NOT routinely receive alteplase. 1, 2
• In comprehensive stroke centers with DOAC level testing and reversal agents, thrombolysis may be considered with hematology consultation. 1
• Patients on warfarin with INR ≤1.7 and PT <15 seconds may receive alteplase. 1, 2
• Recent LMWH use within 24 hours is a contraindication. 2

Post-Alteplase Antiplatelet Management

• Hold ALL antiplatelet agents for 24 hours after alteplase administration. 2
• Initiate antiplatelet therapy only after 24-hour post-thrombolysis imaging excludes intracranial hemorrhage. 2
• Glycoprotein IIb/IIIa receptor inhibitors should NOT be administered concurrently with alteplase. 1

Special Clinical Scenarios

Mild Stroke Symptoms

• Within 0-3 hours, treatment of mild nondisabling symptoms may be considered but requires weighing risks versus benefits. 1
• For 3-4.5 hour window, alteplase may be reasonable for mild strokes but evidence is less certain. 1

Rapidly Improving Symptoms

• Alteplase is reasonable for patients with moderate-to-severe stroke who improve early but remain moderately impaired and potentially disabled. 1

Preexisting Disability

• Preexisting disability (mRS ≥2) does not independently increase sICH risk but may result in less neurological improvement. 1
• Treatment may be reasonable considering quality of life, social support, patient/family preferences, and goals of care. 1

Seizure at Onset

• Alteplase is reasonable if evidence suggests residual impairments are from stroke rather than postictal phenomenon. 1

Extracranial Cervical Dissection

• Alteplase is reasonably safe and probably recommended for stroke associated with extracranial cervical arterial dissection within 4.5 hours. 1

Intracranial Arterial Dissection

• Risk and benefit remain uncertain and not well established. 1

Unruptured Intracranial Aneurysm

• Administration is reasonable for small or moderate-sized (<10 mm) unruptured, unsecured aneurysms. 1
• Risk with giant unruptured aneurysms is uncertain. 1

End-Stage Renal Disease

• Alteplase is recommended for patients on hemodialysis with normal aPTT. 1

Recent Procedures

• Lumbar puncture within 7 days: alteplase may be considered. 1
• Major surgery within 14 days (non-head): may be carefully considered, weighing surgical bleeding risk against stroke disability. 1
• Arterial puncture of noncompressible vessel within 7 days: safety and efficacy uncertain. 1

Menstruation

• Alteplase is probably indicated for menstruating women without menorrhagia history, though patients should be warned of potentially increased menstrual flow. 1
• May be considered for recent/active menorrhagia without significant anemia or hypotension. 1

Hemorrhagic Complications Management

Symptomatic Intracranial Hemorrhage

• Occurs in approximately 2-3% of treated patients. 1, 3, 4
• There is insufficient evidence to support routine use of cryoprecipitate, FFP, prothrombin complex concentrates, tranexamic acid, factor VIIa, or platelet transfusions for alteplase-associated bleeding. 1
• Use of these agents should be decided case-by-case. 1

Angioedema

• Manage with staged response using antihistamines, glucocorticoids, and standard airway management per local protocol. 1, 2

Endovascular Thrombectomy Integration

• Patients eligible for both alteplase and EVT should receive alteplase, which can be initiated while simultaneously preparing for EVT. 1
• EVT is indicated for patients who received alteplase and those ineligible for alteplase. 1
• Eligible patients should receive EVT within 6 hours of symptom onset (arterial access within 6 hours). 1

Critical Pitfalls to Avoid

1. Never use the myocardial infarction dosing protocol for stroke—this is incorrect and potentially harmful. 1, 2
2. Do not delay treatment for "perfect" workup when within time window; treat based on non-contrast CT alone. 2
3. Do not administer alteplase to DOAC patients without specialized testing and reversal agent availability. 1, 2
4. Do not start antiplatelet agents until 24-hour post-treatment imaging excludes hemorrhage. 2
5. Do not treat beyond 4.5 hours as this increases mortality and reverses risk-benefit balance. 3