What are the criteria for thrombolysis with alteplase (tissue plasminogen activator) in patients with acute ischemic stroke?

Stroke Thrombolysis Criteria

IV alteplase (0.9 mg/kg, maximum 90 mg) is indicated for acute ischemic stroke patients within 4.5 hours of symptom onset who meet specific inclusion criteria and have no absolute contraindications. 1, 2

Time Windows and Eligibility

Standard Window (0-3 hours)

• All eligible patients should receive IV alteplase within 3 hours of symptom onset or last known well 1, 2
• Age ≥18 years 2
• Measurable neurological deficit on examination 2
• Even patients with mild symptoms may be considered if potentially disabling 3, 2
• Patients with extensive early ischemic changes (>1/3 MCA territory) can still be treated within 3 hours 1

Extended Window (3-4.5 hours)

• IV alteplase is effective and recommended for patients presenting 3-4.5 hours after onset 4
• Additional exclusions apply: age >80 years, oral anticoagulant use regardless of INR, NIHSS >25, or history of both stroke and diabetes 5
• For patients >80 years presenting in this window, alteplase is safe and effective despite older exclusion criteria 3, 1

Wake-Up Stroke and Unknown Onset

• For patients with unknown onset time or wake-up stroke >4.5 hours from last known well, IV alteplase can be given within 4.5 hours of symptom recognition if MRI shows DWI-FLAIR mismatch 1
• This represents salvageable tissue with recent ischemia 1

Extended Window Beyond 4.5 Hours (Emerging Evidence)

• A 2025 randomized trial (HOPE) demonstrated that alteplase administered 4.5-24 hours after onset in patients with salvageable tissue on perfusion imaging increased functional independence (40% vs 26%, P=0.004) 6
• This approach requires perfusion imaging showing salvageable tissue and no initial plan for thrombectomy 6
• Symptomatic intracranial hemorrhage was higher (3.8% vs 0.5%) but mortality was unchanged 6
• Current AHA guidelines do not yet incorporate this evidence, as they predate this trial 1

Absolute Contraindications

Hemorrhage Risk

• CT or MRI showing intracranial hemorrhage 2
• History of intracranial hemorrhage 3, 2
• Active internal bleeding 2
• Subarachnoid hemorrhage 3
• GI malignancy or GI bleeding within 21 days 3

Recent Procedures/Trauma

• Intracranial or intraspinal surgery within 3 months 3, 2
• Serious head trauma within 3 months 3, 2
• Ischemic stroke within 3 months 3

Coagulation Abnormalities

• INR >1.7 3, 2
• aPTT >40 seconds 3
• PT >15 seconds 3
• Platelet count <100,000/mm³ 3, 2
• Treatment dose LMWH within 24 hours 3
• Direct oral anticoagulants (DOACs) within 48 hours with elevated sensitive laboratory tests 3, 2

Other Absolute Contraindications

• Blood pressure persistently >185/110 mmHg despite treatment 2
• Blood glucose <50 mg/dL 3, 2
• Extensive regions of clear hypoattenuation on CT (>1/3 cerebral hemisphere) 3, 2
• Infective endocarditis 3
• Aortic arch dissection 3
• Intra-axial intracranial neoplasm 3

Relative Considerations and Special Situations

Anticoagulation

• Warfarin use with INR ≤1.7 and PT <15 seconds may be reasonable 3
• DOACs: alteplase should not be given unless appropriate laboratory tests are normal or >48 hours since last dose with normal renal function 3

Stroke Severity

• Mild stroke (NIHSS <5): may be considered within 3 hours if symptoms potentially disabling 3, 2
• Very severe stroke (NIHSS >25) in 3-4.5 hour window: benefit uncertain 3

Preexisting Conditions

• Preexisting disability (mRS ≥2) or dementia: may be reasonable, considering quality of life, social support, and patient/family preferences 3
• Seizure at stroke onset: reasonable if residual deficits are from stroke, not postictal 3, 2
• 1-10 cerebral microbleeds on prior MRI: may be treated 2

Glucose Abnormalities

• Initial glucose <50 or >400 mg/dL that is subsequently normalized may be reasonable 3
• Hyperglycemia >11.1 mmol/L significantly increases hemorrhage risk 5

Recent Procedures

• Lumbar puncture within 7 days: may be considered 3
• Major surgery within 14 days: may be considered, weighing surgical hemorrhage risk against stroke disability 3
• Arterial puncture of noncompressible vessel within 7 days: uncertain safety 3

Early Improvement

• Patients with moderate-severe stroke showing early improvement but remaining moderately impaired should still receive alteplase 3

Administration Protocol

Dosing

• 0.9 mg/kg body weight (maximum 90 mg total) 1, 2, 5
• 10% as IV bolus over 1 minute 1, 2, 5
• Remaining 90% infused over 60 minutes 1, 2, 5

Time Targets

• Door-to-needle time <60 minutes in 90% of patients, with median target of 30 minutes 1, 2
• Only blood glucose assessment must precede administration 1, 5
• Other tests (CBC, electrolytes, creatinine, INR, aPTT, troponin, ECG) should be obtained but not delay treatment 1

Blood Pressure Management

• BP must be lowered to <185/110 mmHg before initiating thrombolysis 1, 2, 5

Integration with Mechanical Thrombectomy

Key Principles

• Eligible patients should receive IV alteplase even if mechanical thrombectomy is being considered 1, 5
• Do NOT wait to assess clinical response to alteplase before proceeding with thrombectomy—any delay worsens outcomes 1, 5
• Patients with suspected large vessel occlusion should have non-invasive angiography (CTA) 1, 5

Critical Pitfalls to Avoid

Timing Errors

• Delaying treatment for non-essential laboratory tests 1
• Waiting to assess alteplase response before initiating thrombectomy evaluation 1, 5
• Miscalculating time windows—use last known well time if onset unclear 1, 2

Inappropriate Exclusions

• Excluding patients >80 years in the 3-4.5 hour window (this is outdated) 3, 1
• Withholding treatment for mild symptoms that are actually disabling 3, 2
• Refusing treatment for early improvement if patient remains moderately impaired 3

Coagulation Mismanagement

• Initiating treatment without confirming INR ≤1.7 in warfarin users 3, 2
• Treating patients on DOACs without appropriate laboratory confirmation or adequate time since last dose 3
• Not recognizing that platelet count can be checked after starting treatment if no thrombocytopenia history, but must stop if <100,000 3