What are the indications and contraindications for intravenous alteplase (tPA) in an adult acute ischemic stroke presenting within 4.5 hours with a disabling neurological deficit, including required imaging, blood pressure, platelet count, glucose, INR, and considerations for low NIH Stroke Scale scores or large‑vessel occlusion?

Indications for Thrombolysis in Acute Ischemic Stroke

Intravenous alteplase (0.9 mg/kg, maximum 90 mg) should be administered to adult patients with acute ischemic stroke who present within 4.5 hours of symptom onset and meet eligibility criteria, with treatment initiated as rapidly as possible after CT scan excludes hemorrhage. 1, 2

Standard Time Window (0-3 Hours)

For patients presenting within 3 hours of symptom onset, IV alteplase should be offered to improve functional outcomes if they meet NINDS inclusion/exclusion criteria. 1 This represents a Level A recommendation with the strongest evidence base. 1

Required Pre-Treatment Assessment:

• Non-contrast CT scan to exclude intracranial hemorrhage 2
• Blood glucose measurement (must be 60-400 mg/dL; correct if outside this range) 3, 2
• Blood pressure must be lowered below 185/110 mmHg before initiating thrombolysis 3, 2
• Other laboratory tests (CBC, INR, PTT, electrolytes, troponin) should be obtained but must not delay treatment 2

Dosing Protocol:

• 0.9 mg/kg body weight (maximum 90 mg total) 2, 4
• 10% given as IV bolus over 1 minute 1, 4
• Remaining 90% infused over 60 minutes 1, 4

Target Metrics:

• Door-to-needle time <60 minutes in 90% of patients 2
• Median door-to-needle time of 30 minutes 2

Extended Time Window (3-4.5 Hours)

For patients presenting between 3 to 4.5 hours after symptom onset, IV alteplase should be considered if they meet ECASS III inclusion/exclusion criteria. 1 This carries a Level B recommendation. 1

Additional Exclusion Criteria for 3-4.5 Hour Window:

• Age >80 years 4
• Patients on oral anticoagulants regardless of INR 4
• NIHSS score >25 4
• History of both prior stroke AND diabetes mellitus 4

The ECASS III trial demonstrated that alteplase administered in this window improved favorable outcomes (52.4% vs 45.2% with placebo, OR 1.34, P=0.04), though symptomatic intracranial hemorrhage was higher (2.4% vs 0.2%). 5

Wake-Up Stroke and Unknown Onset Time (Within 4.5 Hours of Recognition)

For patients who awaken with stroke symptoms or have unclear onset time, IV alteplase can be beneficial if administered within 4.5 hours of symptom recognition when MRI demonstrates DWI-FLAIR mismatch. 2 This indicates stroke onset likely within the treatment window. 3

Required Imaging:

• MRI with DWI showing acute infarction 3
• FLAIR sequence showing no corresponding hyperintensity (negative FLAIR) 3

Extended Window Beyond 4.5 Hours (4.5-24 Hours)

For highly selected patients presenting 4.5-9 hours (or up to 24 hours with robust mismatch) after symptom onset, IV alteplase may be considered when advanced imaging demonstrates salvageable tissue AND mechanical thrombectomy is not indicated or planned. 3, 6

Critical Selection Requirements:

• CT or MRI perfusion imaging showing core/perfusion mismatch 3
• Ischemic core ≤70 mL, penumbra ≥10 mL, mismatch ratio ≥20% 2
• ASPECTS score ≥6 2
• Mechanical thrombectomy must NOT be indicated 3 - this is a crucial distinction, as patients with large vessel occlusion should proceed directly to thrombectomy in this window
• CT angiography to exclude large vessel occlusion 3

The 2025 HOPE trial demonstrated that alteplase administered 4.5-24 hours after onset in perfusion-selected patients improved functional independence (40% vs 26%, adjusted RR 1.52, P=0.004), though symptomatic ICH was higher (3.8% vs 0.51%). 6 This represents the most recent high-quality evidence supporting extended window treatment with appropriate patient selection.

Special Populations and Considerations

Mild Stroke Symptoms:

• Within 3 hours, treatment may be considered even for mild symptoms if judged potentially disabling 2
• The benefit-risk ratio must be carefully weighed, as "mild" strokes can still result in significant disability. 2

Elderly Patients:

• Patients >80 years presenting within 3 hours should receive alteplase 2
• Patients >80 years in the 3-4.5 hour window are excluded per ECASS III criteria 4

Anticoagulation Status:

• Warfarin use with INR ≤1.7 is reasonable for treatment 2
• DOACs: Do not routinely administer alteplase 2 - however, emerging evidence suggests 0.6 mg/kg dosing may be safe in DOAC patients (Japanese protocol), though this is not standard in Western guidelines 7

Seizure at Onset:

• Treatment is reasonable if evidence suggests residual deficits are from stroke, not postictal phenomenon 2

Absolute Contraindications (Key Examples)

• Intracranial hemorrhage on imaging 3
• Active internal bleeding 3
• Blood pressure >185/110 mmHg despite treatment 3, 2
• Blood glucose <60 mg/dL or >400 mg/dL 3
• Recent major surgery or trauma 3
• Extensive early ischemic changes (>1/3 MCA territory within standard window) 3

Critical Pitfalls to Avoid

• Never delay alteplase to observe clinical response before mechanical thrombectomy - any delay worsens outcomes 2
• Never use myocardial infarction dosing protocols - stroke requires 0.9 mg/kg, not the higher MI doses 4
• Do not wait for all laboratory results - only glucose is mandatory before treatment 2
• Do not assume mild symptoms will remain mild - early treatment prevents deterioration 2
• Ensure institutional systems are in place for safe administration - effectiveness is less established without proper protocols 1