Indications of Thrombolysis in Stroke

Indications (Inclusion Criteria)

0-3 Hour Window (FDA-approved)

3-4.5 Hour Window (ECASS III criteria - approved in Europe/Canada; used off-label in US)

• Age ≤80 years (some guidelines now permit >80 with careful selection)
• No history of both diabetes mellitus AND prior stroke
• NIHSS score ≤25
• No use of oral anticoagulants
• No imaging evidence of ischemia >1/3 of MCA territory

Dosing

• IV rtPA (alteplase): 0.9 mg/kg (max 90 mg total) - 10% as IV bolus, remainder over 60 minutes
• Tenecteplase: Single IV bolus (emerging alternative, simpler administration)
• Lower dose (0.6 mg/kg) used in Japan and some Asian countries due to higher hemorrhage risk in this population

Absolute Contraindications

Relative/Special Considerations

• Anticoagulated patients: Low-dose DOAC or warfarin with INR <1.7 may still receive thrombolysis with careful assessment
• Seizure at onset: Not a contraindication if deficit is due to ischemia, not post-ictal
• Mild or improving symptoms: Mild but disabling deficits still qualify - do not withhold thrombolytics solely because symptoms are mild
• Prior stroke + diabetes: Combination is a contraindication in the 3-4.5h window (single diagnosis alone is not)
• Pregnancy: Relative contraindication; risk-benefit analysis required
• Recent MI: Generally not a contraindication; case-by-case assessment

Key Clinical Points

1. Time is brain - every 30-minute delay reduces benefit. Door-to-needle time should be <60 minutes.
2. The benefit is clear: NINDS showed a 12% absolute increase in good neurological outcome at 3 months (NNT ~8-9).
3. Symptomatic intracranial hemorrhage risk is ~6.4% with rtPA vs. 0.6% with placebo - but overall outcomes still favour treatment in eligible patients.
4. Thrombolysis does not preclude subsequent mechanical thrombectomy - both can be combined in large vessel occlusion.
5. BP must be controlled to <185/110 mmHg before and during infusion.

• Harrison's Principles of Internal Medicine, 22nd Ed. (2025) - Table 438-1 and IV Thrombolysis section
• Tintinalli's Emergency Medicine - Table 167-1, AHA/ASA 2018 Inclusion/Exclusion Criteria for IV Alteplase
• Chinese Stroke Association Guidelines 2024 (PMID 39832918) - recent reperfusion therapy guideline update

Thrombolysis in Acute Ischemic Stroke - 2026 AHA/ASA Guideline

Drug Choice - Major Change

Tenecteplase at 0.4 mg/kg is explicitly NOT recommended - it does not improve outcomes and may cause harm.

Time Windows

Standard Window (Class I)

• Within 4.5 hours of symptom onset or last known well (LKW) for eligible adults
• No change from prior guideline in this window

Wake-up / Unknown Onset (Class IIa)

• IVT is reasonable if DWI lesion <1/3 MCA territory AND no visible FLAIR signal change ("DWI-FLAIR mismatch")
• Benefit window: within 4.5 hours of stroke symptom recognition, or awakening within 9 hours from midpoint of sleep

Extended Window with Advanced Imaging - NEW (Class IIa)

• Patients 4.5 to 9 hours from LKW with salvageable ischemic penumbra on CT/MRI perfusion imaging
• Large vessel occlusion (LVO) patients with salvageable tissue even beyond 9 hours (up to 24h in select cases) if perfusion imaging criteria met

Inclusion Criteria

• Clinical diagnosis of ischemic stroke with disabling neurologic deficit (any NIHSS - no lower or upper limit)
• Age ≥18 years (no upper age limit for the <3h window; individualized assessment for 3-4.5h window)
• CT/MRI showing no hemorrhage, no edema >1/3 MCA territory
• BP controlled to <185/110 mmHg before infusion

Key Contraindication Updates - MODIFIED

Still Absolute

• Active intracranial hemorrhage on imaging
• Recent intracranial/spinal surgery or severe head trauma (<3 months)
• Subarachnoid hemorrhage
• Platelet count <100,000; INR >1.7
• Infective endocarditis (high hemorrhage/emboli risk)

Now More Permissive (Previously Often Excluded)

• Age >80 years: No longer an absolute contraindication; treated case-by-case
• Mild but disabling strokes: Must be treated - do not withhold based on low NIHSS alone
• Prior stroke + diabetes together: Still a relative caution in 3-4.5h window
• DOAC patients: Reversal agents (idarucizumab for dabigatran; andexanet alfa for Xa inhibitors) may enable thrombolysis - assess case-by-case
• Recent MI: Not a blanket contraindication
• Seizure at onset: Not a contraindication if deficit is ischemic in origin

BP Management - Updated

• Must lower BP to <185/110 mmHg before giving IVT
• After IVT: maintain <180/105 mmHg for 24 hours
• New: The 2026 guideline recommends less intensive BP lowering post-IVT compared to prior versions - avoid aggressive reduction that might compromise cerebral perfusion

Imaging - Do Not Delay

• Extended time window decisions
• EVT candidacy assessment (which should run in parallel, not sequentially)

Pediatric Stroke - New in 2026

• Alteplase may be considered within 4.5 hours for disabling deficits
• Evidence supports safety; efficacy remains uncertain
• This guidance was largely absent in prior iterations

Summary of Key Changes vs. 2018/2019 Guidelines