# Acute Ischemic Stroke: Thrombolysis and the Time Window

## Overview

Acute ischemic stroke is a medical emergency in which rapid reperfusion of brain tissue is the single most important determinant of patient outcome. Intravenous thrombolysis with alteplase has been the cornerstone of hyperacute stroke treatment for nearly three decades, and extended time window protocols using perfusion imaging have significantly expanded the pool of patients who can benefit from reperfusion therapy. More recently, tenecteplase has emerged as a practical alternative to alteplase, offering logistical advantages that may reshape how thrombolysis is delivered in both comprehensive and community stroke settings.

## Pathophysiology of Acute Ischemic Stroke

When a cerebral artery is acutely occluded, the downstream brain tissue divides into two zones. The ischemic core consists of tissue that has already been irreversibly damaged and cannot be salvaged. Surrounding this core is the penumbra, a region of hypoperfused but still viable brain tissue that represents the therapeutic target. Restoring blood flow before the penumbra progresses to infarction is the fundamental goal of all acute stroke interventions. The oft-quoted statistic that approximately 1.9 million neurons are lost per minute in an untreated large vessel occlusion captures the urgency of this race against time. However, the rate at which the penumbra converts to core varies substantially between patients, largely determined by the robustness of collateral circulation. Some patients maintain viable penumbra for many hours, while others lose it rapidly.

## IV Alteplase (tPA)

### Evidence Base

The NINDS trial in 1995 established alteplase (0.9 mg/kg, maximum 90 mg) given within 3 hours of symptom onset as a transformative treatment for acute ischemic stroke, demonstrating a 30% relative increase in excellent neurological outcome at 90 days. The trade-off was a 6.4% rate of symptomatic intracerebral hemorrhage. ECASS III in 2008 extended the treatment window to 4.5 hours, confirming that benefit persisted in this later window, though with a smaller effect size and a symptomatic ICH rate of 2.4% compared to 0.2% with placebo. In practical terms, the number needed to treat is approximately 7 to 8 within 3 hours and roughly 14 within the 3-to-4.5-hour window.

### Eligibility and Contraindications (Standard Window 0-4.5 hours)

| Absolute Contraindications to IV Thrombolysis |
|---|
| Active internal bleeding |
| Head trauma or stroke within 3 months |
| Intracranial neoplasm, AVM, or aneurysm |
| INR > 1.7 or therapeutic DOAC use |
| Platelet count < 100,000 |
| Blood glucose < 50 mg/dL |
| Intracranial hemorrhage on CT |
| Blood pressure > 185/110 despite treatment |

| Trial | Year | Time Window | Key Finding | NNT |
|---|---|---|---|---|
| NINDS | 1995 | 0–3 hours | 30% relative increase in excellent outcome | ~7–8 |
| ECASS III | 2008 | 3–4.5 hours | Benefit persists in extended window | ~14 |
| EXTEND | 2019 | 4.5–9 hours | Perfusion-selected IV tPA effective | — |
| WAKE-UP | 2018 | Unknown onset | DWI-FLAIR mismatch guides treatment | — |
| AcT | 2022 | 0–4.5 hours | Tenecteplase non-inferior to alteplase | — |

To be eligible for thrombolysis, a patient must have a measurable neurological deficit attributable to acute ischemic stroke and a clearly established time of symptom onset or last known well. Key absolute contraindications include active internal bleeding, recent head trauma or stroke within three months, intracranial neoplasm, current anticoagulation with an INR exceeding 1.7 or therapeutic DOAC use, a platelet count below 100,000, and blood glucose under 50 mg/dL. For the extended 3-to-4.5-hour window based on ECASS III criteria, additional exclusions historically included age over 80, NIHSS above 25, a history of both diabetes and prior stroke, and any oral anticoagulant use regardless of INR, though many of these are now considered relative rather than absolute contraindications. Blood pressure must be brought below 185/110 mmHg before administration and maintained below 180/105 mmHg afterward.

### Administration Protocol

Alteplase is dosed at 0.9 mg/kg with a maximum of 90 mg. Ten percent of the total dose is administered as an intravenous bolus over one minute, and the remaining 90% is infused over 60 minutes. The door-to-needle time target is under 60 minutes, with an aspirational goal of under 45 minutes. No antiplatelets or anticoagulants should be given for 24 hours following thrombolysis, and a CT head should be obtained at 24 hours before starting antithrombotic therapy.

### Complications of IV Alteplase

Symptomatic intracerebral hemorrhage occurs in approximately 6 to 7% of treated patients by the NINDS definition. Angioedema develops in roughly 2% of cases and is more common in patients taking ACE inhibitors; it should be treated with epinephrine, diphenhydramine, and methylprednisolone. Systemic bleeding, including gastrointestinal and genitourinary sites, requires close monitoring.

## Extended Time Window: Perfusion-Based Selection

### DAWN Trial (2018)

The DAWN trial compared thrombectomy (with or without IV tPA) to medical management alone in patients presenting 6 to 24 hours from last known well. Patient selection relied on CT perfusion or MRI-DWI to identify a clinical-imaging mismatch, meaning a high NIHSS score relative to a small infarct core. The primary endpoint of 90-day utility-weighted mRS strongly favored thrombectomy. DAWN represented a paradigm shift, moving stroke treatment from a purely time-based approach to a tissue-based approach.

### DEFUSE-3 Trial (2018)

DEFUSE-3 evaluated thrombectomy versus medical management in the 6-to-16-hour window, using CT perfusion or MRI perfusion to identify a target mismatch (ischemic core under 70 mL, mismatch ratio exceeding 1.8, and penumbra greater than 15 mL). The trial demonstrated significant benefit in functional independence at 90 days.

### EXTEND Trial (2019)

The EXTEND trial tested IV alteplase versus placebo in the 4.5-to-9-hour window, including patients with wake-up stroke, using perfusion-diffusion mismatch for selection. Alteplase showed significant benefit, extending the role of IV thrombolysis beyond 4.5 hours for patients with favorable perfusion imaging profiles.

### MR WITNESS and Wake-Up Stroke

For patients with unwitnessed symptom onset, the DWI-FLAIR mismatch on MRI provides a tissue clock: a lesion that is positive on DWI but negative on FLAIR suggests that the stroke occurred within approximately 4.5 hours. The WAKE-UP trial in 2018 demonstrated significant benefit of IV alteplase guided by this mismatch pattern.

## Tenecteplase vs. Alteplase

### Advantages of Tenecteplase

Tenecteplase offers several practical advantages over alteplase. It is administered as a single IV bolus rather than a one-hour infusion, has greater fibrin specificity and a longer half-life, and is logistically simpler, enabling faster administration, easier use in drip-and-ship transfer models, and more rapid transition to the thrombectomy suite.

### Evidence

The AcT trial in 2022 demonstrated that tenecteplase at 0.25 mg/kg is non-inferior to alteplase for excellent outcome at 90 to 120 days. Additional supportive data from NOR-TEST and EXTEND-IA TNK have reinforced its role, particularly for large vessel occlusion patients proceeding to thrombectomy. The AHA/ASA 2024 guidelines now endorse tenecteplase 0.25 mg/kg as an alternative to alteplase, and many comprehensive stroke centers have adopted it as first-line therapy.

## Door-to-Needle Quality Metrics

The national target is a door-to-needle time under 60 minutes for at least 75% of eligible patients. Best-practice strategies include pre-notification by EMS, immediate CT scanner availability, point-of-care INR and glucose testing, pre-mixed tPA, bolus administration in the CT scanner, and pharmacy pre-authorization. Telestroke networks have been instrumental in extending thrombolysis access to rural and underserved communities.

## Blood Pressure Management

Before thrombolysis, blood pressure should be lowered to below 185/110 mmHg using IV labetalol, nicardipine, or clevidipine. After thrombolysis, blood pressure should be maintained below 180/105 mmHg for 24 hours. For patients who do not receive thrombolysis, permissive hypertension is generally appropriate, allowing blood pressure up to 220/120 mmHg unless there is another indication for treatment such as aortic dissection, heart failure, or hypertensive encephalopathy.

<image>A timeline infographic illustrating the evolution of acute ischemic stroke treatment windows. The horizontal axis represents time from symptom onset (0 to 24 hours). The 0-3 hour window is labeled "NINDS (1995) - IV alteplase," the 3-4.5 hour window is labeled "ECASS III (2008) - IV alteplase," the 4.5-9 hour window is labeled "EXTEND (2019) / WAKE-UP (2018) - perfusion or DWI-FLAIR mismatch selected IV alteplase," and the 6-24 hour window is labeled "DAWN (2018) / DEFUSE-3 (2018) - perfusion-selected thrombectomy." Each window is color-coded with the strength of evidence and selection criteria annotated. A note emphasizes the shift from time-based to tissue-based decision-making.</image>

<image>A step-by-step clinical protocol flowchart for acute ischemic stroke thrombolysis. Starting with stroke code activation and rapid NIHSS assessment, proceeding to emergent non-contrast CT head (rule out hemorrhage), point-of-care glucose and labs, blood pressure management, eligibility checklist (inclusion/exclusion criteria), alteplase or tenecteplase dosing and administration steps, post-tPA monitoring (neuro checks every 15 minutes for 2 hours, then every 30 minutes for 6 hours, then hourly for 16 hours), and 24-hour follow-up CT before starting antithrombotics. Decision points for angioedema management and symptomatic ICH management are included as side branches.</image>

<image>A comparison diagram of CT perfusion imaging in acute ischemic stroke showing three maps side by side: cerebral blood flow (CBF) map showing the ischemic core, time-to-maximum (Tmax) map showing the area of hypoperfusion, and the mismatch map highlighting the penumbra (tissue at risk). An example patient with a large penumbra and small core is shown as a "favorable mismatch" eligible for extended-window treatment, contrasted with a patient showing a large core with minimal mismatch as "unfavorable" for intervention. The DAWN and DEFUSE-3 selection criteria thresholds are annotated on each example.</image>

## Clinical Pearls

The phrase "time is brain" remains foundational, but the modern paradigm has expanded to "physiology is brain," recognizing that perfusion imaging can identify patients who benefit from treatment well beyond traditional time windows. The single most impactful quality improvement metric is door-to-needle time; every 15-minute reduction is associated with reduced mortality. Tenecteplase as a single IV bolus is a practical game-changer, especially in drip-and-ship models where patients need transfer for thrombectomy. An NIHSS of 0 or rapidly improving symptoms is a common reason to withhold tPA, but clinicians should exercise caution because disabling deficits such as isolated aphasia or hemianopia may produce deceptively low NIHSS scores. Blood glucose must always be checked before thrombolysis, as hypoglycemia can convincingly mimic stroke. Post-tPA angioedema occurs more frequently in patients concurrently taking ACE inhibitors, and treatment should be readily available. The WAKE-UP trial validated the DWI-FLAIR mismatch as a tissue clock for patients whose symptom onset was unwitnessed.

## References
- National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587.
- Hacke W, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke (ECASS III). N Engl J Med. 2008;359(13):1317-1329.
- Nogueira RG, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct (DAWN). N Engl J Med. 2018;378(1):11-21.
- Albers GW, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging (DEFUSE 3). N Engl J Med. 2018;378(8):708-718.
- Menon BK, et al. Alteplase compared with tenecteplase in acute ischaemic stroke (AcT). Lancet. 2022;400(10359):161-169.
- Thomalla G, et al. MRI-guided thrombolysis for stroke with unknown time of onset (WAKE-UP). N Engl J Med. 2018;379(7):611-622.