Stroke thrombolysis
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"ischemic stroke"[MeSH Terms] AND "thrombolytic therapy"[MeSH Terms]
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Stroke Thrombolysis
Mechanism
IV thrombolytic therapy restores perfusion to ischemic brain tissue not yet infarcted. The agents used are recombinant tissue plasminogen activators (rt-PA), which convert plasminogen to plasmin, dissolving the fibrin clot occluding the cerebral artery. Time-dependence is critical — every minute of delay means additional neuronal loss.
Agents & Dosing
Alteplase (standard)
- Dose: 0.9 mg/kg IV (maximum 90 mg)
- Method: 10% of total dose as bolus over 1 minute, then remainder over 60 minutes
- FDA approval: Within 3 hours of symptom onset
- Low-dose alteplase (0.6 mg/kg) is standard in Japan; the ENCHANTED trial showed it was noninferior for death/disability at 90 days with fewer symptomatic ICHs, but current AHA/ASA guidelines still recommend 0.9 mg/kg
Tenecteplase (emerging preferred option)
- Dose: 0.25 mg/kg IV (maximum 25 mg) as a single bolus
- Moderate-to-high quality evidence shows similar rates of functional outcome, symptomatic ICH, and 90-day mortality vs alteplase
- The EXTEND-IA TNK trial showed higher reperfusion rates and better functional outcomes vs alteplase in patients also undergoing endovascular therapy
- Can be used in place of alteplase in patients eligible for mechanical thrombectomy — simpler administration (bolus vs 1-hour infusion)
Time Windows (2019 AHA/ASA Guidelines)
| Window | Recommendation |
|---|---|
| 0–3 hours | IV alteplase recommended for eligible patients ≥18 years, regardless of age ≤80 or >80. Recommended even for severe stroke despite higher hemorrhagic transformation risk. |
| 3–4.5 hours | IV alteplase recommended for selected patients: age ≤80, no history of both diabetes AND prior stroke, NIHSS ≤25, not on oral anticoagulants, no imaging ischemia >1/3 MCA territory |
| >4.5 hours | Thrombolysis not recommended; decision for thrombectomy based on perfusion imaging (up to 6–24 h window for thrombectomy) |
| Wake-up stroke / unknown onset | The WAKE-UP trial supported MRI-based thrombolysis (DWI-FLAIR mismatch as proxy for <4.5 h onset) |
BP prerequisite: Must be <185/110 mmHg before administration (see BP management table below).
Eligibility — Key Inclusions
- Age ≥18 (no upper age limit within 3 h)
- Disabling neurological deficit
- CT excluding hemorrhage
- Blood glucose >50 mg/dL
- Early ischemic changes on CT acceptable if mild-moderate (non-hypodense)
- Pre-existing antiplatelet therapy (aspirin, clopidogrel, or combination): benefit outweighs small increased sICH risk
Contraindications & Exclusions (2019 AHA/ASA)
Absolute (do not give):
| Condition | Timeframe |
|---|---|
| Intracranial hemorrhage on CT | Any |
| Subarachnoid hemorrhage signs/symptoms | Any |
| Severe head trauma | Within 3 months |
| Intracranial/spinal surgery | Within 3 months |
| Prior ischemic stroke | Within 3 months |
| Active internal bleeding | Current |
| Platelets <100,000/mm³ | — |
| INR >1.7, aPTT >40 s, PT >15 s | — |
| Full-dose LMWH | Within 24 hours |
| Endocarditis | — |
| Aortic arch dissection | — |
Relative / Caution (weigh risk vs benefit):
| Condition | Notes |
|---|---|
| Mild non-disabling stroke (NIHSS 0–5) | Not recommended in either 0–3 h or 3–4.5 h window |
| Large hypodense territory on CT (>1/3 MCA) | Poor prognosis; not recommended |
| GI malignancy or GI bleed | Within 21 days — potentially harmful |
| Infective endocarditis | Risk of mycotic aneurysm rupture |
| Pregnancy | Not absolute contraindication; case-by-case |
| Prior stroke + diabetes (for 3–4.5 h window) | Excluded from extended window |
Pre-Treatment BP Management
BP must be ≤185/110 mmHg before starting alteplase:
| BP Level | Treatment |
|---|---|
| Systolic 180–230 or diastolic 105–120 | Labetalol 10 mg IV over 1–2 min; may repeat q10–20 min (max 300 mg); or labetalol infusion 2–8 mg/min |
| Systolic >230 or diastolic 121–140 | As above, or nicardipine infusion 5 mg/h, titrate to max 15 mg/h; if uncontrolled, consider sodium nitroprusside |
Post-treatment: Monitor BP every 15 min during infusion, then q30 min for 6 h, then q1 h for 16 h.
Complications
Symptomatic Intracranial Hemorrhage (sICH)
- The principal serious complication (~6% in NINDS trial)
- Risk factors: severe stroke (high NIHSS), advanced age, hyperglycemia, hypertension
- If suspected: stop alteplase immediately, urgent CT, neurosurgical consult
- No proven reversal agent for alteplase; cryoprecipitate (fibrinogen replacement) and antifibrinolytics (tranexamic acid) may be considered
Orolingual Angioedema
- Occurs in ~1–5% of patients
- More common with concurrent ACE inhibitor use
- Treat with antihistamines, epinephrine, steroids; secure airway if severe
Thrombolysis + Thrombectomy
- IV thrombolysis does not replace mechanical thrombectomy in large-vessel occlusion (LVO)
- Combined approach: thrombolysis bridges time to thrombectomy
- A 2023 Lancet meta-analysis (PMID 37640037) of 6 RCTs found IV thrombolysis before thrombectomy did not improve functional outcomes in LVO, while increasing sICH — but analysis by time-to-treatment suggests benefit when door-to-puncture time is long
- Current guidelines still recommend IV alteplase if eligible, even if proceeding to thrombectomy
Extended Window Thrombolysis (>4.5 h) — Recent Evidence
A 2025 meta-analysis (PMID 39882605) of RCTs including EXTEND, ECASS4, and WAKE-UP found that thrombolysis beyond 4.5 h in imaging-selected patients (perfusion/DWI-FLAIR mismatch) is associated with improved functional outcomes, at the cost of increased sICH. MRI or CT-perfusion selection identifies patients with viable penumbra.
Tenecteplase vs Alteplase — Updated Evidence
A 2024 meta-analysis of phase III trials (PMID 37640500) confirmed tenecteplase is non-inferior to alteplase for 90-day functional outcomes and sICH rates. Its single-bolus administration, longer half-life, and higher fibrin specificity make it the preferred agent in many centers, especially when LVO is identified and the patient is going to the angio suite.
Key Targets ("Time is Brain")
| Target | Goal |
|---|---|
| Door-to-CT | ≤25 minutes |
| Door-to-needle (alteplase) | ≤60 minutes |
| Symptom onset to needle | <3 hours (ideal); <4.5 h (extended) |
Sources: ROSEN's Emergency Medicine, 9th ed., Chapter 87 (Table 87.5 — 2019 AHA/ASA Guidelines); Bradley and Daroff's Neurology in Clinical Practice; Harrison's Principles of Internal Medicine, 22e; Recent meta-analyses PMID 37640037, 37640500, 39882605
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