Eligibility:

1. 18 years or older

2. Clinical diagnosis of ischemic stroke causing a measurable neurologic deficit

3. Onset of symptoms < 3 hours before beginning treatment

Contraindications:

1. Significant head trauma or prior stroke in previous 3 months

2. Intracranial or intraspinal surgery within prior 3 months

3. Known history of intracranial hemorrhage

4. Elevated Blood Pressure (SBP > 185 mmHg or DPB > 110 mm Hg) (Aggressive treatment required to lower blood pressure was also exclusionary in the original trial)

5. Symptoms suggestive of SAH, even if CT is negative

6. Arterial puncture at noncompressible site in previous 7 days

7. Acute bleeding diathesis

   • Heparin received in prior 48 hrs and elevated PTT

   • Current use of warfarin and INR > 1.7 or PT > 15s

   • Platelets < 100,000 (need not delay tPA to check platelets unless there is suspicion of thrombocytopenia)

   • Current use of direct thrombin inhibitors or direct factor Xa inhibitors with elevated sensitive laboratory tests (such as aPTT, INR, platelet count, and ECT; TT; or appropriate factor Xa activity assays

     • with normal renal function and last dose > 48 hours ago, tPA not precluded

   • INR > 1.7 or PT > 15s

   • Treatment dose of LMWH within the previous 24 hours

8. Symptoms consistent with infective endocarditis

9. Known or suspected aortic arch dissection

10. Serum glucose < 50mg/dL

11. Active internal bleeding (acute trauma (fracture) on exam added in 2003 guidelines, not found in 2013)

12. CT demonstrates multilobar infarction (hypodensity greater than 1/3 cerebral hemisphere NOT referring to early ischemic changes)

13. Intraaxial intracranial neoplasm - potentially harmful (2018 guidelines)

14. Known arteriovenous malformation, neoplasm, or aneurysm (risks and benefits not well established, reasonable to consider tPA for severe stroke deficits)

Relative Contraindications:

1. Seizure at onset with postictal residual neurological impairments

2. Only minor or rapidly improving stroke symptoms (see PRISMS trial)

3. Pregnancy (May be considered when benefits of treating moderate to severe stroke outweigh risks of uterine bleeding. Post-partum period not well established. Urgent consultation with an OBGYN +/- perinatologist is recommended)

4. Major surgery or serious trauma within previous 14 days

5. Recent GI or urinary tract hemorrhage (within previous 21 days) or structural GI malignancy

6. Recent acute myocardial infarction (within previous 3 months)

7. Dural Puncture

Additional relative contraindications for 3-4.5 hour window:

1. Age > 80 years - IV tPA safe in this window and can be as effective as in younger patients

2. Severe stroke (NIHSS score >25) (ECASS III trial also included clinical exclusion for involvement of more than 1/3 MCA territory) - Uncertain benefit

3. History of both diabetes and prior ischemic stroke - May be as effective as in 0-3 hour window, may be reasonable

4. Taking an oral anticoagulant regardless of INR - If INR ≤ 1.7, IV tPA appears safe and may be beneficial in this window

EXTEND (4.5-9 hours) Eligibility:

1. NIHSS 4-26

2. Pre-stroke mRS < 2

3. In wake-up stroke, approximate last known well is calculated by:

   • (bedtime - symptom discovery time)/2

4. CTP results

   • Mismatch:Core ratio > 1.2

   • Mismatch volume > 10 cc

   • Infarct Core ≤ 70 cc

5. Patients with LVO anticipating thrombectomy are excluded from EXTEND protocol IV tPA