What are the indications for recombinant tissue plasminogen activator (rtPA) in medicine, particularly in a young to middle-aged adult with no significant medical history?

Indications for rtPA in Medicine

Recombinant tissue plasminogen activator (rtPA) is FDA-approved for acute ischemic stroke within 3 hours of symptom onset, with extended use up to 4.5 hours supported by guidelines, and represents the only proven thrombolytic therapy for stroke treatment. 1

Primary Indication: Acute Ischemic Stroke

Standard 0-3 Hour Window

The FDA approved intravenous rtPA in 1996 based on the NINDS trial, which demonstrated that 31-50% of treated patients achieved favorable outcomes compared to 20-38% with placebo. 1 For patients presenting within 3 hours of symptom onset, rtPA (0.9 mg/kg IV, maximum 90 mg) should be administered with 10% as bolus over 1 minute and 90% infused over 60 minutes. 1, 2

Key inclusion criteria for the 0-3 hour window include: 1, 3

• Diagnosis of ischemic stroke causing measurable neurologic deficit
• Age ≥18 years
• Symptom onset <3 hours before treatment initiation
• CT scan excluding hemorrhage

Absolute contraindications that must be screened include: 1, 3

• Any history of intracranial hemorrhage (permanent exclusion regardless of timing)
• Head trauma or prior stroke within previous 3 months
• Systolic BP >185 mmHg or diastolic BP >110 mmHg
• Active bleeding or acute bleeding diathesis
• Platelet count <100,000/mm³
• INR >1.7 or PT >15 seconds
• Blood glucose <50 mg/dL
• CT showing multilobar infarction (hypodensity >1/3 cerebral hemisphere)

Extended 3-4.5 Hour Window

Based on the ECASS-3 trial, rtPA can be administered between 3-4.5 hours after symptom onset, though this remains off-label in the US. 1 This extended window has additional exclusion criteria beyond the standard contraindications: 1, 3

• Age >80 years
• Severe stroke (NIHSS >25)
• Taking any oral anticoagulant regardless of INR
• History of both diabetes mellitus AND prior ischemic stroke

The benefit decreases with time: odds ratios decline from 2.81 within 1.5 hours to 1.55 at 1.5-3 hours, 1.40 at 3-4.5 hours, and only 1.15 at 4.5-6 hours. 1, 2

Critical Safety Considerations

The major risk is symptomatic intracranial hemorrhage, occurring in 6.4% of rtPA-treated patients versus 0.6% with placebo. 1 However, mortality rates at 3 months were similar (17% vs 20%). 1 The SITS-ISTR Registry of 11,865 patients confirmed safety with 1.6% experiencing substantial parenchymal hematoma and 56.3% achieving favorable outcomes. 1

Common pitfalls that increase hemorrhage risk include: 4

• Protocol violations occurred in 32.6% of cases in the STARS study
• Treatment beyond 3 hours (13.4% of violations)
• Anticoagulant use within 24 hours of rtPA (9.3%)
• Administering rtPA despite BP >185/110 mmHg (6.7%)

Treatment can be initiated before coagulation results return in patients without recent anticoagulant use, but must be discontinued immediately if INR >1.7 or platelets <100,000/mm³ when results become available. 1, 3

Institutional Requirements

rtPA should only be administered by physicians with a clearly defined protocol, knowledgeable team, and institutional commitment to acute stroke care. 1 German data showed increased mortality risk in hospitals treating <5 patients per year, emphasizing that clinical outcomes vary significantly based on institutional experience. 1

The door-to-needle time should be within 60 minutes of hospital arrival, as earlier treatment provides superior outcomes. 5

Emerging and Investigational Uses

Intra-arterial rtPA administration after initial intravenous dosing (0.6 mg/kg) may benefit patients with NIHSS ≥10 presenting within 3 hours, though this remains investigational. 1 The IMS study showed 16% mortality with combined therapy versus 21% with IV rtPA alone, with similar symptomatic hemorrhage rates (6.3% vs 6.6%). 1

Combination with transcranial ultrasound showed promise in the CLOT-BUST study, achieving 49% complete MCA recanalization versus 30% with rtPA alone. 1

What rtPA Should NOT Be Used For

No neuroprotective agent including Cerebrolysin has proven beneficial for acute ischemic stroke and should not delay or replace rtPA. 2 The ATLANTIS trial definitively showed no benefit for rtPA administered between 3-5 hours without advanced imaging selection, with increased symptomatic ICH (7.0% vs 1.1%) and fatal ICH (3.0% vs 0.3%). 6

Hyperbaric oxygen is contraindicated except for air embolization-related stroke, and induced hypothermia lacks sufficient evidence for routine use. 1