How tPA Works in Acute Ischemic Stroke
Tissue plasminogen activator (tPA) is a thrombolytic enzyme that converts plasminogen to plasmin, which then breaks down fibrin clots occluding cerebral arteries, restoring blood flow to ischemic brain tissue. 1, 2
Mechanism of Action
tPA works by enzymatically cleaving plasminogen into its active form, plasmin, which degrades the fibrin mesh that stabilizes blood clots. 3 This fibrinolytic cascade specifically targets the thrombus blocking cerebral blood vessels in acute ischemic stroke, allowing reperfusion of oxygen-deprived brain tissue. 4
Key Pharmacologic Properties
tPA has high fibrin specificity, meaning it preferentially activates plasminogen that is bound to fibrin in clots rather than circulating plasminogen, which theoretically reduces systemic bleeding risk. 3
The drug has a relatively short half-life, requiring continuous infusion over 60 minutes after an initial bolus to maintain therapeutic levels. 2
Standard dosing is 0.9 mg/kg (maximum 90 mg total), with 10% given as an IV bolus over 1 minute and the remaining 90% infused over 60 minutes. 1, 2
Clinical Efficacy and Time-Dependent Benefits
The benefit of tPA is highly time-dependent, with earlier treatment producing substantially better outcomes. 1 The NINDS trial demonstrated an absolute difference of 13% for excellent functional outcomes (modified Rankin Scale 0-1) when given within 3 hours, yielding a number needed to treat of 8. 5
Time Window Stratification
- 0-90 minutes: Greatest benefit with odds ratio of 2.55 for good outcome 5
- 91-180 minutes: Odds ratio of 1.64 for good outcome 5
- 181-270 minutes: Odds ratio of 1.32 for good outcome 5
- Beyond 4.5 hours: Strongly contraindicated (Grade 1B recommendation) 1, 6
Mechanism of Harm: Hemorrhagic Transformation
While tPA restores blood flow, it also activates matrix metalloproteases that disrupt the blood-brain barrier, increasing the risk of symptomatic intracranial hemorrhage (sICH). 4 This occurs because delayed recanalization in the presence of mature infarction damages already compromised cerebrovascular structures, leading to reperfusion injury. 4
- Baseline sICH rate is 6.4% with tPA versus 0.6% with placebo when proper dosing and patient selection criteria are followed. 2
- Patients on antiplatelet therapy have a 3% absolute increased risk of sICH but can still receive standard-dose tPA. 1
- Patients on direct oral anticoagulants (DOACs) should NOT receive tPA due to substantially elevated bleeding risk. 1, 7
Clinical Application Algorithm
Blood pressure must be reduced to <185/110 mmHg before initiating tPA, or the drug is absolutely contraindicated. 2 Use labetalol or nicardipine for blood pressure control. 2
Administration Protocol
- Calculate dose: Patient weight in kg (maximum 100 kg) × 0.9 mg/kg, with maximum total dose of 90 mg 2
- Give 10% as IV bolus over 1 minute 2
- Infuse remaining 90% over 60 minutes 2
- Monitor blood pressure every 15 minutes during infusion and for 2 hours after, then every 30 minutes for 6 hours, then hourly for 16 hours 2
- Do NOT give anticoagulants or antiplatelet agents for 24 hours after tPA 2
Post-Treatment Management
After 24 hours, initiate aspirin 160-325 mg for patients not receiving anticoagulation (Grade 1A recommendation). 1 For minor stroke or high-risk TIA, consider dual antiplatelet therapy (aspirin plus clopidogrel) for 21 days when initiated within 12-24 hours. 1
Common Pitfalls to Avoid
Never administer tPA if systolic BP remains >185 mmHg or diastolic >110 mmHg despite treatment. 2 Protocol violations occurred in 32.6% of patients in the STARS study, including treating beyond 3 hours (13.4%), giving anticoagulants within 24 hours (9.3%), and administering tPA despite elevated blood pressure (6.7%). 8
Avoid tPA in patients with hemorrhagic transformation (HI2 or higher) in existing infarcts or extensive early ischemic changes (>1/3 MCA territory). 1 These imaging findings predict substantially higher bleeding risk. 1