What is tPA (Alteplase)?
Tissue plasminogen activator (tPA), marketed as alteplase (Activase), is a thrombolytic agent used to dissolve blood clots in life-threatening conditions. It is a serine protease that converts plasminogen to plasmin, the enzyme responsible for breaking down fibrin in blood clots. tPA is produced naturally by endothelial cells and is also manufactured using recombinant DNA technology for clinical use.
tPA is considered the gold standard thrombolytic for acute ischemic stroke and is widely used in pulmonary embolism, acute myocardial infarction, and catheter-directed therapy for deep vein thrombosis. Its fibrin specificity makes it more targeted than older thrombolytics like streptokinase, though bleeding remains the primary risk.
Mechanism of Action
tPA works by binding to fibrin within a thrombus (blood clot). Once bound, it activates plasminogen that is also bound to the fibrin mesh, converting it to plasmin. Plasmin then enzymatically degrades the fibrin strands, breaking apart the clot structure. This fibrin-specific mechanism means tPA preferentially acts at the site of the clot rather than causing systemic fibrinolysis, although systemic effects still occur and contribute to bleeding risk.
The half-life of alteplase is approximately 4-5 minutes in the circulation, which is why it is administered as a combination of bolus and continuous infusion to maintain therapeutic levels. The rapid clearance is primarily through hepatic metabolism.
Dosing by Indication
Acute Ischemic Stroke
10% as IV bolus over 1 minute
Remaining 90% as IV infusion over 60 minutes
The stroke dosing protocol is the most weight-dependent regimen. It is critical that the total dose does not exceed 90 mg regardless of patient weight. Blood pressure must be maintained below 185/110 mmHg before and during administration.
Pulmonary Embolism
- 10 mg IV bolus over 1-2 minutes
- 90 mg IV infusion over 2 hours
Accelerated: 0.6 mg/kg (max 50 mg) IV over 15 minutes
The standard PE protocol uses a fixed dose of 100 mg regardless of weight. The accelerated protocol is sometimes used in cardiac arrest or peri-arrest situations. Heparin is typically held during the infusion and restarted when aPTT is less than twice the upper limit of normal.
Acute MI (STEMI)
- 15 mg IV bolus
- 0.75 mg/kg over 30 min (max 50 mg)
- 0.5 mg/kg over 60 min (max 35 mg)
The MI protocol uses a three-stage approach. Concurrent heparin and aspirin are given. This regimen is primarily used when primary PCI is not available within 120 minutes of first medical contact.
DVT (Catheter-Directed)
Duration: Up to 24 hours
Typical total dose: 12-24 mg
Catheter-directed thrombolysis uses much lower doses because the tPA is delivered directly to the clot. This approach significantly reduces the systemic bleeding risk compared to systemic thrombolysis.
| Indication | Total Dose | Bolus | Infusion | Max Dose |
|---|---|---|---|---|
| Acute Ischemic Stroke | 0.9 mg/kg | 10% over 1 min | 90% over 60 min | 90 mg |
| Pulmonary Embolism (Std) | 100 mg fixed | 10 mg over 1-2 min | 90 mg over 2 hr | 100 mg |
| PE (Accelerated) | 0.6 mg/kg | Full dose over 15 min | N/A | 50 mg |
| Acute MI | Weight-based | 15 mg | 2-phase infusion | 100 mg |
| DVT (Catheter) | 0.5-1 mg/hr | N/A | Continuous up to 24 hr | ~24 mg |
Time Windows
| Indication | Time Window | Notes |
|---|---|---|
| Acute Ischemic Stroke | 0 – 3 hours (standard) 3 – 4.5 hours (extended) | Extended window: age <80, no diabetes+prior stroke combo, NIHSS ≤25, no oral anticoagulant use |
| Pulmonary Embolism | Within 14 days of symptom onset | Most beneficial when given early; massive PE with hemodynamic instability |
| Acute MI (STEMI) | Within 12 hours of symptom onset | Greatest benefit within first 3 hours; used only when PCI unavailable within 120 min |
| DVT | Within 14 days (acute DVT) | Best outcomes in iliofemoral DVT with symptom duration <14 days |
tPA Dosing Diagram
Contraindications
Absolute Contraindications
- Active internal bleeding (excluding menses)
- History of hemorrhagic stroke or stroke of unknown origin
- Ischemic stroke within 3 months (except current acute stroke)
- Intracranial neoplasm, AVM, or aneurysm
- Known bleeding diathesis (platelets <100,000, INR >1.7, aPTT >40s)
- Active use of direct oral anticoagulants within 48 hours
- Severe uncontrolled hypertension (unresponsive to treatment)
- Recent intracranial or spinal surgery (within 3 months)
- Head trauma (within 3 months)
Relative Contraindications
- Major surgery or trauma within 14 days
- GI or urinary tract hemorrhage within 21 days
- Arterial puncture at non-compressible site within 7 days
- Seizure at onset of stroke (if residual deficits are post-ictal)
- Pregnancy
- Age >80 for the extended time window (3-4.5 hours)
- Blood glucose <50 mg/dL
Bleeding Risk
| Complication | Stroke Protocol | PE Protocol | MI Protocol |
|---|---|---|---|
| Symptomatic ICH | 6-7% | 1-3% | 0.5-1% |
| Major systemic bleeding | 1-2% | 5-10% | 5-10% |
| Minor bleeding (puncture site) | 5-10% | 10-15% | 10-15% |
| Fatal hemorrhage | 1-2% | 1-2% | <1% |
The most feared complication is symptomatic intracranial hemorrhage (sICH), particularly in stroke patients. Risk factors for sICH include older age, higher NIHSS score, elevated blood glucose, early ischemic changes on CT, and protocol violations (especially exceeding the dose cap or time window).
Worked Example
A 70 kg patient presenting with acute ischemic stroke within 2 hours of symptom onset:
Bolus = 10% × 63 = 6.3 mg IV over 1 minute
Infusion = 90% × 63 = 56.7 mg IV over 60 minutes
Infusion rate = 56.7 / 60 = 0.95 mg/min
Frequently Asked Questions
What is the time window for tPA in stroke?
The standard window is within 3 hours of symptom onset. An extended window of 3-4.5 hours is available for selected patients who meet additional criteria: age under 80, no combination of diabetes and prior stroke, NIHSS score 25 or less, and no oral anticoagulant use. The earlier tPA is given, the better the outcomes — the benefit decreases significantly with each passing minute.
Why is the stroke dose lower than the PE dose?
The stroke dose (0.9 mg/kg, max 90 mg) is lower than the PE dose (100 mg) because the brain is much more vulnerable to hemorrhagic complications. Studies showed that higher doses in stroke led to unacceptably high rates of intracranial hemorrhage without additional benefit. The PE dose is higher because the clot burden is typically larger and the brain is not at direct risk from the thrombolytic.
Can tPA be re-dosed if the clot does not dissolve?
Re-dosing tPA is generally not recommended for stroke. If symptoms do not improve, mechanical thrombectomy should be considered for large vessel occlusions. For PE, a repeat dose may occasionally be considered if hemodynamic instability persists, but this significantly increases bleeding risk and requires careful clinical judgment.
What is the antidote if bleeding occurs?
There is no specific antidote for alteplase. Management of tPA-related bleeding includes: stopping the infusion immediately, administering cryoprecipitate (to replenish fibrinogen), tranexamic acid or aminocaproic acid (antifibrinolytics), platelet transfusion if thrombocytopenic, and supportive care including blood pressure management and potential neurosurgical intervention for intracranial hemorrhage.