Stroke is a leading cause of death and disability worldwide. Timely treatment is critical for stroke patients to prevent long-term impairments. Tissue plasminogen activator or tPA is a drug that has revolutionized the treatment of acute ischemic stroke.


What is tPA?

Tissue plasminogen activator (tPA) is a protein naturally present in our body. It plays a key role in dissolving blood clots. tPA breaks down plasminogen into plasmin. Plasmin then breaks down fibrin which forms the scaffolding of a blood clot. By breaking down fibrin, tPA indirectly causes lysis or dissolution of blood clots.

For treatment of stroke, tPA is administered as a recombinant version called recombinant tissue plasminogen activator (rtPA). It works by dissolving the clot causing the ischemic stroke. rtPA was approved by the US FDA in 1996 for treating acute ischemic stroke. It remains the only FDA approved treatment for dissolving clots causing strokes.

How does tPA work?

During an ischemic stroke, a clot forms in an artery supplying blood to the brain, cutting off oxygen supply. This leads to damage or death of brain cells. Tissue Plasminogen Activator works by directly acting on the clot. It promotes the conversion of plasminogen to plasmin which then breaks down the clot. Within minutes of administering tPA intravenously, it reaches the clot site and initiates clot breakdown. This restores blood flow to the brain and prevents further damage.

The mechanisms of action of tPA involve both fibrinolysis dependent and independent pathways. In fibrinolysis dependent mechanism, tPA converts plasminogen to plasmin which degrades fibrin in the clot. This directly leads to clot lysis. Additionally, tPA also enhances endogenous fibrinolysis by activating Factor XII of the coagulation cascade. In fibrinolysis independent pathways, tPA may directly or indirectly activate or inactivate various receptors, enzymes and cell signaling pathways involved in neuroprotection, neurorepair and reperfusion.

Benefits of tPA treatment

Studies have demonstrated significant benefits of tPA treatment in acute ischemic stroke patients treated within 4.5 hours of symptom onset. Some key benefits include:

- 50% relative improvement in clinical outcomes - around 50% higher odds of having little or no disability compared to placebo.

- Restoration of blood flow - Imaging studies showed restoration of blood flow to the ischemic brain regions in over 60% of tPA treated patients.

- Substantial cost savings - By reducing long-term disability, tPA treatment has been projected to save over $6 billion annually in US healthcare costs.

- Extension of treatment window - Recent trials evaluating tPA treatment between 4.5-9 hours found benefits with improved safety profile compared to previous trials. This may help more stroke patients get treated.

- Improved long-term outcomes - Long-term follow up studies found reduced risk of recurrent strokes, reduced mortality rates and better quality of life with tPA treatment.

Safety and Risks of tPA treatment

While highly effective when used appropriately, tPA does carry certain risks given its mechanism of action:

- Bleeding risk - The major risk is symptomatic intracranial hemorrhage which occurs in 6-7% of treated patients and increases mortality risk. Older age and severity of stroke increases this risk.

- Allergic reactions - Minor allergic reactions like rash, fever, nausea occur in 10-15% patients but serious allergic reactions are rare.

- Other rare risks - Include angioedema, arrhythmias, hypotension but occur in less than 3% patients.

- Treatment window - Risk of bleeding and poor outcomes increases if given outside 4.5 hour window. So benefits only apply when given early.

However, the risks are far outweighed by the benefits when used appropriately in eligible stroke patients within 4.5 hours of onset. Strict patient selection, dosage calculation and neuroimaging help maximize benefits and minimize risks.



Tissue plasminogen activator revolutionized stroke treatment with early administration now standard of care. While only a small percentage of patients receive tPA due to narrow treatment window, continued research into mechanical thrombectomy and extending tPA window holds promise. Larger community education and systems to facilitate faster diagnosis and treatment remain crucial to utilize this highly effective therapy to optimize stroke outcomes.

 

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