Why does tenecteplase (tissue plasminogen activator) cause intracranial hemorrhage?

Mechanism of Tenecteplase-Induced Intracranial Hemorrhage

Tenecteplase causes intracranial hemorrhage primarily through its fibrinolytic action, which disrupts the hemostatic balance in cerebral vasculature, particularly in patients with pre-existing vascular vulnerability or when used at higher doses. 1

Pharmacological Mechanism

Tenecteplase is a genetically engineered variant of tissue plasminogen activator (tPA) with:

• Higher fibrin specificity than standard tPA
• Longer half-life (allowing single bolus administration)
• Enhanced binding to fibrin in thrombi
• Resistance to plasminogen activator inhibitor-1 (PAI-1)

When administered, tenecteplase:

1. Binds to fibrin in blood clots
2. Converts plasminogen to plasmin
3. Plasmin degrades fibrin networks in thrombi
4. This process extends beyond the target thrombus to affect systemic coagulation

Pathophysiology of Intracranial Hemorrhage

The intracranial hemorrhage occurs through several mechanisms:

• Disruption of hemostatic plugs: Tenecteplase dissolves protective hemostatic plugs that may be present in cerebral vessels with pre-existing damage 2
• Breakdown of blood-brain barrier: The fibrinolytic activity can degrade components of the blood-brain barrier, increasing permeability 3
• Reperfusion injury: Rapid restoration of blood flow to ischemic areas can cause reperfusion injury and vessel wall damage 3
• Systemic hypofibrinogenemia: Though more fibrin-specific than non-selective agents, tenecteplase still causes some degree of systemic fibrinolysis 3

Risk Factors for Tenecteplase-Induced ICH

Several patient factors significantly increase the risk of intracranial hemorrhage:

• Age >75 years: Elderly patients have a substantially higher risk of ICH 2, 4
• Female gender: Women have been identified as having higher risk in multiple studies 5, 4
• Lower body weight <67 kg: Particularly concerning in combination with advanced age 5
• History of hypertension: Independent predictor of ICH 4
• Higher baseline NIHSS scores: More severe strokes carry greater bleeding risk 4
• Elevated admission blood glucose: Associated with increased ICH risk 4
• Concurrent anticoagulant use: Particularly when combined with heparin or antiplatelet agents 1

Comparative Risk with Other Thrombolytics

Recent evidence suggests tenecteplase may actually have a more favorable bleeding profile compared to alteplase:

• Non-cerebral bleeding: Tenecteplase is associated with significantly less non-cerebral bleeding (4.66% vs. 5.94%) and reduced need for blood transfusion compared to alteplase 5
• Intracranial hemorrhage rates: Recent studies show lower rates of symptomatic ICH with tenecteplase (0.65%) compared to alteplase (5%) 6
• Mortality benefit: A large retrospective study demonstrated lower 30-day mortality with tenecteplase versus alteplase (8.2% vs 9.8%) 7

Prevention and Management of ICH

To minimize the risk of intracranial hemorrhage:

• Strict adherence to contraindications: Absolute contraindications include previous intracranial hemorrhage, known cerebral vascular lesion, ischemic stroke within 3 months, active bleeding, and severe uncontrolled hypertension 3, 2
• Appropriate dosing: Weight-adjusted dosing is critical, with consideration of reduced dosing in high-risk populations 2
• Avoid concurrent medications that impair hemostasis when possible 1
• Careful blood pressure management: Maintain SBP <180 mmHg and DBP <110 mmHg 3
• Avoid unnecessary invasive procedures during and shortly after administration 1

If ICH occurs:

1. Immediately discontinue tenecteplase infusion
2. Perform urgent CT scan
3. Obtain neurosurgical consultation
4. Control blood pressure (target SBP <140-160 mmHg)
5. Consider reversal agents and blood product administration as needed 2

Clinical Implications

Despite the risk of intracranial hemorrhage, tenecteplase offers several advantages over other thrombolytics:

• Single bolus administration (versus 90-minute infusion for alteplase)
• Greater fibrin specificity
• Longer half-life
• Potentially lower rates of symptomatic ICH in recent studies 6, 7

These advantages have led to increasing adoption of tenecteplase for stroke thrombolysis, with current clinical practice guidelines including it as a second-tier option, particularly at 0.25 mg/kg for large vessel occlusions 8.