What are the contraindications for thrombolysis with alteplase (tissue plasminogen activator) in acute ischemic stroke?

Contraindications for Thrombolysis in Acute Ischemic Stroke

IV alteplase should not be administered to patients with acute intracranial hemorrhage on CT, recent severe head trauma or intracranial surgery within 3 months, history of intracranial hemorrhage, coagulopathy (platelets <100,000/mm³, INR >1.7, aPTT >40s), treatment dose LMWH within 24 hours, or time from symptom onset >4.5 hours. 1

Absolute Contraindications (Class III: Harm)

Imaging-Based Contraindications

• Intracranial hemorrhage on CT: Any evidence of acute intracranial hemorrhage on non-contrast CT is an absolute contraindication. 1, 2
• Extensive hypoattenuation: Obvious hypodensity representing irreversible injury involving large regions of brain tissue contraindicates alteplase, as these patients have poor prognosis regardless of treatment. 1

Time-Based Contraindications

• Symptom onset >4.5 hours: Patients with unclear or unwitnessed symptom onset where time last known well exceeds 3-4.5 hours should not receive alteplase. 1
• Wake-up stroke >4.5 hours: Patients who awoke with stroke symptoms and were last known well >4.5 hours prior are excluded. 1

Recent Neurological Events

• Ischemic stroke within 3 months: Prior ischemic stroke within the preceding 3 months is potentially harmful. 1, 2
• Severe head trauma within 3 months: Recent severe head trauma contraindicates alteplase due to bleeding risk, including posttraumatic infarction during acute hospitalization. 1, 2
• Intracranial/spinal surgery within 3 months: Any neurosurgical procedure in the prior 3 months is potentially harmful. 1
• History of intracranial hemorrhage: Any prior intracranial hemorrhage at any time is a contraindication. 1, 2

Active Hemorrhage

• Subarachnoid hemorrhage: Symptoms and signs consistent with SAH contraindicate alteplase. 1
• GI malignancy or bleeding within 21 days: Structural GI malignancy or recent GI bleeding within 21 days represents high risk. 1

Coagulopathy and Anticoagulation

• Thrombocytopenia: Platelet count <100,000/mm³ contraindicates treatment (though treatment can be initiated before results are available and discontinued if platelets are low). 1, 2
• Elevated INR/PT: INR >1.7 or PT >15 seconds contraindicates alteplase (can initiate before results in patients without recent anticoagulant use). 1, 2
• Elevated aPTT: aPTT >40 seconds contraindicates treatment. 1, 2
• LMWH within 24 hours: Treatment dose low molecular weight heparin within the previous 24 hours is a contraindication. 1, 2
• Direct oral anticoagulants: Direct thrombin inhibitors or factor Xa inhibitors contraindicate alteplase unless laboratory tests (aPTT, INR, ecarin clotting time, thrombin time, or direct factor Xa assays) are normal OR the patient has not received a dose for >48 hours with normal renal function. 1

Concurrent Medications

• Glycoprotein IIb/IIIa inhibitors: These antiplatelet agents should not be administered concurrently with alteplase outside clinical trials. 1

Important Clinical Caveats

Laboratory Testing Pragmatics

Treatment can be initiated before laboratory results are available in appropriate patients, but must be discontinued if contraindications are discovered. 1 Specifically:

• Start alteplase before platelet count in patients without thrombocytopenia history, but stop if platelets <100,000/mm³. 1
• Start before coagulation studies in patients without recent anticoagulant use, but stop if INR >1.7 or PT elevated. 1

Conditions That Are NOT Contraindications

Several clinical scenarios warrant clarification as they are not contraindications despite common misconceptions:

• Antiplatelet monotherapy or dual therapy: Prior aspirin, clopidogrel, or combination therapy is not a contraindication; alteplase is recommended despite slightly increased bleeding risk. 1
• End-stage renal disease on hemodialysis: Alteplase is recommended if aPTT is normal. 1
• Cervical artery dissection: More than 50 reported cases demonstrate safety and efficacy; this should not be considered a contraindication. 1
• Menstruation: Active menstruation is not a contraindication, though increased menstrual flow may occur. 1
• Pregnancy: Limited evidence (approximately 30 cases, 6 for stroke) suggests alteplase does not cross the placenta and appears safe; risks and benefits must be weighed but pregnancy alone is not an absolute contraindication. 1

Special Situations Requiring Careful Evaluation

• Intracardiac thrombus: Not an established contraindication, but carries risk of embolization; limited data (5 reported cases) show mixed outcomes with some recurrent embolic events. 1
• Unruptured intracranial aneurysm or AVM: Very limited case reports exist; 2 uncomplicated cases with unruptured aneurysms reported, but 2 fatal hemorrhages occurred after intraarterial thrombolysis with detected aneurysms. 1
• Recent myocardial infarction: Not included in European guidelines as contraindication, but poses theoretical risk of hemopericardium and tamponade. 1
• Infective endocarditis: Patients with symptoms consistent with endocarditis require careful evaluation. 1

Extended Time Window Considerations

For the 3-4.5 hour window, additional exclusion criteria apply beyond standard contraindications: 3, 4

• Age >80 years
• Oral anticoagulant use regardless of INR
• NIHSS score >25
• History of both prior stroke AND diabetes mellitus

Recent evidence from the HOPE trial (2025) demonstrates that alteplase administered 4.5-24 hours after onset in patients with salvageable tissue on perfusion imaging improved functional independence (40% vs 26%, P=0.004), though symptomatic ICH increased (3.8% vs 0.51%). 5 This represents evolving practice beyond current guideline recommendations and requires advanced imaging selection.

Blood Pressure Management

Blood pressure must be lowered to <185/110 mmHg before initiating alteplase. 2, 3 This is a prerequisite for safe administration, not a contraindication per se, but failure to achieve this target precludes treatment.