What are the contraindications to thrombolysis with alteplase (tissue plasminogen activator) in patients with acute cerebral vascular disease (CVD)?

Contraindications to Thrombolysis in Acute Cerebrovascular Disease

Intravenous alteplase should not be administered to patients with acute intracranial hemorrhage on CT, recent severe head trauma or intracranial/spinal surgery within 3 months, history of intracranial hemorrhage, coagulopathy (INR >1.7, aPTT >40s, platelets <100,000/mm³), treatment-dose LMWH within 24 hours, direct oral anticoagulants (unless normal labs or >48 hours since last dose with normal renal function), or symptom onset >4.5 hours. 1, 2

Absolute Contraindications

Imaging-Based Contraindications

• Any acute intracranial hemorrhage on CT is an absolute contraindication, as administration would be harmful 1, 2
• Extensive hypoattenuation (frank hypodensity representing irreversible injury involving large regions) contraindicates alteplase due to poor prognosis regardless of treatment 1, 2

Time-Based Contraindications

• Symptom onset >4.5 hours from last known well is a contraindication 1, 2
• Unclear or unwitnessed symptom onset where time last known at baseline exceeds 3-4.5 hours excludes treatment 1, 2
• Wake-up stroke where patient was last known well >4.5 hours prior is contraindicated 1, 2

Recent Neurological Events

• Ischemic stroke within 3 months may be harmful and contraindicates alteplase 1, 2
• Severe head trauma within 3 months contraindicates treatment due to bleeding risk, including posttraumatic infarction during acute hospitalization 1, 2
• Intracranial or spinal surgery within 3 months is potentially harmful 1, 2
• History of intracranial hemorrhage at any time is an absolute contraindication 1, 2

Active Bleeding and Hemorrhage Risk

• Symptoms consistent with subarachnoid hemorrhage contraindicate alteplase 1, 2
• GI malignancy or GI bleeding within 21 days represents high bleeding risk 1, 2

Coagulation Abnormalities

• Platelet count <100,000/mm³ contraindicates treatment, though you can initiate alteplase before results are available in patients without thrombocytopenia history and stop if platelets are low 1, 2
• INR >1.7 or PT >15 seconds contraindicates alteplase, though treatment can be started before results in patients without recent anticoagulant use 1, 2
• aPTT >40 seconds is a contraindication 1, 2
• Treatment-dose LMWH within 24 hours contraindicates alteplase 1, 2
• Direct oral anticoagulants (direct thrombin inhibitors or factor Xa inhibitors) contraindicate treatment unless laboratory tests are normal or patient has not received a dose for >48 hours with normal renal function 1, 2

Additional Absolute Contraindications

• Hypersensitivity to alteplase or any component of the formulation 3
• Infective endocarditis contraindicates treatment 2, 4
• Aortic arch dissection is a contraindication 4
• Intra-axial intracranial neoplasm contraindicates alteplase 4

Additional Exclusion Criteria for 3-4.5 Hour Window (ECASS III)

Beyond the standard contraindications, patients treated in the 3-4.5 hour window must meet stricter criteria:

• Age >80 years was an original ECASS III exclusion, though more recent evidence suggests treatment may be safe in this population 1, 4, 5
• NIHSS score >25 (severe stroke) excludes treatment in the 3-4.5 hour window 1, 4
• Any oral anticoagulant use regardless of INR excludes treatment in the 3-4.5 hour window 4
• History of BOTH diabetes mellitus AND prior stroke excludes treatment in the 3-4.5 hour window 1, 4
• Imaging evidence of ischemic injury involving >1/3 of MCA territory contraindicates treatment in the 3-4.5 hour window 1, 4

Blood Pressure Requirements

• Blood pressure must be safely lowered to <185/110 mmHg before initiating alteplase, with physician assessment of BP stability 1, 4, 5

Conditions That Are NOT Contraindications

Safe to Treat

• Antiplatelet monotherapy or dual therapy (including aspirin plus clopidogrel) is not a contraindication, despite slightly increased symptomatic ICH risk 1, 2
• End-stage renal disease on hemodialysis is not a contraindication if aPTT is normal 1, 2
• Glucose >50 mg/dL allows treatment in otherwise eligible patients 1
• Mild to moderate early ischemic changes on CT (other than frank hypodensity) do not contraindicate treatment 1

Special Situations Requiring Careful Evaluation

• Cervical artery dissection is not a contraindication, with >50 reported cases demonstrating safety and efficacy without new deficits, subarachnoid hemorrhage, or carotid rupture 1, 2
• Menstruation is not a contraindication, though increased menstrual flow may occur and transfusion may be needed 1, 2
• Pregnancy is not an absolute contraindication, as alteplase does not cross the placenta and limited evidence suggests safety, though risks and benefits must be carefully weighed 1, 2
• Intracardiac thrombus is not an established contraindication but carries embolization risk with mixed outcomes in limited case reports 1, 2
• Unruptured intracranial aneurysm or AVM requires careful evaluation, with very limited case reports and some fatal hemorrhages reported after intraarterial thrombolysis 1, 2
• Recent myocardial infarction poses theoretical risk of hemopericardium and tamponade, though not included as contraindication in European guidelines 1, 2

Critical Clinical Pitfalls to Avoid

• Do not delay treatment for non-essential laboratory tests - you can initiate alteplase before platelet count in patients without thrombocytopenia history, and before coagulation studies in patients without recent anticoagulant use, but must stop if contraindications are discovered 2, 5
• Do not exclude patients >80 years in the 3-4.5 hour window based on outdated ECASS III criteria, as more recent evidence supports treatment safety 4, 5
• Do not withhold treatment for mild symptoms if potentially disabling 5
• Do not wait to assess alteplase response before initiating thrombectomy evaluation in suspected large vessel occlusion 5
• Target door-to-needle time <60 minutes in 90% of patients, with median goal of 30 minutes 5

Dosing Protocol

• 0.9 mg/kg body weight (maximum 90 mg total) given over 60 minutes, with initial 10% of dose as bolus over 1 minute 4, 5