Contraindications for Thrombolysis in Acute Ischemic Stroke

Absolute Contraindications

• The American Heart Association recommends that 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, treatment dose LMWH within 24 hours, or time from symptom onset >4.5 hours 1, 2, 3
• Intracranial hemorrhage on CT is an absolute contraindication for alteplase, as evidenced by any acute intracranial hemorrhage on non-contrast CT 1, 4, 5
• Extensive hypoattenuation, representing irreversible injury involving large regions of brain tissue, contraindicates alteplase due to poor prognosis regardless of treatment 1, 2, 3
• Symptom onset >4.5 hours is a contraindication for alteplase, with patients having unclear or unwitnessed symptom onset where time last known well exceeds 3-4.5 hours not receiving alteplase 1, 2, 3
• Wake-up stroke >4.5 hours, where patients awoke with stroke symptoms and were last known well >4.5 hours prior, is excluded from alteplase treatment 1, 2
• Ischemic stroke within 3 months is potentially harmful and contraindicates alteplase 1, 2, 6
• Severe head trauma within 3 months contraindicates alteplase due to bleeding risk, including posttraumatic infarction during acute hospitalization 1, 2, 6
• Intracranial/spinal surgery within 3 months is potentially harmful and contraindicates alteplase 1, 2, 6
• History of intracranial hemorrhage at any time is a contraindication for alteplase 1, 6, 4
• Subarachnoid hemorrhage symptoms and signs consistent with SAH contraindicate alteplase 1, 6, 4
• GI malignancy or bleeding within 21 days represents high risk and contraindicates alteplase 1, 6, 4
• Thrombocytopenia, with platelet count <100,000/mm³, contraindicates treatment, though treatment can be initiated before results are available and discontinued if platelets are low 1, 2, 6, 4
• Elevated INR/PT, with INR >1.7 or PT >15 seconds, contraindicates alteplase, though treatment can be initiated before results in patients without recent anticoagulant use 1, 2, 6, 4
• Elevated aPTT, with aPTT >40 seconds, contraindicates treatment 1, 2, 6, 4
• LMWH within 24 hours is a contraindication for alteplase, with treatment dose low molecular weight heparin within the previous 24 hours not receiving alteplase 1, 2, 3, 6
• Direct oral anticoagulants, including direct thrombin inhibitors or factor Xa inhibitors, contraindicate alteplase unless laboratory tests are normal or the patient has not received a dose for >48 hours with normal renal function 1, 2, 6, 4

Relative Contraindications

• Glycoprotein IIb/IIIa inhibitors should not be administered concurrently with alteplase outside clinical trials 4

Important Clinical Caveats

• Treatment can be initiated before laboratory results are available in appropriate patients, but must be discontinued if contraindications are discovered, with the American Heart Association recommending careful evaluation of patients before initiating alteplase 1, 2, 6
• Start alteplase before platelet count in patients without thrombocytopenia history, but stop if platelets <100,000/mm³, as recommended by the American Heart Association 1, 2, 6
• Start alteplase before coagulation studies in patients without recent anticoagulant use, but stop if INR >1.7 or PT elevated, with careful monitoring of coagulation parameters 1, 2, 6

Conditions That Are NOT Contraindications

• Antiplatelet monotherapy or dual therapy is not a contraindication, with the American Heart Association recommending alteplase despite slightly increased bleeding risk 3, 6
• End-stage renal disease on hemodialysis is not a contraindication, with alteplase recommended if aPTT is normal 1, 3
• Cervical artery dissection is not a contraindication, with more than 50 reported cases demonstrating safety and efficacy 7
• Menstruation is not a contraindication, though increased menstrual flow may occur, as reported in the literature 7
• Pregnancy is not an absolute contraindication, with limited evidence suggesting alteplase does not cross the placenta and appears safe, though risks and benefits must be weighed 7

Special Situations Requiring Careful Evaluation

• Intracardiac thrombus is not an established contraindication, but carries risk of embolization, with limited data showing mixed outcomes 7
• Unruptured intracranial aneurysm or AVM requires careful evaluation, with very limited case reports existing and 2 fatal hemorrhages occurring after intraarterial thrombolysis with detected aneurysms 7
• Recent myocardial infarction poses theoretical risk of hemopericardium and tamponade, though not included in European guidelines as contraindication 8
• Infective endocarditis requires careful evaluation, with patients having symptoms consistent with endocarditis needing thorough assessment 4

Contraindications and Considerations for Intravenous Alteplase in Acute Ischemic Stroke

Absolute Contraindications

• Intravenous alteplase is absolutely contraindicated when a non‑contrast CT shows intracranial hemorrhage, when the patient has had severe traumatic brain injury or any intracranial/spinal surgery within the preceding 3 months, when a coagulopathy is present, or when the time from symptom onset exceeds 4.5 hours. 9, 10
• Onset‑to‑treatment time > 4.5 hours (including unknown onset or last known well > 4.5 h) precludes alteplase administration. 9, 10
• Wake‑up strokes in which the patient was last known well > 4.5 hours ago are excluded from alteplase therapy. 9, 10
• Extensive hypodensity on CT indicating irreversible injury of > 1/3 of the middle cerebral artery territory is an absolute exclusion because of the poor prognosis. 9, 10
• A prior ischemic stroke within the previous 3 months may be harmful if alteplase is given. 9, 10
• Any history of intracranial hemorrhage (including subarachnoid hemorrhage) is a contraindication. 9, 10
• Severe traumatic brain injury within 3 months carries a high risk of bleeding and contraindicates alteplase. 9, 10
• Recent gastrointestinal bleeding or a malignant gastrointestinal tumor within 21 days places the patient at high bleeding risk and excludes alteplase. 9, 10
• Platelet count < 100 000/µL contraindicates treatment; therapy may be started before results but must be stopped if the count is low. 9, 10
• International Normalized Ratio > 1.7 or prothrombin time > 15 seconds contraindicates alteplase; therapy may be initiated before labs if no recent anticoagulant exposure, but must be halted if values are elevated. 9, 10
• Activated partial thromboplastin time > 40 seconds is a contraindication. 9, 10
• Therapeutic dose of low‑molecular‑weight heparin administered within the previous 24 hours precludes alteplase. 9, 10
• Direct thrombin inhibitors or factor Xa inhibitors are contraindications when laboratory tests are abnormal or when a dose was given > 48 hours ago in patients with normal renal function. 9, 10
• Blood pressure must be safely reducible to < 185/110 mm Hg before alteplase can be given. 9

Additional Exclusion Criteria for the 3–4.5‑Hour Window (ECASS III)

• Age > 80 years excludes patients from alteplase treatment in the 3–4.5 hour window. 9
• National Institutes of Health Stroke Scale (NIHSS) score > 25 (severe stroke) is an exclusion. 9
• The combination of diabetes mellitus and a prior stroke in the medical history excludes alteplase in this time window. 9

Situations Not Considered Contraindications

• Antiplatelet monotherapy or dual antiplatelet therapy does not preclude alteplase; the American Heart Association recommends treatment despite a modest increase in bleeding risk. 9
• End‑stage renal disease on chronic hemodialysis is not a contraindication provided the aPTT is normal. 9
• Cervical artery dissection is not a contraindication; > 50 reported cases demonstrate safety and efficacy of alteplase. 11

Special Situations Requiring Careful Assessment

• Intracardiac thrombus is not an established contraindication but carries a potential embolization risk. 11
• Unruptured intracranial aneurysm or arteriovenous malformation warrants meticulous evaluation because limited case reports describe fatal intracerebral hemorrhage after intra‑arterial thrombolysis. 11
• Recent myocardial infarction presents a theoretical risk of hemopericardium and tamponade; it is not listed as a contraindication in current European guidelines. 11

Practical Clinical Guidance

• In patients without known thrombocytopenia, alteplase may be started before platelet results are available, with the requirement to stop the infusion if the count falls below 100 000/µL. 9
• In patients without recent anticoagulant exposure, alteplase may be initiated before coagulation studies are completed, but the infusion must be halted if INR > 1.7 or PT is prolonged. 9
• Treatment should be initiated as rapidly as possible within the approved time windows because each minute of delay is associated with worse functional outcomes. 9

Timing of Recent Surgery Before Administering IV Alteplase in Cancer‑Associated Acute Ischemic Stroke

Guideline Recommendation

• Patients with systemic malignancy who have undergone major surgery must wait at least 14 days before receiving intravenous alteplase for acute ischemic stroke; surgery performed within this window is an absolute contraindication. This recommendation is based on observational data reported by the Stroke journal (2007) and is incorporated into contemporary stroke‑thrombolysis guidelines. 12

Intravenous Alteplase Use in Acute Ischemic Stroke Patients with Liver Malignancy

Guideline Position on Systemic Malignancy

• The 2018 American Heart Association/American Stroke Association (AHA/ASA) guidelines classify systemic malignancy as a relative contraindication to intravenous alteplase; safety and efficacy are not well established (Class IIb; Level of Evidence C‑LD)【13】.
• Patients with systemic malignancy who have a life expectancy > 6 months and no additional bleeding‑risk factors may still benefit from alteplase, because malignancy alone is not an absolute contraindication【13】.

Specific Contraindications and Eligibility Criteria

Absolute Contraindications (must be absent)

• Gastrointestinal (GI) malignancy or GI bleeding within the prior 21 days is an absolute contraindication (Class III: Harm)【14】【13】.
• Intra‑axial intracranial neoplasm (including intracranial metastases) is an absolute contraindication (Class III: Harm)【14】【13】.

Relative/Non‑Contraindicated Conditions

• Liver malignancy is not listed among absolute contraindications; it falls under “systemic malignancy” and requires careful evaluation but does not automatically preclude alteplase【14】【13】.

Laboratory and Physiologic Requirements (all must be met)

• Platelet count ≥ 100 000 /mm³【14】【13】.
• International Normalized Ratio (INR) ≤ 1.7【14】【13】.
• Activated partial thromboplastin time (aPTT) ≤ 40 seconds【14】【13】.
• Prothrombin time (PT) ≤ 15 seconds【14】【13】.
• No active internal bleeding (e.g., hematemesis, melena, hematuria)【14】【13】.

Prognostic Considerations

• Life expectancy > 6 months from the underlying liver malignancy is required to justify alteplase use【13】.
• Treatment is appropriate when the anticipated stroke‑related disability outweighs the bleeding risk, after confirming the above eligibility criteria【13】.

Practical Recommendations for Administration

• Proceed with the standard alteplase dosing regimen (0.9 mg/kg, maximum 90 mg, with 10 % given as an initial bolus) and monitor for hemorrhagic complications during and after infusion【13】.
• Do not delay alteplase for extensive cancer staging if acute imaging shows no intracranial metastases and all eligibility criteria are satisfied; treatment should be given within the therapeutic window【13】.
• Avoid conflating liver malignancy with GI malignancy; only structural GI cancer or recent GI bleeding constitutes an absolute contraindication【14】【13】.
• Confirm hepatic synthetic function (INR, PT, platelet count) before initiating therapy, as liver disease can impair coagulation despite normal laboratory values【14】【13】.