Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 13/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Evidence of hemorrhage Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 14/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 15/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Options to treat hypertension before and during reperfusion therapy for acu te ischemic stroke Patient otherwise eligible for acute reperfusion therapy except that blood pressure is >185/110 mmHg* Labetalol 10 to 20 mg intravenously over 1 to 2 minutes, may repeat one time; or Nicardipine 5 mg/hour intravenously, titrate up by 2.5 mg/hour every 5 to 15 minutes, maximum 15 mg/hour; when desired blood pressure reached, adjust to maintain proper blood pressure limits; or Clevidipine 1 to 2 mg/hour intravenously, titrate by doubling the dose every 2 to 5 minutes, maximum 21 mg/hour, until desired blood pressure reached ; or Other agents (hydralazine, enalaprilat, etc) may also be considered If blood pressure is not maintained at or below 185/110 mmHg, do not administer alteplase Management to maintain blood pressure at or below 180/105 mmHg during and after acute reperfusion therapy* Monitor blood pressure every 15 minutes for 2 hours from the start of rtPA therapy, then every 30 minutes for 6 hours, and then every hour for 16 hours If systolic blood pressure is >180 to 230 mmHg or diastolic is >105 to 120 mmHg: Labetalol 10 mg intravenously followed by continuous infusion 2 to 8 mg/min; or Nicardipine 5 mg/hour intravenously, titrate up to desired effect by 2.5 mg/hour every 5 to 15 minutes, maximum 15 mg/hour; or Clevidipine 1 to 2 mg/hour intravenously, titrate by doubling the dose every 2 to 5 minutes, maximum 21 mg/hour, until desired blood pressure reached If blood pressure is not controlled or diastolic blood pressure >140 mmHg, consider intravenous sodium nitroprusside Different treatment options may be appropriate in patients who have comorbid conditions that may benefit from acute reductions in blood pressure, such as acute coronary event, acute heart failure, aortic dissection, or preeclampsia/eclampsia. Clevidipine has been included as part of the 2018 guidelines for the early management of patients with acute ischemic stroke [1] . Reference: 1. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2018; 49:e46. Adapted with permission. Stroke. 2013: 44:870-947. Copyright 2013 American Heart Association, Inc. https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 16/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Graphic 50725 Version 15.0 https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 17/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Management of intracerebral hemorrhage after thrombolysis for ischemic stroke 1. Consider bleeding the likely cause of neurologic worsening after use of a thrombolytic drug until a brain scan confirms or refutes hemorrhage 2. Immediately discontinue ongoing infusion of thrombolytic drug 3. Obtain stat noncontrast head CT or MRI 4. Obtain blood samples for type and cross match, complete blood count, platelet count, PT, INR, aPTT, and fibrinogen 5. If symptomatic intracerebral hemorrhage is confirmed by imaging: Give cryoprecipitate 10 units infused over 10 to 30 minutes and more as needed to achieve a serum fibrinogen level of 150 to 200 mg/dL Consider aminocaproic acid 4 to 5 g IV over one hour followed by 1 g/hour for 8 hours until bleeding is controlled, or tranexamic acid 10 to 15 mg/kg IV over 10 to 20 minutes For patients on warfarin therapy prior to alteplase treatment, consider vitamin K and PCC as adjunctive therapy to cryoprecipitate, or FFP if PCC is not available For patients with thrombocytopenia (platelet count <100,000/microL), give 6 to 8 units of platelets For patients receiving unfractionated heparin for any reason, give 1 mg of protamine for every 100 units of UFH received in the preceding four hours 6. Obtain neurosurgery and hematology consultations; consider evacuation of the hematoma CT: computed tomography; MRI: magnetic resonance imaging; PT: prothrombin time; INR: international normalized ratio; aPTT: activated partial thromboplastin time; IV: intravenous; PCC: prothrombin complex concentrate; FFP: fresh frozen plasma; UFH: unfractionated heparin. Graphic 68717 Version 7.0 https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 18/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Contributor Disclosures Jamary Oliveira-Filho, MD, MS, PhD No relevant financial relationship(s) with ineligible companies to disclose. Owen B Samuels, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator- initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 19/19