Contraindications to intravenous thrombolysis

Created 12/09/2022, last revision 21/04/2023

ESO 2021
AHA-ASA 2019
Many of the contraindications listed in the 2016 and 2019 guidelines have become relative or obsolete (see comments on IVT)
  • mild, non-disabling stroke
  • stroke > 4.5 hours from the onset in unselected patients
    • except for BAO and IVT guided by advanced imaging (see indications for IVT and comments on IVT contraindications)
  • patients with extensive regions of clear hypoattenuation on CT and extensive DWI lesions (severe stroke) (AHA/ASA 2019 III/A)
    • see comments; IVT may be used in selected cases
  • severe head trauma < 3 months
  • use of IV alteplase in patients with a prior ischemic stroke within 3 months  (AHA/ASA 2019 III/B-NR)
    • relative contraindication; see comments
  • recent intracranial or spinal surgery (< 3 months)
  • history of ICH
    • relative contraindication; see comments
  • acute SAH/ICH
  • GI tract tumor with high bleeding risk / recent GI bleeding (< 3 weeks) – IVT is potentially harmful
  • coagulopathy
    • platelet count < 100 000/mm3
    • antiplatelet therapy is not a contraindication to IVT   (AHA/ASA 2019 I/A  resp. I/B-NR)
  • known or suspected infective endocarditis   (AHA/ASA 2019 III/C-LD)
  • aortic dissection   (AHA/ASA 2019 III/C-EO)
  • intra-axial brain tumor – IVT is potentially harmful  (AHA/ASA 2019 III/C-EO)
  • BP > 185/110 mmHg despite intensive parenteral treatment
  • glycemia < 2.7 mmol/l (50 mg/dl) or  > 22 mmol/l (400 mg/dl)
    • relative contraindication; see comments

Other recommendations
(most relative contraindications are discussed in the comments on IVT)

  • Wake-Up Stroke (WUS)  –  DWI lesion < 1/3 of MCA territory  + negative FLAIR (DWI/FLAIR mismatch according to the WAKE-UP trial)    (AHA/ASA 2019  IIa/B-R)
  • premorbid disability (including cognitive deficit) – IVT may be considered after evaluation of the premorbid status, quality of life, and risk-benefit ratio
  • dural puncture in < 7 days – IVT may be considered (AHA/ASA 2019 IIb/C-EO)
  • IC malformation – the benefit and risk of IVT are unclear; given the increased risk of bleeding, it may be considered in patients with a severe deficit if the benefits of treatment outweigh the risks
  • acute MI – IVT is not contraindicated    (AHA/ASA 2019 IIa/C-EO)
  • periprocedural stroke – IVT may be considered; prefer direct MT if eligible
  • malignancy – patients with survival > 6 months may benefit from IVT without other malignancy-related contraindications (e.g., coagulopathy, recent surgery, etc.)
  • drug-induced stroke – IVT may be administered in the absence of other significant contraindications (AHA/ASA 2019 IIa/C-LD)
  • eye disease – IVT may be administered in patients with a history of hemorrhagic retinopathy or other hemorrhagic ocular condition; always weigh the benefits against the risk of complications   (AHA/ASA 2019 IIa/B-NR)
  • sickle cell disease – IVT may be beneficial   (AHA/ASA 2019 IIa/B-NR)
Comments to some contraindications
  • more and more patients, especially in experienced centers, are successfully treated with IVT despite some of the originally published contraindications (off-label thrombolysis)
  • this practice was reflected in the recent guidelines and recommendations, where some contraindications became relative or were abandoned (e.g., advanced age)
    • most of the relative contraindications listed in the ESO guidelines 2021 refer to the 0-4.5h time window (with increasing experience, it can be expected to be officially extended to the 4.5-9h window in selected patients)
  • typical contraindications that are not respected:
    • advanced age
    • history of stroke AND diabetes
    • 4.5 hour window
    • mild or resolving deficit or, conversely, severe stroke
    • aggressive treatment with parenteral antihypertensives to achieve target blood pressure before starting IVT
    • use of oral anticoagulants
  • always carefully consider risk/benefit
  • low risk of sICH (→ see here for thrombolysis-related ICH classification)
    • according to SITS-ISTR, the risk of parenchymal hematoma in stroke mimics was 1.2%     [Keselman, 2019]
    • according to meta-analyses, the risk of sICH is approx. 0.5%   [Tsivgoulis, 2015]
  • always exclude isodense SDH ⇒ high risk of bleeding complications!!
  • imaging methods may help confirm true stroke (CTA/MRA, CTP/MRP, DWI)
  • seizures are a common stroke mimic, but may also be present in acute stroke patients as well (seizure at stroke onset)
  • evidence of occlusion on CTA or CTP or early signs of ischemia on NCCT may help to confirm the stroke
  • if there is no clear suspicion of mimics or head trauma, then IVT is more likely to be performed (ESO guidelines 2021)
    • particularly in more severe deficits, it is probably a bigger mistake to withhold IVT in a patient with stroke than to thrombolyse mimics. The risk of thrombolysis-related bleeding in seizure is very low (as it is generally for all mimics)   [Polymeris, 2019]
  • according to a meta-analysis of the WAKE-UP, EXTEND, THAWS, and ECASS-4 trials, IVT indicated by advanced imaging is safe and effective [Thomalla, 2020]
  • if the patient is a candidate for both IVT and MT, then IVT is more likely to be performed before MT  (ESO Guidelines 2021 expert consensus)
  • IVT can be performed in WUS patients who have (according to guidelines):
    • DWI/FLAIR mismatch –  DWI lesion < 1/3 of MCA territory + negative FLAIR – meets the WAKE-UP trial criteria (AHA/ASA 2019 IIa/B-R) (ESO 2021)
    • evidence of penumbra on multimodal CT (criteria used in the EXTEND trial)  (ESO 2021)
  • ESO 2021 guidelines do not recommend IVT in the 4.5-9h time window after stroke onset or in WUS based on NCCT alone
  • this section applies to
    • TIA (NIHSS 0)
    • minor stroke (NIHSS 1-4)
    • rapidly improving stroke – NIHSS improvement of ≥ 4 points
    • special syndromes (hemianopsia, Gerstmann syndrome, posterior circulation stroke, monocular blindness due to CRAO)
  • up to 50% of patients with NIHSS 0-6 will develop an infarction, and 40% will have an unfavorable outcome [Strbian, 2013]
  • advanced imaging can help decide whether to administer tPA
  • it is recommended to thrombolyse patients with:
    • mild disabling deficit (e.g., homonymous hemianopsia, mild aphasia or dysarthria in an actor, mild paresis in a pianist, etc.)  (ESO guidelines 2021) (AHA/ASA 2019 I/B-R)
    • rapidly improving but still disabling deficit
      • 1/3 of patients will progress and develop a permanent deficit after initial improvement [Smith, 2005]   [Smith, 2011]
      • there is potential benefit of IVT (even mild deficits can be bothersome) and the low risk of ICH
    • mild non-disabling deficit + persistent cerebral artery occlusion (ESO 2021 – expert consensus)
      • neurological deficits may fluctuate; many patients with acute arterial occlusion will eventually progress  if recanalization is not achieved (END – Early Neurological Deterioration)
      • CT perfusion with the RAPID system is a valuable tool in the detection of peripheral occlusions
  • if IVT is not indicated due to regression of the deficit, the patient should be closely monitored throughout the entire thrombolytic window
  • a mild non-disabling deficit should not be thrombolyzed (ESO guidelines 2021) (AHA/ASA 2019 III/B-R)
    • see the PRISMS trial results (2018)
  • “severe stroke” criteria:
    • NIHSS > 25
    • presence of early signs of ischemia > 1/3 of the MCA territory
    • ASPECTS < 7
  • it seems that even in this group of patients, there may be a benefit of IVT and there may not be an increased risk of bleeding
    • a joint analysis of the ECASS, NINDS, and Atlantis trials showed a benefit of IVT but with an increased risk of poor outcome
    • the benefit of IVT was shown in patients with NIHSS > 22 [Frank, 2013]
  • in patients with clinically severe stroke of <4.5 h duration, IVT is recommended
  • for patients with severe stroke (defined by the extent of early ischemic changes on CT) of <4.5 h duration,  IVT should be considered in selected cases (ESO 2021)
  • if bleeding risk is further increased (extensive leukoencephalopathy, known microbleeds, etc.) consider direct MT
  • previous ICH
    • patients with previous ICH were excluded from thrombolytic trials, and IVT is generally not recommended for them; we only have data from case series and small non-randomized cohorts where no exaggerated increase in ICH was observed [Zhao, 2019]
    • the risk of ICH depends on the etiology of previous bleeding
      • amyloid angiopathy or untreated vascular malformations carry a high risk
      • relatively low risk is present in patients with hypertonic bleeding > 12 months ago
    • the decision on IVT is individual (ESO guidelines 2021 – expert consensus)  (ESO guidelines 2021 – expert consensus)
      • administration of IVT may be recommended if a long time has elapsed since the hemorrhage, for non-recent subcortical ICH, for bleeding from a secured source, for bleeding caused by the anticoagulant agent overdose, etc.
  • cerebral microbleeds (CMBs)
    • there is an increased risk of bleeding with CMBs > 10 (OR 13 !) ⇒ it is recommended not to perform IVT ( (ESO guidelines 2021)   [Zand, 2017]   [Fiehler, 2007]
    • for patients with unknown or low cerebral microbleed burden (e.g., <10), IVT is suggested (ESO guidelines 2021)
      • probability of finding > 10 CMBs is approx. 0.6-2.7% – MRI screening to assess cerebral microbleeds before making a treatment decision regarding IVT is not recommended
  • TIA
    • data only from case reports and small series of patients
    • patients with a previous TIA (<1 month) do not appear to be at higher risk of bleeding complications or worse outcome after IVT  [De Leciñena, 2012]
    • IVT seems to be safe even in patients with very recent TIA [Tsivgoulis, 2014]
  • recent stroke
    • IVT can be used in selected cases (e.g., lacunar infarction, infarction occurring > 1 month ago with good recovery) (ESO guidelines 2021)
    • a meta-analysis of 900 patients did not find a higher incidence of sICH or a worse outcome  [Tsivgoulis, 2019]
    • a higher risk is seen in recent stroke (within 14 days); the location and extent of ischemia and the etiology of the previous stroke should also be considered (higher risk of sICH in cardioembolic stroke) [Tan, 2014]
    • IVT appears to be safe in asymptomatic infarcts detected on DWI [Stösser, 2020]
  • for patients with an initial BP of >185/110 mmHg that has been lowered (with/without antihypertensive drugs) to <185 and <110 mm Hg, IVT is recommended (ESO guidelines 2021)
    • a subanalysis of the IST-3 trial and other smaller studies have not shown an increased risk of bleeding in patients treated aggressively for hypertension [Martin-Schild, 2008]
    • strict BP control is required for 24 h after thrombolysis
    • another analysis showed a higher incidence of sICH in patients with BP > 185/110; however, they had a better clinical outcome (mRS) compared to controls [Frank, 2013]
  • for patients with persistently increased BP >185/110 mmHg even after antihypertensive treatment, intravenous thrombolysis is not recommended  (ESO guidelines 2021)
  • originally, IVT was contraindicated in hypoglycemia  (< 2.7 mmol/l / 50 mg/dL) or hyperglycemia ( > 22 mmol/L / 400 mg/dL)
    • hypoglycemia in particular can lead to “stroke mimics”
    • hyperglycemia is associated with a worse outcome and ↑  risk of sICH
  • according to expert recommendations:
    • no contraindication in case of proven stroke  (CT/CTA/CTP or MR-DWI)
    • IVT is suggested in the presence of glycemia > 22 mmol/l (400 mg/dl) even without evidence of arterial occlusion (ESO guidelines 2021)
    • if hypoglycemia is corrected and deficit persists, then IVT can be performed (administration of IVT in patients with stroke mimics is relatively safe)
  • IVT should not prevent the administration of insulin therapy in acute stroke patients with high blood glucose
  • IVT is not recommended when the platelet count is < 100 000 /mm3 (ESO guidelines 2021)
  • IVT can be considered (off-label) if the platelet count is 70 000-100 000 /mm3   [Tsivgoulis, 2021]
  • if the platelet count is unknown and there is no reason to expect abnormal values, IVT can be started while waiting for lab results (ESO guidelines 2021)
  • DAPT is associated with only a modest increase in ICH and does not worsen outcome  [Malhotra, 2020]
    • mortality 17.9% vs. 16.6%, sICH 2.9% v.s. 1.5% (according to SITS-MOST criteria)  [Tsivgoulis, 2018]
  • IVT is not contraindicated in patients with single or dual antiplatelet therapy (AHA/ASA 2019 I/B-NR)   (ESO guidelines 2021)


  • intra-axial tumors remain a contraindication to IVT due to the high risk of sICH
  • patients with extra-axial tumors (typically meningiomas) can be treated with IVT after an individual risk-benefit assessment
  • optimally, MRI should be done to detect microbleeds in the tumor and to assess the extent of any collateral edema
  • renal failure is generally not a contraindication to IVT
  • severe CKD (<30 mL/min per 1.73 m2) is associated with higher mortality and worse outcome, but not with increased sICH; it may be a consequence of comorbidities, not of IVT itself
  • avoid IVT in case of unfavorable risk-benefit ratio (e.g., minor stroke + poorly controlled hypertension or multiple relative CIs)
  • APTT must be normal
  • IVT appears to be safe for saccular aneurysms, including larger ones (> 10 mm) [Virta, 2021]
  • IVT can be performed in patients with unruptured aneurysms (without specifying the size)  (ESO guidelines 2021)
  • patients with AVMs, cavernomas, and DAVFs should be treated individually – data are limited
  • according to older European recommendations, the interval between IVT and surgery should be 3 months; according to AHA/ASA 14 days, new ESO guidelines 2021 call for 14 days
  • IVT may be safely performed in postoperative patients as an off-label procedure, evaluate the risk-benefit according to the type of surgery and the compressibility of the surgical field
  • in a cohort of patients thrombolyzed after previous surgical procedures, including major procedures, the risk of bleeding was 7%, of which 3% were major; the risk was higher with recent procedures (< 10 days, OR 10) [Voelkel, 2017]
  • a relative contraindication
  • according to the available data, it is better not to administer IVT for recent GIT bleeding (< 3 weeks) and severe traumatic brain injury (TBI) in < 3 months (consider the type and extent of the injury and CT findings)
  • recent extracranial trauma (< 14d) – IVT can be considered (AHA/ASA 2019)
  • isolated extracranial carotid dissection – IVT recommended (ESO guidelines 2021)
  • aortic arch dissection – absolute contraindication to IVT! (ESO guidelines 2021)
  • intracranial dissection – IVT should be avoided  (ESO guidelines 2021 – expert consensus)
  • even extensive leukoencephalopathy is not a clear contraindication to IVT (ESO guidelines 2021)

→ quantification of white matter lesions (FAZEKAS)

  • acute myocardial infarction (MI) (< 6h) is not a contraindication to IVT (standard tPA dose 0.9 mg/kg is used)
  • subacute MI (> 6h – 7 days) with ST elevation – IVT is not recommended (ESO guidelines 2021)
  • subacute MI (>1 week and < 3 months) was the official contraindication to IVT (↑ risk of hemopericardium and tamponade); however, according to AHA/ASA guidelines 2018 and ESO guidelines 2021, IVT may be performed in non-STEMI and considered in STEMI of inferior wall, right heart and left anterior wall   (ESO guidelines 2021)
    • most complications occur in recent STEMI  ( < 1 week from onset)
    • the extent of myocardial infarction and available TTE findings should be taken into account
  • infective endocarditis IVT is not recommended for patients with a definite or suspected diagnosis of infective endocarditis (ESO guidelines 2021)
  • pericarditis – IVT can be considered in severe stroke; the benefit in mild stroke is unclear; consult a cardiologist
  • intracardiac thrombus – IVT should be considered in severe stroke; the benefit in mild stroke is unclear
  • myxoma and fibroelastoma  – IVT should be considered in severe stroke; the benefit in mild stroke is unclear
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Intravenous thrombolysis (IVT)

  • due to its large molecule size, tPA does not cross the placental barrier; there is no evidence of teratogenicity
  • there are concerns about placental abruption, intrauterine hemorrhage, preterm delivery, or fetal death
  • there are no data from RCTs (pregnancy was an exclusion criterion)
  • most case reports and small series are from patients who received thrombolysis for non-stroke diagnoses than stroke (PE, valvular thrombosis, DVT, stroke, myocardial infarction)
    • in 8 published cases of IVT, only 1 case of uterine bleeding occurred
    • according to a published cohort of 28 patients, the risk of TL-related abortion was 8%, and the maternal risk of IVT did not differ from that of non-pregnant patients  [Leonhardt, 2006]
    • case reports of successful IVT for stroke in late pregnancy have also been published [Wiese, 2006]  [Daprich, 2006]
  • all recommendations are based on expert consensus (ESO guidelines 2022)
  • IVT may be considered on an individual basis for moderate and especially severe stroke when the expected benefit of IVT outweighs the risk of uterine bleeding (ESO guidelines 2022 – expert consensus)  (AHA/ASA 2019 IIb/C-LD)
  • factors favoring IVT:
    • severe, debilitating deficit
    • likely benefit of IVT
      • MR DWI/PWI mismatch and small lesion on DWI
      • likely peripheral occlusion – from M2 distally
    • if MT is available and LVO is involved, direct MT is preferable to bridging therapy
  • stroke occurring shortly after delivery
    • the safety and efficacy of IVT shortly after delivery (<10 days) are not established (AHA/ASA 2019 IIb/C-LD)
    • if the stroke occurs > 10 days after delivery, IVT may be given after individual consideration  (ESO guidelines 2022 – expert consensus)
      if MT is available and there is a presumption of increased bleeding risk, dMT is preferred   (ESO guidelines 2022 – expert consensus)

Mechanical recanalization

  • there is a relatively limited experience with MT in pregnant women; no RCTs are available
  • direct MT may be preferable to bridging therapy for LVO during pregnancy and shortly after delivery
  • fetal shielding with lead vests is required
IVT in children
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Contraindications to intravenous thrombolysis