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Stroke Associated with COVID-19 Vaccines

  • Maryam Kakovan
    Affiliations
    School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
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  • Samaneh Ghorbani Shirkouhi
    Affiliations
    School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran

    Neuroscience Research Center, Poursina Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
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  • Mojtaba Zarei
    Affiliations
    Institute of Medical Science and Technology, Shahid Beheshti University, Tehran, Iran

    Department of Neurology, Odense University Hospital, University of Southern Denmark, Odense, Denmark

    Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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  • Sasan Andalib
    Correspondence
    Address correspondence to Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
    Affiliations
    Department of Clinical Research, University of Southern Denmark, Odense, Denmark

    Research Unit of Clinical Physiology and Nuclear Medicine, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark

    Steno Diabetes Center Odense, Department of Clinical Research, University of Southern Denmark, Odense, Denmark

    BRIDGE: Brain Research – Interdisciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark

    Neuroscience Research Center, Guilan University of Medical Sciences, Rasht, Iran
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Open AccessPublished:March 03, 2022DOI:https://doi.org/10.1016/j.jstrokecerebrovasdis.2022.106440

      Abstract

      Objectives

      Development of safe and effective vaccines against coronavirus disease 2019 (COVID-19) remains the cornerstone of controlling this pandemic. However, there are increasing reports of various types of stroke including ischemic stroke, and hemorrhagic stroke, as well as cerebral venous sinus thrombosis (CVST) after COVID-19 vaccination. This paper aims to review reports of stroke associated with COVID-19 vaccines and provide a coherent clinical picture of this condition.

      Materials and methods

      A literature review was performed with a focus on data from recent studies.

      Results

      Most of such patients are women under 60 years of age and who had received ChAdOx1 nCoV-19 vaccine. Most studies reported CVST with or without secondary ischemic or hemorrhagic stroke, and some with Vaccine-induced Thrombotic Thrombocytopenia (VITT). The most common clinical symptom of CVST seen after COVID-19 vaccination was headache. The clinical course of CVST after COVID-19 vaccination may be more severe than CVST not associated with COVID vaccination. Management of CVST following COVID-19 vaccination is challenging and may differ from the standard treatment of CVST. Low molecular weight heparin is commonly used in the treatment of CVST; however, it may worsen outcomes in CVST associated with VITT. Furthermore, administration of intravenous immunoglobulin and high-dose glucocorticoids have been recommended with various success rates.

      Conclusion

      These contradictory observations are a source of confusion in clinical decision-making and warrant further study and development of clinical guidelines. Clinicians should be aware of clinical presentation, diagnosis, and management of stroke associated with COVID-19 vaccination.

      Key Words

      Introduction

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      Management and treatment of stroke are usually challenging, but it is more so in VITT-associated stroke. This review paper summarizes reports of stroke after COVID-19 vaccination and gives account of its clinical picture, management, and treatment. For this review, we searched PubMed and Google Scholar databases for the following keywords: Stroke, cerebral venous sinus thrombosis, CVST, cerebral venous thrombosis, CVT, cerebrovascular accident, CVA, cerebrovascular event, thrombosis, ischemic stroke, intracerebral hemorrhage, intracranial hemorrhage, ICH, hemorrhage, vaccine, COVID-19, SARS-CoV-2, corona, complication, side effect.

      Different types of COVID-19 vaccines: how they work

      COVID-19 vaccines motivate the immune system to create antibodies against SARS-CoV-2. The vaccines use a harmless structure similar to spike (S) protein, which is present on the surface of SARS-CoV-2 and is used for viral endocytosis to the host cells. The COVID-19 vaccines include messenger RNA (mRNA), vector, protein subunit, and inactivated/weakened vaccines.

      Myoclinic: Different types of COVID-19 vaccines: how they work. Availabe online: https://www.mayoclinic.org/diseases-conditions/coronavirus/in-depth/different-types-of-covid-19-vaccines/art-20506465 (accessed on 6 Oct 2021)

      ,

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      Engineered mRNA COVID-19 vaccines namely Pfizer-BioNTech (BNT162b2) and the Moderna (mRNA-1273) give the cells instructions to make S protein which may generate antibodies. After delivering instructions, the mRNA is broken down immediately and does not enter the nucleus of the host cells. In vector COVID-19 vaccines viz Ad26.COV2.S, Sputnik V (rAd26-S and rAd5-S), and ChAdOx1 nCoV-19 SARS-COV-2’s, genetic material is inserted in a viral vector. The vector delivers the genetic material to the host cells that make copies of the S protein on their surfaces. The immune system then responds by creating antibodies and defensive white blood cells. Protein subunit COVID-19 vaccines such as Novavax (NVX-CoV2373) include only harmless S protein which stimulates the immune system. Inactivated or weakened COVID-19 vaccines do not cause disease, but still, stimulate the immune system.

      Vaccine-induced neurological complications

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      COVID-19 vaccines may trigger stroke with thrombotic thrombocytopenia with or without the presence of anti-platelet factor 4 antibody (anti-PF4 antibody). Such association between thrombocytopenia and thrombosis with a catastrophic clinical picture has raised clinical attention. Association of thrombosis and thrombocytopenia rarely occurs in thrombotic thrombocytopenic purpura, heparin-induced thrombocytopenia (HIT), autoimmune HIT, antiphospholipid syndrome (APS),
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      The clinical picture mirrors what is seen in HIT.
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      suggested that anti-PF4 antibody do not cross-react with the S protein.
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      showed that intravenous injection of ChAdOx1 nCov-19 triggers platelet-targeted autoimmunity in the spleen that may result in thrombocytopenia syndrome. Hence, aspiration (to ensure the needle is not in a blood vessel) prior to injection of the vaccine could be a potential preventive measure for this important side effect.
      Most of the reports of stroke after COVID-19 are from Europe. In addition, most of the patients were women within an age range of 18-77 years and within 1-24 days after the ChAdOx1 nCov-19 vaccination.

      Ischemic stroke after COVID-19 vaccination

      In ischemic stroke, a region of the brain is dispossessed of blood flow which can be due to thrombosis of an artery or, in rare instances, a vein. Thrombosis can occur in the vessels following COVID-19 vaccination. They are usually seen in the context of VITT. These cases were mostly diagnosed following ChAdOx1 nCoV-19 vaccine, especially with the involvement of the middle cerebral artery (MCA). The emergence of persistent or unusual neurological symptoms after receiving the COVID-19 vaccines should urgently be evaluated for VITT with neuroimaging techniques and laboratory tests.
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      carried out clot analysis after thrombectomy in patients with ischemic stroke following the ChAdOx1 nCoV-19 vaccine and suggested that the clot collected during the first thrombectomy was mainly composed of platelets (85% of the total material examined) and was massively infiltrated by neutrophils with scarce evidence of karyorrhexis. Histological features consistent with the presence of neutrophil DNA extracellular traps (NETs) were also observed. Furthermore, the clot collected during the second endovascular procedure was a red-blood-cell-rich thrombus (90% of red blood cells and 10% fibrin and platelets) with scarce neutrophils. Normally, platelet-rich thrombi are formed by Von Willebrand factor, neutrophil extracellular traps, and fibrin.
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      Table 1 shows that most of the patients with ischemic stroke after COVID-19 vaccination were women within the age range of 26-60 years and after vaccination with ChAdOx1 nCoV-19 vaccines and within 1 to 21 days after the vaccination.
      Table 1Summary of reports of ischemic stroke cases following the COVID-19 vaccination.
      VaccineNumber of casesAge Gender (F, M)Interval (days) between vaccination and diagnosisClinical presentationImaging and lab findingsTreatmentOutcomeAuthor, year, ref
      ChAdOx1 nCoV-19 (AstraZeneca)335-43

      F = 2, M = 1
      11-21Case 1: headache, left hemiparesis, right gaze preference, and drowsiness

      Case 2: diffuse headache, left visual field loss, confusion, and left arm weakness

      Case 3: dysphasia
      Case 1: MCA infarct

      Case 2: ICA infart and CVST

      Case 3: MCA infarct

      Thrombocytopenia, positive anti-PF4 antibody, and increased D-dimer in all three patients
      Case 1: IVIg, plasmapheresis, Fondaparinux, and decompressive hemicraniectomy

      Case2: IVIg, plasmapheresis, methylprednisolone, and Fondaparinux

      Case 3: platelet transfusion, IVIg, and Fondaparinux
      Case1: death

      Case 2: improved clinically

      Case3: discharged with favorable clinical outcome
      Al-Mayhani et al., 2021
      • Al-Mayhani T.
      • Saber S.
      • Stubbs M.J.
      • et al.
      Ischaemic stroke as a presenting feature of ChAdOx1 nCoV-19 vaccine-induced immune thrombotic thrombocytopenia.
      160

      F = 1
      8headache and leftweakness and eye deviation to the rightIschemic stroke in the territory of ICA and MCA

      Thrombocytopenia, positive anti-PF4 antibody, and increased D-dimer
      Hydrocortisone, platelet concentrates, hemicraniectomy, and dalteparinDeathBlauenfeldt et al., 2021(53)
      126

      F = 1
      1Persistent nausea and headache and right hemiplegia and aphasiaIschemic stroke in the territory of MCA

      Thrombocytopenia, positive anti-PF4 antibody, decreased fibrinogen level
      Corticosteroids, plasmatic exchange, and anticoagulantsOnly gripping difficulties and minor phasic troubles were remainingGarnier et al., 2021
      • Garnier M.
      • Curado A.
      • Billoir P.
      • et al.
      Imaging of Oxford/AstraZeneca® COVID-19 vaccine-induced immune thrombotic thrombocytopenia.
      2321-77

      (mean:46)

      F = 14 M = 9
      6-24 (mean:12)NMThirteen cases of CVST

      Two cases of ischemic stroke

      antiPF4 antibody was positive in 22 patients

      Thrombocytopenia in 22 patients, low fibrinogen levels in 13 patients, and increased D-dimer levels in 21 patients
      NMSeven patients diedScully et al., 2021
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      • et al.
      Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination.
      131

      M=1
      8Acute headache, aphasia, and hemiparesisOcclusion of MCA with the source of thrombus ipsilateral in the carotid bulb,

      elevated D-dimer level slightly, and positive anti-PF-4 antibody
      IV thrombolysis, Aspirin, Danaparoid, PhenprocoumonFavorable clinical outcomeWalter et al., 2021
      • Walter U.
      • Fuchs M.
      • Grossmann A.
      • et al.
      Adenovirus-vectored COVID-19 vaccine-induced immune thrombosis of carotid artery: a case report.
      2Case 1 = 55, Case 2 = 57

      F=2
      Case 1 = 9, Case 2 = 10Case 1: left hemiplegia, right gaze deviation, dysarthria, and left neglect

      Case 2: aphasia, right hemiparesis, generalized seizures, and coma
      Ischemic stroke

      Thrombocytopenia, positive anti-PF4 antibody, and increased D-dimer level
      Case 1: mechanical thrombectomy, platelet transfusion, IVbetamethasone, IVIg, plasma exchange, fondaparinux

      Case 2: IVIg and dexamethasone
      Case 1: critical condition

      Case 2: Brain death
      De Michele et al., 2021
      • De Michele M.
      • Iacobucci M.
      • Chistolini A.
      • et al.
      Malignant cerebral infarction after ChAdOx1 nCov-19 vaccination: a catastrophic variant of vaccine-induced immune thrombotic thrombocytopenia.
      Note: MCA: Middle Cerebral Artery; CVST: Cerebral Venous Sinus Thrombosis; Anti-PF4-antibody: anti-platelet factor 4 antibody; IVIg: Intravenous Immunoglobulin; IV: Intravenous.

      Hemorrhagic stroke after COVID-19 vaccination

      Hemorrhagic strokes occur when a blood vessel ruptures. ICH and subarachnoid hemorrhage (SAH) can occur after COVID-19 vaccination, which can be primary or secondary to venous thrombosis.
      • Bjørnstad-Tuveng T.H.
      • Rudjord A.
      • Anker P.
      Fatal cerebral haemorrhage after COVID-19 vaccine.
      ,
      • Castelli G.P.
      • Pognani C.
      • Sozzi C.
      • et al.
      Cerebral venous sinus thrombosis associated with thrombocytopenia post-vaccination for COVID-19.
      • D’Agostino V.
      • Caranci F.
      • Negro A.
      • et al.
      A rare case of cerebral venous thrombosis and disseminated intravascular coagulation temporally associated to the COVID-19 vaccine administration.
      • Franchini M.
      • Testa S.
      • Pezzo M.
      • et al.
      Cerebral venous thrombosis and thrombocytopenia post-COVID-19 vaccination.
      • Mehta P.R.
      • Apap Mangion S.
      • Benger M.
      • et al.
      Cerebral venous sinus thrombosis and thrombocytopenia after COVID-19 vaccination-a report of two UK cases.
      • de Melo Silva M.L.
      • Lopes D.P.
      Large hemorrhagic stroke after ChAdOx1 nCoV-19 vaccination: a case report.
      • Ikenberg B.
      • Demleitner A.F.
      • Thiele T.
      • et al.
      Cerebral venous sinus thrombosis after ChAdOx1 nCov-19 vaccination with a misleading first cerebral MRI scan.
      While ICH after COVID-19 vaccination can occur in the context of VITT, Silva et al.
      • de Melo Silva M.L.
      • Lopes D.P.
      Large hemorrhagic stroke after ChAdOx1 nCoV-19 vaccination: a case report.
      described primary hemorrhagic stroke following ChAdOx1 nCoV-19 vaccination in a patient without thrombocytopenia, coagulation disorder, or coagulation risk factors. Argument for such a causal relation is that arterial hypertension
      • Meylan S.
      • Livio F.
      • Foerster M.
      • et al.
      Stage III hypertension in patients after mRNA-based SARS-CoV-2 vaccination.
      and ICH
      • Bjørnstad-Tuveng T.H.
      • Rudjord A.
      • Anker P.
      Fatal cerebral haemorrhage after COVID-19 vaccine.
      ,
      • Greinacher A.
      • Thiele T.
      • Warkentin T.E.
      • et al.
      Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination.
      are complications of COVID-19 vaccination. More to the point, hypertension is an important risk factor of ICH.
      Finsterer et al.
      • Finsterer J.
      • Korn M.
      Aphasia seven days after second dose of an mRNA-based SARS-CoV-2 vaccine.
      suggested that the second dose of SARS-CoV-2 vaccination may be followed by ICH even when the first dose was uneventful Table 2. summarizes reports of ICH following COVID-19 vaccination. As can be noted, most of the cases were reported following administration of ChAdOx1 nCoV-19 vaccine and in people 30–57 years of age, 5–12 days after the vaccination Table 2. shows the summary of reports of ICH following the COVID-19 vaccination.
      Table 2Summary of reports of ICH following the COVID-19 vaccination.
      VaccineNumber of casesAge Gender (F, M)Interval (days) between vaccination and diagnosisClinical presentationImaging and lab findingsTreatmentOutcomeAuthor, year, ref
      ChAdOx1 nCoV-19 (AstraZeneca)1In her thirties

      F = 1
      10Headache, lethargy, uncoordinated movements, reduced consciousness, aphasia, central left facial paresis with right gaze deviation, and left hemiparalysisICH (MCA)

      Thrombocytopenia and positive anti-PF4 antibody

      Thrombi in the transverse sinus in autopsy
      IV tranexamic acidDeathBjørnstad et al., 2021
      • Bjørnstad-Tuveng T.H.
      • Rudjord A.
      • Anker P.
      Fatal cerebral haemorrhage after COVID-19 vaccine.
      157

      F=1
      5Fever, headache, left hemiparesis, vomiting, and somnolenceICHDecompressive craniectomyOn Day 15 left hemiparetic, obeying simple tasks, kept on tracheostomySilva et al., 2021
      • de Melo Silva M.L.
      • Lopes D.P.
      Large hemorrhagic stroke after ChAdOx1 nCoV-19 vaccination: a case report.
      mRNA-based SARS-CoV-2 vaccine152

      M=1
      7aphasiaICH in temporal lobeSacubitril/valsartan, atorvastatin, and bisoprolol in the rehabilitationAphasia resolvedFinsterer et al., 2021
      • Finsterer J.
      • Korn M.
      Aphasia seven days after second dose of an mRNA-based SARS-CoV-2 vaccine.


      ChAdOx1 nCoV-19 (Vaxzervia)
      152

      M = 1
      12Intense headache, GCS;6ICH

      Thrombocytopenia, elevated fibrin D-dimer level, low fibrinogen level, slightly increased INR
      Tranexamic acid, platelet concentrateDeathWolthers et al.,2021
      • Wolthers S.A.
      • Stenberg J.
      • Nielsen H.B.
      • et al.
      [Intracerebral haemorrhage twelve days after vaccination with ChAdOx1 nCoV-19].
      Note: MCA: Middle Cerebral Artery; Anti-PF4-antibody: anti-platelet factor 4 antibody; ICH: Intracerebral Hemorrhage; INR: International Normalized Ratio; IV: Intravenous; GCS: Glasgow Coma Scale.

      Cerebral venous sinus thrombosis after COVID-19 vaccination

      CVST is a rare form of stroke occurring often in young and middle-aged women.
      • Sadeghi-Hokmabadi E.
      • Sakhinia E.
      • Farhoudi M.
      • et al.
      Common prothrombotic gene mutations in cerebral venous sinus thrombosis in North-West of Iran.
      Partial or complete occlusion of cerebral venous sinus system or its small-caliber draining veins leads to venous hypertension, localized parenchymal edema, raised intracranial pressure (ICP), infarction, and rarely ICH. The most common manifestation of CVST is headache,
      • Thakur K.T.
      • Tamborska A.
      • Wood G.K.
      • et al.
      Clinical review of cerebral venous thrombosis in the context of COVID-19 vaccinations: evaluation, management, and scientific questions.
      which may be generalized or focal and is often progressive. CVST has been reported in COVID-19 patients and is paradoxically associated with thrombocytopenia.
      • Cavalcanti D.D.
      • Raz E.
      • Shapiro M.
      • et al.
      Cerebral venous thrombosis associated with COVID-19.
      ,
      • Dakay K.
      • Cooper J.
      • Bloomfield J.
      • et al.
      Cerebral venous sinus thrombosis in COVID-19 infection: a case series and review of the literature.
      This phenomenon can be explained by systemic platelet consumption and sequestration through agglutination triggered by COVID-19 vaccine immunization process, which may lead to thrombosis.
      • Ciccone A.
      SARS-CoV-2 vaccine-induced cerebral venous thrombosis.
      The peculiarities of CVST following COVID-19 vaccination warranted the specific term of VITT.
      • Ciccone A.
      SARS-CoV-2 vaccine-induced cerebral venous thrombosis.
      VITT is characterized by its unusual sites of thrombosis and the absence of common risk factors of CVST after COVID-19 vaccination in these patients. The unusual sites can include the cerebral venous sinus, splanchnic venous system, pulmonary thromboembolism (PTE), deep vein thrombosis (DVT), or acute arterial thrombosis.
      • Cines D.B.
      • Bussel J.B.
      SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia.
      ,
      • Greinacher A.
      • Thiele T.
      • Warkentin T.E.
      • et al.
      Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination.
      ,
      • Smadja D.M.
      • Yue Q.Y.
      • Chocron R.
      • et al.
      Vaccination against COVID-19: insight from arterial and venous thrombosis occurrence using data from VigiBase.
      • Douxfils J.
      • Favresse J.
      • Dogné J.M.
      • et al.
      Hypotheses behind the very rare cases of thrombosis with thrombocytopenia syndrome after SARS-CoV-2 vaccination.
      • Franchini M.
      • Liumbruno G.M.
      • Pezzo M.
      COVID-19 Vaccine-associated Immune Thrombosis and Thrombocytopenia (VITT): diagnostic and therapeutic recommendations for a new syndrome.
      • Schultz N.H.
      • Sorvoll I.H.
      • Michelsen A.E.
      • et al.
      Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination.
      CVST after COVID-19 vaccination was first reported following vaccination with ChAdOx1 nCoV-19; however, it was subsequently reported following adenovirus-based vaccine Ad26.COV2.S.
      • Bikdeli B.
      • Chatterjee S.
      • Arora S.
      • et al.
      Cerebral venous sinus thrombosis in the US population, after adenovirus-based SARS-CoV-2 vaccination, and after COVID-19.
      European Medicines Agency (EMA) reported 169 possible cases of CVST from 34 million recipients of the ChAdOx1 nCoV-19 vaccine; 35 possible cases of CVST from 54 million recipients of the BNT162b2 mRNA vaccine, and 5 possible, but unvetted, cases of CVST from 4 million recipients of the mRNA-1273 vaccine.
      • Cines D.B.
      • Bussel J.B.
      SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia.
      Six possible cases of CVST were reported from more than 7 million recipients of the Ad26.COV2.S vaccine.
      • Cines D.B.
      • Bussel J.B.
      SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia.
      The frequency of atypical thrombosis after COVID-19 vaccination should be weighed against thrombosis in the general population. These statistics should be considered in comparison with stroke that occurs in patients with COVID-19. In these patients, thrombosis occurs at least 100-fold more often in the unvaccinated people compared to the vaccinated.
      • Elalamy I.
      • Gerotziafas G.
      • Alamowitch S.
      • et al.
      SARS-CoV-2 vaccine and thrombosis: an expert consensus on vaccine-induced immune thrombotic thrombocytopenia.
      According to EMA data, of nearly 25 million people vaccinated with ChAdOx1 nCoV-19 vaccine in the UK, 62 developed CVT, and 24 had splanchnic venous thrombosis. The incidence of CVT in the vaccinated people was 2.6 per million people within 4-month after vaccination with ChAdOx1 nCoV-19 vaccine. However, the estimated incidence of CVT was 3-4 cases per million per year in unselected populations.
      • Stam J.
      Thrombosis of the cerebral veins and sinuses.
      In contrast, mRNA vaccines, compared to hormonal contraceptive use, do not show a disproportional rate of thromboembolic events in younger women.
      • Sessa M.
      • Kragholm K.
      • Hviid A.
      • et al.
      Thromboembolic events in younger women exposed to Pfizer-BioNTech or Moderna COVID-19 vaccines.
      A multicenter cohort study
      • Perry R.J.
      • Tamborska A.
      • Singh B.
      • et al.
      Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study.
      collected data from 43 hospitals across the UK and between April 1st and May 20th, 2021, reporting 95 patients with stroke, of which 70 had VITT. The median age of the VITT group was 47 years, compared to that in the non-VITT group, which was 57 years (p=0·005). The primary outcome of death or dependency occurred more frequently in the patients with VITT-associated CVT (33/70), compared with the non-VITT control group (4/25) (p=0·0061). This adverse outcome was less frequent in the patients with VITT who received non-heparin anticoagulants (18/50), compared with those who did not receive non-heparin anticoagulants (15/20) (p=0·0031), and in those who received IVIg (22/55), compared with those who did not receive IVIg (11/15) (p=0·022). In this study, it was also suggested that non-heparin anticoagulants and immunoglobulin treatment might improve outcomes of VITT-associated CVT.
      CVST after vaccination mostly occurs with adenoviral COVID-19 vector vaccines, especially ChAdOx1 nCoV-19 vaccine; nonetheless, CVST may also occur following mRNA-based COVID-19 vaccines. rAd26-S and rAd5-S is another recombinant adenovirus vaccine but no CVT cases have been reported following its use. Nonetheless, that is not to say that CVT does not occur following this vaccine.
      CVST usually has a good prognosis. However, CVST after COVID-19 vaccination may follow a catastrophic course. The outcome for these patients may be poor due to refractory increased ICP; indeed, almost half of patients with CVT in the context of VITT die within a few days and death often occurs following brain infarction often associated with ICH.
      • Scully M.
      • Singh D.
      • Lown R.
      • et al.
      Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination.
      ,
      • Greinacher A.
      • Thiele T.
      • Warkentin T.E.
      • et al.
      Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination.
      ,
      • Schultz N.H.
      • Sørvoll I.H.
      • Michelsen A.E.
      • et al.
      Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination.
      Table 3 summarizes reports of CVST following the COVID-19 vaccination. The table shows that most of the patients were female at 24-56 years of age. Most of these CVST cases were reported following ChAdOx1 nCoV-19 vaccine administration. Furthermore, all of the patients received the vaccine 7-20 days before the diagnosis of stroke.
      Table 3Summary reports of CVST following the COVID-19 vaccination.
      VaccineNumber of casesAge, Gender (F, M)Interval (days) between vaccination and diagnosisClinical presentationImaging and lab findingsTreatmentOutcomeAuthor, year, ref
      ChAdOx1 nCoV-19, BNT162b2 mRNA, and mRNA-1273A total of 213

      ChAdOx1 nCoV-19 (187 patients), BNT162b2 mRNA (25 patients), and mRNA-1273 (1 patient)
      Median of age: 46

      75% women in ChAdOx1 nCoV-19 recipients and 77% in mRNA vaccine recipients

      Nine days in the ChAdOx1 nCov-19 group and 7 days in the mRNA vaccine groupNMCVST in all of the patients

      Thrombocytopenia in 107 patients amongst 187 patients receiving the ChAdOx1 nCoV-19 vaccine
      NMOf the 117 patients with a reported outcome in the ChAdOx1 nCov- 19 group, 44 died, compared to 2 deaths out of 10 deaths with reported outcome in the mRNA vaccine group and 3 deaths out of 100 patients with reported outcome in the pre- COVID- 19 group.Krzywicka et al., 2021
      • Krzywicka K.
      • Heldner M.R.
      • Sánchez van Kammen M.
      • et al.
      Post-SARS-CoV-2-vaccination cerebral venous sinus thrombosis: an analysis of cases notified to the European Medicines Agency.
      149

      M=1
      20New-onset of mild to moderate headache and giddinessCVSTClexane, clopidogrel, and apixabanSymptoms gradually improvedZakaria et al., 2021
      • Zakaria Z.
      • Sapiai N.A.
      • Ghani ARI.
      Cerebral venous sinus thrombosis 2 weeks after the first dose of mRNA SARS-CoV-2 vaccine.
      ChAdOx1 nCoV-19 (COVISHIELD)156

      M=1
      14Persistent holocranial headache associated with vomiting, and double vision in horizontal gazeCVSTLMWH and warfarinSignificant improvement in clinical statusDutta et al., 2021
      • Dutta A.
      • Ghosh R.
      • Bhattacharya D.
      • et al.
      Anti-PF4 antibody negative cerebral venous sinus thrombosis without thrombocytopenia following immunization with COVID-19 vaccine in an elderly non-comorbid Indian male, managed with conventional heparin-warfarin based anticoagulation.
      ChAdOx1 nCoV-19 (AstraZeneca)

      152

      M = 1
      10Nausea and thunderclap headache and pain on the left side of the neckCVST

      Thrombocytopenia, positive anti-PF4 antibody, and elevated D-dimer level
      Apixaban and IVIgDischarged without any symptomsGuan et al., 2021
      • Guan C.Y.
      • Tsai S.H.
      • Fan J.S.
      • et al.
      A rare case of a middle-age Asian male with cerebral venous thrombosis after COVID-19 AstraZeneca vaccination.
      2NMNMNMCVT

      thrombocytopenia
      Heparin, corticosteroid, IVIg in one patient, and

      decompressive craniectomy in both patients
      DeathGeeraerts et al., 2021
      • Geeraerts T.
      • Montastruc F.
      • Bonneville F.
      • et al.
      Oxford-AstraZeneca COVID-19 vaccine-induced cerebral venous thrombosis and thrombocytopaenia: a missed opportunity for a rapid return of experience.
      136

      F=1
      14Fever with vomiting and severe headache, and

      sudden onset of focal left-sided convulsions for 5 min followed by weakness in the left arm.
      CVST

      Thrombocytopenia, hypofibrinogenemia, leukocytosis, anemia, increased D-dimer level, and liver enzymes, high creatinine severe acidosis (acute kidney injury), and prolonged PT, PTT, and INR
      Enoxaparin, antibiotics, and antiviralsDeathAladdin et al., 2021
      • Aladdin Y.
      • Algahtani H.
      • Shirah B.
      Vaccine-induced immune thrombotic thrombocytopenia with disseminated intravascular coagulation and death following the ChAdOx1 nCoV-19 vaccine.
      224,39

      F = 2
      8, 12Case 1: severe holocephalic headache(before admission), new left dull occipital headache(during admission)

      Case 2: severe persisting headache
      Case 1: CVST

      Case 2: CVT with related small frontal right juxtacortical hemorrhage

      Thrombocytopenia, positive anti-PF4 antibody, increased D-dimer and decreased fibrinogen level
      Case 1: danaparoid, dexamethasone, IVIg, argatroban, and dabigatran

      Case 2: IVIg, dexamethasone, and argatroban
      Cases 1 and 2: discharged without any symptomsGattringer et al., 2021
      • Gattringer T.
      • Gressenberger P.
      • Gary T.
      • et al.
      Successful management of vaccine-induced immune thrombotic thrombocytopenia-related cerebral sinus venous thrombosis after ChAdOx1 nCov-19 vaccination.
      Ad26.COV2.S (Johnson & Johnson/ Jansen)140

      F = 1
      12Headache, sinus pressure, myalgias, and sore throat with tonsillar exudate, photophobia, and intermittent dizzinessCVST

      Thrombocytopenia increased D-dimer levels, and mild elevation of serum transaminases
      Bivalirudin, IVIg, prednisoneResolution of headache and a steady improvement in laboratory markers of thrombocytopeniaClark et al., 2021
      • Clark R.T.
      • Johnson L.
      • Billotti J.
      • et al.
      Early outcomes of bivalirudin therapy for thrombotic thrombocytopenia and cerebral venous sinus thrombosis after Ad26.COV2.S vaccination.
      148

      F = 1
      14New-onset headacheCVST

      Severe thrombocytopenia, low fibrinogen level, prolonged activated partial thromboplastin time, and marked elevation of the D-dimer level
      UFH, Argatroban and IVIgRemained critically illMuir et al., 2021
      • Muir K.L.
      • Kallam A.
      • Koepsell S.A.
      • et al.
      Thrombotic thrombocytopenia after Ad26.COV2.S vaccination.
      143

      F=1
      10Generalized headache, fever, body aches, chills, and mild dyspnea, and lightheadednessCVST

      Thrombocytopenia, positive anti-PF4 antibody, and elevated D-dimer level
      IVIg and fondaparinuxTIA one day after discharge

      Malik et al., 2021
      • Malik B.
      • Kalantary A.
      • Rikabi K.
      • et al.
      Pulmonary embolism, transient ischaemic attack and thrombocytopenia after the Johnson & Johnson COVID-19 vaccine.
      Note: CVST: Cerebral Venous Sinus Thrombosis; Anti-PF4-antibody: anti-platelet factor 4 antibody; TIA: Transient Ischemic Attack; LMWH:Low Molecular Weight Heparin; IVIg: Intravenous Immunoglobulin; UFH: Unfractionated Heparin; NM: Not Mentioned; CRP: C-Reactive Protein); mRNA: messenger Ribonucleic Acid; COVID-19: coronavirus disease 2019; PT: Prothrombin Time; PTT: Partial Thromboplastin Time; INR: International Normalized Ratio; aPTT: activated Partial Thromboplastin Time.

      Ischemic and hemorrhagic stroke subsequet to CVST after COVID-19 vaccination

      Ischemic or hemorrhagic stroke may occur with CVST subsequent to COVID-19 vaccination. Obstruction of the brain's venous system increases ICP and may rupture blood vessels leading to hemorrhagic stroke. Furthermore, hypercoagulable state may cause further clot formation causing ischemic stroke. These complications have a direct impact on the treatment strategy.
      Table 4 summarizes reports of CVST with ischemic or hemorrhagic stroke. The table shows that most of the patients were female at 18-77 years of age. Most of these CVST cases were reported following ChAdOx1 nCoV-19 vaccine administration. Moreover, these patients received the vaccine 2-24 days before the diagnosis of stroke.
      Table 4Summary of reports of CVST with ischemic or hemorrhagic stroke.
      VaccineNumber of casesAge Gender (F, M)Interval (days) between vaccination and diagnosisClinical presentationImaging and lab findingsTreatmentOutcomeAuthor, year, ref
      ChAdOx1 nCoV-19 (AstraZeneca)2321-77

      (mean:46)

      F = 14 M = 9
      6-24 (mean:12)NMThirteen cases of CVST

      Two cases of ischemic stroke

      Positive antiPF4 antibody in 22 patients

      Thrombocytopenia in 22 patients, low fibrinogen levels in 13 patients, and increased D-dimer levels in 21 patients
      NMSeven patients diedScully et al., 2021
      • Scully M.
      • Singh D.
      • Lown R.
      • et al.
      Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination.
      ChAdOx1 nCoV-19 (AstraZeneca)150

      M = 1
      11Headache, slight deviation of the right buccal rim, loss of strength in the right lower limb, unstable walking, and slight visual impairmentICH

      CVST

      Thrombocytopenia, low fibrinogen level, increased amounts of D-dimer, CRP, and homocysteine
      Bilateral decompressive craniectomyBrain deathCastelli et al., 2021
      • Castelli G.P.
      • Pognani C.
      • Sozzi C.
      • et al.
      Cerebral venous sinus thrombosis associated with thrombocytopenia post-vaccination for COVID-19.


      ChAdOx1 nCoV-19 (AstraZeneca)154

      F = 1
      12Left side signsICH

      CVST

      Thrombocytopenia, and elevated D-dimer level
      NMDeathD'Agostino et al., 2021
      • D’Agostino V.
      • Caranci F.
      • Negro A.
      • et al.
      A rare case of cerebral venous thrombosis and disseminated intravascular coagulation temporally associated to the COVID-19 vaccine administration.


      ChAdOx1 nCoV-19 (AstraZeneca)150

      M=1
      11Headache, unconsciousnessICH

      CVST

      Thrombocytopenia, positive anti-PF4 antibody, increased prothrombin time and D-dimer, low fibrinogen level, hypohomocysteinemia, and low folic acid level
      Red blood cell and platelet apheresis transfusion, infusion of fibrinogen concentrate, neurosurgical interventionDeathFranchini et al., 2021
      • Franchini M.
      • Testa S.
      • Pezzo M.
      • et al.
      Cerebral venous thrombosis and thrombocytopenia post-COVID-19 vaccination.


      ChAdOx1 nCoV-19 (AstraZeneca)2Case 1 = 25, Case 2 = 32

      M=2
      Case 1 = 6, Case 2 = 9Case 1: thunderclap headache, left- incoordination, and hemiparesis

      Case 2: headache with photophobia, neck stiffness, visual disturbances, associated with a non-blanching petechial rash over lower limbs, bleeding of gums, left hemiparesis and hemisensory loss, and focal motor seizures
      ICH, SAH

      CVST

      Thrombocytopenia and low fibrinogen level
      Case 1: no specific hematological or immunological treatments were administered

      Case 2: UFH, platelet transfusions, dexamethasone, IVIg
      Brain stem deathMehta et al., 2021
      • Mehta P.R.
      • Apap Mangion S.
      • Benger M.
      • et al.
      Cerebral venous sinus thrombosis and thrombocytopenia after COVID-19 vaccination-a report of two UK cases.


      ChAdOx1 nCoV-19 (AstraZeneca)1In early 30s

      F=1
      10Mild myalgia, holocephalic headache, chills, and persisting headachesCVST

      ICH

      Thrombocytopenia, positive anti-PF4 antibody, elevated D-dimer level
      Argatroban, IVIg, and argatrobanPersistent minimal gait ataxia and amnestic deficitsIkenberg et al., 2021
      • Ikenberg B.
      • Demleitner A.F.
      • Thiele T.
      • et al.
      Cerebral venous sinus thrombosis after ChAdOx1 nCov-19 vaccination with a misleading first cerebral MRI scan.
      ChAdOx1 nCoV-19 (AstraZeneca)169

      F=1
      13Headache associated with behavioral symptoms and decreased level of consciousnessCVST

      ICH

      Thrombocytopenia, positive anti-PF4 antibody
      NMBrain deathJamme et al., 2021
      • Jamme M.
      • Mosnino E.
      • Hayon J.
      • et al.
      Fatal cerebral venous sinus thrombosis after COVID-19 vaccination.


      ChAdOx1 nCoV-19 (AstraZeneca)133

      M=1
      12Headache, vomiting, sudden onset of a tingling in the right arm, mental change, drowsiness, dysarthria, and right hemiparesisICH, SAH, and CVT

      Thrombocytopenia, elevated D-dimer level, low fibrinogen level, and positive anti-PF4 antibody
      FFP, platelet concentrate, IVIg, methylprednisolone, and thrombectomyDeathChoi et al., 2021
      • Choi J.K.
      • Kim S.
      • Kim S.R.
      • et al.
      Intracerebral hemorrhage due to thrombosis with thrombocytopenia syndrome after vaccination against COVID-19: the first fatal case in Korea.


      ChAdOx1 nCoV-19322-46

      F=3
      7-17Case 1: new frontally accentuated headache, a self-limited generalized epileptic seizure

      Case 2: severe headache, mild aphasia, hemianopia to the right, somnolence

      Case 3: severe headache, acute somnolence and right-hand hemiparesis
      Case 1:CVST, SAH

      Case 2: CVST. ICH

      Case 3: CVST

      Thrombocytopenia and positive anti-PF4 antibody in all the three patients
      Case 1: endovascular rheolysis, levetiracetam, enoxaparin, and dabigatran

      Case 2: enoxaparin, danaparoid, and dabigatran

      Case 3: danaparoid, endovascular rheolysis, enoxaparin, and dabigatran
      Case 1: mRS 0

      Case 2: mRS 1

      Case 3: mRS 0
      Wolf et al., 2021
      • Wolf M.E.
      • Luz B.
      • Niehaus L.
      • et al.
      Thrombocytopenia and intracranial venous sinus thrombosis after “COVID-19 vaccine AstraZeneca” Exposure.
      ChAdOx1 nCoV-19 (AstraZeneca)

      1122-49

      F = 9: M = 2
      5-16NMCVST in 9 patients

      ICH in one patient

      Thrombocytopenia in all of the patients, and positive anti-PF4 antibody in one patient
      NM

      Death in 6 patients,

      recovery in 4 patients,

      No information about one patient

      Greinacher et al., 2021
      • Greinacher A.
      • Thiele T.
      • Warkentin T.E.
      • et al.
      Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination.
      ChAdOx1 nCoV-19 (AstraZeneca)

      441-67

      F = 4
      5-11Case 1: headache, somnolence, dysphasia, right hemiparesis, and arterial

      hypertension

      Case 2: headache

      Case 3: headache and diplopia

      Case 4: headache, dysarthria, left- hemiplegia, and conjugated gaze palsy
      Case 1: CVST and ICH

      Case 2: cortical infarctions and aortic arch thrombi

      Case 3: no pathology in imaging findings

      Case 4: ischemic stroke in ICA and MCA territory with hemorrhagic transformation

      Thrombocytopenia, increased D-dimer level, positive anti-PF4 antibody in all of the patients

      Case 1: heparin and eculizumab

      Case 2: argatroban and IVIg

      Case 3: argatroban

      Case 4: argatroban and IVIg
      Case 1: Recovering

      Case 2, 3, and 4: Recovered
      Tiede et al., 2021
      • Tiede A.
      • Sachs U.J.
      • Czwalinna A.
      • et al.
      Prothrombotic immune thrombocytopenia after COVID-19 vaccination.
      ChAdOx1 nCoV-19 (AstraZeneca)

      437-54

      F= 4
      7-10Case 1: fever and persistent headaches

      Case 2: headaches, reduced consciousness

      Case 3: headache

      Case 4: hemiparesis
      Case 1: CVST and ICH

      Case 2: CVST and hemorrhagic infarction

      Case 3: CVT and hemorrhagic infarction

      Case 4: ICH and CVT

      Thrombocytopenia and positive anti-PF4 antibody in all of the patients
      Case 1: platelet transfusions and decompressive craniectomy

      Case 2: hemicraniectomy, dalteparin, methylprednisolone, IVIg

      Case 3: dalteparin, prednisolone and IVIg

      Case 4: platelet transfusion, methylprednisolone, IVIg, thrombectomy, UFH, and decompressive hemicraniectomy
      Case 1: death

      Case 2: death

      Case 3: full recovery

      Case 4: death
      Schultz et al., 2021
      • Schultz N.H.
      • Sørvoll I.H.
      • Michelsen A.E.
      • et al.
      Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination.
      ChAdOx1 nCoV-19 (AstraZeneca)

      127

      M=1
      12Intermittent headache associated with eye floaters and vomiting.CVST

      ICH

      Thrombocytopenia, positive anti-PF4 antibody, raised D- dimer, low platelets, and fibrinogen levels
      IVIg, dabigatan, idarucizumab, and prednisoloneDeathSuresh et al., 2021
      • Suresh P.
      • Petchey W.
      ChAdOx1 nCOV-19 vaccine-induced immune thrombotic thrombocytopenia and cerebral venous sinus thrombosis (CVST).
      ChAdOx1 nCoV-19 (AstraZeneca)

      162

      M = 1
      13Fever, weakness in the right arm, and mental confusionCVST,

      SAH,

      Large parietal hematoma (after receiving heparin),

      Acute myocardial infarction

      Increased CRP, leukocytosis, thrombocytopenia, increased D-dimer level, increased high-sensitivity cardiac troponin I level, positive anti-PF4 antibody
      Antibiotics, platelet concentrate, UFH, intravenous methylprednisoloneDeathBérezné et al., 2021
      • Bérezné A.
      • Bougon D.
      • Blanc-Jouvan F.
      • et al.
      Deterioration of vaccine-induced immune thrombotic thrombocytopenia treated by heparin and platelet transfusion: Insight from functional cytometry and serotonin release assay.
      ChAdOx1 nCoV-19 (Covishield)132

      F = 1
      11Headache associated with blurredvision and giddiness, weakness on the left upper and lower limbCVST and

      ICH

      Thrombocytopenia, increased D-dimer, positive anti-PF4 antibody
      Enoxaparin, parietal decompressive hemicraniectomy, fondaparinux, IVIg, tracheostomyDischarged with home neurorehabilitation serviceKotal et al., 2021
      • Kotal R.
      • Jacob I.
      • Rangappa P.
      • et al.
      A rare case of vaccine-induced immune thrombosis and thrombocytopenia and approach to management.
      Ad26.COV2.S (Johnson & Johnson/ Jansen)1218-60

      F = 12
      6-15Eleven patients initially presented with headache and one patient initially showed back pain and later developed a headacheCVST

      (of the 12 patients with CVST, seven also had ICH)

      Thrombocytopenia and elevated D-dimer level and decreased fibrinogen level
      Heparin treatment (later changed to non-heparin anticoagulant) in 6 patients;

      No

      anticoagulant therapy in 2 patients

      Non-heparin anticoagulant initially for CVST treatment in 4 patients. In addition to anticoagulation, seven patients received IVIg of which three also received systemic corticosteroids and four had platelet transfusions.
      Death (n = 3), ICU care (n = 3), non-ICU hospitalization (n = 2), and discharged (n = 4)See et al., 2021
      • See I.
      • Su J.R.
      • Lale A.
      • et al.
      US case reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, March 2 to April 21, 2021.
      mRNA-1273145

      M = 1
      8Headache, neck pain, altered mental, state after a witnessed seizure (GCS: 3)ICH,SAH, and

      CVST
      Heparin and coumadinDischarged with no neurological sequelSyed et al., 2021
      • Syed K.
      • Chaudhary H.
      • Donato A.
      Central venous sinus thrombosis with subarachnoid hemorrhage following an mRNA COVID-19 vaccination: are these reports merely Co-incidental?.
      BNT162b2 mRNA(Pfizer)247, 67

      F=2
      3, 6Case 1: persistent headache, nausea, photophobia, and sudden left motor deficit

      Case 2: sudden right lower limb clonic movements followed by motor deficit, loss of consciousness, and headache
      Case 1: CVST and SAH

      Case 2: CVST
      Case 1: enoxaparin and warfarin

      Case 2: enoxaparin, and dabigatran
      Case 1: slight gait instability at two-month follow-up

      Case 2:

      discharged without neurological deficits
      Dias et al., 2021
      • Dias L.
      • Soares-Dos-Reis R.
      • Meira J.
      • et al.
      Cerebral venous thrombosis after BNT162b2 mRNA SARS-CoV-2 vaccine.
      BNT162b2 mRNA (Pfizer-Biontech354-62

      F = 2 M = 1
      2-9Case 1: headache, vomiting, and left hemiparesis

      Case 2: headache and vomiting

      Case 3: right ataxic hemiparesis
      Case 1: ICH and CVST

      Case 2: ICH, SAH, and CVST

      Case 3: ICH, SAH, and CVST
      Case 1: UFH and LMWH

      Case 2: UFH, LMWH, warfarin, and decompressive craniectomy

      Case 3: LMWH,

      warfarin
      Cases 1 and 2: Left hemiparesis, on rehabilitation

      Case 3: Full recovery
      Fan et al., 2021
      • Fan B.E.
      • Shen J.Y.
      • Lim X.R.
      • et al.
      Cerebral venous thrombosis post BNT162b2 mRNA SARS-CoV-2 vaccination: a black swan event.
      Note: MCA: Middle Cerebral Artery; ICA: Internal Carotid Artery; CVST: Cerebral Venous Sinus Thrombosis; CVT: Cerebral Venous Thrombosis; Anti-PF4-antibody: anti-platelet factor 4 antibody; ICH: Intracerebral Hemorrhage; SAH: Subarachnoid Hemorrhage; LMWH: Low Molecular Weight Heparin; IVIg: Intravenous Immunoglobulin; UFH: Unfractionated Heparin; ICU: Intensive Care Unit; mRS: modified Rankin Scale; NM: Not Mentioned; CRP: C-Reactive Protein; FFP: Fresh Frozen Plasma; GCS: Glasgow Coma Scale.

      Comparison of different vaccines associated with stroke

      Since the basic characteristics of vaccine recipients are different, it is not easy to compare various COVID-19 vaccines triggering stroke. The manufacturing technology for mRNA-based vaccines is different from that for adenovirus-based vaccines, and hence the mechanism of thrombosis formation differs in these vaccines.
      • Dias L.
      • Soares-Dos-Reis R.
      • Meira J.
      • et al.
      Cerebral venous thrombosis after BNT162b2 mRNA SARS-CoV-2 vaccine.
      CVST after ChAdOx1 nCov-19 vaccination is more frequent and is associated with venous thrombotic events and a higher mortality rate than that after the BNT162b2 and mRNA-1273 vaccines.
      • Krzywicka K.
      • Heldner M.R.
      • Sánchez van Kammen M.
      • et al.
      Post-SARS-CoV-2-vaccination cerebral venous sinus thrombosis: an analysis of cases notified to the European Medicines Agency.
      In addition, thrombocytopenia and positive anti-PF4 antibodies have been reported more frequently after the ChAdOx1 nCov-19 vaccine than after the mRNA-based vaccine.
      • Krzywicka K.
      • Heldner M.R.
      • Sánchez van Kammen M.
      • et al.
      Post-SARS-CoV-2-vaccination cerebral venous sinus thrombosis: an analysis of cases notified to the European Medicines Agency.
      Furthermore, the clinical manifestations of CVST after ChAdOx1 nCov-19 vaccine and mRNA-based vaccine are different. CVST after ChAdOx1 nCov-19 vaccination has a clinical picture different from CVST patients unrelated to vaccination; however, CVST which occurs after receiving mRNA vaccines is similar to pre-COVID-19 CVST cases unrelated to vaccination.
      • Krzywicka K.
      • Heldner M.R.
      • Sánchez van Kammen M.
      • et al.
      Post-SARS-CoV-2-vaccination cerebral venous sinus thrombosis: an analysis of cases notified to the European Medicines Agency.
      These differences can even extend to differences between vaccines that are made with similar technology. Indeed, patients who received the Ad26.COV.2.S vaccine tend to develop clinical manifestations later than those receiving ChAdOx1 nCoV-19.
      • Hwang J.
      • Lee S.B.
      • Lee S.W.
      • et al.
      Comparison of vaccine-induced thrombotic events between ChAdOx1 nCoV-19 and Ad26.COV.2.S vaccines.
      Additionally, D-dimer and activated Partial Thromboplastin Time (aPTT) levels might be lower in patients after Ad26.COV.2.S than subjects receiving ChAdOx1 nCoV-19.
      • Hwang J.
      • Lee S.B.
      • Lee S.W.
      • et al.
      Comparison of vaccine-induced thrombotic events between ChAdOx1 nCoV-19 and Ad26.COV.2.S vaccines.
      Also, the probability of a positive platelet function test in ChAdOx1 nCoV-19 recipients is much higher than in the Ad26.COV.2.S recipients; nonetheless, in both groups, most patients are positive for HIT antibody test using ELISA.
      • Hwang J.
      • Lee S.B.
      • Lee S.W.
      • et al.
      Comparison of vaccine-induced thrombotic events between ChAdOx1 nCoV-19 and Ad26.COV.2.S vaccines.
      Notably, patients with CVT after Ad26.COV.2.S administration is more likely to suffer ICH and internal jugular vein thrombosis than those with CVT after ChAdOx1 nCoV-19.
      • Hwang J.
      • Lee S.B.
      • Lee S.W.
      • et al.
      Comparison of vaccine-induced thrombotic events between ChAdOx1 nCoV-19 and Ad26.COV.2.S vaccines.
      There are no significant differences between the two vaccines in mortality and presenting symptoms, viz headache, visual disturbance, hemiparesis, and fever.
      • Hwang J.
      • Lee S.B.
      • Lee S.W.
      • et al.
      Comparison of vaccine-induced thrombotic events between ChAdOx1 nCoV-19 and Ad26.COV.2.S vaccines.
      Beyond the comparison between different COVID-19 vaccines, Pawlowski et al.
      • Pawlowski C.
      • Rincón-Hekking J.
      • Awasthi S.
      • et al.
      Cerebral venous sinus thrombosis is not significantly linked to COVID-19 vaccines or Non-COVID vaccines in a large multi-state health system.
      assessed the association of COVID-19 vaccines and non-COVID-19 vaccines with CVST in a cohort of 771,805 vaccination events across 266,094 patients in the Mayo Clinic Health System between 01/01/2017 and 03/15/2021 and found that the risk of CVST is similar in the 30 days prior to COVID-19 vaccination compared to that in the 30 days after vaccination. In addition, the risk of CVST within 30 days following COVID-19 vaccination is similar to the risk of CVST within 30 days after all analyzed non-COVID vaccinations. Finally, the authors suggested that CVST is rare and not significantly associated with COVID-19 vaccination in their study.

      Recommendations for diagnosis and management of CVST after COVID-19 vaccination

      Many cases of stroke after COVID-19 vaccination is associated with VITT. Following the first post-COVID-19 vaccination VITT reports several international scientific societies and panels of experts made recommendations on the management of patients with suspected VITT syndrome from diagnosis to treatment. Management of stroke associated with VITT is challenging and complex. In addition, clinicians should be aware that management recommendations of CVST after COVID-19 vaccination markedly differ from the routine treatment of CVST.
      The diagnosis of VITT is rather challenging owing to its diverse clinical manifestations. Clinicians should maintain a high degree of suspicion in patients with symptoms suggestive of thrombotic events after COVID-19 vaccination, and along with this, wise comprehensive diagnostic criteria can be advantageous. The Expert Hematology Panel (EHP) of UK

      Pavord D, Makris M, Scully M, Hunt B. Guidance from the am panel (EHP) on Covid-19 vaccine-induced immune thrombocytopenia and thrombosis (VITT). Available online: https://b-s-h.org.uk/media/19590/guidance-version-17 -on-mngmt-of-vitt-20210420.pdf (accessed on 17 May 2021).

      and the American Society of Hematology (ASH)

      Bussel JM, Cines, DB, Dunbar, C, et al. Thrombosis with thrombocytopenia syndrome (Also Termed Vaccine-Induced Thrombotic Thrombocytopenia). Available online: https: //www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia (accessed on 17 May 2021).

      produced recommendations for the diagnosis of VITT that included receipt of a COVID-19 vaccine (Janssen/Vaxzevria) 4 to 30 days previously, thrombosis (often cerebral or abdominal), thrombocytopenia, and positive PF4-HIT test using ELISA. They also recommended urgent medical evaluation for VITT if any of the symptoms including severe headache, visual changes, abdominal pain, nausea and/or vomiting, backache, shortness of breath, leg pain or swelling, petechiae, or easy bruising develop 4 to 30 days after vaccination. Urgent diagnostic workup in suspected VITT also includes complete blood count (CBC) and peripheral blood smear, PF4-ELISA (HIT assay) using blood drawn prior to any therapies, fibrinogen level, and imaging for thrombosis based on signs/symptoms.

      Pavord D, Makris M, Scully M, Hunt B. Guidance from the am panel (EHP) on Covid-19 vaccine-induced immune thrombocytopenia and thrombosis (VITT). Available online: https://b-s-h.org.uk/media/19590/guidance-version-17 -on-mngmt-of-vitt-20210420.pdf (accessed on 17 May 2021).

      ,

      Bussel JM, Cines, DB, Dunbar, C, et al. Thrombosis with thrombocytopenia syndrome (Also Termed Vaccine-Induced Thrombotic Thrombocytopenia). Available online: https: //www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia (accessed on 17 May 2021).

      In addition to the above-mentioned recommendations for lab tests, a D-dimer check seems useful for the diagnosis of VITT associated with COVID-19 vaccination. Scully et al.
      • Scully M.
      • Singh D.
      • Lown R.
      • et al.
      Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination.
      demonstrated that D-dimer levels in patients with thrombosis and thrombocytopenia after receiving the ChAdOx1 nCoV-19 vaccine were much higher than what was expected in patients with acute venous thromboembolism. In addition, the EHP

      Pavord D, Makris M, Scully M, Hunt B. Guidance from the am panel (EHP) on Covid-19 vaccine-induced immune thrombocytopenia and thrombosis (VITT). Available online: https://b-s-h.org.uk/media/19590/guidance-version-17 -on-mngmt-of-vitt-20210420.pdf (accessed on 17 May 2021).

      classifies clinical presentation of VITT as follows: patients presenting with acute thrombosis and new-onset thrombocytopenia within 28 days of receiving COVID-19 vaccination (possible case), patients with either a low platelet count without thrombosis or with a D-dimer count at or about normal levels (< 2000 µg/L) but with and normal fibrinogen (2–4 g/L) levels (unlikely case), increased D-dimers (>4000 µg/ L > 2000 with a strong clinical suspicion) (probable case), and cases usually present 5–28 days after vaccination and are characterized by thrombocytopenia, elevated D-dimer level and thrombosis, which often rapidly deteriorate (definite case). In addition to diagnostic criteria and laboratory findings, radiological imaging should be used to confirm the diagnosis. In the event of acute onset of CVST, a non-contrast brain computed tomography (CT) should be the first evaluation. Nevertheless, a non-contrast CT has poor sensitivity since it only displays indirect and suggestive alterations of CVST in 30% of patients.
      • Garcia-Azorin D.
      Diagnostic and treatment recommendations from the FACME ad-hoc expert working group on the management of cerebral venous sinus thrombosis associated with COVID-19 vaccination.
      Consequently, if CVST is suspected, non-contrast CT should be carried out along with a contrast CT scan to create a three-dimensional venous reconstruction (CT venography).
      • Linn J.
      • Pfefferkorn T.
      • Ivanicova K.
      • et al.
      Noncontrast CT in deep cerebral venous thrombosis and sinus thrombosis: comparison of its diagnostic value for both entities.
      • Buyck P.J.
      • Zuurbier S.M.
      • Garcia-Esperon C.
      • et al.
      Diagnostic accuracy of noncontrast CT imaging markers in cerebral venous thrombosis.
      • Bonatti M.
      • Valletta R.
      • Lombardo F.
      • et al.
      Accuracy of unenhanced CT in the diagnosis of cerebral venous sinus thrombosis.
      • Tayyebi S.
      • Akhavan R.
      • Shams M.
      • et al.
      Diagnostic value of non-contrast brain computed tomography in the evaluation of acute cerebral venous thrombosis.
      • Xu W.
      • Gao L.
      • Li T.
      • et al.
      The performance of CT versus MRI in the differential diagnosis of cerebral venous thrombosis.
      • Gao L.
      • Xu W.
      • Li T.
      • et al.
      Accuracy of magnetic resonance venography in diagnosing cerebral venous sinus thrombosis.
      In patients with subacute onset, magnetic resonance imaging (MRI) is, however, the study of choice.
      • Garcia-Azorin D.
      Diagnostic and treatment recommendations from the FACME ad-hoc expert working group on the management of cerebral venous sinus thrombosis associated with COVID-19 vaccination.
      In a meta-analysis study, CT and MRI showed similar diagnostic performance for CVST diagnosis.
      • Xu W.
      • Gao L.
      • Li T.
      • et al.
      The performance of CT versus MRI in the differential diagnosis of cerebral venous thrombosis.
      Although Kennedy et al.
      • Kennedy V.E.
      • Wong C.C.
      • Hong J.M.
      • et al.
      VITT following Ad26.COV2.S vaccination presenting without radiographically demonstrable thrombosis.
      reported a case of VITT following Ad26.COV2.S COVID-19 vaccination without radiographically thrombosis demonstrable by radiography (Brain MRI) at presentation. Withal, Ikenberg et al.
      • Ikenberg B.
      • Demleitner A.F.
      • Thiele T.
      • et al.
      Cerebral venous sinus thrombosis after ChAdOx1 nCov-19 vaccination with a misleading first cerebral MRI scan.
      reported a patient whose initial brain MRI was seemingly normal, but follow-up brain MRI findings indicated an extensive CVST, and laboratory report confirmed VITT. Therefore, if clinical suspicion of CVST after COVID-19 persists, a repeat MRI is useful.
      Treatment of stroke in the setting of VITT is challenging. What is important is to act according to the existing guidelines considering the specific condition of each patient. The key element of management of VITT-associated CVT is high-dose IVIg and anticoagulation using direct oral anticoagulants.
      • Franchini M.
      • Liumbruno G.M.
      • Pezzo M.
      COVID-19 Vaccine-associated Immune Thrombosis and Thrombocytopenia (VITT): diagnostic and therapeutic recommendations for a new syndrome.
      ,
      • Cattaneo M.
      Thrombosis with Thrombocytopenia Syndrome associated with viral vector COVID-19 vaccines.
      ,
      • Warkentin TE.
      High-dose intravenous immunoglobulin for the treatment and prevention of heparin-induced thrombocytopenia: a review.
      The use of non-heparin anticoagulants and IVIg can be related to a low probability of VITT-associated CVT death or dependency at the end of hospital admission.
      • Perry R.J.
      • Tamborska A.
      • Singh B.
      • et al.
      Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study.
      IVIg prevents platelet activation by PF4 antibodies and rapidly restores the platelet count.
      • Choi J.K.
      • Kim S.
      • Kim S.R.
      • et al.
      Intracerebral hemorrhage due to thrombosis with thrombocytopenia syndrome after vaccination against COVID-19: the first fatal case in Korea.
      Immune globulin prevents antibody-mediated platelet clearance and may down-regulate platelet activation by immune complexes by blocking platelet FcRγIIA receptors.
      • Warkentin TE.
      High-dose intravenous immunoglobulin for the treatment and prevention of heparin-induced thrombocytopenia: a review.
      Therefore, prompt initiation of IVIg (1g/kg over two days if needed) that is likely to influence the disease process, regardless of the severity of thrombocytopenia, and continuing to review the clinical course, is recommended for VITT.
      • Islam A.
      • Bashir M.S.
      • Joyce K.
      • et al.
      An update on COVID-19 vaccine induced thrombotic thrombocytopenia syndrome and some management recommendations.
      Contrastingly, clinicians should avoid all forms of heparin (i.e. unfractionated heparin, even for line flushes, or LMWH e.g. enoxaparin) in VITT-associated CVT.
      • Mehta P.R.
      • Apap Mangion S.
      • Benger M.
      • et al.
      Cerebral venous sinus thrombosis and thrombocytopenia after COVID-19 vaccination-a report of two UK cases.
      However, non-heparin-based anticoagulants such as direct thrombin inhibitors (including bivalirudin, argatroban, and dabigatran), direct factor Xa inhibitors (e.g., rivaroxaban, apixaban, and edoxaban), and indirect antithrombin dependent Xa inhibitors (e.g., fondaparinux) are not contraindicated in VITT.
      • Mohseni Afshar Z.
      • Babazadeh A.
      • Janbakhsh A.
      • et al.
      Vaccine-induced immune thrombotic thrombocytopenia after vaccination against Covid-19: a clinical dilemma for clinicians and patients.
      Administration of anticoagulation should not be avoided in VITT patients with low fibrinogen levels or bleeding associated with VITT, particularly if the platelet count is >20,000/µL or increases following IVIg initiation.

      Pavord D, Makris M, Scully M, Hunt B. Guidance from the am panel (EHP) on Covid-19 vaccine-induced immune thrombocytopenia and thrombosis (VITT). Available online: https://b-s-h.org.uk/media/19590/guidance-version-17 -on-mngmt-of-vitt-20210420.pdf (accessed on 17 May 2021).

      ,

      Bussel JM, Cines, DB, Dunbar, C, et al. Thrombosis with thrombocytopenia syndrome (Also Termed Vaccine-Induced Thrombotic Thrombocytopenia). Available online: https: //www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia (accessed on 17 May 2021).

      Furthermore, continuing systemic anticoagulation for at least three months in patients with documented thrombosis in the context of VITT is recommended.
      • Oldenburg J.
      • Klamroth R.
      • Langer F.
      • et al.
      Diagnosis and management of vaccine-related thrombosis following astrazeneca COVID-19 vaccination: guidance statement from the GTH.
      However, warfarin is not recommended in this setting due to a paradoxical increase in thrombotic tendency.
      • Mohseni Afshar Z.
      • Babazadeh A.
      • Janbakhsh A.
      • et al.
      Vaccine-induced immune thrombotic thrombocytopenia after vaccination against Covid-19: a clinical dilemma for clinicians and patients.
      In order to continue these VITT treatment recommendations, platelet transfusions should be avoided unless the bleeding is associated with paradoxical thrombosis, and risk/benefit assessment should be conducted in patients with severe bleeding and/or the need for surgical intervention.

      Pavord D, Makris M, Scully M, Hunt B. Guidance from the am panel (EHP) on Covid-19 vaccine-induced immune thrombocytopenia and thrombosis (VITT). Available online: https://b-s-h.org.uk/media/19590/guidance-version-17 -on-mngmt-of-vitt-20210420.pdf (accessed on 17 May 2021).

      ,

      Bussel JM, Cines, DB, Dunbar, C, et al. Thrombosis with thrombocytopenia syndrome (Also Termed Vaccine-Induced Thrombotic Thrombocytopenia). Available online: https: //www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia (accessed on 17 May 2021).

      Severe bleeding and/or the need for surgical intervention may favor platelet transfusion following the initiation of IVIg, non-heparin anti-coagulation, and fibrinogen replacement if its level is less than 1.5 g/L.

      Pavord D, Makris M, Scully M, Hunt B. Guidance from the am panel (EHP) on Covid-19 vaccine-induced immune thrombocytopenia and thrombosis (VITT). Available online: https://b-s-h.org.uk/media/19590/guidance-version-17 -on-mngmt-of-vitt-20210420.pdf (accessed on 17 May 2021).

      ,

      Bussel JM, Cines, DB, Dunbar, C, et al. Thrombosis with thrombocytopenia syndrome (Also Termed Vaccine-Induced Thrombotic Thrombocytopenia). Available online: https: //www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia (accessed on 17 May 2021).

      Platelet transfusion should be considered in life-threatening bleeding situations.
      • Islam A.
      • Bashir M.S.
      • Joyce K.
      • et al.
      An update on COVID-19 vaccine induced thrombotic thrombocytopenia syndrome and some management recommendations.
      In other words, platelet transfusion is an optional treatment to support anticoagulation, and its superiority to critical care by argatroban (low dose) without platelet transfusion has not yet been confirmed.

      Pavord D, Makris M, Scully M, Hunt B. Guidance from the am panel (EHP) on Covid-19 vaccine-induced immune thrombocytopenia and thrombosis (VITT). Available online: https://b-s-h.org.uk/media/19590/guidance-version-17 -on-mngmt-of-vitt-20210420.pdf (accessed on 17 May 2021).

      ,

      Bussel JM, Cines, DB, Dunbar, C, et al. Thrombosis with thrombocytopenia syndrome (Also Termed Vaccine-Induced Thrombotic Thrombocytopenia). Available online: https: //www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia (accessed on 17 May 2021).

      Expressly, if urgent neurosurgical intervention is needed, platelet transfusion to >100 × 109/L and cryoprecipitate to maintain fibrinogen over 1.5 g/L should be considered.

      Pavord D, Makris M, Scully M, Hunt B. Guidance from the am panel (EHP) on Covid-19 vaccine-induced immune thrombocytopenia and thrombosis (VITT). Available online: https://b-s-h.org.uk/media/19590/guidance-version-17 -on-mngmt-of-vitt-20210420.pdf (accessed on 17 May 2021).

      ,

      Bussel JM, Cines, DB, Dunbar, C, et al. Thrombosis with thrombocytopenia syndrome (Also Termed Vaccine-Induced Thrombotic Thrombocytopenia). Available online: https: //www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia (accessed on 17 May 2021).

      However, since it is still unclear that platelet transfusion can exacerbate CVST, a definite recommendation cannot be given.
      • Islam A.
      • Bashir M.S.
      • Joyce K.
      • et al.
      An update on COVID-19 vaccine induced thrombotic thrombocytopenia syndrome and some management recommendations.
      In addition, fibrin injection is controversial, and it should be measured to ensure that its level does not drop below 1.5 g/L.
      • Islam A.
      • Bashir M.S.
      • Joyce K.
      • et al.
      An update on COVID-19 vaccine induced thrombotic thrombocytopenia syndrome and some management recommendations.
      Moreover, steroids may be useful, although whether their benefits outweigh the potential harm is uncertain.
      • Islam A.
      • Bashir M.S.
      • Joyce K.
      • et al.
      An update on COVID-19 vaccine induced thrombotic thrombocytopenia syndrome and some management recommendations.
      Plasma exchange could also be helpful in patients with severe or resistant diseases. For VITT patients who are refractory relative to repeated doses of IVIg treatment and plasma exchange, treatment with rituximab may be helpful.
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      In addition to pharmacological treatments, non-pharmacological methods such as Endovascular Mechanical Thrombectomy (EMT) can be efficient for selected patients. EMT can restore normal venous outflow, decrease venous congestion, and reduce increased ICP through rapid and definite recanalization of occluded venous sinuses.
      • Lee S.K.
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      ,
      • Ilyas A.
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      Wolf et al.
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      reported 3 cases of CVT after COVID-19 vaccination who were successfully treated by endovascular rheolysis. Although the outcome of EMT in the case report by Choi et al
      • Choi J.K.
      • Kim S.
      • Kim S.R.
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      Intracerebral hemorrhage due to thrombosis with thrombocytopenia syndrome after vaccination against COVID-19: the first fatal case in Korea.
      was not satisfactory, they suggested that if the EMT is done at early stages, and before the beginning of cortical venous occlusion, the outcome might be better. Therefore, if VITT-associated CVT is clinically suspected and the symptoms deteriorate quickly, early EMT intervention is necessary.
      • Choi J.K.
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      Another non-pharmacological procedure is decompressive craniectomy, which should be decided based on the patient's condition. The association between decompressive hemicraniectomy and the poor outcome probably reflects the selection of patients with the most serious CVT for this invasive procedure.
      • Perry R.J.
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      Anticoagulation with argatroban can be a useful treatment option for VITT among other medications. This is because, first of all, it has a short half-life, which is useful in case of bleeding complications.
      • Gattringer T.
      • Gressenberger P.
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      Successful management of vaccine-induced immune thrombotic thrombocytopenia-related cerebral sinus venous thrombosis after ChAdOx1 nCov-19 vaccination.
      Second, it also inhibits platelets.
      • Lunven C.
      • Gauffeny C.
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      • et al.
      Inhibition by argatroban, a specific thrombin inhibitor, of platelet activation by fibrin clot-associated thrombin.
      Third, a thrombin inhibitor acts at the bottom of the coagulation cascade with less potential effect on the other coagulation factors.
      • Gattringer T.
      • Gressenberger P.
      • Gary T.
      • et al.
      Successful management of vaccine-induced immune thrombotic thrombocytopenia-related cerebral sinus venous thrombosis after ChAdOx1 nCov-19 vaccination.
      Furthermore, bivalirudin can be used as a heparin alternative in VITT for its immediate onset of action, renal elimination, short half-life (w25 min), and ease of reversibility in the event of life-threatening bleeding.
      • Clark R.T.
      • Johnson L.
      • Billotti J.
      • et al.
      Early outcomes of bivalirudin therapy for thrombotic thrombocytopenia and cerebral venous sinus thrombosis after Ad26.COV2.S vaccination.

      Conclusion

      Many recent studies reported the occurrence of stroke after administration of COVID-19 vaccination. All forms of stroke including ischemic, ICH, and CVST have been encountered. Most of the evidence pertaining to stroke following COVID-19 vaccination are case reports, therefore, the incidence of stroke after COVID-19 vaccination is not precisely known. Most patients who suffered from stroke after COVID-19 vaccination were women, under 60 years of age, and after the ChAdOx1 nCoV-19 vaccine.
      Clinicians should be aware of the possible stroke after COVID-19 vaccination to ensure rapid diagnosis and treatment. CVST is an important phenomenon that may occur after COVID-19 vaccination and is mostly associated with VITT. The diagnosis of VITT-associated stroke should be made with high suspicion because of its rapid and diverse clinical manifestations. Stroke should be considered when a patient develops any neurological complaints, especially constant headaches, within 4 weeks of COVID-19 vaccination. These patients should urgently be evaluated for possible VITT with laboratory tests such as platelet count, D-dimer, anti-PF4 antibody, fibrinogen level, and brain imaging, especially cerebral venography. Concurrent thrombosis including DVT, PTE, and splanchnic venous thrombosis should be ruled out in patients who suffered from VITT-associated CVST. Furthermore, other differential diagnoses including APS, DIC, ITP, thrombotic-thrombocytopenic purpura, atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, and underlying malignant diseases should be taken into account. Notably, the latest guidelines should be considered for VITT management; however, clinicians should eventually act according to the specific condition of each patient. Since the management of VITT is challenging, they should be managed by a multidisciplinary team from different disciplines including hematology, neurology, stroke, neurosurgery, and neuroradiology. Finally, since the advantages of COVID-19 vaccination outweigh the risk of stroke or any other neurological complication, the public should be reassured that the vaccination program is still the best way to combat COVID-19.

      Declaration of Competing Intrest

      The authors declare no conflict of interest with respect to the present review study.

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