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Rapid Communication| Volume 30, ISSUE 8, 105906, August 2021

Cerebral Venous Thrombosis after BNT162b2 mRNA SARS-CoV-2 vaccine

  • Author Footnotes
    1 Both authors contributed equally to the work.
    Leonor Dias
    Correspondence
    Corresponding author.
    Footnotes
    1 Both authors contributed equally to the work.
    Affiliations
    Department of Neurology, Centro Hospitalar Universitário de São João, E.P.E., Porto, Portugal

    Clinical Neurosciences and Mental Health Department, Faculty of Medicine of the University of Porto, Portugal
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  • Author Footnotes
    1 Both authors contributed equally to the work.
    Ricardo Soares-dos-Reis
    Footnotes
    1 Both authors contributed equally to the work.
    Affiliations
    Department of Neurology, Centro Hospitalar Universitário de São João, E.P.E., Porto, Portugal

    Clinical Neurosciences and Mental Health Department, Faculty of Medicine of the University of Porto, Portugal

    i3S - Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
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  • João Meira
    Affiliations
    Department of Neurossurgery, Centro Hospitalar Universitário de São João, E.P.E., Porto, Portugal
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  • Diana Ferrão
    Affiliations
    Stroke Unit, Department of Internal Medicine, Centro Hospitalar Universitário São João, E.P.E., Porto, Portugal
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  • Pedro Ribeirinho Soares
    Affiliations
    Stroke Unit, Department of Internal Medicine, Centro Hospitalar Universitário São João, E.P.E., Porto, Portugal
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  • Ana Pastor
    Affiliations
    Stroke Unit, Department of Internal Medicine, Centro Hospitalar Universitário São João, E.P.E., Porto, Portugal
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  • Guilherme Gama
    Affiliations
    Stroke Unit, Department of Internal Medicine, Centro Hospitalar Universitário São João, E.P.E., Porto, Portugal
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  • Luísa Fonseca
    Affiliations
    Stroke Unit, Department of Internal Medicine, Centro Hospitalar Universitário São João, E.P.E., Porto, Portugal

    Medicine Department, Faculty of Medicine of the University of Porto, Portugal
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  • Vítor Fagundes
    Affiliations
    Stroke Unit, Centro Hospitalar Tâmega e Sousa, E.P.E., Portugal
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  • Marta Carvalho
    Affiliations
    Department of Neurology, Centro Hospitalar Universitário de São João, E.P.E., Porto, Portugal

    Clinical Neurosciences and Mental Health Department, Faculty of Medicine of the University of Porto, Portugal
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  • Author Footnotes
    1 Both authors contributed equally to the work.
Published:May 25, 2021DOI:https://doi.org/10.1016/j.jstrokecerebrovasdis.2021.105906
Cerebral Venous Thrombosis after BNT162b2 mRNA SARS-CoV-2 vaccine
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      Abstract

      The development of SARS-CoV-2 vaccines has raised several concerns regarding venous thromboembolism, namely cerebral venous thrombosis. Although cerebral venous thrombosis has been reported after administration of a viral vector vaccine, due to a possible auto-immune mechanism inducing thrombocytopenia, the same has not happened in mRNA vaccines. We report two cases of cerebral venous thrombosis, shortly after administration of mRNA vaccine. In both patients, there was no evidence of thrombocytopenia or antiplatelet antibodies, and alternative causes for cerebral venous thrombosis were found. As such, despite the temporal relation of both cases to vaccine administration, these types of cerebral venous thrombosis do not seem to be pathophysiological different from cerebral venous thrombosis not associated to SARS-CoV-2 vaccination. Continuous pharmacovigilance is necessary to monitor possible new events and clarify this association.

      Keywords

      SARS-CoV-2 vaccine development raised several concerns regarding adverse events, particularly venous thromboembolism.
      • Østergaard SD
      • Schmidt M
      • Horváth-Puhó E
      • et al.
      Thromboembolism and the Oxford–AstraZeneca COVID-19 vaccine: side-effect or coincidence?.
      Lancet. 2021; 397: 1441-1443
      ,
      • Wise J.
      Covid-19: European countries suspend use of Oxford-AstraZeneca vaccine after reports of blood clots.
      BMJ. 2021; 372 (Epub ahead of print)https://doi.org/10.1136/bmj.n699
      Cerebral venous thrombosis (CVT) was recently reported in patients vaccinated with AstraZeneca's vaccine and Janssen's vaccine.

      European Medicines Agency. Vaxzevria (previously COVID-19 Vaccine AstraZeneca): link between the vaccine and the occurrence of thrombosis in combination with thrombocytopenia. 2021-04-13, https://www.ema.europa.eu/en/medicines/dhpc/vaxzevria-previously-covid-19-vaccine-astrazeneca-link-between-vaccine-occurrence-thrombosis (Accessed 9 May 2021).

      , 
      • Muir K-L
      • Kallam A
      • Koepsell SA
      • et al.
      Thrombotic Thrombocytopenia after Ad26.COV2.S vaccination.
      N Engl J Med. 2021; (Epub ahead of print 14 April)https://doi.org/10.1056/NEJMc2105869
      , 

      European Medicines Agency. COVID-19 Vaccine Janssen: link between the vaccine and the occurrence of thrombosis in combination with thrombocytopenia. 2021-04-26, https://www.ema.europa.eu/en/medicines/dhpc/covid-19-vaccine-janssen-link-between-vaccine-occurrence-thrombosis-combination-thrombocytopenia (Accessed 9 May 2021).

      , 
      • See I
      • Su JR
      • 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.
      JAMA. 2021; (Epub ahead of print 30 April)https://doi.org/10.1001/jama.2021.7517
      This side effect has not been previously reported in mRNA vaccines. We hereby report two CVT cases in patients who took an mRNA vaccine (BNT162b2, Comirnaty®, Pfizer/BioNTech).
      Case 1: A 47-year-old female, who had iron-deficiency anemia due to adenomyosis and used combined oral contraceptives, developed persistent headache, nausea and photophobia six days after the first vaccine dose. Three days later, she presented a sudden left motor deficit. Papilledema, left visual extinction, right gaze deviation, and left hemiparesis were documented. Brain MRI with venography revealed thrombosis of superior sagittal, right lateral, transverse, sigmoid sinuses and jugular vein and left sigmoid sinus, together with right frontal subarachnoid hemorrhage and a cortical venous infarct. Admission PCR test for SARS-CoV-2 was negative. Complete blood count revealed microcytic hypochromic anemia (9.3 g/dL) and normal platelet count (343.000/µL). Coagulation tests-aPTT, Quick test, fibrinogen-were normal. Prothrombotic screening-lupus anticoagulant, anticardiolipin antibodies, protein C, RAPC, antithrombin III, and prothrombin mutation-was negative except for low protein S (0.40, N>0.54). Autoimmune screening-immunoglobulins, complement, antinuclear antibodies-was negative. A chest-abdomen-pelvis CT excluded occult neoplasms. She started acetazolamide and enoxaparin 60 mg bid, later switched to warfarin. At two-month follow-up, slight gait instability was the only deficit. Antiplatelet-PF4-antibodies, measured 2 months after the event with ELISA technique, were negative. Anti-SARS-CoV-2 IgG was positive at low titers [anti-RBD IgG 17 U/mL (N<10), anti-S1 IgG 11 U/mL (N<10), anti-S2 and anti-N negative]. The second dose of the vaccine was never administered.
      Case 2: A 67-year-old female had a history of multiple cerebral cavernous malformations, hypertension, diabetes, dyslipidemia, viral myocarditis, and depression. Three days after the second vaccine dose, she presented with sudden right lower limb clonic movements, followed by motor deficit, loss of consciousness and headache. Tongue bite was evident. Brain MRI showed thrombosis of high convexity cortical veins, superior sagittal, right transverse, and sigmoid sinus and jugular vein. There were no signs of hemorrhage. Admission PCR test for SARS-CoV-2 was negative. Complete blood count, including platelet count (164.000/µL) and coagulation tests were normal. An elevation of erythrocyte sedimentation rate was noticed (53 mm/1st hour), with no other elevation of inflammatory biomarkers. Prothrombotic and autoimmune screening were unremarkable. Electroencephalography showed focal polymorphic delta slowing, located in the right frontal-temporal region, and epileptiform discharges. A chest-abdomen-pelvis CT showed a probable renal cell carcinoma. She started levetiracetam 500 mg bid and enoxaparin 80 mg bid, later switched to dabigatran 150 mg bid. Antiplatelet-PF4-antibodies, 20 days after the event, were negative. Anti-SARS-CoV-2 IgG was positive (anti-RBD IgG >100 U/mL, anti-S1 IgG >100 U/mL, anti-S2 72 U/mL, anti-N negative). She was discharged without neurological deficits, awaiting an urgent Urology referral.

      Discussion

      The Pfizer/BioNTech vaccine contains mRNA particles that are translated into a spike protein, whose immune recognition leads to antibody production.
      • Polack FP
      • Thomas SJ
      • Kitchin N
      • et al.
      Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.
      N Engl J Med. 2020; 383: 2603-2615
      Before translation, mRNA may bind to pattern recognition receptors inducing pro-inflammatory cascades.
      • Talotta R.
      Do COVID-19 RNA-based vaccines put at risk of immune-mediated diseases? In reply to “potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases.
      Clin Immunol. 2021; 224108665
      This immune response might, theoretically, contribute as a trigger for thromboembolic events. This mechanism is different from the AstraZeneca vaccine (ChAdOx1 nCoV-19, Vaxzevria®) and Janssen vaccine (Ad26.COV2.S), which use a viral vector.
      Up to 08/05, 70 cases of CVT with AstraZeneca's vaccine have been reported in EudraVigilance and 5 cases with Janssen's, most occurring in women aged under 60, up to 2 weeks post-vaccination.

      European Medicines Agency. Vaxzevria (previously COVID-19 Vaccine AstraZeneca): link between the vaccine and the occurrence of thrombosis in combination with thrombocytopenia. 2021-04-13, https://www.ema.europa.eu/en/medicines/dhpc/vaxzevria-previously-covid-19-vaccine-astrazeneca-link-between-vaccine-occurrence-thrombosis (Accessed 9 May 2021).

      ,

      European Medicines Agency. COVID-19 Vaccine Janssen: link between the vaccine and the occurrence of thrombosis in combination with thrombocytopenia. 2021-04-26, https://www.ema.europa.eu/en/medicines/dhpc/covid-19-vaccine-janssen-link-between-vaccine-occurrence-thrombosis-combination-thrombocytopenia (Accessed 9 May 2021).

      ,

      European Medicines Agency. EudraVigilance - European database of suspected adverse drug reaction reports, http://www.adrreports.eu / (Accessed 9 May 2021).

      These cases had thrombocytopenia and antiplatelet-PF4-antibodies, with a probable auto-immune mechanism leading to an atypical form of immune thrombocytopenia.

      Agency EM. AstraZeneca's COVID-19 vaccine: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets. European Medicines Agency, https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood (2021, accessed 7 April 2021).

      Although the exact pathophysiological mechanism for this type of thrombosis is still not clear, patients seem to benefit from immunomodulatory therapy (with intravenous immunoglobulin and high dose corticosteroids), and a proposed treatment mechanism with immunomodulation and non-heparin-anticoagulation has recently been published
      • Scully M
      • Singh D
      • Lown R
      • et al.
      Pathologic antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 vaccination.
      N Engl J Med. 2021; (Epub ahead of print 16 April)https://doi.org/10.1056/NEJMoa2105385
      .
      However, our cases did not exhibit thrombocytopenia nor antiplatelet antibodies. There was no clinical or laboratory worsening after the start of enoxaparin. Moreover, both had good clinical outcome, with no or minor neurological deficits, and had additional CVT risk factors: combined hormonal contraception and a likely malignant renal neoplasm. Thus, despite the temporal relation with vaccination, these cases do not seem to be pathophysiologically different from regular CVT. Continuous pharmacovigilance is necessary to monitor adverse events and clarify this association.

      Funding

      This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

      Informed consent

      The patients gave their consent to the publication of the data. Details that might disclose the identity of the subjects under study have been omitted.

      Ethical approval

      Not applicable.

      Guarantor

      LD.

      Contributorship

      LD researched literature. RR, JM, DF, PRS, AP, GG, LF, VF, and MC were involved in the clinical care and management of the patients. LD, RR and MC acquired, analysed, and interpreted the data and drafted the manuscript. RR and MC provided supervision and a critical revision of the paper. LD wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript. Written consent for publication was obtained from the patients.

      Declaration of Competing Interest

      The authors declare no conflict of interest.

      Acknowledgments

      The authors want to express their gratitude to Professor José Ferro (Neurology Department, Centro Hospitalar Universitário Lisboa Norte) for his help in the discussion of the follow up study of these patients.

      References

        • Østergaard SD
        • Schmidt M
        • Horváth-Puhó E
        • et al.
        Thromboembolism and the Oxford–AstraZeneca COVID-19 vaccine: side-effect or coincidence?.
        Lancet. 2021; 397: 1441-1443
        View in Article
        • Wise J.
        Covid-19: European countries suspend use of Oxford-AstraZeneca vaccine after reports of blood clots.
        BMJ. 2021; 372 (Epub ahead of print)https://doi.org/10.1136/bmj.n699
        View in Article

      3. European Medicines Agency. Vaxzevria (previously COVID-19 Vaccine AstraZeneca): link between the vaccine and the occurrence of thrombosis in combination with thrombocytopenia. 2021-04-13, https://www.ema.europa.eu/en/medicines/dhpc/vaxzevria-previously-covid-19-vaccine-astrazeneca-link-between-vaccine-occurrence-thrombosis (Accessed 9 May 2021).

        View in Article
        • Muir K-L
        • Kallam A
        • Koepsell SA
        • et al.
        Thrombotic Thrombocytopenia after Ad26.COV2.S vaccination.
        N Engl J Med. 2021; (Epub ahead of print 14 April)https://doi.org/10.1056/NEJMc2105869
        View in Article

      5. European Medicines Agency. COVID-19 Vaccine Janssen: link between the vaccine and the occurrence of thrombosis in combination with thrombocytopenia. 2021-04-26, https://www.ema.europa.eu/en/medicines/dhpc/covid-19-vaccine-janssen-link-between-vaccine-occurrence-thrombosis-combination-thrombocytopenia (Accessed 9 May 2021).

        View in Article
        • See I
        • Su JR
        • 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.
        JAMA. 2021; (Epub ahead of print 30 April)https://doi.org/10.1001/jama.2021.7517
        View in Article
        • Polack FP
        • Thomas SJ
        • Kitchin N
        • et al.
        Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.
        N Engl J Med. 2020; 383: 2603-2615
        View in Article
        • Talotta R.
        Do COVID-19 RNA-based vaccines put at risk of immune-mediated diseases? In reply to “potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases.
        Clin Immunol. 2021; 224108665
        View in Article

      9. European Medicines Agency. EudraVigilance - European database of suspected adverse drug reaction reports, http://www.adrreports.eu / (Accessed 9 May 2021).

        View in Article

      10. Agency EM. AstraZeneca's COVID-19 vaccine: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets. European Medicines Agency, https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood (2021, accessed 7 April 2021).

        View in Article
        • Scully M
        • Singh D
        • Lown R
        • et al.
        Pathologic antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 vaccination.
        N Engl J Med. 2021; (Epub ahead of print 16 April)https://doi.org/10.1056/NEJMoa2105385
        View in Article

      Article info

      Publication history

      Published online: May 25, 2021
      Accepted: May 17, 2021
      Received in revised form: May 13, 2021
      Received: April 26, 2021

      Footnotes

      This study did not receive grant support.

      Identification

      DOI: https://doi.org/10.1016/j.jstrokecerebrovasdis.2021.105906

      Copyright

      © 2021 Elsevier Inc. All rights reserved.

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