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The importance of recognizing cerebral venous thrombosis following anti-COVID-19 vaccination

  • Alfonso Ciccone
    Correspondence
    Corresponding author at: Department of Neurology with neurosurgical activity and stroke unit, ASST di Mantova, Strada Lago Paiolo 10, 46100 Mantova, Italy.
    Affiliations
    Department of Neurology with neurosurgical activity and stroke unit, ASST di Mantova, Mantova, Italy
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  • Bruno Zanotti
    Affiliations
    Department of Neurology with neurosurgical activity and stroke unit, ASST di Mantova, Mantova, Italy
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  • The working group on cerebral venous thrombosis after COVID-19 vaccination
    Author Footnotes
    1 The list of the working group is in the Appendix.
  • Author Footnotes
    1 The list of the working group is in the Appendix.
      To the Editor.
      In March 2021, the reporting of cases of thrombosis post-COVID-19 vaccine AstraZeneca raised safety concerns and determined the temporary suspension of vaccinations in some countries in Europe [
      • Wise J.
      Covid-19: European countries suspend use of Oxford-AstraZeneca vaccine after reports of blood clots.
      ]. On the 18th of March, EMA published its preliminary review of cases concluding that “the benefit of the vaccine in combating the still widespread threat of COVID-19 (which itself results in clotting problems and may be fatal) continue to outweigh the risk of side effects” []. On the same day, a one-week campaign was launched in Italy through the secretariat of the Hospital Neurosciences Society (SNO) to gather all cases of cerebral venous thrombosis within one month of anti-COVID-19 vaccine administration. The purpose of this campaign is to identify, through an exhaustive collection of post-COVID-19 vaccine cerebral venous thrombosis cases, a common pattern among demographic, clinical, laboratory and risk factors, to support a possible causal link between COVID-19 vaccine and cerebral thrombosis.
      The most remarkable findings of the cases observed (Table 1) are early platelet consumption (82%), extra-cerebral thrombosis (73%) and poor outcome (only one patient without neurological deficit) with high mortality (45%), compared to expected mortality of less than 5% in patients with cerebral sinus thrombosis not exposed to the COVID-19 vaccine [
      • Ferro JM
      • Canhao P
      • Stam J
      • Bousser MG
      • Barinagarrementeria F
      • Investigators ISCVT
      Prognosis of cerebral vein and dural sinus trombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT).
      ]. Clinical manifestation appeared during the first 11 days after the vaccination.
      Table 1Characteristics of patients with cerebral vein thrombosis following COVID-19 vaccine. We considered the day of vaccination as day 0.
      Patient No.SexAge (yrs)Type of vaccineRisk factorsOnset of neurological symptomsCerebral vein involvedType of cerebral damageExtracerebral thrombosisNo. of platelets (*103/uL)I.N.R, aPTT ratioD-Dimer (ng/mL)TreatmentsOutcome
      upon first admission to the hospital
      1M50AstraZeneca, first doseSmokerHeadache on day 7Superior sagittal, left straight and sigmoid sinuses, gulf of the jugular veinMassive brain hemorrhage with trans-tentorial herniationPulmonary embolism151.19,

      0.88
      >10000S.c. enoxaparin, i.v. mannitol, craniectomyDeath on day 13
      2F42AstraZeneca, first doseMutation factor IIHeadache, fever on day 0Superior sagittal, right straight and sigmoid sinuses, gulf of the jugular veinBrain hemorrhagic infarctionSuprahepatic vein591,31,

      0.9
      31458S.c. enoxaparin, i.v. mannitol, thrombectomy, craniectomy.In a coma on day 23
      3F55Pfizer, second doseObesityHeadache on day 1Right straight and sigmoid sinuses, jugular veinBrain hemorrhageSuspected pulmonary embolism591.33

      0.83
      9000S.c. enoxaparinDeath on day 5
      4F32AstraZeneca, first doseThrombocytopenia in infancy with brain hemorrhage, oral contraceptiveHeadache, orbital bruising, abdominal pain and fever, on day 1Left straight and sigmoid sinusesCerebella hemorrhagic infarction with tonsillar herniationEpigastric and periuterin veins thrombosis, renal infarction301.28,

      1.14
      11332Fondaparinux, metil-prednisolonDeath on day 24
      5F35AstraZeneca, first doseOral contraceptiveHeadache, nausea and vomiting on day 6Superior sagittal, right straight and sigmoid sinusesBrain hemorrhagic infarction with and midline shiftPortal and mesenteric veins441.03

      0.86
      >8000I.v. mannitol, i.v. metil-prednisolon, i.v. fresh plasma, c.c. enoxaparin, plasmapheresisIn a coma on day 13
      6F51AstraZeneca, first doseHeterozygosis for factor V Leiden and MTHFRHeadache, vomiting and drowsiness on day 10Left straight and sigmoid sinuses, jugular vein, Galeno and internal cerebral veinsBilateral deep brain hemorrhagic infarction with brain swellingPelvic district.501.14

      0.83,
      35200I.v. remifentanil and noradrenalin, ventriculostomyDeath on day 13
      7M64AstraZeneca, first doseSinusitisHeadache and vomiting on day 4inferior sagittal, anterior part of the superior sagittal, left straight and sigmoid sinusesNoneNone187NA,

      1.03
      2500S.c. enoxaparinNo neurological deficit on day 20
      8F40AstraZeneca, first doseAnamnestic spontaneous abortionHeadache on day 5Inferior sagittal, left straight and sigmoid sinuses and jugular veinBrain hemorrhagic infarctionBrain hemorrhagic infarction401.06

      0.82,
      27546S.c. fondaparinuxAphasia and right hemiparesis on day 15
      9F49AstraZeneca, first doseContraceptive vaginal ring, migraine with auraHeadache on day 11Left straight and sigmoid sinuses, jugular veinBrain hemorrhagic infarction with swellingNone2780.96

      0.73
      14700S.c. enoxaparin, i.v. mannitolSignificant disability at day 20
      10F54AstraZeneca, first doseNoneHeadache and vomiting on day 2Superior sagittal sinus, Galen vein.Brain hemorrhagic infarction, subarachnoid hemorrhage, brainstem infarction and swellingAortic arch, thoracic aorta, portal, suprahepatic, right coronary, pulmonary and basilar arteries131.3

      0.83
      78254S.c. enoxaparin, s.c. fondaparinux, desametasoneDeath on day 15
      11F55AstraZeneca, first doseNoneHeadache and fever on day 6Left jugular veinCerebellar hemorrhagic infarction with swellingPulmonary thromboembolism, portal vein and inferior cava311.34

      0.92,
      >10000S.c. fondaparinux, i.v. metil-prednisolone, i.v. mannitol, craniectomyIn a coma on day 25
      These issues led to speculation that COVID-19 vaccine might determine cerebral venous thrombosis due to an immune thrombocytopenia [
      • Perricone C
      • Ceccarelli F
      • Nesher G
      • et al.
      Immune thrombocytopenic purpura (ITP) associated with vaccinations: a review of reported cases.
      ] as described in SARS-CoV-2 infection, through molecular mimicry between virus and platelet antigens [
      • Bhattacharjee S
      • Banerjee M.
      Immune Thrombocytopenia Secondary to COVID-19: a Systematic Review.
      ]. Similarly, after vaccination, the antibodies produced against the spike proteins might cross-react with specific antigens expressed on the platelet surface. The reason why such a chain of events sporadically occurs remains obscure.
      Therefore, cerebral venous thrombosis after COVID-19 vaccination can be the first manifestation of a much more complex disorder mimicking heparin-induced thrombocytopenia. An inclusive awareness of the clinical and laboratory features of these events plays a crucial role in the early identification of patients at their first clinical manifestation, in order to undertake all the possible measures to prevent the dramatic consequences of immune thrombocytopenia. Although from these case series there is no evidence of any predisposing conditions to identify patients at risk, the widespread knowledge of this possible severe adverse event of COVID-19 vaccination is already a valid prevention strategy.

      Declaration of Competing Interest

      None.

      Appendix

      Italian working group on cerebral venous thrombosis after COVID-19 vaccination: Maria Pia Mazzaferro, MD, Roberto Acampora, MD, and Fabrizio Fasano, MD (Ospedale del Mare, ASL Napoli 1 Centro, Napoli); Carla Zanferrari, MD, Simona Fanucchi, MD, and Lucio Liberato, MD (Azienda Socio Sanitaria Territoriale Melegnano e Martesana); Paolo Candelaresi, MD, and Mario Muto, MD (Azienda Ospedaliera di Rilievo Nazionale Antonio Cardarelli, Napoli); Francesco Sica, MD, Fabrizia Monteleone, MD, and Maria Carmelina Costa, MD (Ospedale Santa Maria Goretti - ASL Latina); Rosa Musolino, MD, Francesco Grillo, MD, and Cristina Dell'Aere, MD (Policlinico Universitario Messina); Francesca Romana Pezzella, MD, PhD, BSc (Azienda Ospedaliera San Camillo Forlanini, Roma); Giovanni Frisullo, MD, Giacomo Della Marca, MD, and Anselmo Caricato, MD (Fondazione Policlinico Universitario Agostino Gemelli –IRCCS, Roma); Bruno Bonetti, MD, PhD, and Manuel Cappellari, MD (Azienda Ospedaliera Universitaria Integrata, Verona); Domenico Sergio Zimatore, MD, Luigi Chiumarulo, MD, and Alessandro Introna, MD (Azienda Ospedaliero Universitaria Consorziale Policlinico, Bari); Florindo d’Onofrio, MD, Daniele Spitaleri, MD, and Elisabetta Iannaccone, MD (Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati, Avellino); Renato Gigli, MD (UPMC Salvator Mundi International Hospital, Roma).

      References

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        Covid-19: European countries suspend use of Oxford-AstraZeneca vaccine after reports of blood clots.
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        • Canhao P
        • Stam J
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        Immune thrombocytopenic purpura (ITP) associated with vaccinations: a review of reported cases.
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        Immune Thrombocytopenia Secondary to COVID-19: a Systematic Review.
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