Cerebral Venous Sinus Thrombosis After a Third Dose of mRNA COVID-19 Vaccine in an Adolescent: A case report

Cerebral Venous Sinus Thrombosis After a Third Dose of mRNA COVID-19 Vaccine in an Adolescent: A case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Cerebral Venous Sinus Thrombosis After a Third Dose of mRNA COVID-19 Vaccine in an Adolescent: A case report Shinsuke Mizuno, Junji Koyama, Shogo Horikawa, Kenji Kishimoto, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2702585/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : Several effective vaccines against Coronavirus disease 2019 (COVID-19) have been developed to control the spread of the disease. A few cases of thrombosis have been reported post-vaccination, especially among young adult women immunized with viral vector-based vaccines; although pediatric cases of cerebral venous sinus thrombosis (CVST) have been rarely reported after messenger ribonucleic acid (mRNA) vaccine administration. Case presentation: Here, we report a case of CVST in a 14-year-old girl immunized with the BNT16B2b2 vaccine. Other than this recent COVID-19 vaccination, there were no precipitant risk factors in her medical history. Laboratory work-up showed low levels of protein S activity. Further research revealed no pathological gene mutation. She was treated with anticoagulant therapy and discharged with mildly impaired coordination/movement of the fingers. Conclusion : CVST may occur following a mRNA COVID-19 vaccination, even among children. Further investigations are needed to establish whether thrombotic events are merely incidental or are a complication associated with mRNA-based vaccines. COVID-19 mRNA vaccine cerebral venous sinus thrombosis acquired protein S deficiency Figures Figure 1 Figure 2 Article Summary Our patient did not have a typical thrombosis with thrombocytopenia syndrome profile, indicating a peculiar pathophysiology following third mRNA COVID-19 vaccination. Background Since the first reported case in 2019, coronavirus disease 2019 (COVID-19) has spread worldwide, resulting in rapid production of several effective vaccines. Five such vaccines have been authorized by the Japanese Ministry of Health, Labor, and Welfare for use in adults: Pfizer-BioNTech, Moderna, AstraZeneca, Johnson and Johnson/Janssen, and Novax. Each has a different action mechanism. The Pfizer-Biotech and Moderna vaccines are both messenger ribonucleic acid (mRNA) -based, while the AstraZeneca and Johnson and Johnson/Janssen vaccines are replication-incompetent adenoviral vector-based. Novax is a recombinant nanoparticle vaccine. All are designed to produce coronavirus spike proteins and trigger an immune response. 1 Only the Pfizer-BioNTech vaccine has been approved in Japan for use in children aged 6 months through 17 years. Initial trials of these vaccines reported rare cases of anaphylaxis and low rates of serious adverse events. However, as the vaccines began to be used widely, some serious adverse effects were reported, including myocarditis and cerebral venous sinus thrombosis (CVST). 2 – 7 CVST is a rare but serious neurovascular condition defined as occlusion of venous sinuses, leading to increased venous pressure. This disrupts venous return, resulting in infarction and hemorrhage. 8 Thrombosis of the cerebral venous sinus is an uncommon form of stroke, usually affecting young adult women. 9 , 10 Risk factors for pediatric CVST include birth complications, infection of the head or neck, cancer, traumatic head injury, acquired or inherited thrombophilia, and use of hormonal contraceptives. 8 , 11 , 12 Due to the seriousness of CVST, studies have focused on its incidence after vaccinations. A few cases of thrombosis with thrombocytopenia syndrome (TTS) were reported following vaccinations with adenovirus vector-based vaccines. 2 , 6 , 13 Several mechanistic models have been proposed to explain such vaccine-induced immune thrombosis. Immune tolerance and production of autoantibodies specific for platelet factor-4 (PF4) in such cases resemble heparin-induced thrombocytopenia (HIT). 5 However, there has been no reported case of CVST in a child/adolescent receiving an mRNA COVID-19 vaccine. Here, we report a case of CVST following administration of a third dose of the BNT162b2 (Pfizer-BioNTech) vaccine to a 14-year-old girl with no particular medical history. This is the first pediatric case of CVST associated with an mRNA vaccine and, as such, provides insight into the elusive mechanisms underlying CVST following a mRNA vaccination. Case Presentation A 14-year-old, right-handed, healthy Japanese girl presented with a 1-day history of persistent headache, vomiting, paresthesia of the bilateral extremities, and seizure. She reported no recent infection, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Both medical and surgical history were unremarkable. Regarding drug history, she received the Pfizer-BioNTech mRNA COVID-19 vaccine 7 days prior to presentation, and reported no use of oral contraceptive pills or any other medications of clinical relevance. Her family history was unremarkable. On examination, her temperature was 36.4°C, pulse 75 beats per minute, blood pressure 118/82 mmHg, and oxygen saturation 96% on ambient air. Cardiopulmonary examination indicated no murmurs, and bilateral auscultation showed clear lung fields. An abdominal examination demonstrated a soft, non-tender abdomen, with no organomegaly. Neurological examination revealed disturbed consciousness and bilateral weakness of the upper extremities; muscle strength was 4 in the upper limbs and 5 in the lower limbs for manual muscle testing. Laboratory findings, including complete blood counts, and the results of coagulation tests and blood chemistry, are summarized in the Table. The data revealed elevation of D-dimer (6 times the upper normal limit on hospitalization day 3). On hospitalization day 2, the platelet count was slightly low at 169 × 109/L. The following test results were normal: white blood cell count, hemoglobin, platelet count, prothrombin time, partial thromboplastin time, fibrinogen, blood urine nitrogen, creatinine, electrolytes, bilirubin, lactate dehydrogenase, alkaline phosphatase, albumin, total protein, aminotransferases of aspartate aminotransferase, and alanine aminotransferase. Non-contrast brain computed tomography (CT) and brain magnetic resonance imaging showed hemorrhage in the right temporal region and angioedema in the left frontal and temporal regions on hospitalization day 1. Brain CT angiography revealed a filling defect within the superior sagittal sinus (Fig. 1 ). These findings are consistent with CVST. Since no clear precipitating factors were found in her clinical history, we ordered a thrombophilia (protein C and S, anti-thrombin III, anti-B2GP1 immunoglobulin G/immunoglobulin M, anticardiolipin, and lupus anticoagulant) work-up. Protein S activity on admission was low and returned to normal on hospitalization day 4. However, low values presented again during her follow-up as an outpatient. We also measured anti-platelet factor-4 (PF-4) antibodies, which were negative. A polymerase chain reaction assay for SARS-CoV-2 was negative. After CVST was confirmed, we wondered whether vaccine-induced TTS was a possible cause. Therefore, we administered argatroban (0.7 mcg/kg/d) and levetiracetam (40 mg/kg/d). The patient did not meet the Center for Disease Control and Prevention criteria for a TTS case definition due to the absence of a low platelet count and negativity for anti-PF-4 antibodies; however, we continued argatroban for 11 days and then switched to warfarin. Her headache and upper limb paralysis improved greatly, and subsided completely by hospitalization day 3. MRI performed on hospitalization day 7 and MR venography on hospitalization day 17 showed improvement of the abnormal hyperintensity area at sagittal sinus (Fig. 2 ). The patient was discharged with only mildly impaired coordination/movement of the fingers on hospitalization day 17. Further investigation for protein S deficiency revealed there was no mutation of protein S (PS) gene ( PROS1 gene). Discussion And Conclusion To the best of our knowledge, this is the first pediatric case of CVST associated with a mRNA vaccine. The patient experienced CVST with elevated D-dimers, but without severe thrombocytopenia or anti-PF4 antibodies. In most instances, CVST is triggered by single or multiple pre-disposing factors, or even by transient factors such as a systemic or local infection. At least one precipitant risk factor is identified in more than 85% of the cases, and multiple risk factors are found in approximately half. 5 , 11 , 12 In our patient, a recent mRNA COVID-19 vaccination and low level of PS activity were noted by precise history and detailed laboratory work-up. CVST is a rare, although increasing, adverse event that can occur after a COVID-19 vaccination. Most COVID-19 vaccine-related cases of CVST are associated with vector-based vaccines. They are usually accompanied by TTS. 2 , 6 , 13 , 14 The median platelet count at diagnosis is approximately 20,000 to 30,000×109/L, and in almost every patient, high levels of antibodies to PF4 are identified by enzyme-linked immunosorbent assay. However, our patient developed CVST without TTS following her third dose of a mRNA COVID-19 vaccine (BENT126b2; Pfizer-BioNTech). To date, there are a few reports of adult cases of mRNA COVID-19 vaccine-related CVST in the absence of TSS. 14 – 16 The estimated incidence of CVST is 0.4 to 0.7 per 100,000 children per year. 11 , 12 The reporting event rate of CVST after the Pfizer-BioNTech vaccine from December 12, 2020 to 16 March 16, 2021, was 0.4% (4/1197), less than that for viral vector vaccine-related CVST within the same period, which was 1.1% (7/639). 17 Likewise, an CVST analysis after vaccination in European countries noted that it occurred far more frequently after an AstraZeneca (vector-based) vaccination than after a mRNA vaccination. 6 Nevertheless, SARS-CoV-2 infection itself is associated with a markedly increased incidence of CVST when compared with the general population, patients with influenza, and people who have received the Pfizer-BioNTech or Moderna vaccines. 18 These data suggest that healthcare providers, parents, and patients should be aware of the safety profiles for COVID-19 vaccines, although the benefits overweight the risks associated with a SARS-CoV-2 infection. The main mechanism of CVST associated with viral vector vaccines is vaccine-induced immune thrombotic thrombocytopenia, which is similar to HIT. 5 The mechanism underlying mRNA vaccine-related CVST is unclear, although the following have been proposed: first, the interaction between the spike glycoprotein and platelets leads to platelet aggregation 19 ; second, binding of the spike glycoprotein to the angiotensin converting enzyme receptor activates endothelial cells and up-regulates expression of cell adhesion molecules, which promotes thrombogenesis and causes CVST 20 ; and third, in vitro studies have shown that spike proteins can activate the alternative complement pathway, which plays a role in immune-mediated thrombogenesis. 21 In our patient, in addition to these hypotheses, acquired PS deficiency secondary to the immune-mediated reaction to the mRNA vaccine may have contributed to the CVST onset. PS deficiency is caused by inherited or acquired deficiencies, such as, liver disease, severe infection or other illness, and pregnancy and certain medications. Inherited PS deficiency is uncommon. PROS1 is found on chromosome 3 (3q11.1) and, to date, the reported detection rate of causative gene mutation in suspected PS deficiency is approximately 50%. 22 Therefore, inherited PS deficiency was not excluded completely. The exact mechanism of acquired PS deficiency is not known, although it may be acquired through the induced autoantibodies and epigenetic etiology. Since thrombotic events following administration of a mRNA COVID-19 vaccine are very rare, causality cannot be confirmed. This case may add to the evidence supporting a possible relationship between mRNA COVID-19 vaccines and thrombotic events, and raises the awareness of health care providers associated with pediatric care, as well as parents and patients, regarding this rare, critical adverse event; early recognition allows early treatment to prevent complications. In conclusion, CVST may occur following any COVID-19 vaccination, even among children. Our patient lacked the typical TTS profile, which can occur following administration of vector-based vaccine (low platelet counts and the presence of anti-PF4 antibodies). This may indicate a peculiar pathophysiology associated with thrombotic events following a mRNA vaccination. Further investigations are needed to establish whether thrombotic events are merely incidental or are a complication associated with mRNA-based vaccines. Abbreviations COVID-19: coronavirus disease 2019 CT: computed tomography CVST: cerebral venous sinus thrombosis HIT: heparin-induced thrombocytopenia mRNA: messenger ribonucleic acid PF4: platelet factor-4 PS: protein S SARS-CoV-2: severe acute respiratory syndrome coronavirus 2 TTS: thrombosis with thrombocytopenia syndrome Declarations Ethics approval: This study was approved by Hyogo Prefectural Kobe Children’s Review Board (no. R4-64). Consent to participate and consent for publication: Informed consent was obtained from patient and patient’s parents. Availability of data and materials: Deidentified individual participant data (including data dictionaries) will be made available, in addition to study protocols, the statistical analysis plan, and the informed consent form. The data will be made available upon publication to researchers who provide a methodologically sound proposal for use in achieving the goals of the approved proposal. Proposals should be submitted to [email protected] . Competing interests: The authors declare that they have no competing interests. Funding: None. Author’s contributions: SM conceptualized the study, collected, analyzed, and interpreted data, drafted the initial manuscript, and critically reviewed and revised the manuscript. JK, SH, KK, DH, YK, and MK collected data, drafted the initial manuscript, and reviewed and revised the manuscript. All authors approved the final manuscript as submitted, and agree to be accountable for all aspects of the work. Acknowledgements Thank you to Dr. Hiroshi Kurosawa for his contribution in collecting patient’s clinical data. Thank you also to Dr. Naoya Morisada for his help in collecting and interpreting the genetic data. References Mascellino MT, Di Timoteo F, De Angelis M, Oliva A. Overview of the main anti-SARS-CoV-2 vaccines: Mechanism of action, efficacy and safety. Infect Drug Resist. 2021;14:3459-3476. doi: 10.2147/IDR.S315727. Sharifian-Dorche M, Bahmanyar M, Sharifian-Dorche A, Mohammadi P, Nomovi M, Mowla A. Vaccine- induced immune thrombotic thrombocytopenia and cerebral venous sinus thrombosis post COVID-19 vaccination; A systematic review. J Neurol Sci. 2021;428:117607. doi: 10.1016/j.jns.2021.117607. Perry RJ, Tamborska A, Singh B, et al. Cerebral venous thrombosis after vaccination against COVID-19 in the UK: A multicentre cohort study. Lancet. 2021;398(10306):1147-1156. doi: 10.1016/S0140-6736(21)01608-1. Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F, ISCVT Investigators. Prognosis of cerebral vein and dural sinus thrombosis: Results of the International Study on cerebral vein and Dural Sinus Thrombosis (ISCVT). Stroke. 2004;35(3):664-670. doi: 10.1161/01.STR.0000117571.76197.26. Rizk JG, Gupta A, Sardar P, et al. Clinical characteristics and pharmacological management of COVID-19 vaccine-induced immune thrombotic thrombocytopenia with cerebral venous sinus thrombosis: A review. JAMA Cardiol. 2021;6(12):1451-1460. doi: 10.1001/jamacardio.2021.3444. Krzywicka K, Heldner MR, 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. Eur J Neurol. 2021;28(11):3656-3662. doi: 10.1111/ene.15029. Schulz JB, Berlit P, Diener HC, et al. COVID-19 vaccine-associated cerebral venous thrombosis in Germany. Ann Neurol. 2021;90(4):627-639. doi: 10.1002/ana.26172. Saposnik G, Barinagarrementeria F, Brown RD, et al. and the Council on Epidemiology and Prevention. Diagnosis and management of cerebral venous thrombosis: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(4):1158-1192. doi: 10.1161/STR.0b013e31820a8364. Coutinho JM, Ferro JM, Canhão P, et al. Cerebral venous and sinus thrombosis in women. Stroke. 2009;40(7):2356-2361. doi: 10.1161/STROKEAHA.108.543884. Coutinho JM, Gerritsma JJ, Zuurbier SM, Stam J. Isolated cortical vein thrombosis: Systematic review of case reports and case series. Stroke. 2014;45(6):1836-1838. doi: 10.1161/STROKEAHA.113.004414. deVeber G, Andrew M, Adams C, et al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345(6):417-423. doi: 10.1056/NEJM200108093450604. Ichord RN, Benedict SL, Chan AK, Kirkham FJ, Nowak-Göttl U, International Paediatric Stroke Study Group. Paediatric cerebral sinovenous thrombosis: Findings of the International Paediatric Stroke Study. Arch Dis Child. 2015;100(2):174-179. doi: 10.1136/archdischild-2014-306382. See 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;325(24):2448-2456. doi: 10.1001/jama.2021.7517. Syed K, Chaudhary H, Donato A. Central venous sinus thrombosis with sub- arachnoid hemorrhage following an mRNA COVID-19 vaccination: Are these reports merely co-incidental? Am J Case Rep. 2021;22:e933397. doi: 10.12659/AJCR.933397. Fan BE, Shen JY, Lim XR, et al. Cerebral venous thrombosis post BNT162b2 mRNA SARS-CoV-2 vaccination: A black swan event. Am J Hematol. 2021;96(9):E357-E361. doi: 10.1002/ajh.26272. Dias L, Soares-Dos-Reis R, Meira J, et al. Cerebral venous thrombosis after BNT162b2 mRNA SARS-CoV-2 vaccine. J Stroke Cerebrovasc Dis. 2021;30(8):105906. doi: 10.1016/j.jstrokecerebrovasdis.2021.105906. Smadja DM, Yue QY, Chocron R, Sanchez O, Lillo-Le Louet A. Vaccination against COVID-19: Insight from arterial and venous thrombosis occurrence using data from VigiBase. Eur Respir J. 2021;58(1):2100956. doi: 10.1183/13993003.00956-2021. Taquet M, Husain M, Geddes JR, Luciano S, Harrison PJ. Cerebral venous thrombosis: a retrospective cohort study of 513,284 confirmed COVID-19 cases and a comparison with 489,871 people receiving a COVID-19 mRNA vaccine. medRxiv. 2021.04.27.21256153 Zhang S, Liu Y, Wang X, et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. J Hematol Oncol. 2020;13(1):120. doi: 10.1186/s13045-020-00954-7. Buzhdygan TP, DeOre BJ, Baldwin-Leclair A, et al. The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier. Neurobiol Dis. 2020;146:105131. doi: 10.1016/j.nbd.2020.105131. Yu J, Yuan X, Chen H, Chaturvedi S, Braunstein EM, Brodsky RA. Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition. Blood. 2020;136(18):2080-2089. doi: 10.1182/blood.2020008248. Alhenc-Gelas M, Plu-Bureau G, Horellou MH, Rauch A, Suchon P, GEHT genetic thrombophilia group. PROS1 genotype phenotype relationships in a large cohort of adults with suspicion of inherited quantitative protein S deficiency. Thromb Haemost. 2016;115(3):570-579. doi: 10.1160/TH15-05-0391. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2702585","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":184812808,"identity":"c06d425d-9ec5-4070-819b-39fdf13e4747","order_by":0,"name":"Shinsuke Mizuno","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIiWNgGAWjYBACxgbGhgMfDGxAzMYDRGlhbmM+eHBGQRpYN3Fa2NvYkg/zfDgM5hCnhXd+j8EBHoPzdmvbDwNtqbGJJqhFso3H4ICEwe3kbWcSgVqOpeU2ENJiCNJiANRidgCohbHhMGEt9seAWhIMziWbnX9IpBbGNraEAwcMDtiZ3SDWFsa25AMHGwySE8xuAG1JIMYvjM0Hmz//+WNnb3Y+/eGDDzU2hLXAQCJYZQKxykHAnhTFo2AUjIJRMMIAAG3cTRMzPrKwAAAAAElFTkSuQmCC","orcid":"","institution":"Hyogo Prefectural Kobe Children’s Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Shinsuke","middleName":"","lastName":"Mizuno","suffix":""},{"id":184812809,"identity":"c9bf9458-c13e-4f93-81b8-788fbf26af4c","order_by":1,"name":"Junji Koyama","email":"","orcid":"","institution":"Hyogo Prefectural Kobe Children’s Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Junji","middleName":"","lastName":"Koyama","suffix":""},{"id":184812810,"identity":"330b50f1-a67b-42d8-a03b-198a6af5108f","order_by":2,"name":"Shogo Horikawa","email":"","orcid":"","institution":"Hyogo Prefectural Kobe Children’s Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shogo","middleName":"","lastName":"Horikawa","suffix":""},{"id":184812811,"identity":"7c73a9eb-17ed-4e53-ae62-c11a945a5a77","order_by":3,"name":"Kenji Kishimoto","email":"","orcid":"","institution":"Hyogo Prefectural Kobe Children’s Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kenji","middleName":"","lastName":"Kishimoto","suffix":""},{"id":184812812,"identity":"b57ee69a-1389-4eb2-bdf3-d3a639fb193b","order_by":4,"name":"Daiichiro Hasegawa","email":"","orcid":"","institution":"Hyogo Prefectural Kobe Children’s Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Daiichiro","middleName":"","lastName":"Hasegawa","suffix":""},{"id":184812813,"identity":"20513974-a295-4e4c-8051-8fc414344051","order_by":5,"name":"Yoshiyuki Kosaka","email":"","orcid":"","institution":"Hyogo Prefectural Kobe Children’s Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yoshiyuki","middleName":"","lastName":"Kosaka","suffix":""},{"id":184812814,"identity":"3f8367d6-886f-4106-b062-3d36bd4eeca1","order_by":6,"name":"Masashi Kasai","email":"","orcid":"","institution":"Hyogo Prefectural Kobe Children’s Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Masashi","middleName":"","lastName":"Kasai","suffix":""}],"badges":[],"createdAt":"2023-03-17 01:44:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2702585/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2702585/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":34653764,"identity":"f9cffb07-faef-4fb4-a080-99f88789fae0","added_by":"auto","created_at":"2023-03-22 14:38:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1852536,"visible":true,"origin":"","legend":"\u003cp\u003eBrain CT on hospitalization day 1:\u003c/p\u003e\n\u003cp\u003eNon-contrast CT, revealing right temporal lobe intracerebral hemorrhage [A]. CT angiography, revealing a filling deficit within the superior sagittal sinus (arrowhead) [B]. A triangular filling defect in the in the superior sagittal sinus as the positive empty delta sign (arrow) [C].\u003c/p\u003e","description":"","filename":"Fig1tif.png","url":"https://assets-eu.researchsquare.com/files/rs-2702585/v1/6bbdb39b3095dea28ad49e95.png"},{"id":34653765,"identity":"d7ce3e85-15a5-417b-8aec-b5de636a41e1","added_by":"auto","created_at":"2023-03-22 14:38:16","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1576297,"visible":true,"origin":"","legend":"\u003cp\u003eBrain MRI during hospitalization\u003c/p\u003e\n\u003cp\u003eT2 FLAIR-weighted magnetic resonance imaging (MRI) on hospitalization day 7 showing an abnormal hyperintensity area (arrow) in the dilated superior sagittal sinus and intracranial hemorrhage in the subacute phase [A]. An MRI venogram on hospitalization day 17, demonstrating the absence of opacification in the superior sagittal sinus (arrowhead) and intracranial hemorrhage in the chronic phase [B].\u003c/p\u003e","description":"","filename":"Fig2tif.png","url":"https://assets-eu.researchsquare.com/files/rs-2702585/v1/0216b4e52c64f333bc09b23b.png"},{"id":34823690,"identity":"154a6513-9f53-4d35-8865-e6d49e248adc","added_by":"auto","created_at":"2023-03-26 11:14:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1431555,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2702585/v1/5a7eeefc-ea0b-4f44-9a97-45501e3e237e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cerebral Venous Sinus Thrombosis After a Third Dose of mRNA COVID-19 Vaccine in an Adolescent: A case report","fulltext":[{"header":"Article Summary ","content":"\u003cp\u003eOur patient did not have a typical thrombosis with thrombocytopenia syndrome profile, indicating a peculiar pathophysiology following third mRNA COVID-19 vaccination.\u003c/p\u003e"},{"header":"Background","content":"\u003cp\u003eSince the first reported case in 2019, coronavirus disease 2019 (COVID-19) has spread worldwide, resulting in rapid production of several effective vaccines. Five such vaccines have been authorized by the Japanese Ministry of Health, Labor, and Welfare for use in adults: Pfizer-BioNTech, Moderna, AstraZeneca, Johnson and Johnson/Janssen, and Novax. Each has a different action mechanism. The Pfizer-Biotech and Moderna vaccines are both messenger ribonucleic acid (mRNA) -based, while the AstraZeneca and Johnson and Johnson/Janssen vaccines are replication-incompetent adenoviral vector-based. Novax is a recombinant nanoparticle vaccine. All are designed to produce coronavirus spike proteins and trigger an immune response.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Only the Pfizer-BioNTech vaccine has been approved in Japan for use in children aged 6 months through 17 years.\u003c/p\u003e \u003cp\u003eInitial trials of these vaccines reported rare cases of anaphylaxis and low rates of serious adverse events. However, as the vaccines began to be used widely, some serious adverse effects were reported, including myocarditis and cerebral venous sinus thrombosis (CVST).\u003csup\u003e\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCVST is a rare but serious neurovascular condition defined as occlusion of venous sinuses, leading to increased venous pressure. This disrupts venous return, resulting in infarction and hemorrhage.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Thrombosis of the cerebral venous sinus is an uncommon form of stroke, usually affecting young adult women.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Risk factors for pediatric CVST include birth complications, infection of the head or neck, cancer, traumatic head injury, acquired or inherited thrombophilia, and use of hormonal contraceptives.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Due to the seriousness of CVST, studies have focused on its incidence after vaccinations. A few cases of thrombosis with thrombocytopenia syndrome (TTS) were reported following vaccinations with adenovirus vector-based vaccines.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Several mechanistic models have been proposed to explain such vaccine-induced immune thrombosis. Immune tolerance and production of autoantibodies specific for platelet factor-4 (PF4) in such cases resemble heparin-induced thrombocytopenia (HIT).\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e However, there has been no reported case of CVST in a child/adolescent receiving an mRNA COVID-19 vaccine.\u003c/p\u003e \u003cp\u003eHere, we report a case of CVST following administration of a third dose of the BNT162b2 (Pfizer-BioNTech) vaccine to a 14-year-old girl with no particular medical history. This is the first pediatric case of CVST associated with an mRNA vaccine and, as such, provides insight into the elusive mechanisms underlying CVST following a mRNA vaccination.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 14-year-old, right-handed, healthy Japanese girl presented with a 1-day history of persistent headache, vomiting, paresthesia of the bilateral extremities, and seizure. She reported no recent infection, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Both medical and surgical history were unremarkable. Regarding drug history, she received the Pfizer-BioNTech mRNA COVID-19 vaccine 7 days prior to presentation, and reported no use of oral contraceptive pills or any other medications of clinical relevance. Her family history was unremarkable. On examination, her temperature was 36.4\u0026deg;C, pulse 75 beats per minute, blood pressure 118/82 mmHg, and oxygen saturation 96% on ambient air. Cardiopulmonary examination indicated no murmurs, and bilateral auscultation showed clear lung fields. An abdominal examination demonstrated a soft, non-tender abdomen, with no organomegaly. Neurological examination revealed disturbed consciousness and bilateral weakness of the upper extremities; muscle strength was 4 in the upper limbs and 5 in the lower limbs for manual muscle testing.\u003c/p\u003e \u003cp\u003eLaboratory findings, including complete blood counts, and the results of coagulation tests and blood chemistry, are summarized in the Table. The data revealed elevation of D-dimer (6 times the upper normal limit on hospitalization day 3). On hospitalization day 2, the platelet count was slightly low at 169 \u0026times; 109/L. The following test results were normal: white blood cell count, hemoglobin, platelet count, prothrombin time, partial thromboplastin time, fibrinogen, blood urine nitrogen, creatinine, electrolytes, bilirubin, lactate dehydrogenase, alkaline phosphatase, albumin, total protein, aminotransferases of aspartate aminotransferase, and alanine aminotransferase.\u003c/p\u003e \u003cp\u003eNon-contrast brain computed tomography (CT) and brain magnetic resonance imaging showed hemorrhage in the right temporal region and angioedema in the left frontal and temporal regions on hospitalization day 1. Brain CT angiography revealed a filling defect within the superior sagittal sinus (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). These findings are consistent with CVST. Since no clear precipitating factors were found in her clinical history, we ordered a thrombophilia (protein C and S, anti-thrombin III, anti-B2GP1 immunoglobulin G/immunoglobulin M, anticardiolipin, and lupus anticoagulant) work-up. Protein S activity on admission was low and returned to normal on hospitalization day 4. However, low values presented again during her follow-up as an outpatient. We also measured anti-platelet factor-4 (PF-4) antibodies, which were negative. A polymerase chain reaction assay for SARS-CoV-2 was negative.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAfter CVST was confirmed, we wondered whether vaccine-induced TTS was a possible cause. Therefore, we administered argatroban (0.7 mcg/kg/d) and levetiracetam (40 mg/kg/d). The patient did not meet the Center for Disease Control and Prevention criteria for a TTS case definition due to the absence of a low platelet count and negativity for anti-PF-4 antibodies; however, we continued argatroban for 11 days and then switched to warfarin. Her headache and upper limb paralysis improved greatly, and subsided completely by hospitalization day 3. MRI performed on hospitalization day 7 and MR venography on hospitalization day 17 showed improvement of the abnormal hyperintensity area at sagittal sinus (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The patient was discharged with only mildly impaired coordination/movement of the fingers on hospitalization day 17. Further investigation for protein S deficiency revealed there was no mutation of protein S (PS) gene (\u003cem\u003ePROS1\u003c/em\u003e gene).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion And Conclusion","content":"\u003cp\u003eTo the best of our knowledge, this is the first pediatric case of CVST associated with a mRNA vaccine. The patient experienced CVST with elevated D-dimers, but without severe thrombocytopenia or anti-PF4 antibodies.\u003c/p\u003e \u003cp\u003eIn most instances, CVST is triggered by single or multiple pre-disposing factors, or even by transient factors such as a systemic or local infection. At least one precipitant risk factor is identified in more than 85% of the cases, and multiple risk factors are found in approximately half.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e In our patient, a recent mRNA COVID-19 vaccination and low level of PS activity were noted by precise history and detailed laboratory work-up. CVST is a rare, although increasing, adverse event that can occur after a COVID-19 vaccination. Most COVID-19 vaccine-related cases of CVST are associated with vector-based vaccines. They are usually accompanied by TTS.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e The median platelet count at diagnosis is approximately 20,000 to 30,000\u0026times;109/L, and in almost every patient, high levels of antibodies to PF4 are identified by enzyme-linked immunosorbent assay. However, our patient developed CVST without TTS following her third dose of a mRNA COVID-19 vaccine (BENT126b2; Pfizer-BioNTech). To date, there are a few reports of adult cases of mRNA COVID-19 vaccine-related CVST in the absence of TSS.\u003csup\u003e\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe estimated incidence of CVST is 0.4 to 0.7 per 100,000 children per year.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e The reporting event rate of CVST after the Pfizer-BioNTech vaccine from December 12, 2020 to 16 March 16, 2021, was 0.4% (4/1197), less than that for viral vector vaccine-related CVST within the same period, which was 1.1% (7/639).\u003csup\u003e17\u003c/sup\u003e Likewise, an CVST analysis after vaccination in European countries noted that it occurred far more frequently after an AstraZeneca (vector-based) vaccination than after a mRNA vaccination.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Nevertheless, SARS-CoV-2 infection itself is associated with a markedly increased incidence of CVST when compared with the general population, patients with influenza, and people who have received the Pfizer-BioNTech or Moderna vaccines.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e These data suggest that healthcare providers, parents, and patients should be aware of the safety profiles for COVID-19 vaccines, although the benefits overweight the risks associated with a SARS-CoV-2 infection.\u003c/p\u003e \u003cp\u003eThe main mechanism of CVST associated with viral vector vaccines is vaccine-induced immune thrombotic thrombocytopenia, which is similar to HIT.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e The mechanism underlying mRNA vaccine-related CVST is unclear, although the following have been proposed: first, the interaction between the spike glycoprotein and platelets leads to platelet aggregation\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e; second, binding of the spike glycoprotein to the angiotensin converting enzyme receptor activates endothelial cells and up-regulates expression of cell adhesion molecules, which promotes thrombogenesis and causes CVST\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e; and third, in vitro studies have shown that spike proteins can activate the alternative complement pathway, which plays a role in immune-mediated thrombogenesis.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e In our patient, in addition to these hypotheses, acquired PS deficiency secondary to the immune-mediated reaction to the mRNA vaccine may have contributed to the CVST onset.\u003c/p\u003e \u003cp\u003ePS deficiency is caused by inherited or acquired deficiencies, such as, liver disease, severe infection or other illness, and pregnancy and certain medications. Inherited PS deficiency is uncommon. \u003cem\u003ePROS1\u003c/em\u003e is found on chromosome 3 (3q11.1) and, to date, the reported detection rate of causative gene mutation in suspected PS deficiency is approximately 50%.\u003csup\u003e22\u003c/sup\u003e Therefore, inherited PS deficiency was not excluded completely. The exact mechanism of acquired PS deficiency is not known, although it may be acquired through the induced autoantibodies and epigenetic etiology.\u003c/p\u003e \u003cp\u003eSince thrombotic events following administration of a mRNA COVID-19 vaccine are very rare, causality cannot be confirmed. This case may add to the evidence supporting a possible relationship between mRNA COVID-19 vaccines and thrombotic events, and raises the awareness of health care providers associated with pediatric care, as well as parents and patients, regarding this rare, critical adverse event; early recognition allows early treatment to prevent complications. In conclusion, CVST may occur following any COVID-19 vaccination, even among children. Our patient lacked the typical TTS profile, which can occur following administration of vector-based vaccine (low platelet counts and the presence of anti-PF4 antibodies). This may indicate a peculiar pathophysiology associated with thrombotic events following a mRNA vaccination. Further investigations are needed to establish whether thrombotic events are merely incidental or are a complication associated with mRNA-based vaccines.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCOVID-19: coronavirus disease 2019\u003c/p\u003e\n\u003cp\u003eCT: computed tomography\u003c/p\u003e\n\u003cp\u003eCVST: cerebral venous sinus thrombosis\u003c/p\u003e\n\u003cp\u003eHIT: heparin-induced thrombocytopenia\u003c/p\u003e\n\u003cp\u003emRNA: messenger ribonucleic acid\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePF4: platelet factor-4\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePS: protein S\u003c/p\u003e\n\u003cp\u003eSARS-CoV-2: severe acute respiratory syndrome coronavirus 2\u003c/p\u003e\n\u003cp\u003eTTS: thrombosis with thrombocytopenia syndrome\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by Hyogo Prefectural Kobe Children\u0026rsquo;s Review Board (no. R4-64). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate and consent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from patient and patient\u0026rsquo;s parents.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDeidentified individual participant data (including data dictionaries) will be made available, in addition to study protocols, the statistical analysis plan, and the informed consent form. The data will be made available upon publication to researchers who provide a methodologically sound proposal for use in achieving the goals of the approved proposal. Proposals should be submitted to [email protected].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSM conceptualized the study, collected, analyzed, and interpreted data, drafted the initial manuscript, and critically reviewed and revised the manuscript.\u003c/p\u003e\n\u003cp\u003eJK, SH, KK, DH, YK, and MK collected data, drafted the initial manuscript, and reviewed and revised the manuscript. All authors approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThank you to Dr. Hiroshi Kurosawa for his contribution in collecting patient\u0026rsquo;s clinical data. Thank you also to Dr. Naoya Morisada for his help in collecting and interpreting the genetic data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMascellino MT, Di Timoteo F, De Angelis M, Oliva A. Overview of the main anti-SARS-CoV-2 vaccines: Mechanism of action, efficacy and safety. Infect Drug Resist. 2021;14:3459-3476. doi: 10.2147/IDR.S315727.\u003c/li\u003e\n\u003cli\u003eSharifian-Dorche M, Bahmanyar M, Sharifian-Dorche A, Mohammadi P, Nomovi M, Mowla A. Vaccine- induced immune thrombotic thrombocytopenia and cerebral venous sinus thrombosis post COVID-19 vaccination; A systematic review. J Neurol Sci. 2021;428:117607. doi: 10.1016/j.jns.2021.117607.\u003c/li\u003e\n\u003cli\u003ePerry RJ, Tamborska A, Singh B, et al. Cerebral venous thrombosis after vaccination against COVID-19 in the UK: A multicentre cohort study. Lancet. 2021;398(10306):1147-1156. doi: 10.1016/S0140-6736(21)01608-1.\u003c/li\u003e\n\u003cli\u003eFerro JM, Canh\u0026atilde;o P, Stam J, Bousser MG, Barinagarrementeria F, ISCVT Investigators. Prognosis of cerebral vein and dural sinus thrombosis: Results of the International Study on cerebral vein and Dural Sinus Thrombosis (ISCVT). Stroke. 2004;35(3):664-670. doi: 10.1161/01.STR.0000117571.76197.26.\u003c/li\u003e\n\u003cli\u003eRizk JG, Gupta A, Sardar P, et al. Clinical characteristics and pharmacological management of COVID-19 vaccine-induced immune thrombotic thrombocytopenia with cerebral venous sinus thrombosis: A review. JAMA Cardiol. 2021;6(12):1451-1460. doi: 10.1001/jamacardio.2021.3444.\u003c/li\u003e\n\u003cli\u003eKrzywicka K, Heldner MR, S\u0026aacute;nchez van Kammen M, et al. Post-SARS-CoV-2-vaccination cerebral venous sinus thrombosis: An analysis of cases notified to the European Medicines Agency. Eur J Neurol. 2021;28(11):3656-3662. doi: 10.1111/ene.15029.\u003c/li\u003e\n\u003cli\u003eSchulz JB, Berlit P, Diener HC, et al. COVID-19 vaccine-associated cerebral venous thrombosis in Germany. Ann Neurol. 2021;90(4):627-639. doi: 10.1002/ana.26172.\u003c/li\u003e\n\u003cli\u003eSaposnik G, Barinagarrementeria F, Brown RD, et al. and the Council on Epidemiology and Prevention. Diagnosis and management of cerebral venous thrombosis: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(4):1158-1192. doi: 10.1161/STR.0b013e31820a8364.\u003c/li\u003e\n\u003cli\u003eCoutinho JM, Ferro JM, Canh\u0026atilde;o P, et al. Cerebral venous and sinus thrombosis in women. Stroke. 2009;40(7):2356-2361. doi: 10.1161/STROKEAHA.108.543884.\u003c/li\u003e\n\u003cli\u003eCoutinho JM, Gerritsma JJ, Zuurbier SM, Stam J. Isolated cortical vein thrombosis: Systematic review of case reports and case series. Stroke. 2014;45(6):1836-1838. doi: 10.1161/STROKEAHA.113.004414.\u003c/li\u003e\n\u003cli\u003edeVeber G, Andrew M, Adams C, et al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345(6):417-423. doi: 10.1056/NEJM200108093450604.\u003c/li\u003e\n\u003cli\u003eIchord RN, Benedict SL, Chan AK, Kirkham FJ, Nowak-G\u0026ouml;ttl U, International Paediatric Stroke Study Group. Paediatric cerebral sinovenous thrombosis: Findings of the International Paediatric Stroke Study. Arch Dis Child. 2015;100(2):174-179. doi: 10.1136/archdischild-2014-306382.\u003c/li\u003e\n\u003cli\u003eSee 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;325(24):2448-2456. doi: 10.1001/jama.2021.7517.\u003c/li\u003e\n\u003cli\u003eSyed K, Chaudhary H, Donato A. Central venous sinus thrombosis with sub- arachnoid hemorrhage following an mRNA COVID-19 vaccination: Are these reports merely co-incidental? Am J Case Rep. 2021;22:e933397. doi: 10.12659/AJCR.933397.\u003c/li\u003e\n\u003cli\u003eFan BE, Shen JY, Lim XR, et al. Cerebral venous thrombosis post BNT162b2 mRNA SARS-CoV-2 vaccination: A black swan event. Am J Hematol. 2021;96(9):E357-E361. doi: 10.1002/ajh.26272.\u003c/li\u003e\n\u003cli\u003eDias L, Soares-Dos-Reis R, Meira J, et al. Cerebral venous thrombosis after BNT162b2 mRNA SARS-CoV-2 vaccine. J Stroke Cerebrovasc Dis. 2021;30(8):105906. doi: 10.1016/j.jstrokecerebrovasdis.2021.105906.\u003c/li\u003e\n\u003cli\u003eSmadja DM, Yue QY, Chocron R, Sanchez O, Lillo-Le Louet A. Vaccination against COVID-19: Insight from arterial and venous thrombosis occurrence using data from VigiBase. Eur Respir J. 2021;58(1):2100956. doi: 10.1183/13993003.00956-2021.\u003c/li\u003e\n\u003cli\u003eTaquet M, Husain M, Geddes JR, Luciano S, Harrison PJ. Cerebral venous thrombosis: a retrospective cohort study of 513,284 confirmed COVID-19 cases and a comparison with 489,871 people receiving a COVID-19 mRNA vaccine. medRxiv. 2021.04.27.21256153\u003c/li\u003e\n\u003cli\u003eZhang S, Liu Y, Wang X, et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. J Hematol Oncol. 2020;13(1):120. doi: 10.1186/s13045-020-00954-7.\u003c/li\u003e\n\u003cli\u003eBuzhdygan TP, DeOre BJ, Baldwin-Leclair A, et al. The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier. Neurobiol Dis. 2020;146:105131. doi: 10.1016/j.nbd.2020.105131.\u003c/li\u003e\n\u003cli\u003eYu J, Yuan X, Chen H, Chaturvedi S, Braunstein EM, Brodsky RA. Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition. Blood. 2020;136(18):2080-2089. doi: 10.1182/blood.2020008248.\u003c/li\u003e\n\u003cli\u003eAlhenc-Gelas M, Plu-Bureau G, Horellou MH, Rauch A, Suchon P, GEHT genetic thrombophilia group. PROS1 genotype phenotype relationships in a large cohort of adults with suspicion of inherited quantitative protein S deficiency. Thromb Haemost. 2016;115(3):570-579. doi: 10.1160/TH15-05-0391.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, mRNA vaccine, cerebral venous sinus thrombosis, acquired protein S deficiency","lastPublishedDoi":"10.21203/rs.3.rs-2702585/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2702585/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Several effective vaccines against Coronavirus disease 2019 (COVID-19) have been developed to control the spread of the disease. A few cases of thrombosis have been reported post-vaccination, especially among young adult women immunized with viral vector-based vaccines; although pediatric cases of cerebral venous sinus thrombosis (CVST) have been rarely reported after messenger ribonucleic acid (mRNA) vaccine administration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation: \u003c/strong\u003eHere, we report a case of CVST in a 14-year-old girl immunized with the BNT16B2b2 vaccine. Other than this recent COVID-19 vaccination, there were no precipitant risk factors in her medical history. Laboratory work-up showed low levels of protein S activity. Further research revealed no pathological gene mutation. She was treated with anticoagulant therapy and discharged with mildly impaired coordination/movement of the fingers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: CVST may occur following a mRNA COVID-19 vaccination, even among children. Further investigations are needed to establish whether thrombotic events are merely incidental or are a complication associated with mRNA-based vaccines.\u003c/p\u003e","manuscriptTitle":"Cerebral Venous Sinus Thrombosis After a Third Dose of mRNA COVID-19 Vaccine in an Adolescent: A case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-03-22 14:38:11","doi":"10.21203/rs.3.rs-2702585/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"096698d7-650a-4c5c-b58a-b8681dd44534","owner":[],"postedDate":"March 22nd, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-03-26T11:14:24+00:00","versionOfRecord":[],"versionCreatedAt":"2023-03-22 14:38:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2702585","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2702585","identity":"rs-2702585","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}