key: cord-0926128-nrqa43dr authors: Ciccone, Alfonso title: SARS-CoV-2 vaccine-induced cerebral venous thrombosis date: 2021-05-25 journal: Eur J Intern Med DOI: 10.1016/j.ejim.2021.05.026 sha: 5d5a14607a032dcb53b5c06f507b5a3d8d60ca65 doc_id: 926128 cord_uid: nrqa43dr The nosological entity of the cerebral venous thrombosis caused by the SARS-CoV-2 vaccination differs from the common cerebral venous thrombosis in that it is due to immune thrombocytopenia triggered by vaccination. Cerebral venous thrombosis is one of several manifestations of this type of immune thrombocytopenia. Albeit many general aspects of management of cerebral venous thrombosis are similar, immune thrombocytopenia requires a specific therapeutic approach, which is not normally adopted for cerebral venous thrombosis due to other causes, therefore its early recognition is essential. The nosological entity of the cerebral venous thrombosis caused by the SARS-CoV-2 vaccination differs from the common cerebral venous thrombosis in that it is due to immune thrombocytopenia triggered by vaccination. Cerebral venous thrombosis is one of several manifestations of this type of immune thrombocytopenia. Albeit many general aspects of management of cerebral venous thrombosis are similar, immune thrombocytopenia requires a specific therapeutic approach, which is not normally adopted for cerebral venous thrombosis due to other causes, therefore its early recognition is essential. 4 What is a cerebral venous thrombosis? Cerebral venous thrombosis (CVT) is a rare cause of stroke and intracranial hypertension syndrome. Compared to arterial stroke, CVT affects younger people, predominantly women, has a different risk factors profile, and a subtle and multiform clinical presentation. Risk factors include pregnancy and puerperium, oral contraceptives, inherited thrombophilia, malignancy, infections, obesity, diagnostic and treatment procedures. The wide spectrum of clinical presentations make the diagnosis difficult. The three main connected syndromes are isolated intracranial hypertension syndrome (headache with or without vomiting and papilloedema), focal syndrome (focal deficit such as paresis and aphasia, seizures or both), and encephalopathy (drowsiness, delirium, and consciousness disturbances up to coma) 1 . Non-invasive imaging studies, such as MR imaging with MR venography or CT with CT venography, should be used to confirm the diagnosis; MR with T2*weighted gradient recalled echo or susceptibility-weighted imaging, allow for the detection of intravenous thrombosis; non-contrast CT, instead, can be normal or have non-specific findings in most patients 2 . Therefore, clinical diagnostic suspicion must guide the correct neuroimaging investigations. The main therapies for the acute phase are the anticoagulant treatment with either unfractionated intravenous heparin or subcutaneous low molecular weight heparin followed by oral anticoagulation 2 (vitamin K antagonists or dabigatran 3 ), even when in presence of brain hemorrhage, and measures to reduce intracranial pressure 1,2 . Early recognition and improvement in CVT 5 treatment has contributed to improve outcome and mortality, which declined below 5% in the last decades 4 . The clinicians like myself, who had the chance of coming across a case of CVT following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, realized in the field that this condition is completely different from what we had experienced before. The first clinical aspect that stroked me at the initial observation in the emergency room was the result of the blood tests: the drop of platelet count and the high D-dimers level. While hematological diseases are known risk factor for CVT, these generally include conditions such as essential thrombocythemia, myeloproliferative malignancies, primary and secondary polycythemia, paroxysmal nocturnal hemoglobinuria 5 , but not typically thrombocytopenia, which is more frequently linked to hemorrhagic than thrombotic complications. However, cases of CVT have been reported in the course of thrombocytopenia in systemic lupus 6 and of immune thrombocytopenia 7 . The coexistence of thrombosis with thrombocytopenia seems paradoxical 7 , unless we explain the phenomenon by a mechanism of systemic platelet consumption and sequestration through agglutination triggered by the vaccine, which ultimately leads to systemic thrombosis. In fact, the reported cases had a median platelet count at diagnosis of 20,000-30,000 per cubic millimeter and almost invariably a high title of antibodies to platelet factor 4 (PF4)-polyanion complexes [8] [9] [10] . These issues led to speculation 6 that the SARS-CoV-2 vaccine might determine CVT due to an autoimmune mechanism similar to the one of heparin-induced thrombocytopenia 11 . An alike syndrome heparin-induced thrombocytopenia was already described both after vaccination with other anti-viral vaccines, albeit without thrombosis, 12 The second remarkable aspect was the absence of the common risk factors for CVT. CVTs have many different causes and risk factors; most of the cases we face are women under oral contraceptive pill or hormonal replacement therapy 17 . The patient I visited was a healthy man in his fifties, with no prothrombotic risk factors. Most of the cases reported after the SARS-CoV-2 vaccination are women younger than 50 years of age but few of them were receiving oral contraceptives or hormonal replacement therapy [8] [9] [10] . Therefore, the trigger of the vaccine-induced immune thrombocytopenia is unknown and it appears to have nothing to do with common CVT risk factors. The last unusual aspect I experienced in my patient with CVT after SARS-CoV-2 vaccination, was the catastrophic disease course: the subject died within 24 hours from the first observation from a massive brain venous hemorrhagic infarction and with pulmonary embolism, despite treatment with low molecular heparin, steroids, platelet transfusion, and hemicraniectomy. The prognosis for CVT is generally good: the mortality with the current treatments is less than 5% 4 , and approximately 75% of the affected subjects make a full recovery 5 . In contrast, almost 1 out of 2 patients with CVT as a manifestation of VITT, die within few days [8] [9] [10] . Death can occur both due to brain infarction, often hemorrhagic, caused directly by CVT, and due to extra cerebral thrombosis, such as pulmonary embolism, portal and splanchnic thrombosis [8] [9] [10] . These aspects underline the fact that we are faced with a systemic disease where thrombosis can be localized anywhere. Why look for the vaccine-induced immune thrombotic thrombocytopenia? 8 The occurrence of VITT is rare and is estimated on about 1 subject every 150,000 vaccinated, not far away from the CVT incidence in the general population. This explains why these complications were not seen in SARS-CoV-2 vaccine trials, which involved less than 30,000 subjects per arm. Although Cerebral Venous Thrombosis: an Update European Stroke Organization guideline for the diagnosis and treatment of cerebral venous thrombosis -endorsed by the European Academy of Neurology Safety and Efficacy of Dabigatran Etexilate vs Dose-Adjusted Warfarin in Patients With Cerebral Venous Thrombosis: A Randomized Clinical Trial Declining mortality in cerebral venous thrombosis: a systematic review Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) Cerebral Venous Sinus Thrombosis in Systemic Lupus Erythematosus Cerebral Venous Thrombosis in a Patient with Immune Thrombocytopenia, an Apparent Paradox Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination Autoimmune heparin-induced thrombocytopenia Immune thrombocytopenic purpura (ITP) associated with vaccinations: a review of reported cases Cerebral Venous Thrombosis Associated with COVID-19 Immune Thrombocytopenia Secondary to COVID-19: a Systematic Review SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia D-dimer testing in the diagnosis of cerebral vein thrombosis: a systematic review and a meta-analysis of the literature Cerebral venous and sinus thrombosis in women Management of cerebral and splanchnic vein thrombosis associated with thrombocytopenia in subjects previously vaccinated with Vaxzevria (AstraZeneca): a position statement from the Italian Society for the Study of Haemostasis and Thrombosis (SISET) Guidance produced from the Expert Haematology Panel (EHP) focussed on syndrome of Thrombosis and Thrombocytopenia occurring after coronavirus Vaccination on behalf of the Drugs & Biologics Clinical P ractice G uidelines W orking G roup a nd t he O ntario C OVID-19 Science Advisory Table. Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) following Availavble at: https://covid19-sciencetable.ca/sciencebrief/vaccine-induced-prothrombotic-immune-thrombocytopenia-vipitfollowing-astrazeneca-covid-19-vaccination-interim-guidance-for-healthcare-professionals-inemergency-department-and-inpatient-settings