SPECIAL REPORT Diagnosis and Management of Cerebral Venous Sinus Thrombosis With Vaccine-Induced Immune Thrombotic Thrombocytopenia Karen L. Furie , MD, MPH; Mary Cushman , MD, MSc; Mitchell S.V. Elkind , MD, MS; Patrick D. Lyden , MD; Gustavo Saposnik , MD, MPH; on behalf of the American Heart Association/American Stroke Association Stroke Council Leadership Cerebral venous sinus thrombosis (CVST) is a rare manifestation of cerebrovascular disease.1–4 Recent reports from the Centers of Disease Con- trol and the US Food and Drug Administration identified 6 cases of CVST associated with thrombocytopenia in US patients who had received the Ad26.COV2.S (Janssen) coronavirus disease 2019 (COVID-19) vac- cine. Similar thromboembolic events were reported in Europe following ChAdOx1 nCoV-19 (AstraZeneca) vaccination. Both the Ad26.COV2.S and ChAdOx1 nCoV-19 vaccines contain adenoviral vectors. In con- trast, there have been no cases of CVST reported with thrombocytopenia following administration of 182 mil- lion mRNA severe acute respiratory syndrome corona- virus 2 (SARS-Cov2) vaccines.5 While awaiting further information on the causal nature of the relationships of vaccines to CVST with thrombocytopenia, clinicians should be aware of the symptoms to facilitate recog- nition of potential cases of CVST in patients receiving these vaccinations. The goal of this report is to heighten awareness of the apparent association between adeno- virus SARS-CoV2 vaccinations and CVST with vaccine- induced immune thrombotic thrombocytopenia (VITT) and suggest approaches to management. CVST EPIDEMIOLOGY AND RISK FACTORS CVST is an uncommon cerebrovascular disorder.1–4 There are other terms used in literature, including dural sinus thrombosis, venous sinus thrombosis, and cerebral venous thrombosis. Previous studies and sys- tematic reviews highlighted the epidemiology and risk factors.1–4 CVST most commonly affects young adults (mean age 35–40 years), predominantly women of childbearing age.1,6,7 Risk factors for CVST are similar to those for venous thromboembolism; over 80% of patients with CVST have at least one identifiable risk factor for thrombosis and half have multiple predis- posing factors. Most common transient risks factors include temporary medical conditions, such as preg- nancy and puerperium, exposure to drugs (oral contra- ceptives, chemotherapy), central nervous system or ear and face infections, and head trauma.1,6,8 Chronic risk factors include hereditary or acquired thrombophilias, autoimmune diseases, and cancer.1,6,8 Thrombocytope- nia is an uncommon primary cause of CVST.9 Before the COVID-19 pandemic, registries showed a low prevalence and magnitude of the association between thrombocytopenia and CVST (Table 1). It is important to recognize that infection with SARS- CoV2, or COVID-19, is a risk factor for CVST. A retro- spective analysis using electronic health records showed the incidence of CVST after COVID-19 was 39.0 per million people (95% CI, 25.2–60.2) compared with any 2-week period in the pre-COVID-19 epoch (0.41 per million people).15 One study (initially published as a pre- print) showed that the incidence of CVST associated with COVID-19 was 10-fold higher than after receiving BNT162b2 (Pfizer) or mRNA-1273 (Moderna) vaccines (39.0 per million people [95% CI, 25.2–60.2] versus Key Words: goals ◼ pregnancy ◼ thrombocytopenia ◼ thrombosis ◼ vaccination Correspondence to: Karen L. Furie, MD, MPH, Neurologist-in-Chief, Rhode Island Hospital, Chair of Neurology, The Warren Alpert Medical School of Brown University, 593 Eddy St, APC 521, Providence, RI 02903. Email karen_furie@brown.edu For Sources of Funding and Disclosures, see page 2482. © 2021 American Heart Association, Inc. 2478 July 2021 Stroke. 2021;52:2478–2482. DOI: 10.1161/STROKEAHA.121.035564 Stroke Stroke is available at www.ahajournals.org/journal/str D o w n l o a d e d f r o m h t t p : / / a h a j o u r n a l s . o r g b y o n O c t o b e r 4 , 2 0 2 2 S P E C I A L R E P O R T Nonstandard Abbreviations and Acronyms COVID-19 CVST DOAC HIT PF4 SARS-CoV2 VITT coronavirus disease 2019 cerebral venous sinus thrombosis direct oral anticoagulant heparin-induced thrombocytopenia platelet factor 4 severe acute respiratory syndrome coronavirus 2 vaccine-induced immune thrombotic thrombocytopenia 4.1 per million people [95% CI, 1.1–14.9], adjusted RR, 6.36; P<0.001).15 SYMPTOMS OF CVST The signs and symptoms of CVST are diverse and may mimic many other neurological disorders, making diag- nosis challenging. Symptoms reflect the location of the vein or sinus affected; in some cases, multiple loca- tions may be affected simultaneously. Presentations of CVST may be roughly divided into 4 syndromes: (1) isolated headache or increased intracranial pres- sure; (2) focal neurological presentations; (3) subacute encephalopathy; and (4) cavernous sinus syndrome/ multiple cranial neuropathies. Headache is frequent in CVST, present in ≈90% of patients.9 Headache may be accompanied by increased intracranial pressure, due to failure of blood to drain properly from the brain, with papilledema and sixth Table 1. Thrombocytopenia and CVST nerve palsies. In one series of 160 consecutive patients with sinus thrombosis, 37% had isolated intracranial hypertension without focal signs or symptoms.16 Most had papilledema, and sixth nerve palsies could be either unilateral or bilateral. Visual loss from optic nerve dam- age also occurred in some cases. In another study, how- ever, 17 (14%) of 123 consecutive patients with CVST presented with isolated headache, without evidence of increased intracranial pressure, indicating the need for a high index of suspicion for the disorder in patients presenting with headache.17 In 15 of these 17 patients, the lateral sinus was involved. The headache in CVST may be diffuse or localized, it is persistent and often progresses over days to weeks.18 In some cases, it is intermittent. Severity is variable. It is usually refractory to analgesics. The headache may worsen with recumbency or Valsalva maneuver, as is typical with increased intra- cranial pressure. More acute presentations consistent with migraine or thunderclap headache may occur. On rare occasions, scalp edema or dilated scalp or orbital veins may also be seen. Patients often present with focal neurological defi- cits and seizures. Focal deficits depend on the area of the brain affected but most often include hemiparesis, aphasia, or visual loss. One feature that may distinguish the focal deficits of CVST from those of more commonly encountered ischemic infarcts and primary intracerebral hemorrhage is their bilateral nature, particularly when the superior sagittal sinus, which drains both hemispheres and is the most commonly involved venous sinus (62%), is affected.9 Another distinguishing characteristic is their progressive nature, as the deficit in arterial occlusions tends to be maximal at onset, particularly for cardiac emboli. In the International Study on Cerebral Vein and Unrelated to COVID-19 vaccines COVID-vaccine era Asian CVT registry10 VENOST registry11 ISCVT registry9 COVID-vaccine12 COVID-vaccine13 COVID-vaccine14 N Age in years, mean (SD) or median (range) 812 31 (NA) 1144 80% aged <50 y (NA) 624 39 (NA) 11 5 6 36 (22–49) 39 (32–54) 33 (18–48) Sex, female (%) 479 (59) No. of countries 9 777 (68) 1 Ethnic groups (%) South-Asian White (100) 9 (82) 2 NR 4 (80) 1 NR 6 (100) 1 NR 465 (75) 21 White (79) Black (5) Hispanic (9) Asian (3) Others (3) Europe Geographic location Asia Turkey N (%) thrombocytopenia 3 (0.3) NR (thrombocytosis reported as 1.1%) NR (thrombocytosis reported as <3%) Germany and Austria Norway United States 10/11 (91) 5/5 (100) 6/6 (100) Number PF4 positive (%) NR NR NR 9/11 (82) 5/5 (100) 5/6 (83) Numbers between brackets represent %, unless otherwise indicated. COVID-19 indicates coronavirus disease 2019; CVT, cerebral venous thrombosis; CVST, cerebral venous sinus thrombosis; ISCVT, International Study on Cerebral Vein and Dural Sinus Thrombosis; NR, not reported; PF4, platelet-activating antibodies directed against platelet factor 4; and VENOST, Multicenter Cerebral Venous Thrombosis Study. Stroke. 2021;52:2478–2482. DOI: 10.1161/STROKEAHA.121.035564 July 2021 2479 Furie et al CVST With Vaccine-Induced Thrombocytopenia D o w n l o a d e d f r o m h t t p : / / a h a j o u r n a l s . o r g b y o n O c t o b e r 4 , 2 0 2 2 T R O P E R L A I C E P S Dural Sinus Thrombosis, symptom onset was <48 hours in about 1/3 of patients, 48 hours to 30 days in just over half of patients, and >30 days in almost 10% of patients. Seizures also occur more commonly with CVST (≈40%) than with other stroke subtypes.9 Some patients with thrombosis of the deep cerebral veins may develop a subacute encephalopathy, with con- fusion and lethargy.1 This syndrome is due to edema of bilateral thalami, basal ganglia, or other deep structures drained by these veins. If untreated, the syndrome can progress to coma and death. Imaging may appear to show devastating injury, but with timely treatment, recov- ery can be complete as edema resolves. CVST ASSOCIATED WITH VACCINE- INDUCED THROMBOCYTOPENIA The Ad26.COV2.S (Janssen) and ChAdOx1 nCoV-19 (AstraZeneca) vaccines contain replication-incompetent adenoviral vectors, human Ad26.COV2.S and chimpanzee ChAdOx1, respectively, that encode the spike glycopro- tein on SARS-CoV2. It is believed that leakage of DNA from the adenovirus infected cells binds to PF4 (platelet factor 4) and triggers the production of autoantibodies.5 CLINICAL CHARACTERISTICS OF CVST WITH VITT Among the symptoms of the women who experienced CVST after receiving the Ad26.COV2.S (Janssen) ade- novirus-based SARS-CoV2 vaccine in the United States, the most common symptom was headache.5 Symptom onset occurred 6 to 13 days after receipt of the vaccine. The age range was 18 to 48 years. Five of 6 patients presented with headache, one of whom also had vomit- ing and one lethargy. A sixth patient had back pain. Two had hemiparesis, one aphasia, one neglect, and one loss of consciousness. Two patients had abdominal pain due to portal vein thrombosis. Several of the cerebral sinuses were affected. Patients were treated with heparin (n=4), nonheparin anticoagulants (n=5), platelets (n=3), intra- venous immunoglobulin (n=3). At least one patient died. Additional clinical details are described in Table 2. Similar reports from Europe describe thrombocytope- nia and venous thrombosis after the ChAdOx1 nCoV-19 vaccine (AstraZeneca). Symptoms began 5 to 24 days after the first dose of the 2-shot vaccination. All had thrombocytopenia. In Germany, 11 patients (9 women) aged 22 to 49 developed venous thrombosis. Nine had CVST, 3 had splanchnic-vein thrombosis, and 3 had pul- monary embolism.12 In Norway, 5 patients presented with venous thrombosis and thrombocytopenia 7 to 10 days after receiving the first dose of ChAdOx1 nCoV- 19 (AstraZeneca) vaccine. The patients were 32 to 54 years of age.13 In the United Kingdom, 23 patients with antibodies to PF4 after ChAdOx1 nCoV-19 vaccination were described. The age range was 21 to 77 years and 61% were female. Of the 22 patients who presented with thrombosis, 13 had suspected CVST, others had pulmonary embolism (n=4) deep venous thrombosis and bilateral adrenal hemorrhage consistent with infarction (n=1), middle cerebral artery territory ischemic stroke (n=2), and portal vein thrombosis (n=2).19 DIAGNOSTIC TESTING In cases of suspected CVST, either magnetic resonance imaging with venogram or computed tomography with venogram can accurately detect CVST.1 A conventional angiogram is rarely necessary. Blood tests should include complete blood count with platelet count and peripheral smear, a prothrombin time, partial thromboplastin time, fibrinogen, D-dimer, and a PF4 antibody ELISA. In a UK study, PF4 testing with the chemiluminescence Hemo- sIL AcuStar HIT IgG assay (Werfen) was negative but testing with an ELISA was positive. ELISAs included the Lifecodes PF4 IgG assay (Immucor) and the Assera- chrom HPIA IgG assay (Stago).19 Finally, a confirmatory PF4 platelet activation assay (serotonin release assay, P-selectin expression assay, or HIPA) can be obtained if locally available, and the PF4 ELISA is low positive or if there is uncertainty regarding the diagnosis. MANAGEMENT Acute Management There is limited information about optimal treatment of CVST with VITT, but recommendations follow those of heparin-induced thrombocytopenia (HIT) given similar- ities in the 2 conditions.12,13,20 It is strongly suggested that care be provided collaboratively by vascular neu- rology and hematology, vascular medicine, or other consultant with expertise in managing HIT with cere- bral or systemic thrombosis. Based upon evidence of response in HIT, although there are no published data on efficacy in VITT, intra- venous immunoglobulin 1 g/kg body weight daily for 2 days, has been recommended after laboratory testing for PF4 antibodies has been sent.12,20,21 No heparin products in any dose should be given. Some experts recommend administration of steroids.22 Anticoagulation should follow recent guidelines on HIT with thrombosis that recommend alternative anticoagu- lants to heparin including argatroban, bivalirudin, danapa- roid, fondaparinux, or a direct oral anticoagulant (DOAC) at therapeutic anticoagulant dose intensity.23 Dosing strategy may require alteration if there is severe thrombo- cytopenia (ie, <20 000 per mm3) or low fibrinogen. Anti- coagulation should be used in CVST even in the presence of secondary intracranial hemorrhage as it is necessary to 2480 July 2021 Stroke. 2021;52:2478–2482. DOI: 10.1161/STROKEAHA.121.035564 Furie et al CVST With Vaccine-Induced Thrombocytopenia D o w n l o a d e d f r o m h t t p : / / a h a j o u r n a l s . o r g b y o n O c t o b e r 4 , 2 0 2 2 Table 2. Characteristics of Post-Ad26.COV2.S Vaccine (Janssen) Patients With CVST (n=6)5 Patient 1 Presenting symp- toms Headache, lethargy Location of CVST Patient 2 Headache Patient 3 Patient 4 Patient 5 Headache, vomiting, fever Headache, chills, myalgia Headache, chills, dyspnea, fever Patient 6 Back pain, bruising Right transverse and sigmoid sinuses Left transverse and sigmoid sinuses, straight sinus, con- fluence of the sinuses Superior and inferior sinuses, straight sinus None None None Right transverse and sigmoid sinuses Portal vein and Pulmonary artery Right transverse and sigmoid sinuses Right trans- verse sinus Bilateral lower extrem- ity and internal jugular vein Portal vein Right temporo- parietal Left temporal Bilateral frontal and intraventricular None None Occipital S P E C I A L R E P O R T 12 000 69 000 18 000 127 000 10 000 14 000 Systemic throm- bosis Location of intracerebral hemorrhage Platelet count nadir (per mm3) CVST indicates cerebral venous sinus thrombosis. prevent progressive thrombosis to control this bleeding.1 In severely ill patients, parenteral agents with short half- life are preferred. Platelet transfusion should be avoided. System: https://vaers.hhs.gov/reportevent.html. In addi- tion, analysis of all CVST cases during the COVID pan- demic would provide a better estimate of incidence and reduce case ascertainment bias. Subacute/Chronic Management Once there is full platelet count recovery, most patients can be transitioned to an oral anticoagulant if there are no contraindications. The American Society of Hematol- ogy 2018 HIT guideline panel provided a conditional rec- ommendation for HIT patients with thrombosis to prefer a DOAC over vitamin K antagonist.23 With CVST in the absence of HIT, some experts recommend a DOAC over vitamin K antagonist based upon three factors, observa- tional study data documenting efficacy and safety, one randomized controlled trial, and the known lower rate of cerebral hemorrhage with DOACs compared with vitamin K antagonist’s.24 In the RE-SPECT open-label random- ized trial (A Clinical Trial Comparing Efficacy and Safety of Dabigatran Etexilate With Warfarin in Patients With Cere- bral Venous and Dural Sinus Thrombosis) of 120 patients with acute CVST, after an initial course of 5 to 15 days of heparin or low molecular weight heparin, patients were randomized to dabigatran 150 mg twice daily or warfa- rin.6 Over 6 months, the primary outcome (major bleeding or recurrent venous thromboembolism) occurred in one (1.7%) patient with dabigatran and 2 (3.3%) patients with warfarin. These were all major bleeding events, and there were similar rates of recanalization and functional recov- ery in the 2 groups. Taken together, we suggest consid- eration of patient factors and use of a DOAC or vitamin K antagonists once there is full platelet count recovery. REPORTING Reporting of certain vaccine side effects is required of US clinicians, and we recommend all thrombosis cases after SARS-CoV2 vaccines (as well as any suspected adverse events) be reported to the Department of Health and Human Services Vaccine Adverse Event Reporting LIMITATIONS AND FUTURE DIRECTIONS Much about COVID-19 associated neurological com- plications remains unknown. There is a considerable risk to patients if scientific data are taken out of con- text and without appropriate caveats.25 For example, reports of vaccine-associated CVST may increase vac- cine hesitancy, yet the risk of CVST associated with COVID-19 infection is far greater than that associ- ated with vaccination.15 The particular comorbidities that might predispose to CVST after vaccination are unknown. Although the presence of PF4 antibodies has been confirmed in cases of vaccine-associated CVST with thrombocytopenia, the true prevalence and risk of this antibody are unknown, and case selection bias affecting current knowledge is possible. Asymp- tomatic individuals after vaccination have not been tested, so whether an association between the vaccine and PF4 antibody, thrombocytopenia, and thrombosis exists or not is not definitive. Future research must address several critical ques- tions. Most importantly, unbiased population surveys are needed to assess the true risk, if any, of vaccination and CVST. Since spurious associations are always possible in rare disease research, the true prevalence of PF4 anti- body formation, thrombocytopenia, and CVST after vac- cination must be clarified. Further case series must be viewed with the utmost care and skepticism until popula- tion prevalence rates are measured in an unbiased man- ner. Other research questions concern the mechanisms of venous thrombosis in infected persons. There is a rich literature possible, with many fruitful directions to pur- sue. Investigators should be encouraged, and funded, to delineate the molecular and cellular mechanisms under- lying CVST in COVID-19 or after vaccination. Stroke. 2021;52:2478–2482. DOI: 10.1161/STROKEAHA.121.035564 July 2021 2481 Furie et al CVST With Vaccine-Induced Thrombocytopenia D o w n l o a d e d f r o m h t t p : / / a h a j o u r n a l s . o r g b y o n O c t o b e r 4 , 2 0 2 2 ARTICLE INFORMATION Affiliations Warren Alpert Medical School of Brown University, Providence, RI (K.L.F.). Larner College of Medicine, University of Vermont, Burlington (M.C.). Vagelos College of Physicians and Surgeons, Columbia University, NY (M.S.V.E.). Keck School of Medicine of USC, Los Angeles, CA (P.D.L.). St. Michael's Hospital, University of Toronto, ON, Canada (G.S.). T R O P E R L A I C E P S Sources of Funding None. Disclosures Dr Elkind reports other from UpToDate outside the submitted work, and Dr Elkind serves as an unpaid Officer of the American Heart Association. Dr Saposnik is the Section Editor of Emerging Therapies for the Stroke journal and the Editor-in- Chief of the World Stroke Academy for the World Stroke Organization. The other authors report no conflicts. REFERENCES 1. Saposnik G, Barinagarrementeria F, Brown RD Jr, Bushnell CD, Cucchiara B, Cushman M, deVeber G, Ferro JM, Tsai FY; American Heart Association Stroke Council and the Council on Epidemiology and Prevention. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare pro- fessionals from the American Heart Association/American Stroke Associa- tion. Stroke. 2011;42:1158–1192. doi: 10.1161/STR.0b013e31820a8364 2. Ulivi L, Squitieri M, Cohen H, Cowley P, Werring DJ. Cerebral venous throm- bosis: a practical guide. Pract Neurol. 2020;20:356–367. doi: 10.1136/ practneurol-2019-002415 3. Alet M, Ciardi C, Alemán A, Bandeo L, Bonardo P, Cea C, Cirio J, Cossio J, Cuculic M, Esnaola MM, et al; Argentinian Stroke and Cerebrovascular Diseases Study Group - Argentine Neurological Society. Cerebral venous thrombosis in Argentina: clinical presentation, predisposing factors, out- comes and literature review. J Stroke Cerebrovasc Dis. 2020;29:105145. doi: 10.1016/j.jstrokecerebrovasdis.2020.105145 4. Idiculla PS, Gurala D, Palanisamy M, Vijayakumar R, Dhandapani S, Nagarajan E. Cerebral venous thrombosis: a comprehensive review. Eur Neurol. 2020;83:369–379. doi: 10.1159/000509802 5. Advisory Committee on Immunization Practices. Reports of cerebral venous sinus thrombosis with thrombocytopenia after Janssen COVID-19 vaccine. National Center for Immunization & Respiratory Diseases. Https://www. Cdc.Gov/vaccines/acip/meetings/downloads/slides-2021-04/03-covid- shimabukuro-508.Pdf. Accessed April 12, 2021. 6. Ferro JM, Aguiar de Sousa D. Cerebral venous thrombosis: an update. Curr Neurol Neurosci Rep. 2019;19:74. doi: 10.1007/s11910-019-0988-x 7. Silvis SM, de Sousa DA, Ferro JM, Coutinho JM. Cerebral venous thrombosis. Nat Rev Neurol. 2017;13:555–565. doi: 10.1038/ nrneurol.2017.104 8. Bushnell C, Saposnik G. Evaluation and management of cerebral venous thrombosis. Continuum (Minneap Minn). 2014;20(2 Cerebrovascular Dis- ease):335–351. doi: 10.1212/01.CON.0000446105.67173.a8 9. Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F; ISCVT Investigators. Prognosis of cerebral vein and dural sinus throm- bosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke. 2004;35:664–670. doi: 10.1161/01.STR. 0000117571.76197.26 10. Wasay M, Kaul S, Menon B, Dai AI, Saadatnia M, Malik A, Khalifa A, Borhani-Haghighi A, Mehndiratta M, Khan M, et al. Asian study of cerebral venous thrombosis. J Stroke Cerebrovasc Dis. 2019;28:104247. doi: 10.1016/j. jstrokecerebrovasdis.2019.06.005 11. Duman T, Uluduz D, Midi I, Bektas H, Kablan Y, Goksel BK, Milanlioglu A, Necioglu Orken D, Aluclu U; VENOST Study Group. A multicenter study of 1144 patients with cerebral venous thrombosis: the VENOST study. J Stroke Cerebrovasc Dis. 2017;26:1848–1857. doi: 10.1016/j. jstrokecerebrovasdis.2017.04.020 12. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic thrombocytopenia after chadox1 ncov-19 vaccination. N Engl J Med. 2021:NEJMoa2104840. doi: 10.1056/NEJMoa2104840 13. Schultz NH, Sørvoll IH, Michelsen AE, Munthe LA, Lund-Johansen F, Ahlen MT, Wiedmann M, Aamodt AH, Skattør TH, Tjønnfjord GE, et al. Thrombosis and thrombocytopenia after chadox1 ncov-19 vaccination. New Engl J Med. 2021. doi: 10.1056/NEJMoa2104882 14. Chougar L, Mathon B, Weiss N, Degos V, Shor N. Atypical deep cerebral vein thrombosis with hemorrhagic venous infarction in a patient posi- tive for COVID-19. AJNR Am J Neuroradiol. 2020;41:1377–1379. doi: 10.3174/ajnr.A6642 15. Taquet M HM, 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. https://osf.io/a9jdq/. osf.io Preprint Verison 2 posted online April 15, 2021. 16. Biousse V, Ameri A, Bousser MG. Isolated intracranial hypertension as the only sign of cerebral venous thrombosis. Neurology. 1999;53:1537–1542. doi: 10.1212/wnl.53.7.1537 17. Cumurciuc R, Crassard I, Sarov M, Valade D, Bousser MG. Headache as the only neurological sign of cerebral venous thrombosis: a series of 17 cases. J Neurol Neurosurg Psychiatry. 2005;76:1084–1087. doi: 10.1136/ jnnp.2004.056275 18. Agostoni E. Headache in cerebral venous thrombosis. Neurol Sci. 2004;25(suppl 3):S206–S210. doi: 10.1007/s10072-004-0287-3 19. Scully M, Singh D, Lown R, Poles A, Solomon T, Levi M, Goldblatt D, Kotoucek P, Thomas W, Lester W. Pathologic antibodies to platelet factor 4 after chadox1 ncov-19 vaccination. N Engl J Med. 2021. 20. Oldenburg J, Klamroth R, Langer F, Albisetti M, von Auer C, Ay C, Korte W, Scharf RE, Pötzsch B, Greinacher A. Diagnosis and management of vaccine-related thrombosis following astrazeneca covid-19 vacci- nation: guidance statement from the gth. Hamostaseologie. 2021. doi: 10.1055/a-1469-7481 21. Warkentin TE. High-dose intravenous immunoglobulin for the treatment and prevention of heparin-induced thrombocytopenia: a review. Expert Rev Hematol. 2019;12:685–698. doi: 10.1080/17474086.2019.1636645 22. Cines DB, Bussel JB. Sars-cov-2 vaccine-induced immune thrombotic thrombocytopenia. N Engl J Med. 2021:NEJMe2106315. doi: 10.1056/ NEJMe2106315 23. Cuker A. Transitioning patients with immune thrombocytopenia to second- line therapy: challenges and best practices. Am J Hematol. 2018;93:816– 823. doi: 10.1002/ajh.25092 24. Lee GKH, Chen VH, Tan CH, Leow AST, Kong WY, Sia CH, Chew NWS, Tu TM, Chan BPL, Yeo LLL, et al. Comparing the efficacy and safety of direct oral anticoagulants with vitamin K antagonist in cerebral venous thrombosis. J Thromb Thrombolysis. 2020;50:724–731. doi: 10.1007/ s11239-020-02106-7 25. Lyden PD. Stroke, research and science in the time of COVID. Stroke. 2020;51:2613–2614. doi: 10.1161/STROKEAHA.120.031354 2482 July 2021 Stroke. 2021;52:2478–2482. DOI: 10.1161/STROKEAHA.121.035564 Furie et al CVST With Vaccine-Induced Thrombocytopenia D o w n l o a d e d f r o m h t t p : / / a h a j o u r n a l s . o r g b y o n O c t o b e r 4 , 2 0 2 2