key: cord-0019788-o4nv4bb6 authors: Lee, Eun-Ju; Lee, Alfred I title: Cerebral venous sinus thrombosis after vaccination: the UK experience date: 2021-08-06 journal: Lancet DOI: 10.1016/s0140-6736(21)01788-8 sha: 2a7daf0e059b8adde67e577474dfa598ac0d3512 doc_id: 19788 cord_uid: o4nv4bb6 nan An important but rare complication of COVID-19 vaccination is vaccine-induced immune thrombotic thrombocytopenia (VITT) associated with the adenovirus vector vaccines, Ad26.COV2.S (Johnson & Johnson) and ChAdOx1 (Oxford-AstraZeneca). [1] [2] [3] [4] [5] VITT occurs more commonly in women younger than 50 years who present within 5-24 days of vaccination with thrombosis in unusual sites-the majority with cerebral venous sinus thrombosis. 1, 6 Thrombocytopenia, elevated D-dimer, decreased fibrinogen, and positive antibodies against platelet factor 4 (PF4) are commonly observed. [1] [2] [3] [4] [5] [6] Recommended treatments for VITT, based on similarities with autoimmune heparin-induced thrombocytopenia (HIT), 7 include non-heparin anticoagulation, intravenous immunoglobulin, and avoidance of platelet transfusions. 1 Mortality associated with VITT is approximately 40%. 1 In The Lancet, Richard Perry and colleagues 8 report on the largest series to date of patients with VITTassociated cerebral venous sinus thrombosis. In this multicentre cohort study, cerebral venous sinus thrombosis following COVID-19 vaccination was defined as VITT-associated if platelet count nadir was less than 150 × 10⁹ per L and, if measured, D-dimer concentration was greater than 2000 μg/L. Between April 1 and May 20, 2021, the study enrolled 70 patients with VITT-associated cerebral venous sinus thrombosis and 25 patients with cerebral venous sinus thrombosis that did not meet criteria for VITT from 43 hospitals in the UK, as well as a large historical cohort of patients with cerebral venous sinus thrombosis. All cases of VITT-associated cerebral venous sinus thrombosis occurred after a first dose of the ChAdOx1 vaccine. 56 (97%) of 58 patients with VITT for whom anti-PF4 antibody tests were available tested positive using an ELISA. Compared with those without VITT, patients with VITT were younger ( Perry and colleagues' study 8 proposes new diagnostic criteria for VITT based on patients whom the authors suspected of being misclassified according to existing criteria. 1, 2, 9, 10 One patient in the non-VITT group had an elevated D-dimer (4985 μg/L) and positive anti-PF4 antibodies on two different ELISAs yet a platelet nadir of 158 × 10⁹ per L. Two patients with clinical features highly suspicious for VITT were assigned to the non-VITT group on the basis of D-dimer concentrations less than 2000 µg/L, including one with positive HIT antibody testing. Perry and colleagues 8 propose dividing cases of cerebral venous sinus thrombosis following COVID-19 vaccination into possible, probable, and definite VITTassociated cerebral venous sinus thrombosis, allowing for inclusion of atypical presentations with normal platelet counts, normal D-dimer, or negative HIT antibody testing. The utility of the proposed criteria is yet to be determined. The patient with a platelet nadir of 158 × 10⁹ per L would be, to our knowledge, the first reported instance of VITT with a normal platelet count, yet comparisons of presenting versus prevaccination platelet counts were not available in this study. Based on HIT paradigms, a relative decline in platelet count from baseline, rather than absolute thrombocytopenia, is likely to be a uniformly distinguishing feature of VITT. The exact rate and degree of platelet decline in VITT following COVID-19 vaccination are unknown 1, 5, 6 and represent an area of active investigation. Although rare false negatives might occur, ELISA testing in VITT is generally very reliable 11, 12 and it is unclear if patients with negative ELISA tests for anti-PF4 antibodies and functional HIT testing could still be classified as having VITT. A third of patients in Perry and colleagues' study 8 had anti-PF4 antibody testing using a chemiluminescent immunoassay; such immunoassays have poor sensitivity for VITT compared with ELISA testing 11, 12 and could explain some of the negative test results. An important consideration is that 19 (20%) of 95 study patients did not have anti-PF4 antibody testing available. 8 Additional patients in the VITT group could have had negative anti-PF4 antibody testing, and additional patients in the non-VITT group could have had positive testing, and it is possible that a spectrum of VITT might exist, similar to HIT. 13 Other limitations of the study include the small sample size, reflecting the rarity of cerebral venous sinus thrombosis, and a potential confounding bias due to age-based vaccine distribution policies, which might have contributed to the older age of the VITT and non-VITT groups compared with the historical cohort of patients with cerebral venous sinus thrombosis (median age 37 years). The analysis by Perry and colleagues 8 represents a landmark study, which is, to our knowledge, the largest thus far of VITT-associated cerebral venous sinus thrombosis, and the first to directly compare the clinical, laboratory, and radiographic features of VITT-associated and non-VITT-associated cerebral venous sinus thrombosis. The poor outcomes of VITTassociated cerebral venous sinus thrombosis highlight the need for accurate diagnostic tools to guide early recognition of this highly morbid condition. Additional studies are warranted to further guide treatment and management of VITT with the hope of improving outcomes for patients with this rare complication. E-JL serves on the advisory board for Principia Biopharma unrelated to the topic of this Comment. AIL declares no competing interests. *Eun-Ju Lee, Alfred I Lee Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination Adjunct immune globulin for vaccine-induced thrombotic thrombocytopenia US case reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia A spontaneous prothrombotic disorder resembling heparin-induced thrombocytopenia Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study Recommendations for the clinical and laboratory diagnosis of VITT against COVID-19: communication from the ISTH SSC Subcommittee on Platelet Immunology Diagnosis and management of vaccine-related thrombosis following AstraZeneca COVID-19 vaccination: guidance statement from the GTH Evaluation of laboratory assays for anti-platelet factor 4 antibodies after ChAdOx1 nCoV-19 vaccination PF4 immunoassays in vaccine-induced thrombotic thrombocytopenia Vaccine-induced immune thrombotic thrombocytopenia (VITT)-a novel clinico-pathological entity with heterogeneous clinical presentations