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What were the clinical characteristics of the first US patients reported to have cerebral venous sinus thrombosis (CVST) with thrombocytopenia following receipt of the Ad26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccine?
In this case series of 12 patients, all were women, younger than 60 years, and had symptom onset ranging from 6 to 15 days after vaccination requiring hospitalization. Of 11 patients with heparin-platelet factor 4 enzyme-linked immunosorbent assay (ELISA) heparin-induced thrombocytopenia (HIT) antibody test results, all were positive. At last follow-up, outcomes were death (n = 3), intensive care unit (ICU) care (n = 3), non-ICU hospitalization (n = 2), and discharge to home (n = 4).
This case series may inform clinical guidance and investigations into the potential relationship between the Ad26.COV2.S vaccine and CVST with thrombocytopenia.
Cerebral venous sinus thrombosis (CVST) with thrombocytopenia, a rare and serious condition, has been described in Europe following receipt of the ChAdOx1 nCoV-19 vaccine (Oxford/AstraZeneca), which uses a chimpanzee adenoviral vector. A mechanism similar to autoimmune heparin-induced thrombocytopenia (HIT) has been proposed. In the US, the Ad26.COV2.S COVID-19 vaccine (Janssen/Johnson & Johnson), which uses a human adenoviral vector, received Emergency Use Authorization (EUA) on February 27, 2021. By April 12, 2021, approximately 7 million Ad26.COV2.S vaccine doses had been given in the US, and 6 cases of CVST with thrombocytopenia had been identified among the recipients, resulting in a temporary national pause in vaccination with this product on April 13, 2021.
To describe reports of CVST with thrombocytopenia following Ad26.COV2.S vaccine receipt.
Design, Setting, and Participants
Case series of 12 US patients with CVST and thrombocytopenia following use of Ad26.COV2.S vaccine under EUA reported to the Vaccine Adverse Event Reporting System (VAERS) from March 2 to April 21, 2021 (with follow-up reported through April 21, 2021).
Receipt of Ad26.COV2.S vaccine.
Main Outcomes and Measures
Clinical course, imaging, laboratory tests, and outcomes after CVST diagnosis obtained from VAERS reports, medical record review, and discussion with clinicians.
Patients’ ages ranged from 18 to younger than 60 years; all were White women, reported from 11 states. Seven patients had at least 1 CVST risk factor, including obesity (n = 6), hypothyroidism (n = 1), and oral contraceptive use (n = 1); none had documented prior heparin exposure. Time from Ad26.COV2.S vaccination to symptom onset ranged from 6 to 15 days. Eleven patients initially presented with headache; 1 patient initially presented with back pain and later developed headache. Of the 12 patients with CVST, 7 also had intracerebral hemorrhage; 8 had non-CVST thromboses. After diagnosis of CVST, 6 patients initially received heparin treatment. Platelet nadir ranged from 9 ×103/µL to 127 ×103/µL. All 11 patients tested for the heparin-platelet factor 4 HIT antibody by enzyme-linked immunosorbent assay (ELISA) screening had positive results. All patients were hospitalized (10 in an intensive care unit [ICU]). As of April 21, 2021, outcomes were death (n = 3), continued ICU care (n = 3), continued non-ICU hospitalization (n = 2), and discharged home (n = 4).
Conclusions and Relevance
The initial 12 US cases of CVST with thrombocytopenia after Ad26.COV2.S vaccination represent serious events. This case series may inform clinical guidance as Ad26.COV2.S vaccination resumes in the US as well as investigations into the potential relationship between Ad26.COV2.S vaccine and CVST with thrombocytopenia.
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Corresponding Author: Isaac See, MD, Centers for Disease Control and Prevention COVID-19 Response Team, 1600 Clifton Rd, HT 16-3, Atlanta, GA 30329 (firstname.lastname@example.org).
Accepted for Publication: April 26, 2021.
Published Online: April 30, 2021. doi:10.1001/jama.2021.7517
Author Contributions: Drs Lale and See had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: See, Lale, Guh, Shimabukuro, Wheeler, Edwards, Creech, Clark, DeStefano, Broder.
Acquisition, analysis, or interpretation of data: See, Su, Lale, Woo, Guh, Shimabukuro, Streiff, Rao, Wheeler, Beavers, Durbin, Miller, Mba-Jonas, Nair, Nguyen, Talaat, Urrutia, Creech, Clark, Broder.
Drafting of the manuscript: See, Lale, Woo, Guh, Rao, Nguyen, Broder.
Critical revision of the manuscript for important intellectual content: See, Su, Guh, Shimabukuro, Streiff, Wheeler, Beavers, Durbin, Edwards, Miller, Mba-Jonas, Nair, Talaat, Urrutia, Creech, Clark, DeStefano, Broder.
Statistical analysis: See, Su, Lale, Guh.
Administrative, technical, or material support: Su, Lale, Guh, Shimabukuro, Streiff, Rao, Wheeler, Miller, Nair, Nguyen, Talaat, Creech, Clark, Broder.
Supervision: See, Shimabukuro, Edwards, Nair, Clark, DeStefano, Broder.
Other - neurological expertise: Urrutia.
Other - clinical expertise: Wheeler.
Other - reading all serious reports: Woo.
Conflict of Interest Disclosures: Dr Streiff reported receiving grants from Janssen for the Cassini clinical trial of rivaroxaban for prevention of cancer-associated thrombosis; personal fees from Janssen for serving on the advisory board for the Cassini trial; from Bayer, Bristol Myers Squibb, and Dispersol for providing consultative advice; from Bayer for CME lectures; and from Pfizer for CME lectures and serving on the advisory board. Dr Strieff also reported receiving grants from NHLBI for a study on missed doses in VTE prophylaxis, from AHRQ for work on individualized feedback on VTE prophylaxis practices, and from PCORI for research on patient education to improve acceptance of VTE prophylaxis. Dr Durbin reported receiving grants from Pfizer as an investigator for the Pfizer COVID-19 vaccine trial and grants from NIH for serving as the site principal investigator for the AstraZeneca COVID-19 vaccine trial; receiving personal fees from Merck for consultative advice on dengue vaccine development; and serving on the scientific advisory board for Valneva. Dr Edwards reported receiving grants from NIH and providing consultative advice to BioNet and IBM; she also reported serving on data and safety monitoring boards of Pfizer, Moderna, Merck, Sanofi, Roche, X-4 Pharma, and Seqirus. Dr Talaat reported receiving grants from Pfizer for serving as the site principal investigator for the phase 3 adult COVID-19 vaccine study and the phase 1-3 pediatric (under 12) COVID-19 vaccine study, both at Johns Hopkins University; she also reported receiving grants from the NIH-Coronavirus Prevention Network for serving as a co-investigator on the phase 3 AstraZeneca COVID-19 vaccine trial in adults. Dr Urratia reported receiving grants from Genentech Inc for serving as the site principal investigator on the TIMELESS trial and his work on the investigator-sponsored OPTIMIST main trial. Dr Creech reported receiving grants from Merck as well as personal fees from Altimmune, Horizon, Karius, Premier, and Astellas for providing consultative advice. No other disclosures were reported.
Funding/Support: This work was supported by the Centers for Disease Control and Prevention (CDC) Clinical Immunization Safety Assessment (CISA) Project contracts 200-2012-53664 to Johns Hopkins University and 200-2012-50430 to Vanderbilt University Medical Center.
Role of the Funder/Sponsor: CDC provided funding to Drs Creech, Durbin, Edwards, Streiff, Talaat, Urrutia, Walker, and Wheeler. CDC, including CDC authors along with non-CDC coauthors, conducted the investigations; performed collection, management, analysis, and interpretation of the data; was involved in preparation, review, and approval of the manuscript; and made the decision to submit the manuscript for publication.
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC or the Food and Drug Administration (FDA). Mention of a product or company name is for identification purposes only and does not constitute endorsement by the CDC and FDA.
Additional Contributions: We thank the following CDC staff who contributed to this article without compensation aside from their salaries. For data collection: Kathy Byrd, MD, MPH (CDC COVID-19 Response), Margaret Cortese, MD (CDC COVID-19 Response), Amelia Jazwa, MSPH (CDC COVID-19 Response), Anamika Khatri-Dua, MD (CDC COVID-19 Response), Susan Lukacs, DO, MSPH (CDC COVID-19 Response), Mike McNeil, MD, MPH (CDC COVID-19 Response), Monica Parise, MD (CDC COVID-19 Response), Allan Taylor, MD, MPH (CDC COVID-19 Response). For leadership and support: Denise Cardo, MD (CDC COVID-19 Response). We also thank the following individuals who contributed to this article with funding support through the CISA Project. For programmatic support: Paula Campbell, MS, MPH (Vanderbilt University) and Braxton Hern, BS (Vanderbilt University). For vaccine safety expertise: Elizabeth Barnett, MD (Boston University), Neal Halsey, MD (Johns Hopkins University), Thomas Kickler, MD (Johns Hopkins University), Nicola Klein, MD, PhD (Kaiser Permanente Northern California), Philip LaRussa, MD (Columbia University), Stephen Pelton, MD (Boston University), Elizabeth Schlaudecker, MD, MPH (Cincinnati Children’s Hospital Medical Center), Michael Smith, MD, MSCE (Duke University), Mary Staat, MD, MPH (Cincinnati Children’s Hospital Medical Center), Melissa Stockwell (Columbia University), Emmanuel “Chip” Walter, MD, MPH (Duke University), and Jennifer Yui, MD, MS (Johns Hopkins University). We also thank the clinical staff who have cared for these patients and who reported these events to VAERS..
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