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Coagulation Disorders

Frequency of Thrombocytopenia and Platelet Factor 4/Heparin Antibodies in Patients With Cerebral Venous Sinus Thrombosis Prior to the COVID-19 Pandemic

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JAMA

Published Online: July 2, 2021

Original Investigation

Article Information and Disclosures

Author Affiliations

¹Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
²Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
³Department of Hematology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
⁴Department of Neurology, Albert Schweitzer Hospital, Dordrecht, the Netherlands
⁵Experimental Haemostasis Group, Department for BioMedical Research DBMR, University of Bern, Bern, Switzerland
⁶Department of Internal Medicine & Radboud Institute of Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, the Netherlands
⁷National Institute for Health Research University College London Hospitals (UCLH) Biomedical Research Centre, London, United Kingdom
⁸Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
⁹Department of Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
¹⁰Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
¹¹Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
¹²Sina Hospital, Hamadan University of Medical Science, Hamadan, Iran
¹³National Institute of Neurology and Neurosurgery Manuel Velasco Suarez, Mexico-City, Mexico
¹⁴Neurosciences Department, Hospital Dr R.A. Calderón Guardia, CCSS, San José, Costa Rica
¹⁵Department of Neurosciences and Mental Health, Neurology Service, Hospital de Santa Maria/CHULN, University of Lisbon, Lisbon, Portugal
¹⁶Division of Neurology, University of British Columbia, Vancouver Stroke Program, Vancouver, British Columbia, Canada

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Key Points

Question What were the frequencies of thrombocytopenia, heparin-induced thrombocytopenia, and platelet factor 4/heparin antibodies in patients with cerebral venous sinus thrombosis prior to the COVID-19 pandemic?

Findings In a descriptive analysis of a retrospective consecutive sample of 865 patients with cerebral venous sinus thrombosis from 1987 to 2018, baseline thrombocytopenia was observed in 8.4% of patients, and heparin-induced thrombocytopenia was diagnosed in 0.1%. In a convenience sample subset of 93 patients with plasma available for additional laboratory analysis (including 8 who had thrombocytopenia), none had platelet factor 4/heparin antibodies.

Meaning These findings may inform investigations of the possible association between the ChAdOx1 nCoV-19 (AstraZeneca/Oxford) and Ad26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccines and cerebral venous sinus thrombosis with thrombocytopenia.

Abstract

Importance Cases of cerebral venous sinus thrombosis in combination with thrombocytopenia have recently been reported within 4 to 28 days of vaccination with the ChAdOx1 nCov-19 (AstraZeneca/Oxford) and Ad.26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccines. An immune-mediated response associated with platelet factor 4/heparin antibodies has been proposed as the underlying pathomechanism.

Objective To determine the frequencies of admission thrombocytopenia, heparin-induced thrombocytopenia, and presence of platelet factor 4/heparin antibodies in patients diagnosed with cerebral venous sinus thrombosis prior to the COVID-19 pandemic.

Design, Setting, and Participants This was a descriptive analysis of a retrospective sample of consecutive patients diagnosed with cerebral venous sinus thrombosis between January 1987 and March 2018 from 7 hospitals participating in the International Cerebral Venous Sinus Thrombosis Consortium from Finland, the Netherlands, Switzerland, Sweden, Mexico, Iran, and Costa Rica. Of 952 patients, 865 with available baseline platelet count were included. In a subset of 93 patients, frozen plasma samples collected during a previous study between September 2009 and February 2016 were analyzed for the presence of platelet factor 4/heparin antibodies.

Exposures Diagnosis of cerebral venous sinus thrombosis.

Main Outcomes and Measures Frequencies of admission thrombocytopenia (platelet count <150 ×10³/μL), heparin-induced thrombocytopenia (as diagnosed by the treating physician), and platelet factor 4/heparin IgG antibodies (optical density >0.4, in a subset of patients with previously collected plasma samples).

Results Of 865 patients (median age, 40 years [interquartile range, 29-53 years], 70% women), 73 (8.4%; 95% CI, 6.8%-10.5%) had thrombocytopenia, which was mild (100-149 ×10³/μL) in 52 (6.0%), moderate (50-99 ×10³/μL) in 17 (2.0%), and severe (<50 ×10³/μL) in 4 (0.5%). Heparin-induced thrombocytopenia with platelet factor 4/heparin antibodies was diagnosed in a single patient (0.1%; 95% CI, <0.1%-0.7%). Of the convenience sample of 93 patients with cerebral venous sinus thrombosis included in the laboratory analysis, 8 (9%) had thrombocytopenia, and none (95% CI, 0%-4%) had platelet factor 4/heparin antibodies.

Conclusions and Relevance In patients with cerebral venous sinus thrombosis prior to the COVID-19 pandemic, baseline thrombocytopenia was uncommon, and heparin-induced thrombocytopenia and platelet factor 4/heparin antibodies were rare. These findings may inform investigations of the possible association between the ChAdOx1 nCoV-19 and Ad26.COV2.S COVID-19 vaccines and cerebral venous sinus thrombosis with thrombocytopenia.

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Article Information

Corresponding Author: Jonathan M. Coutinho, MD, PhD, Department of Neurology, Amsterdam University Medical Center, Location AMC, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands (j.coutinho@amsterdamumc.nl).

Accepted for Publication: May 31, 2021.

Published Online: July 2, 2021. doi:10.1001/jama.2021.9889

Author Contributions: Drs Sánchez van Kammen and Coutinho 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. Drs Sánchez van Kammen and Heldner shared first authorship. Drs Arnold and Coutinho shared last authorship.

Concept and design: Sánchez van Kammen, Heldner, Kremer Hovinga, Middeldorp, Levi, Ferro, Tatlisumak, Arnold, Coutinho.

Acquisition, analysis, or interpretation of data: Sánchez van Kammen, Heldner, Brodard, Scutelnic, Silvis, Schroeder, Kremer Hovinga, Levi, Hiltunen, Lindgren, Mansour, Arauz, Barboza, Zuurbier, Aguiar de Sousa, Fischer, Field, Jood, Tatlisumak, Putaala, Arnold, Coutinho.

Drafting of the manuscript: Sánchez van Kammen, Heldner, Brodard, Scutelnic, Kremer Hovinga, Arnold, Coutinho.

Critical revision of the manuscript for important intellectual content: Heldner, Brodard, Scutelnic, Silvis, Schroeder, Kremer Hovinga, Middeldorp, Levi, Hiltunen, Lindgren, Mansour, Arauz, Barboza, Zuurbier, Aguiar de Sousa, Ferro, Fischer, Field, Jood, Tatlisumak, Putaala, Arnold.

Statistical analysis: Sánchez van Kammen, Silvis.

Obtained funding: Kremer Hovinga, Coutinho.

Administrative, technical, or material support: Sánchez van Kammen, Heldner, Brodard, Scutelnic, Silvis, Schroeder, Kremer Hovinga, Levi, Barboza, Zuurbier, Tatlisumak, Putaala, Arnold.

Supervision: Kremer Hovinga, Middeldorp, Levi, Zuurbier, Aguiar de Sousa, Ferro, Tatlisumak, Putaala, Arnold, Coutinho.

Conflict of Interest Disclosures: Dr Heldner reported receiving grants from the Swiss Heart Foundation and Bangerter Foundation and travel support from Bayer and serving on the data safety and monitoring board (DSMB) or advisory board of Amgen. Dr Middeldorp reported receiving grants paid to her institution from Bayer, Pzifer, Boehringer Ingelheim, and Daiichi Sankyo and personal fees paid to her institution from Bayer, BMS/Pfizer, Boehringer Ingelheim, AbbVie, Portola/Alexion, and Daiichi Sankyo. Dr Lindgren reported receiving grants from the Swedish Neurological Society, the Elsa and Gustav Lindh Foundation, the P-O Ahl Foundation, and the Rune and Ulla Amlöv Foundation. Dr Barboza reported receiving payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Abbott, Pfizer, Roche, and Bayer. Dr Aguiar de Sousa reported receiving travel support from Boehringer Ingelheim, serving on the DSMB for the SECRET trial, and being a member of the European Stroke Organisation executive committee. Dr Ferro reported receiving personal fees and serving on the DSMB or advisory board for Boehringer Ingelheim and receiving consulting fees from Bayer. Dr Fischer reported receiving grants from Medtronic and the Swiss National Science Foundation and serving on the speakers bureau for Boehringer Ingelheim. Dr Field reported receiving grants from Bayer Canada and in-kind study medication for the SECRET trial and being an expert witness for the Canadian Medical Protective Association. Dr Tatlisumak reported receiving grants from the Sahlgrenska University Hospital, the University of Gothenburg, and the Sigrid Juselius Foundation during the conduct of the study; serving on the advisory boards and steering committees for Bayer and Bristol Myers Squibb and on the advisory boards of Boehringer Ingelheim and Portola. Dr Putaala reported receiving grants paid to his institution from the Academy of Finland, Hospital District of Helsinki and Uusimaa, and Finnish Foundation for Cardiovascular Research; receiving consulting fees from Boehringer Ingelheim, Bayer, and Herantis Pharma; receiving payment for honoraria, lectures, presentations, speakers bureaus, manuscript writing, or educational events from Boehringer Ingelheim, Bayer, and Abbott; serving as president of the Finnish Hypertension Society; and owning stock in Vital Signum. Dr Arnold reported receiving grants from the Swiss Heart Foundation and the Swiss National Science Foundation; honoraria for lectures from AstraZeneca, Bayer, Covidien, and Medtronic, and receiving honoraria for serving on the scientific advisory boards of Amgen, Bayer, Bristol Myers Squibb, Daichi Sankyo, Medtronic, Novartis, and Sanofi. Dr Coutinho reported receiving grants paid to his institution from Boehringer Ingelheim and Bayer, and payments to his institution for serving on a DSMB for Bayer. No other disclosures were reported.

Funding/Support: This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Plasma samples were used from a previous study, which was supported by grants from the Swiss Heart foundation (112/09) and Dutch Thrombosis Society (2012-2).

Role of the Funder/Sponsor: No organizations or companies had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References

Greinacher A , Thiele T , Warkentin TE , Weisser K , Kyrle PA , Eichinger S . Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med. Published online April 9, 2021. doi:10.1056/NEJMoa2104840 PubMed Google Scholar

Schultz NH , Sørvoll IH , Michelsen AE , et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. Published online April 9, 2021. doi:10.1056/NEJMoa2104882 PubMed Google Scholar

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 PubMed Google Scholar Crossref

European Medicines Agency. Assessment report: procedure under Article 5(3) of regulation (EC) No 726/2004—vaxzevira. Accessed May 5, 2021. https://www.ema.europa.eu/en/documents/referral/use-vaxzevria-prevent-covid-19-article-53-procedure-assessment-report_en.pdf

MacNeil JR , Su JR , Broder KR , et al. Updated recommendations from the Advisory Committee on Immunization Practices for use of the Janssen (Johnson & Johnson) COVID-19 vaccine after reports of thrombosis with thrombocytopenia syndrome among vaccine recipients—United States, April 2021. MMWR Morb Mortal Wkly Rep. 2021;70(17):651-656. doi:10.15585/mmwr.mm7017e4 PubMed Google Scholar Crossref

Greinacher A , Selleng K , Warkentin TE . Autoimmune heparin-induced thrombocytopenia. J Thromb Haemost. 2017;15(11):2099-2114. doi:10.1111/jth.13813 PubMed Google Scholar Crossref

Nguyen TH , Medvedev N , Delcea M , Greinacher A . Anti-platelet factor 4/polyanion antibodies mediate a new mechanism of autoimmunity. Nat Commun. 2017;8:14945. doi:10.1038/ncomms14945 PubMed Google Scholar Crossref

Greinacher A . Me or not me? the danger of spontaneity. Blood. 2014;123(23):3536-3538. doi:10.1182/blood-2014-04-566836 PubMed Google Scholar Crossref

Moores G , Warkentin TE , Farooqi MAM , Jevtic SD , Zeller MP , Perera KS . Spontaneous heparin-induced thrombocytopenia syndrome presenting as cerebral venous sinus thrombosis. Neurol Clin Pract. Published online January 14, 2020.Google Scholar

10.

Di Micco P , Ruiz-Giménez N , Nieto JA , et al; RIETE investigators. Platelet count and outcome in patients with acute venous thromboembolism. Thromb Haemost. 2013;110(5):1025-1034. doi:10.1160/TH13-04-0352 PubMed Google Scholar

11.

Heldner MR , Zuurbier SM , Li B , et al. Prediction of cerebral venous thrombosis with a new clinical score and D-dimer levels. Neurology. 2020;95(7):e898-e909. doi:10.1212/WNL.0000000000009998 PubMed Google Scholar Crossref

12.

Lindgren E , Silvis SM , Hiltunen S , et al. Acute symptomatic seizures in cerebral venous thrombosis. Neurology. 2020;95(12):e1706-e1715. doi:10.1212/WNL.0000000000010577 PubMed Google Scholar Crossref

13.

Silvis SM , Reinstra E , Hiltunen S , et al; International CVT Consortium. Anaemia at admission is associated with poor clinical outcome in cerebral venous thrombosis. Eur J Neurol. 2020;27(4):716-722. doi:10.1111/ene.14148 PubMed Google Scholar Crossref

14.

Saposnik G , Barinagarrementeria F , Brown RD Jr , et al; American Heart Association Stroke Council 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 PubMed Google Scholar Crossref

15.

Ferro JM , Bousser MG , Canhão P , et al; European Stroke Organization. European Stroke Organization guideline for the diagnosis and treatment of cerebral venous thrombosis—endorsed by the European Academy of Neurology. Eur J Neurol. 2017;24(10):1203-1213. doi:10.1111/ene.13381 PubMed Google Scholar Crossref

16.

Williamson DR , Albert M , Heels-Ansdell D , et al; PROTECT collaborators, the Canadian Critical Care Trials Group, and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Thrombocytopenia in critically ill patients receiving thromboprophylaxis: frequency, risk factors, and outcomes. Chest. 2013;144(4):1207-1215. doi:10.1378/chest.13-0121 PubMed Google Scholar Crossref

17.

Warkentin TE . Laboratory diagnosis of heparin-induced thrombocytopenia. Int J Lab Hematol. 2019;41(suppl 1):15-25. doi:10.1111/ijlh.12993 PubMed Google Scholar Crossref

18.

Wilson EB . Probable inference, the law of succession, and statistical inference. J Am Stat Assoc. 1927;22:209-212. doi:10.1080/01621459.1927.10502953 Google Scholar Crossref

19.

Nazy I , Sachs UJ , Arnold DM , et al. Recommendations for the clinical and laboratory diagnosis of VITT against COVID-19: Communication from the ISTH SSC Subcommittee on Platelet Immunology. J Thromb Haemost. 2021;19(6):1585-1588. doi:10.1111/jth.15341 PubMed Google Scholar Crossref

20.

Wilson N , Kvalsvig A , Barnard LT , Baker MG . Case-fatality risk estimates for COVID-19 calculated by using a lag time for fatality. Emerg Infect Dis. 2020;26(6):1339-1441. doi:10.3201/eid2606.200320 PubMed Google Scholar Crossref

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Frequency of Thrombocytopenia and Platelet Factor 4/Heparin Antibodies in Patients With Cerebral Venous Sinus Thrombosis Prior to the COVID-19 Pandemic

Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination

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