Frequency of Thrombocytopenia and Platelet Factor 4/Heparin Antibodies in Patients With Cerebral Venous Sinus Thrombosis Prior to the COVID-19 Pandemic | Coagulation Disorders | JAMA | JAMA Network
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Figure 1.  Patient Selection
Patient Selection

CVST indicates cerebral venous sinus thrombosis.

Figure 2.  Admission and Discharge Platelet Counts for 56 Patients With Cerebral Venous Sinus Thrombosis With Thrombocytopenia at Admission and Available Discharge Platelet Count
Admission and Discharge Platelet Counts for 56 Patients With Cerebral Venous Sinus Thrombosis With Thrombocytopenia at Admission and Available Discharge Platelet Count

Change in platelet count between admission and discharge is provided for 56 of 73 patients with thrombocytopenia at admission (platelet count at discharge was missing for the remaining 17 patients). Mild thrombocytopenia: platelet count 100 to 149 ×103/μL; moderate thrombocytopenia: platelet count 50 to 99 ×103/μL; severe thrombocytopenia: platelet count <50 ×103/μL.

Table 1.  Baseline Demographics and Clinical Characteristics of 865 Patients With Cerebral Venous Sinus Thrombosis Prior to the COVID-19 Pandemic
Baseline Demographics and Clinical Characteristics of 865 Patients With Cerebral Venous Sinus Thrombosis Prior to the COVID-19 Pandemic
Table 2.  Clinical Manifestations, Etiology, and Outcomes of Thrombocytopenia in 73 Patients With Cerebral Venous Sinus Thrombosis and Thrombocytopenia
Clinical Manifestations, Etiology, and Outcomes of Thrombocytopenia in 73 Patients With Cerebral Venous Sinus Thrombosis and Thrombocytopenia
1.
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 PubMedGoogle Scholar
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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 PubMedGoogle Scholar
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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.2021.7517PubMedGoogle ScholarCrossref
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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
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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 PubMedGoogle ScholarCrossref
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Greinacher  A, Selleng  K, Warkentin  TE.  Autoimmune heparin-induced thrombocytopenia.   J Thromb Haemost. 2017;15(11):2099-2114. doi:10.1111/jth.13813 PubMedGoogle ScholarCrossref
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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 PubMedGoogle ScholarCrossref
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Greinacher  A.  Me or not me? the danger of spontaneity.   Blood. 2014;123(23):3536-3538. doi:10.1182/blood-2014-04-566836 PubMedGoogle ScholarCrossref
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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
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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 PubMedGoogle Scholar
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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 PubMedGoogle ScholarCrossref
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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 PubMedGoogle ScholarCrossref
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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 PubMedGoogle ScholarCrossref
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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 PubMedGoogle ScholarCrossref
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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 PubMedGoogle ScholarCrossref
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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 PubMedGoogle ScholarCrossref
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Warkentin  TE.  Laboratory diagnosis of heparin-induced thrombocytopenia.   Int J Lab Hematol. 2019;41(suppl 1):15-25. doi:10.1111/ijlh.12993 PubMedGoogle ScholarCrossref
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Wilson  EB.  Probable inference, the law of succession, and statistical inference.   J Am Stat Assoc. 1927;22:209-212. doi:10.1080/01621459.1927.10502953Google ScholarCrossref
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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 PubMedGoogle ScholarCrossref
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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 PubMedGoogle ScholarCrossref
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    Original Investigation
    July 2, 2021

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

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

    Introduction

    Cases of thromboses at unusual sites with associated thrombocytopenia have recently been reported that developed within 4 to 28 days of vaccination with the COVID-19 vaccines ChAdOx1 nCov-19 (AstraZeneca/Oxford) and Ad26.COV2.S (Janssen/Johnson & Johnson).1-3 Many of the reported patients had cerebral venous sinus thrombosis (CVST). After temporary suspension of vaccination with ChAdOx1 nCov-19 in several European countries, vaccination was resumed but restricted to older age groups in most of these countries following a benefit and risk assessment by the European Medicines Agency.4 Vaccination with Ad26.COV2.S was resumed after a temporary halt in the United States following recommendations by the Food and Drug Administration and the Centers for Disease Control and Prevention.5

    In a study involving 10 patients who developed thrombosis and thrombocytopenia (median platelet count nadir, 20 ×103/μL , interquartile range [IQR], 12-64 ×103/μL) 5 to 16 days after vaccination with ChAdOx1 nCov-19, all tested patients had developed antibodies against platelet factor 4 (PF4), which were strongly platelet activating in a functional test, despite the absence of prior heparin treatment.1 To describe this specific response, the authors coined the term vaccine-induced immune thrombotic thrombocytopenia. The response suggests a disease mechanism similar to spontaneous heparin-induced thrombocytopenia (HIT), a form of autoimmune HIT, which has been previously reported to cause CVST, as well as other forms of thrombosis.6-9

    Among patients diagnosed with deep vein thrombosis and pulmonary embolism prior to the COVID-19 pandemic, the estimated proportion with thrombocytopenia was 14%.10 The frequency of thrombocytopenia, HIT, and PF4/heparin antibodies in CVST prior to the COVID-19 pandemic are unknown. Since this information may guide investigations of the possible association between the ChAdOx1 nCoV-19 and Ad26.COV2.S vaccines and CVST with thrombocytopenia, this study sought to elucidate these questions using data of the pre–COVID-19 pandemic era from the International Cerebral Venous Sinus Thrombosis Consortium.11,12

    Methods

    This retrospective study examined the frequency of thrombocytopenia, HIT in particular, in a large multicenter cohort of consecutive patients with CVST recruited prior to the COVID-19 pandemic. Each center had permission from their ethical review board for the collection of observational data. Written informed consent was obtained if required under applicable national laws (eTable 1 in the Supplement). The presence of PF4/heparin antibodies was separately tested in previously collected plasma samples in a subset of patients with CVST.11 Ethical approval for the laboratory analyses was previously granted.

    Study Design and Participants

    Data were included from consecutive adult patients with CVST from 7 hospitals participating in the International Cerebral Venous Sinus Thrombosis Consortium registry: Helsinki University Hospital, Finland; Amsterdam UMC, the Netherlands; Inselspital Bern University Hospital, Switzerland; Sahlgrenska University Hospital, Sweden; National Institute Manuel Velasco Suarez, Mexico; Hamadan University of Medical Science, Iran; and Hospital Dr Calderón Guardia, Costa Rica. Details of this cohort have been published.13 Start of recruitment varied per hospital, the earliest being August 1987 (eTable 2 in the Supplement). Patients diagnosed up to March 2018 were included. Patients who declined or withdrew consent, had incomplete data due to transfer to another hospital, or had a missing baseline platelet count were excluded.

    PF4/heparin antibodies were tested in samples of frozen citrated plasma of a subset of patients participating in a previous study on CVST performed at the Amsterdam UMC and Inselspital, Bern University Hospital, between September 2009 and February 2016.11 This study had aimed to investigate prediction of CVST by admission D-dimer levels. The study cohort consisted of consecutive adult patients who were suspected of having CVST; were not receiving anticoagulant treatment prior to admission; and had not had a diagnosis of deep vein thrombosis, pulmonary embolism, ischemic stroke, or myocardial infarction in the 3 months prior to admission.

    Data Collection and Definitions

    Data on clinical manifestations and ancillary investigations were obtained with a standardized case report form. Diagnosis of CVST was confirmed with computed tomographic venography, magnetic resonance imaging with magnetic resonance venography, catheter angiography, or autopsy, in accordance with international guidelines.14,15 Intracerebral hemorrhage was defined as hemorrhagic infarction or intracerebral hematoma.

    Platelet count was measured in venous blood samples as part of routine clinical care. The first platelet count performed upon hospital arrival, within a maximum of 48 hours after admission, was used for analysis. Thrombocytopenia was defined as a platelet count of less than 150 ×103/μL; normal platelet count, 150 to 450 ×103/μL, and thrombocytosis as a platelet count of more than 450 ×103/μL. Thrombocytopenia was further categorized into mild (platelet count, 100-149 ×103/μL), moderate (50-99 ×103/μL), or severe (<50 ×103/μL).16 For all patients with thrombocytopenia, additional details on presumed underlying causes were obtained through retrospective analysis of the medical records by a local investigator. For all patients in whom immune thrombocytopenic purpura (ITP) was identified by the local investigator, a hematologist (J.A.K.H.) and vascular internist (S.M.) independently reviewed details of the diagnosis and assessed the possibility of a missed diagnosis of autoimmune HIT.

    For the laboratory analysis, an IgG-specific enzyme-linked immunosorbent assay (ELISA) was performed to assess the presence of PF4/heparin IgG antibodies (Lifecodes PF4 IgG, Immucor GTI Diagnostics) according to manufacturer’s instructions, on the frozen citrated plasma collected on hospital admission for CVST from a subset of patients. All samples were drawn prior to start of heparin treatment and were processed and stored frozen at −80 °C immediately after withdrawal, a process by which the stability of PF4/heparin antibodies is maintained.17 An optical density of more than 0.4 was classified as a positive result.

    Outcomes

    The main outcomes of the study were the frequencies of thrombocytopenia, HIT, and PF4/heparin antibodies among patients with CVST prior to the COVID-19 pandemic.

    Statistical Analysis

    A power calculation was not performed for this retrospective analysis but instead data from all patients with an available baseline platelet count were included. Because of the descriptive nature of the study, patients with a missing baseline platelet count were excluded rather than having their platelet counts imputed. Demographics and clinical characteristics of patients with available and missing baseline platelet counts, respectively, can be found in eTable 3 in the Supplement. In the primary analysis, frequencies of thrombocytopenia, HIT, and PF4/heparin antibodies were assessed. Because all patients with an unknown cause of thrombocytopenia were classified as “HIT unlikely,” they were included in the calculation of the frequency of HIT as non-HIT patients, and no variables were missing for the frequency calculations. The Wilson method was used to calculate 95% CIs for these proportions using the following formula: (p+ 1.962/2n ± 1.96{[p(1 p)]/n+ 1.962/4n2})/(1 + 1.962/n) where p is the proportion and n is the sample size.18 In a secondary analysis, clinical and imaging characteristics of patients with thrombocytopenia and patients with a normal platelet count were described. For these descriptive and exploratory analyses, missing data for each variable were again described and no statistical tests were applied. Analyses were performed in RStudio (version 1.2.1335) with the Hmisc package.

    Results

    Of 998 eligible patients with CVST, 46 were excluded from the CVST Consortium registry (19 declined or withdrew consent, and 27 had incomplete data due to transfer to another hospital, Figure 1). Of the 952 patients included in the CVST Consortium registry, 87 (9.1%) patients with a missing baseline platelet count were excluded. Of the remaining 865 patients, 73 (8.4%) had thrombocytopenia, 751 (86.8%) had a normal platelet count, and 41 (4.7%) had thrombocytosis. The 95% CI for frequency of thrombocytopenia ranged from 6.8% to 10.5%. Of the 73 patients with thrombocytopenia, 52 (71%) had mild, 17 (23%) had moderate, and 4 (5%) had severe thrombocytopenia. Admission and discharge platelet counts for the 56 patients with thrombocytopenia at admission and available discharge platelet counts are presented in Figure 2. Thirty-six patients (49%) with thrombocytopenia and 540 (72%) with a normal platelet count were women. The number of patients with thrombocytopenia who had a diagnosis of cancer was 19 (26%); anemia, 29 (40%); and history of thrombosis, 13 (18%), whereas, the number of patients with a normal platelet count who had a diagnosis of cancer was 57 (8%); anemia, 147 (20%); and history of thrombosis, 61 (8%; Table 1). Focal neurological deficits at presentation were seen in 55 patients (75%) with thrombocytopenia and in 439 patients (59%) with a normal platelet count, and intracerebral hemorrhage was present in 32 (44%) with thrombocytopenia and 235 (32%) with a normal platelet count.

    Among patients with thrombocytopenia at admission, the thrombocytopenia was newly diagnosed in 47 patients (64%). Among those with an identified cause of thrombocytopenia (n = 47, 64%), the most common causes were infection (n = 12, 16%), hematologic cancer (n = 12, 16%), and drug-induced thrombocytopenia (n = 9, 12%, Table 2). Details on the specific infections, hematologic cancer types, and drugs presumed to cause thrombocytopenia in these patients are available in eTable 4 in the Supplement. Among 26 patients, the cause of thrombocytopenia could not be identified, of whom 23 had mild and 3 had moderate thrombocytopenia, and none had a decrease in platelet count of more than 40% during admission.

    There were 6 patients in whom ITP was diagnosed by the local physicians. After reevaluation of available data, ITP was confirmed by both adjudicators for 5 of 6 patients. In the other patient, the adjudicators determined that autoimmune HIT could not be ruled out. The patient was an 18-year-old man with CVST, pulmonary embolism, extracranial bleeding, and thrombocytopenia (baseline platelet count, 71 ×103/μL). Despite immunosuppressive therapy including intravenous immunoglobulins, the patient deteriorated and died 4 days after admission. PF4/heparin antibodies were not determined.

    Two other patients were tested for PF4/heparin antibodies as part of routine care, 1 of whom tested positive. This patient was a 35-year-old woman who had an extra-uterine pregnancy that was treated with curettage and uterine embolization. During this hospitalization, she received a prophylactic dose of low-molecular weight heparin. Thirteen days later she was diagnosed with CVST. Her platelet count at that time was 37 ×103/μL. The patient was found to have platelet activating PF4/heparin antibodies and was diagnosed with HIT (based on a positive particle centrifugation immunoassay with a titer of 1:32; an Immunocor GTI anti-PF4/heparin antibody ELISA optical density of >3.000; and a positive heparin-induced platelet aggregation test result) and was treated with lepirudin and endovascular thrombectomy. However, her clinical condition worsened, and she died 3 weeks later due to uncontrollable intracranial hypertension. Thus, HIT was conclusively diagnosed in 1 of 73 patients (1%) with CVST and thrombocytopenia and in 1 of 865 patients (0.1%; 95% CI, <0.1%-0.7%) in the entire CVST cohort.

    Of the 93 patients whose plasma samples were analyzed, 8 of 93 (9%) had baseline thrombocytopenia (6 with mild, 2 with moderate, and none with severe thrombocytopenia). Baseline demographics and clinical characteristics of this subset of patients are detailed in Table 1. None of the 93 patients tested positive for PF4/heparin antibodies (95% CI, 0%-4%). The median optical density of anti-PF4 IgG was 0.106 (interquartile range, 0.088-0.142; range, 0.064-0.357).

    Discussion

    In this study involving 865 patients with CVST prior to the COVID-19 pandemic, thrombocytopenia was uncommon at the time of presentation. In many patients, thrombocytopenia could be explained by comorbidities, like cancer or infection, or by use of alcohol or certain medications. HIT was conclusively identified in only 1 patient. Because patients with CVST were not routinely screened for HIT, additional plasma samples from a subset of 93 patients were tested for the presence of PF4/heparin antibodies, without a single positive test result.

    Together, these data indicate that HIT-associated CVST was very rare prior to the COVID-19 pandemic. These observations suggest that the severe thrombocytopenia reported in association with CVST in many of the cases occurring after ChAdOx1 nCov-19 and Ad.26.COV2.S vaccination is unusual, as is the presence of PF4/heparin antibodies. This may indicate that these CVST cases were associated with the vaccine.1-3 Laboratory investigation with a binding assay (ELISA) to determine the presence of anti–PF4/heparin antibodies is essential in these cases because rapid and chemiluminescence immunoassays may produce false-negative results.19

    These findings should not be interpreted as justification to halt use of the ChAdOx1 nCov-19 or Ad.26.COV2.S vaccines. Reported rates of thrombotic complications with thrombocytopenia associated with the vaccine remain low, whereas rates of morbidity and mortality of COVID-19 are much higher.4,5,20

    Limitations

    This study has several limitations. First, clinical data for this multicenter cohort were collected retrospectively, and information on race/ethnicity was not obtained. Baseline platelet count was not always available, nor was the underlying cause of thrombocytopenia identified or investigated in all cases. This was especially true among patients with mild thrombocytopenia, who constituted 23 of 26 patients with thrombocytopenia of unknown cause. Second, patients were not routinely screened for HIT; thus, it is possible that the point estimate of 0.1% is an underestimation of the frequency of HIT among CVST cases prior to the COVID-19 pandemic. One case was identified in whom autoimmune HIT could not be reliably excluded, but PF4/heparin antibodies were not measured for this patient. However, because analysis of the 93 plasma samples from a convenience sample did not yield a single positive result for PF4/heparin antibodies, and thrombocytopenia was present in only 8% of patients overall, it is unlikely that this potential underrepresentation can fully explain the difference between the post–COVID-19 vaccination CVST with HIT-like disease1,2 and the pre–COVID-19 CVST cohort in this study. Third, of the subset of 93 patients whose plasma samples were analyzed for PF4/heparin antibodies, only 8 had thrombocytopenia and none had severe thrombocytopenia. Fourth, each participating hospital initiated the inclusion of patients with CVST at different time points for a variable length of time. However, because more than 60% of included patients were diagnosed after 2010, the data are presumed to be representative of present-day patients with CVST. Fifth, the data did not allow for the calculation of a population-based incidence rate of CVST with thrombocytopenia. Sixth, despite the CVST Consortium including one of the largest data sets of patients with CVST, due to its rarity, the cohort size remained limited.

    Conclusions

    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.

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