Thrombocytopenia and Platelet Factor 4/Heparin Antibodies in Cerebral Venous Sinus Thrombosis Before COVID-19 | Coagulation Disorders | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

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

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
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.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

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
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
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
8.
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
9.
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 PubMedGoogle 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 PubMedGoogle ScholarCrossref
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 PubMedGoogle ScholarCrossref
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 PubMedGoogle ScholarCrossref
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 PubMedGoogle ScholarCrossref
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 PubMedGoogle ScholarCrossref
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 PubMedGoogle ScholarCrossref
17.
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
18.
Wilson  EB .  Probable inference, the law of succession, and statistical inference.   J Am Stat Assoc. 1927;22:209-212. doi:10.1080/01621459.1927.10502953Google ScholarCrossref
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 PubMedGoogle ScholarCrossref
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 PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close