Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Jul 27;326(4):332-338.
doi: 10.1001/jama.2021.9889.

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

Mayte Sánchez van Kammen  1 , Mirjam R Heldner  2 , Justine Brodard  3 , Adrian Scutelnic  2 , Suzanne Silvis  4 , Verena Schroeder  5 , Johanna A Kremer Hovinga  3 , Saskia Middeldorp  6 , Marcel Levi  7   8 , Sini Hiltunen  9 , Erik Lindgren  10   11 , Maryam Mansour  12 , Antonio Arauz  13 , Miguel A Barboza  14 , Susanna M Zuurbier  1 , Diana Aguiar de Sousa  15 , Jose M Ferro  15 , Urs Fischer  2 , Thalia S Field  16 , Katarina Jood  10   11 , Turgut Tatlisumak  10   11 , Jukka Putaala  9 , Marcel Arnold  2 , Jonathan M Coutinho  1
Affiliations

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

Mayte Sánchez van Kammen et al. JAMA. .

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.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.. Patient Selection
CVST indicates cerebral venous sinus thrombosis.
Figure 2.
Figure 2.. 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.
See this image and copyright information in PMC

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 - DOI - PMC - PubMed
    1. 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 - DOI - PMC - PubMed
    1. 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 - DOI - PMC - PubMed
    1. 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-co...
    1. 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 - DOI - PMC - PubMed

Publication types