Frequency of Thrombocytopenia and Platelet Factor 4

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, MD; Mirjam R. Heldner, MD, MSc; Justine Brodard, MSc; Adrian Scutelnic, MD; Suzanne Silvis, MD, PhD; Verena Schroeder, PhD; Johanna A. Kremer Hovinga, MD; Saskia Middeldorp,MD, PhD; Marcel Levi, MD, PhD; Sini Hiltunen, MD, PhD; Erik Lindgren, MD; MaryamMansour, MD; Antonio Arauz, MD, PhD; Miguel A. Barboza, MD, PhD; Susanna M. Zuurbier,MD, PhD; Diana Aguiar de Sousa, MD, PhD; Jose M. Ferro,MD, PhD; Urs Fischer,MD, MSc; Thalia S. Field, MD, MHSc; Katarina Jood, MD, PhD; Turgut Tatlisumak, MD, PhD; Jukka Putaala, MD, PhD; Marcel Arnold, MD; Jonathan M. Coutinho,MD, PhD

Downloaded from: by the University of Amsterdam

July 2nd, 2021

IMPORTANCE: Cases of cerebral venous sinus thrombosis in combination with thrombocytopenia have recently been reported multiple times 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 extremely rare. These findings may inform investigators of the possible association between the ChAdOx1 nCoV-19 and Ad26

Dr. Robert Gorter:

Together, these data indicate that cerebral sinus thrombosis was very rare prior to the COVID-19 pandemic. These observations suggest that the fast rise of severe thrombocytopenia and thromboses reported occurring after ChAdOx1 nCov-19 and Ad.26.COV2.S vaccination is unusual, as is the presence of PF4/heparin antibodies. This indicates that these fatal cases of thromboses and thrombopenia were associated with the above-mentioned vaccines.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

Here has been shown that the association between cerebral sinus thromboses after vaccination with the above-mentioned vaccines is extremely likely and must be validated immediately.

Spontaneous sinus thrombosis was rare before the SARS-CoV-2 epidemic but is rapidly on the rise from the moment large populations have been inoculated with the above-mentioned experimental vaccines.  The fact that among unvaccinated individuals, brain sinus thromboses are still very rare and the significant increase is only found in vaccinated individuals, all alarm bells should go off among health care providers and politicians (and parents).


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