LAUSR

To the Editor: Rare cases of cerebral venous thrombosis after COVID-19 mRNA vaccines have been reported in real-world post-vaccination data. As phase 3 clinical mRNA vaccine trials do not aim to and are not sufficiently powered to detect rare adverse events, the risks, and benefits of new vaccines are usually not fully known during regulatory approval, particularly following emergency use authorization. National regulatory bodies such as the Food and Drug Administration (FDA) and European Medicines Agency (EMA), and pharmacovigilance databases such as the World Health Organization's (WHO) platform VigiBase, the United States' Vaccine Adverse Event Reporting System (VAERS) and EMA's EudraVigilance are instrumental in ensuring vaccine safety and shaping public health policy. A temporal relation to vaccine administration does not confirm the diagnosis of “vaccineinduced thrombosis.” In addition, available literature on postvaccination thrombosis lacks sufficient power to detect significant associations with rare events like CVT. Hence, we discuss our observations of cerebral venous thrombosis occurring after COVID-19 mRNA vaccination in Singapore. Mass COVID-19 vaccination in Singapore commenced on December 30, 2020 with the Pfizer-BioNTech/Comirnaty BNT162b2 vaccine, while Moderna mRNA-1273 vaccination was initiated on March 12, 2021. We initially reported three cases of CVT in three patients (median age 60) within 10 days of receiving a second dose of mRNA-COVID-19 vaccination, of which two required decompressive craniectomy. Platelet count was normal in these three patients, with two patients further testing negative for heparin-induced platelet aggregation test (HIPA). We performed platelet flow cytometry (Becton Dickinson FACSCanto TM Flow analyzer) on two of these three patients with CVT; both demonstrated increased surface expression of CD62P (platelet P-selectin) and PAC1 (activated GP IIb/IIIa) in response to an ADP agonist. Subsequently, we performed a retrospective cohort study comparing the incidence and clinical characteristics of CVT following SARS-CoV-2 infection or receipt of at least one dose of mRNA-COVID-19 vaccination from January 23, 2020, to August 3, 2021. Among 3 006 662 individuals who received at least one dose of mRNA-COVID-19 vaccines, 1 626 623 (54.1%) were male and the median age was 50 years. Nine CVT cases were identified (seven males; median age: 60 [46–76] years). Six patients received the BNT162b2 vaccine, and three patients received the mRNA-1273 vaccine. None of the nine patients suffered from fatal CVT. They presented (primarily with focal neurological deficits and headaches) 28 (19–39, median IQR) days after the first dose, and 7 (1–11, median IQR) days after the second. Platelet count was normal, and four patients had mildly reduced antithrombin III [n = 2] and protein C [n = 1] levels possibly due to consumption of these natural anticoagulants during acute thrombosis, while two patients had a lupus anticoagulant. One patient was weakly positive for PF4 antibody ELISA, with optical density <1 (Asserachrom HPIA – IgG, Diagnostica Stago; threshold to positivity <0.2). Three patients tested negative for HIPA. The incidence of CVT hospitalizations was 2.93 per 100 000 person-years (95% CI, 1.18–6.04) after receiving two doses of mRNA-COVID-19 vaccine and 2.59 per 100 000 personyears (95% CI, 1.19–4.92) after the first dose of mRNA-COVID-19 vaccine. Recently, the Health Sciences Authority (HSA), a WHO maturity level 4 national regulator of health products in Singapore, reported a small increase in incidence of CVT post-mRNA vaccination. As part of safety updates on COVID-19 vaccination, HSA reported 13 suspected cases of CVT following more than 12.7 million doses of mRNA-COVID-19 vaccination. This data were derived from comparison of CVT incidence during the pre-pandemic period (2019) to CVT incidence during the COVID-19 pandemic from a national database derived from hospitalized cases (ICD10 discharge diagnosis codes of CVT). The key update states that “Very rare cases of CVT have been reported with the [mRNA-] COVID-19 vaccines, both overseas and locally. CVT is a very rare type of blood clot [...] which can happen naturally regardless of [...] vaccinat[ion]. The incidence of CVT has stabilized and remains very rare. Although there is a small increase in incidence of CVT with mRNA vaccines (about 1 additional case per million doses), the risk of CVT after COVID-19 infection is much higher after mRNA vaccination (about 30 cases per million infections), and the benefits of vaccination continue to outweigh the small increased risk of CVT.” Several observational studies evaluating the risk of CVT show discordant findings post mRNA-COVID-19 vaccination but showed a clear signal for modified adenovirus vector vaccines (Table 1). In a nationwide cohort study, Andrews et al. showed no increased incidence of CVT for BNT162b2 vaccine recipients of any age. However, based on the EMA's Eudravigilance database, Krzywicka et al. did not find an increase in the absolute risk of CVT following BNT162b2 (0.6 per million doses, 95% CI 0.5–0.7), or mRNA-1273 vaccination (0.6 per million doses, 95% CI 0.3–1.1). In contrast, a study by Abbattista et al. showed an increased reporting rate of CVT per million person vaccinated-days following BNT162b2 vaccination (1.92, 95% CI 1.71–2.12) and mRNA-1273 vaccination (5.63, 95% CI 4.74–6.64) for CX-024414 (mRNA-1273). These Received: 6 August 2022 Revised: 24 October 2022 Accepted: 25 October 2022