- Bleeding is more prevalent after vaccination with AstraZeneca
- Most likely linked to thrombocytopenia (= low blood platelet count) induced by the #vaccine
Abstract Objective To compare prevalence of skin, nose and gingival bleedings after receipt of adeno-vectored or mRNA-vaccines against COVID-19. The hypothesis is that milder symptoms indicating altered thrombocyte function may affect a larger proportion of vaccinated individuals than the recently reported severe cases with thrombosis and thrombocytopenia. Methods Using an ongoing large, population-based cohort study, more than 80 000 cohort participants were asked through electronic questionnaires about COVID-19 vaccination and potential side effects during weeks 11–13, 2021. The response rate was 58% (81267/138924). Among the vaccinated, 83% were female, 85% health care workers and 80% were aged 40–55 years. The prevalence of self-reported episodes of skin, nose and gingival bleedings were compared after mRNA and adenovirus-vectored vaccination. Estimates were adjusted for age, sex, occupation, previous COVID-19 infection and chronic disease. Results Four of the 3416 subjects (0.2%) who were vaccinated with a single dose of mRNA vaccine reported skin bleeding as a side effect, as opposed to 163 of 5132 subjects (3.2%) vaccinated with a single dose of the adenovirus-vectored vaccine, OR (odds ratio) = 16.0 (95% confidence interval (CI) 7.5–34.1). Corresponding ORs for nose and gingival bleeding were 8.0 (4.0–15.8) and 9.3 (4.3–20.0), respectively. Conclusions These findings could potentially indicate that the adenovirus-vectored vaccine may lead to mild bleeding episodes in a larger proportion of vaccinated individuals, and not only in rare cases with documented thrombosis and thrombocytopenia. Studies are needed to understand the possible mechanisms behind these observations, and to establish or refute whether they share similarities with the severe thromboembolic bleeding complications.
Abbreviations COVID-19coronavirus disease SARS-CoV-2severe acute respiratory syndrome coronavirus MoBaThe Norwegian Mother, Father and Child Cohort Study EMAEuropean Medicines Agency PRACPharmcovigilance Risk Assessment Committee Keywords Bleedings Vaccines Cohort study Adverse events
1. Introduction
In Norway, five patients with thrombosis and thrombocytopenia were hospitalized 7 to 10 days after receiving the first dose of a chimpanzee adenovirus-vectored vaccine (expressing the SARS-CoV-2 spike protein) against COVID-19. [1] In all patients, antibodies to platelet factor 4 was detected, suggesting a likely mechanism induced by vaccination. The same findings are reported from 9 patients in Germany. [2] The cases may represent rare events, or they may be the tip of the iceberg, reflecting a more quantitative phenomenon. We hypothesized that if this mechanism were present in a larger proportion of vaccinated subjects, one would expect bleeding episodes. We had the opportunity to test this hypothesis in a large, ongoing, population-based cohort by comparing the prevalence of bleeding episodes in subjects receiving adeno-vectored vaccine with the prevalence in subjects receiving mRNA vaccine.2. Methods
2.1. Study population
The Norwegian Mother, Father and Child Cohort Study (MoBa) is a population-based cohort including about 280 000 participants based on written informed consent. The main aim is to understand the aetiology of complex diseases. [3] Pregnant women and their partners were recruited from 1999 through 2008. Parents and children have been followed with questionnaires, registry linkages and a series of sub-studies.[4] Since the end of March 2020, all active adult participants (initially about 149 000 subjects aged 25 to 65 years) have received biweekly mobile-phone questionnaires asking about symptoms related to COVID-19. Since vaccination against SARS-CoV-2 commenced in December 2020, we have included questions on vaccine uptake and side effects.
The vaccination policy in Norway was to start with the elderly population, and then to include critical health care personnel.[5] The Pfizer-BioNTech (BNT162b2) mRNA vaccine was the first to be approved in December 2020 followed by the adeno-vectored vaccine from AstraZeneca (ChAdOx1 nCoV-19), and the Moderna mRNA vaccine in February 2021. The adeno-vectored vaccine was recommended for subjects below 65 years and was mainly distributed to health care personnel.
On March 11, the AstraZeneca vaccine was suspended in Norway following a report in Denmark of a death due to thrombosis after vaccination.[6] On March 13, 2021, the Norwegian Medicines Agency was notified of blood clots and bleeding in younger people and also of severe cases of thrombosis and thrombocytopenia.[7] Consequently, we included questions on bleeding episodes in the questionnaire round issued on March 17.
The response rate to the March 17 questionnaire was 58% (81267/138924). Eleven percent (n = 8699) reported that they had received either an mRNA- or an adeno-vectored vaccine. The dataset was linked to the Norwegian Immunisation Registry (SYSVAK)[8] using each citizen’s unique personal identification number. Registration in SYSVAK is mandatory for vaccinations against COVID-19 and was confirmed for 8548 subjects in the dataset. This linked dataset defines the study population. The agreement between reported and registered information on vaccination against COVID-19 was high and a discrepancy was found for only 28 subjects (kappa = 0.99).2.2. Exposure variables
The exposure variable was vaccination against COVID-19. The vaccine registry holds information on date of vaccination, type of vaccine and vaccine doses for all vaccinations. 5132 subjects had received one dose of the adenovirus-vectored vaccine, while 3416 subjects had received one dose of an mRNA vaccine (3315 had received the Pfizer and 101 the Moderna vaccines). No subjects had received two doses of the adeno-vectored vaccine, and 3135 subjects had received two doses of an mRNA vaccine.2.3. Outcome variables
The questionnaire issued to MoBa participants initially covered a standard set of side effects derived from the summary of product characteristics (SPC) for the respective COVID-19 vaccines.[9], [10] We asked for any perceived side effects of vaccination. If confirmed, we asked how long after vaccination the first side effect occurred. Bruising/skin bleeding, nose bleeding, and gingival bleeding when brushing teeth was included in the questionnaire round 26 issued on March 17, 2021. These are the outcome variables. Participants were asked to check off for the presence for each potential side effect listed. Multiple checks were possible. If the respondents had received two doses of a vaccine, they were asked to report side effects after each dose. For each reported side effect, the duration of the side effect was asked for.2.4. Other variables
Information on occupation and chronic diseases were linked to the study population from questionnaire data collected from previous rounds during the COVID-19 pandemic. Information on occupation was collected from questionnaire round 3, issued in May 2020. A list of nine choices was included and multiple checks were possible. Due to the vaccination policy, most of the vaccine recipients were health care personnel, and the variable was categorized into “health care personnel”, “other occupation” and “missing.”
Information on chronic diseases was collected from questionnaire round 2, issued in April 2020. We asked for presence of cancer, asthma, heart disease, diabetes, hypertension or other chronic diseases and multiple checks were possible. The current analyses were performed with each condition separately and combined. Since no association was found for separate conditions, “chronic disease” was categorized and reported as “any chronic disease” defined as “no” and “yes” or “missing.”
Information on having had SARS-CoV-2 confirmed in nasal /oral swabs or saliva samples was collected from the March 17, 2021 questionnaire. Participants answered “no,” “yes” or “don’t know” if they had ever tested positive.2.5. Statistical method
We calculated the prevalence of bleeding episodes and prevalence odds ratios with 95% confidence intervals, comparing bleeding episodes for the mRNA vaccines and the adenovirus-vectored vaccine. To adjust for potentially confounding variables, we used logistic regression. Analyses were performed using IBM SPSS 26.0.2.6. Patient and public involvement
MoBa participants were recruited from the general population. Patients or the public were not involved in the design, or conduct, or reporting or dissemination plans of our research. However, we have interviewed focus groups consisting of participants for input to the maintenance and strategic development of the cohort.3. Results
The age and gender distribution of the recipients of the two vaccine types were similar (Table 1). The majority of participants who received the vaccines (>80%) were health care workers, irrespective of vaccine type. Table 1 also demonstrates that the mRNA vaccines were available a few weeks earlier than the adenovirus-vectored vaccine. The prevalences of chronic diseases and prior SARS-CoV-2 test-positivity were also similar between recipients of the two vaccine types.
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