Blood clots and bleeding events following BNT162b2 and ChAdOx1 nCoV-19 vaccine: An analysis of European data

Abstract

The involvement of viruses and SARS-CoV-2 in autoimmune diseases is well known. The recent demonstration that ChAdOx1 nCoV-19 Covid-19 (AstraZeneca) vaccine (ChA) favors the production of anti-platelet factor 4 (anti-PF4) antibodies, blood clots, and thrombocytopenia raises the question of whether other anti-CoViD-19 vaccines favor the same patterns of events. We assessed the frequency of severe adverse events (SAEs) documented in the EudraVigilance European database up to April 16, 2021 related to thrombocytopenia, bleeding, and blood clots in recipients of ChA compared to that of recipients of the BNT162b2 Covid-19 (Pfizer/BioNTech) vaccine (BNT). ChA administration was associated with a much higher frequency of SAEs in each AE Reaction Group as compared with that elicited by BNT. When considering AEs caused by thrombocytopenia, bleeding and blood clots, we observed 33 and 151 SAEs/1 million doses in BNT and ChA recipients, respectively. When considering patients with AEs related to cerebral/splanchnic venous thrombosis, and/or thrombocytopenia, we documented 4 and 30 SAEs and 0.4 and 4.8 deaths/1 million doses for BNT and ChA recipients, respectively. The highest risk following ChA vaccination is in young people and, likely, women of reproductive age, as suggested by hypothesized scenarios. In conclusion, the immune reaction promoted by ChA vaccine may lead to not only thrombocytopenia and cerebral/splanchnic venous thrombosis but also other thrombotic and thromboembolic SAEs. These events are not favored by BNT vaccine. Our study may help in the evaluation of the benefit/risk profile of the ChA vaccine considering the epidemic curve present in a country.

Keywords: Anti-CoViD-19 vaccines; Risk factors; Severe adverse events; Thrombocytopenia; Venous thrombosis.

Fig. 1

Frequency of individual cases with AEs divided into Reaction Groups following vaccination by BNT or ChAdOx1 nCoV-19. The frequency of individual cases of AEs organized by Reaction Groups, as reported in the EudraVigilance database, was calculated by normalization of the number of individual cases with the doses of vaccines administered in Europe. Non-SAEs (A) and SAEs (B) are reported. Reaction Groups with <1000 individual cases (absolute number) with AEs are not reported.

Fig. 2

Frequency of individual cases with specific AEs among BNT and ChA recipients divided into age groups. The frequency of individual cases with specific AEs divided into age ranges was obtained by normalization of the number of individual cases (Table S7) with the doses supposedly administered to each age range in Europe at week-14 (Table S2). To evaluate the doses supposedly administered to each age range in Europe we considered the doses administered by the European countries providing data regarding administration of each vaccine to age ranges (Figure S1) and set up a method to evaluate the variance of the doses (see the Method sections for details). The frequency (mean ± SD) of individual cases with severe AEs consisting of cerebral venous thrombosis (A), splanchnic venous thrombosis (B), thrombocytopenia (C), and cerebral venous thrombosis and/or splanchnic venous thrombosis and/or thrombocytopenia (D) are reported. The frequency of AEs reported in panel D is lower than the sum of AE frequency reported in panels A, B, and C because one individual case may suffer from 2 or 3 AEs simultaneously. The ordinary two-way ANOVA (Sidak) test was used to assess the difference between ChA and BNT, and “multiplicity adjusted p-values” are reported. ns = p > 0.05, and **** = p < 0.0001.

Fig. 3

Frequency of death due to specific AEs among BNT and ChA recipients divided into age groups. The frequency of death divided into age ranges was obtained by the normalization of death (Table S8) with the doses supposedly administered to each age range in Europe. To evaluate the doses supposedly administered to each age range in Europe, we considered the doses administered by the European countries providing data regarding administration of each vaccine to age ranges (Figure S1) and set up a method to evaluate dose variance (see the Material and methods section for details). The frequency (mean ± SD) of deaths due to cerebral venous thrombosis (A), splanchnic venous thrombosis (B), thrombocytopenia (C), and cerebral venous thrombosis and/or splanchnic venous thrombosis and/or thrombocytopenia (D) are reported. The frequency of deaths reported in panel D is lower than the sum of the frequency of death reported in panels A, B, and C because some patients died due to 2 or 3 AEs. The ordinary two-way ANOVA (Sidak) test was used to assess the difference between ChA and BNT, and “multiplicity adjusted p-values” are reported. ns = p > 0.05, and **** = p < 0.0001.

Fig. 4

Frequency of individual cases with specific AEs among BNT and ChA recipients divided into age groups and sex. The frequency of individual cases with specific AEs divided into age ranges was obtained by normalization of the number of individual cases (Table S7) with the doses supposedly administered to each age range in Europe. To evaluate the doses supposedly administered to each age range in Europe, we considered the doses administered by the European countries providing data regarding administration of each vaccine to age ranges (Figure S1) and supposed that the same distribution was present in Europe. For the sex distribution of vaccine administration, we hypothesized three scenarios: the scenario with female (red):male (blue) = 3:2 is reported with solid lines; the scenarios where the female:male ratio is 4:2 and 2:2 are reported as dotted lines. The mean frequency of individual cases with SAEs consisting of cerebral venous thrombosis (A), splanchnic venous thrombosis (B), thrombocytopenia (C), and cerebral venous thrombosis and/or splanchnic venous thrombosis and/or thrombocytopenia (D) are reported. The frequency of AEs reported in panel D is lower than the sum of the AE frequency reported in panels A, B, and C because one individual case may suffer from 2 or 3 AEs simultaneously. Statistical analyses were not conducted because we could not establish which vaccine administration ratio for females:males was the “true” one, and it may be different at different ages. Therefore, the figure can suggest about the different frequency of AEs, particularly when the red area does not overlap with the blue area (mainly at the age range 25–49 years).