Thrombocytopenia after COVID-19 vaccination

Recent data suggests a link between the Oxford-AstraZeneca adenoviral (ChAdOx1) vector-based COVID-19 vaccine (AZD1222) and immune-mediated thrombotic thrombocytopenia resembling heparin-induced thrombotic thrombocytopenia (HITT) and therefore called VITT (vaccine-induced immune thrombotic thrombocytopenia) [[1], [2], [3]]. However, a case series of 20 patients hospitalized due to thrombocytopenia occurring 1–23 days (median 5 days) after vaccination with the PfizerBioNTech BNT162b2 mRNA Covid-19 vaccine or the Moderna mRNA-1273 SARS-CoV-2 vaccine, including a fatal intracranial hemorrhage, has also been reported [4]. Finally, emerging data has suggested that thrombocytopenia events may likely occur unevenly across the three COVID-19 vaccines, with higher events among individuals vaccinated with the Oxford-AstraZeneca vaccine relative to the PfizerBioNTech vaccine, but further data is needed [5].

Using data from the North Denmark Region (capture population≈600,000 inhabitants), we reviewed cases with thrombocytopenia and associated clinical events among healthcare personnel ≤65 years of age vaccinated with the PfizerBioNTech/Moderna (N = 11,689) or the Oxford-AstraZeneca (N = 16,509) COVID-19 vaccine. Due to the very rare but severe clinical entity of VITT, the use of the AstraZeneca vaccine in Denmark was put on hold on March 11, 2021, and later suspended. Therefore, individuals who were vaccinated with this vaccine in our study only had one injection. Of 2130 individuals with post-vaccination platelet measurements available, 50 (40 women and 10 men) had thrombocytopenia (platelet count <145 × 10⁹/L in men and <165 × 10⁹/L in women). Among 1873 women, 24/813 (3.0 %) vaccinated with the Oxford-AstraZeneca COVID-19 vaccine versus 16/1060 (1.5 %) vaccinated with PfizerBioNTech/Moderna COVID-19 vaccines had thrombocytopenia, odds ratio [95 % confidence interval] for thrombocytopenia of 1.99 [1.05–3.76] for Oxford-AstraZeneca versus PfizerBioNTech/Moderna. Among 257 men, the corresponding odds ratio [95 % confidence interval] was 0.49 [0.14–1.79].

Severe thrombocytopenia (platelet count <50 × 10⁹/L) was seen in three patients vaccinated with Oxford-AstraZeneca (all women between 50 and 60 years of age) versus none among the PfizerBioNTech/Moderna vaccines. One fatal event occurred following adrenal gland bleeding seven days after vaccination, thrombocytopenia (lowest platelet count of 5 × 109/L), massively elevated D-dimer (>100mcg/mL), and ischemic stroke nine days after vaccination [6]. This patient was strongly positive for platelet factor 4 (PF-4) reactive antibodies, imitating what is seen in HITT. The two other cases were evaluated in the emergency department on day 20 and 35 post-vaccination without subsequent hospitalization but referral to outpatient diagnostic work-up. FP4-antibodies were not proven in one of the remaining two cases with severe thrombocytopenia and not tested in the other. None of the three cases had previously received heparin.

A recently published study based on data from the US-based Vaccine Adverse Event Reporting System (VAERS) reported 15 cases of thrombocytopenia among 18,841,309 doses of Pfizer-BioNTech COVID-19 vaccine and 13 cases among 16,260,102 doses of Moderna COVID-19 vaccine, suggesting no safety concern attributable to the use of mRNA COVID-19 vaccines [7]. Also reassuringly, another VAERS-based study of the two mRNA vaccines found that thromboembolic events in younger women, when compared to hormonal contraceptive use, were not disproportionally reported [8]. In continuation, VITT has been suggested to have an incidence risk of 1 in 100,000–600,000 treated cases [9]. In comparison, it is important to emphasize the extremely low incidence of more severe events in the interpretation of our results.

In conclusion, thrombocytopenia appears to be significantly more frequent among women vaccinated with Oxford-AstraZeneca COVID-19 when compared to counterparts vaccinated with the PfizerBioNTech/Moderna COVID-19 vaccines. Of ≈30,000 vaccinated cases, three events of severe thrombocytopenia were seen only among women vaccinated with the Oxford-AstraZeneca COVID-19 vaccine.

Author statement

Kristian Kragholm: Conceptualization, Methodology, Software, Data Curation, Formal analysis, Writing - Original Draft. Maurizio Sessa: Conceptualization, Writing – Review & Editing. Thomas Mulvad: Data Curation, Software. Mikkel Porsborg Andersen: Writing – Review & Editing. Helle Collatz-Christensen: Writing – Review & Editing. Stig Nikolaj Blomberg: Writing – Review & Editing. Freddy Lippert: Writing – Review & Editing. Soren Mikkelsen: Writing – Review & Editing. Peter Leutscher: Data Curation, Writing – Review & Editing. Dorte Melgaard: Data Curation, Writing – Review & Editing. Christian Torp-Pedersen: Supervision, Writing - Review & Editing. Soren Risom Kristensen: Conceptualization, Methodology, Supervision, Writing – Review & Editing. Torben Bjerregaard Larsen: Conceptualization, Methodology, Supervision, Writing – Review & Editing. Peter Sogaard: Conceptualization, Methodology, Supervision, Writing – Review & Editing.

Funding sources

No external funding was used for the study conduct.