Abstract
Hematologic complications, including vaccine-induced immune thrombotic thrombocytopenia (VITT), immune thrombocytopenia (ITP), and autoimmune hemolytic anemia (AIHA), have been associated with the original severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. However, on August 31, 2022, new formulations of the Pfizer-BioNTech and Moderna vaccines were approved for use without clinical trial testing. Thus, any potential adverse hematologic effects with these new vaccines remain unknown. We queried the US Centers for Disease Control Vaccine Adverse Event Reporting System (VAERS), a national surveillance database, through February 3, 2023, all reported hematologic adverse events that occurred within 42 days of administration of either the Pfizer-BioNTech or Moderna Bivalent COVID-19 Booster vaccine. We included all patient ages and geographic locations and utilized 71 unique VAERS diagnostic codes pertaining to a hematologic condition as defined in the VAERS database. Fifty-five reports of hematologic events were identified (60.0% Pfizer-BioNTech, 27.3% Moderna, 7.3% Pfizer-BioNTech bivalent booster plus influenza, 5.5% Moderna bivalent booster plus influenza). The median age of patients was 66 years, and 90.9% (50/55) of reports involved a description of cytopenias or thrombosis. Notably, 3 potential cases of ITP and 1 case of VITT were identified. In one of the first safety analyses of the new SARS-CoV-2 booster vaccines, we identified few adverse hematologic events (1.05 per 1,000,000 doses), most of which could not be definitively attributed to vaccination. However, three reports of possible ITP and one report of possible VITT highlight the need for continued safety monitoring of these vaccines as their use expands and new formulations are authorized.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00277-023-05136-2.
Keywords: COVID-19, SARS-CoV-2, Bivalent vaccine, Autoimmune hemolytic anemia, Immune thrombocytopenia, Vaccine-induced immune thrombotic thrombocytopenia
Introduction
Soon after the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019, reports began to emerge of adverse hematologic effects. It is now recognized that this respiratory virus is a predisposing risk factor for the development of hypercoagulable states and thrombosis [1], immune thrombocytopenia (ITP) [2], and autoimmune hemolytic anemia (AIHA) [3]. With the introduction of vaccines, the prevailing thought was that these hematologic sequelae would likely decrease or even be eliminated. Conversely, a new, rare hematologic complication arose, manifesting with thromboses in unusual anatomic locations in conjunction with thrombocytopenia (vaccine-induced immune thrombotic thrombocytopenia, VITT). While observed following all vaccine types, VITT is most commonly associated with the Ad26.COV2.S (Johnson & Johnson/Janssen) and ChAdOx1 nCoV-19 (AstraZeneca) adenoviral vector vaccines [4]. ITP [5] and AIHA [6, 7] have also been reported following SARS-CoV-2 vaccination, including among patients vaccinated with the mRNA-1273 (Moderna) and BNT162b2 (Pfizer-BioNTech) vaccines at low rates.
As the original vaccine formulations have been in use since their initial implementation in late 2020, most of the studies and publications describing these vaccine-associated hematological events have only focused on these original vaccines. However, on August 31, 2022, the United States (US) Food and Drug Administration (FDA) authorized the use of updated Moderna and Pfizer-BioNTech bivalent vaccine formulations [8]. These bivalent vaccines contain components of both the original SARS-CoV-2 strain and a common strain between the BA.4 and BA.5 lineages of the omicron variant [4]. While these updated vaccines are manufactured utilizing the same messenger RNA (mRNA) technology, the viral strains are inherently different. Though few published reports have found no significant differences in the rates of adverse events overall for the bivalent vaccines compared to the original mRNA vaccines [9], no clinical trials were undertaken prior to their authorization for use. Additionally, to our knowledge, there are no data regarding hematologic adverse events following vaccination with the bivalent booster vaccines. Thus, we sought to ascertain whether hematologic events have been reported following vaccination with the Pfizer-BioNTech and Moderna bivalent vaccines.
To address this question, we queried the US Centers for Disease Control (CDC) Vaccine Adverse Event Reporting System (VAERS). Jointly launched by the CDC and FDA, VAERS serves as a national early warning system for specific adverse events that occur following routine vaccination in the US. Any individual may submit a report to the VAERS database, though vaccine manufacturers and other officials are required to submit reports of all potential adverse events potentially associated with vaccination. All reports are included without determination of causality.
Methods
In this cross-sectional study, we analyzed the CDC VAERS database from inception to February 3, 2023, for all reported hematologic adverse events that occurred within 42 days of administration of either the Pfizer-BioNTech or Moderna Bivalent COVID-19 Booster vaccine. We included all patient ages and geographic locations. To identify reported cases, we utilized 71 unique VAERS diagnostic codes pertaining to a hematologic condition as defined in the VAERS database (Supplemental Table 1). This research did not require institutional review board approval as all data are publicly available and do not contain identifiable patient details.
Results
We identified a total of 55 patients (female, n = 29; male, n = 26) with hematologic events reported to the VAERS database potentially associated with either the Pfizer-BioNTech or Moderna bivalent COVID-19 vaccines (Table 1). Sixty percent (33/55) of patients received the Pfizer-BioNTech bivalent booster, 27.3% (15/55) received the Moderna bivalent booster, 7.3% (4/55) received the Pfizer-BioNTech bivalent booster and the influenza quadrivalent vaccine concomitantly, and 5.5% (3/55) received the Moderna bivalent booster and the influenza quadrivalent vaccine concomitantly. The median age of reported patients was 66 years. The most common hematologic abnormalities included cytopenias (47.3%, 26/55) and thromboembolic events (43.6%, 24/55).
Table 1.
Reports identified in the CDC VAERS database following vaccination with the Pfizer-BioNTech or Moderna bivalent booster
| Age | Sex | Clinical findings | Days to onset | Hospitalization | Vaccine |
|---|---|---|---|---|---|
| 67 | F | Febrile illness for 2 weeks, WBC 0.7 | 7 | 4 days | Pfizer-BioNTech |
| 67 | F | Arthralgias, myalgias, nausea, vomiting, diarrhea, fever, anemia requiring transfusion | 0 | 3 days | Pfizer-BioNTech |
| 74 | M | SARS-CoV-2 pneumonia with secondary bacteremia, hemoptysis, and anemia | 11 | 13 days | Pfizer-BioNTech and influenza high-dose quadrivalent |
| 85 | M | SARS-CoV-2 pneumonia with anemia and thrombocytopenia | 24 | 7 days | Moderna |
| 42 | F | Menorrhagia heavier than normal | 4 | No | Pfizer-BioNTech |
| 60 | F | Night sweats, anemia (hemoglobin 10.9 g/dL) | 2 | No | Pfizer-BioNTech |
| 62 | M | New onset anemia | 21 | No | Pfizer-BioNTech |
| NR | F | New onset anemia | NR | No | Pfizer-BioNTech |
| 86 | M | Acute on chronic anemia | 1 | NR | Pfizer-BioNTech |
| 58 | F | Gastrointestinal bleed | 36 | 6 days | Pfizer-BioNTech |
| 80 | M | New onset anemia in association with intermittent fevers, chills | 1 | No | Pfizer-BioNTech |
| 70 | F | New onset anemia | 28 | No | Moderna |
| 73 | M | Anemia and gastrointestinal bleed | 26 | 1 day | Pfizer-BioNTech |
| 50 | F | New onset anemia and lower extremity venous thrombosis | 7 | 32 days | Moderna |
| 73 | M | Arterial thrombosis | 0 | 3 days | Moderna |
| 68 | M | SARS-CoV-2 with coagulopathy | 3 | 2 days | Pfizer-BioNTech |
| 59 | F | Pre-existing ITP, platelet count decreased from 66/mL to 28/mL | 2 | No | Moderna |
| 51 | F | New onset thrombocytopenia (4000/mL) requiring IV and then oral steroids | 6 | 2 days | Pfizer-BioNTech |
| 66 | F | New onset thrombocytopenia (12,000/mL) treated with oral steroids | 8 | 4 days | Pfizer-BioNTech |
| 67 | M | Acute cervical lymphadenopathy diagnosed as lymphoma | 17 | 3 days | Pfizer-BioNTech |
| 71 | F | Two syncopal episodes and associated lymphopenia (absolute lymphocyte count 0.2 K/uL) | 1 | No | Pfizer-BioNTech |
| 62 | F | Fever, nausea, vomiting, thrombocytopenia (platelet decrease from 102 to 76) | 5 | 5 days | Moderna and influenza quadrivalent |
| 75 | M | Cutaneous vasculitis and thrombocytopenia | 6 | No | Moderna and influenza quadrivalent |
| 65 | F | Thrombocytopenia | 3 | 3 days | Moderna |
| 75 | M | Rash and acute thrombocytopenia | 0 | No | Moderna |
| 35 | M | New onset seizure with elevated troponin, thrombocytopenia, and elevated liver enzymes | 1 | 3 days | Moderna |
| 91 | M | Acute cholecystitis and SARS-CoV-2 positive with thrombocytopenia | 34 | 5 days | Pfizer-BioNTech |
| 43 | F | SARS-CoV-2 pneumonia with thrombocytopenia | 12 | 7 days | Pfizer-BioNTech |
| 66 | F | Thrombocytopenia | 18 | No | Pfizer-BioNTech |
| 79 | M | SARS-CoV-2 pneumonia with thrombocytopenia | 22 | 5 days | Pfizer-BioNTech |
| 38 | M | New onset thrombocytopenia with concern for acute leukemia | 31 | 5 days | Pfizer-BioNTech |
| 51 | M | New onset mesenteric venous thrombosis and mild thrombocytopenia | 6 | Yes | Moderna |
| 73 | M | SARS-CoV-2 pneumonia with thrombocytopenia | 36 | NR | Moderna |
| 70 | M | Splanchnic venous thrombosis | 17 | 3 days | Pfizer-BioNTech |
| 70 | F | Fever, myalgias, epistaxis | 0 | No | Moderna |
| 44 | F | Hematemesis following a choking episode | 5 | No | Pfizer-BioNTech |
| 43 | F | Epistaxis | 1 | No | Pfizer-BioNTech |
| 72 | F | Hematuria associated with Escherichia coli urinary tract infection | 10 | No | Pfizer-BioNTech |
| 55 | F | Lower extremity deep venous thrombosis 3 weeks following SARS-CoV-2 infection | 24 | No | Pfizer-BioNTech |
| 49 | F | Menorrhagia in a postmenopausal female | 1 | No | Pfizer-BioNTech |
| 62 | F | Lower extremity venous thrombosis | 0 | No | Pfizer-BioNTech |
| 59 | M | Lower extremity venous thrombosis | 1 | No | Moderna |
| 61 | F | Lower extremity venous thrombosis | 23 | No | Pfizer-BioNTech and influenza high-dose quadrivalent |
| 66 | M | Thrombosis, myocarditis | 32 | 14 days | Pfizer-BioNTech |
| 74 | M | Hemorrhage and thrombosis at injection site, currently on anticoagulation | 0 | No | Pfizer-BioNTech |
| 62 | M | Lower extremity venous thrombosis | 26 | 3 days | Pfizer-BioNTech and influenza high-dose quadrivalent |
| 80 | F | Pulmonary embolisms in the setting of thrombosis with thrombocytopenia syndrome | 9 | 30 days | Pfizer-BioNTech |
| 79 | M | Lower extremity venous thrombosis | 8 | No | Pfizer-BioNTech |
| 76 | F | Lower extremity venous thrombosis and pulmonary embolism | 1 | 6 days | Moderna |
| 64 | M | Spontaneous spinal epidural hematoma | 3 | 4 days | Moderna and influenza quadrivalent |
| 66 | F | Thrombosed hemorrhoid | 0 | No | Pfizer-BioNTech |
| 62 | F | Thrombosis | 12 | No | Pfizer-BioNTech and influenza high-dose quadrivalent |
| 77 | M | Lower extremity venous thrombosis and pulmonary embolism | 4 | 5 days | Pfizer-BioNTech |
| 24 | M | Thrombosis of upper extremity venous malformation 14 days after SARS-CoV-2 infection | 29 | No | Moderna |
| 46 | F | Lower extremity venous thrombosis | 13 | 4 days | Moderna |
In addition, we identified 2 cases of new onset ITP in 2 females, both following administration of the Pfizer-BioNTech bivalent booster and both requiring treatment with corticosteroids. We also identified 1 case of recurrent ITP in a female following vaccination with the Moderna bivalent booster. One case of VITT was reported in an 80-year-old female with multiple pulmonary emboli and antibodies to platelet factor 4 following receipt of the Pfizer-BioNTech bivalent booster.
Discussion
This study identified 55 cases of hematologic adverse events potentially associated with receipt of either the Pfizer-BioNTech or Moderna bivalent booster vaccines submitted to the VAERS vaccine surveillance database between August 31, 2022, and February 3, 2023, including 3 cases of ITP and 1 case of VITT. As of February 1, 2023, 33,405,201 Pfizer-BioNTech and 18,952,681 Moderna updated bivalent booster vaccine doses had been administered in the USA [10], indicating an event reporting rate of 1.05 hematologic events per 1,000,000 bivalent booster vaccine doses. However, it should be noted that many of the events identified in the VAERS database are unlikely to be related to the vaccine.
In our analysis, we identified three cases of potential vaccine-associated ITP in approximately five months. As the incidence of ITP in adults is estimated to be 3.3 cases per 100,000 persons annually [11], and the bivalent COVID-19 boosters have hitherto been authorized as a one-time dose, provided the assumption that vaccine-associated ITP and vaccination rates remain constant over the next 7 months, this equates to 7 potential vaccine-associated ITP cases among 125,658,917 doses (persons). This results in a calculated vaccine-associated ITP incidence rate of 0.0056 cases per 100,000 persons, significantly lower than the incidence of ITP in the general population.
Various hypotheses as to how both natural infection with, and vaccination against, SARS-CoV-2 may potentiate these hematologic autoimmune phenomena have been posed, including hyperinflammatory responses, immune dysregulation, and antigenic cross-reactivity and molecular mimicry. However, at this time, the precise etiologic mechanism(s) remains poorly understood. Nevertheless, the mounting reports of these life-threatening sequelae are alarming, and further investigation of the underlying pathophysiology as well as adverse event monitoring and correlation with phenotypic associations are needed.
Notably, we did not identify any reports of AIHA, thrombotic thrombocytopenic purpura, or acquired coagulation factor inhibitors in the VAERS database, all of which have been reported in association with the original formulations of the Pfizer-BioNTech and Moderna vaccines [6, 7, 12, 13]. However, we acknowledge that one limitation of VAERS is that it is a passive reporting system, which may contribute to underreporting, therefore biasing the calculated rate and prevalence of reported conditions. This is illustrated by the finding that many of the cases we identified in the VAERS database lacked sufficient detail to substantiate a definitive diagnosis or association with the vaccine. Nevertheless, the national scope of this database and the ability for anyone to submit a potential adverse effect make it advantageous as an early warning system, particularly for severe or unusual conditions, including many of the hematologic events queried in our search.
Likewise, it should be noted that seven individuals received the quadrivalent influenza vaccine and SARS-CoV-2 vaccine concomitantly. Although ITP has been described with influenza vaccination, previous work has demonstrated no increased risk of thromboembolic events, and there are few reports of autoimmune hemolytic anemia following influenza immunization [14–16]. Though the influenza vaccine appears less likely to have precipitated these reports, definitive association cannot be assigned to either vaccine.
In summary, this analysis serves to the best of our knowledge, as the first assessment of the safety of the new bivalent SARS-CoV-2 booster vaccines with regard to hematologic complications. We identified few adverse events, most of which could not be definitively attributed to vaccination. However, three reports of possible ITP and one report of possible VITT highlight the need for continued monitoring of the safety of these vaccines as their use expands, as these vaccines had been authorized for use for only five months at the time of this study. This method of safety monitoring will become even more important as new vaccine formulations are brought to market, especially if these altered formulations continue to bypass the human clinical trial stage.
Supplementary Information
Below is the link to the electronic supplementary material.
Author contribution
JWJ and BDA performed the research, analyzed the data, and drafted the manuscript. BDA and GSB provided supervision and revised the manuscript. All authors approved the final version.
Declarations
Conflict of interest
The authors declare no competing interests.
Footnotes
Publisher's note
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References
- 1.Thilagar B, Beidoun M, Rhoades R. Kaatz S (2021) COVID-19 and thrombosis: searching for evidence [published correction appears in Hematology Am Soc Hematol Educ Program. 2022 Dec 9;2022(1):725] Hematol Am Soc Hematol Educ Program. 2021;1:621–627. doi: 10.1182/hematology.2021000298. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Bhattacharjee S, Banerjee M. Immune thrombocytopenia secondary to COVID-19: a systematic review. SN Compr Clin Med. 2020;2(11):2048–2058. doi: 10.1007/s42399-020-00521-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Jacobs JW, Booth GS. COVID-19 and immune-mediated RBC destruction. Am J Clin Pathol. 2022;157(6):844–851. doi: 10.1093/ajcp/aqab210. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Cines DB, Bussel JB. SARS-CoV-2 Vaccine-induced immune thrombotic thrombocytopenia [published correction appears in N Engl J Med. 2021 Jun 10;384(23):e92] N Engl J Med. 2021;384(23):2254–2256. doi: 10.1056/NEJMe2106315. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Lee EJ, Cines DB, Gernsheimer T, Kessler C, Michel M, Tarantino MD, Semple JW, Arnold DM, Godeau B, Lambert MP, Bussel JB. Thrombocytopenia following Pfizer and Moderna SARS-CoV-2 vaccination. Am J Hematol. 2021;96(5):534–537. doi: 10.1002/ajh.26132. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Jacobs JW. Autoimmune hemolytic anemia and COVID-19 vaccination. Hematol Transfus Cell Ther. 2022 doi: 10.1016/j.htct.2022.08.007.10.1016/j.htct.2022.08.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Jafarzadeh A, Jafarzadeh S, Pardehshenas M, Nemati M, Mortazavi SMJ. Development and exacerbation of autoimmune hemolytic anemia following COVID-19 vaccination: A systematic review. Int J Lab Hematol. 2022 doi: 10.1111/ijlh.13978.10.1111/ijlh.13978. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.US Food and Drug Administration. Coronavirus (COVID-19) update: FDA authorizes Moderna, Pfizer-BioNTech bivalent COVID-19 vaccines for use as a booster dose. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-moderna-pfizer-biontech-bivalent-covid-19-vaccines-use. Accessed December 5, 2022
- 9.Hause AM, Marquez P, Zhang B, et al. Safety monitoring of bivalent COVID-19 mRNA vaccine booster doses among persons aged ≥12 years - United States, August 31-October 23, 2022. MMWR Morb Mortal Wkly Rep. 2022;71(44):1401–1406. doi: 10.15585/mmwr.mm7144a3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.US Centers for Disease Control and Prevention. COVID-19 vaccinations in the United States. https://covid.cdc.gov/covid-data-tracker/#vaccinations_vacc-total-admin-rate-total. Accessed February 5, 2023
- 11.Lambert MP, Gernsheimer TB. Clinical updates in adult immune thrombocytopenia. Blood. 2017;129(21):2829–2835. doi: 10.1182/blood-2017-03-754119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Saluja P, Gautam N, Yadala S, Venkata AN. Thrombotic thrombocytopenic purpura (TTP) after COVID-19 vaccination: a systematic review of reported cases. Thromb Res. 2022;214:115–121. doi: 10.1016/j.thromres.2022.04.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Jacobs JW, Adkins BD, Walker SC, Booth GS, Wheeler AP. Coagulation factor inhibitors in COVID-19: from SARS-CoV-2 vaccination to infection. Res Pract Thromb Haemost. 2022;6(3):e12700. doi: 10.1002/rth2.12700. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Lafaurie M, Lapeyre-Mestre M, Sailler L, Sommet A, Moulis G. Risk of immune thrombocytopenia after influenza vaccine. JAMA Intern Med. 2022;182(4):444–445. doi: 10.1001/jamainternmed.2021.8523. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Montagnani S, Tuccori M, Lombardo G, et al. Autoimmune hemolytic anemia following MF59-adjuvanted influenza vaccine administration: a report of two cases. Ann Pharmacother. 2011;45(1):e8. doi: 10.1345/aph.1P480. [DOI] [PubMed] [Google Scholar]
- 16.Sen A, Bakken IJ, Govatsmark RES, Varmdal T, Bønaa KH, Mukamal KJ, Håberg SE, Janszky I. Influenza vaccination and risk for cardiovascular events: a nationwide self-controlled case series study. BMC Cardiovasc Disord. 2021;21(1):31. doi: 10.1186/s12872-020-01836-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
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