An increased incidence of autoimmune hemolytic anemia (AIHA)—of which cold agglutinin disease (CAD) is a subtype—has been reported following COVID-19 mRNA-based immunization, according to a systematic review published in the International Journal of Laboratory Hematology.

The researchers sought to evaluate the relationship between AIHA and COVID-19 vaccination using the PRISMA guidelines. New onset AIHA and the exacerbation of ongoing AIHA have been observed following vaccination for SARS-CoV-2 infection.

The current review of published articles and abstracts on the subject identified 53 papers for screening. Ultimately, 15 reports were selected, of which 11 discussed new onset AIHA after COVID-19 vaccination and 4 reported on AIHA exacerbation after vaccination. All of the papers included in the analysis were case reports, not randomized clinical trials, thus no disagreement existed between the 2 reviewers with respect to study bias point of view.

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AIHA is caused by immunoglobulin G (IgG) and/or IgM autoantibodies that react with red blood cell (RBC)-related surface antigens. Warm antibodies (mainly of the IgG type) are responsible for between 65% and 75% of all cases of AIHA. In contrast, cold antibodies are usually from the IgM class and account for 20% to 25% of all AIHAs that bind at cold temperatures and rapidly activate complement, thus causing intravascular RBC lysis.

Learn more about HCP resources for cold agglutinin disease

Among 18 cases included in the present review, as of July 3, 2022, 11 patients—7 women and 4 men—who received a COVID-19 vaccine developed new onset AIHA. The median patient age was 67 years. In 7 of the 11 cases and 3 of the 11 cases, symptom onset occurred following the first and second vaccine dose, with median times of onset of 7 days and 14 days, respectively. In 1 of the 11 cases, AIHA occurred on day 17 after booster vaccination. Of the 11 participants evaluated who developed AIHA, 10 received mRNA-based vaccines and 1  received a vector-based vaccine.

Following vaccination, 9 of the 11 patients with AIHA developed warm IgG, 1 of the 11 participants developed cold IgM, and 1 of the 11 individuals developed mixed autoantibodies against RBCs, respectively.

Significant exacerbation of AIHA was observed in 7 participants (4 women and 3 men), with a median age of 73 years. In 4 of the 7 and 2 of the 7 cases of exacerbated AIHA, symptom onset was observed following the first and second vaccine doses, with a median time of 7 days and 3 days, respectively. In 1 of the 7 cases of exacerbated AIHA, symptom onset was observed on day 2 following COVID-19 booster vaccination.

All of the 7 cases of exacerbated AIHA received mRNA-based COVID-19 vaccines, Among these 7 patients who developed exacerbated AIHA, 3 developed IgG and 4 developed IgM against RBCs, respectively.

Most cases of post-COVID-19 vaccination AIHA have been reported in European countries and the United States—places where most of the vaccines used are mRNA based.

The investigators concluded that “post-vaccination AIHA is manageable and the advantages of immunization can exceed these risks.”


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. Published online October 8, 2022. doi:10.1111/ijlh.13978