A case has been published of a cold agglutinin disease (CAD) diagnosis after a third COVID-19 mRNA vaccination, with the authors noting in the International Journal of Hematology that the patient exhibited sustained high titer levels of cold agglutinin for 4 months after follow-up.

“Approximately half of autoimmune hemolytic anemia [AIHA] cases are idiopathic, while secondary cases are often associated with underlying autoimmune or lymphoproliferative diseases,” the authors wrote. “The present case indicates that it is possible for secondary CAD after mRNA vaccination to become chronic, and provides insights to the pathogenesis and treatment strategies.”

The patient is an otherwise healthy 51-year-old woman who presented with severe pain generally and in the finger joints specifically, fatigue, and dark urine. She received a third COVID-19 mRNA vaccination 7 days prior. She had a history of gallstones and migraine.

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Blood tests revealed normocytic, normochromic anemia and abnormal blood coagulation, but normal iron and ferritin levels. She was initially diagnosed with a prolonged reaction to the vaccination and was given analgesics, but the symptoms did not resolve.

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Four months later, she presented at a hematology clinic to check on the anemia. Her hemoglobin was improved but her cold agglutin titer was 1:16,384. Significant agglutination led to the CAD diagnosis, but all tests were negative for any of the common underlying causes of CAD such as cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus, parvovirus, mycoplasma, and hepatitis B and C; flow cytometric immunophenotyping was also negative.

The patient’s red blood cell agglutination persisted and treatment was considered. However, given that rituximab, an available treatment for CAD, carries the risk of leaving patients open to COVID-19 infection, she is currently undergoing careful follow-up without specific treatment.


Suzuki Y, Shiba T. Chronic cold agglutinin disease after a third COVID-19 mRNA vaccination. Int J Hematol. Published online October 29, 2022. doi:10.1007/s12185-022-03480-z