Two patients with COVID-19 were found to have high cold agglutinin (CA) titers without presenting with hemolytic anemia or thrombosis commonly associated with cold agglutinin disease (CAD), according to a recently published article in the Journal of Clinical Laboratory Analysis.

“Several studies of (cold agglutinin syndrome) associated with coronavirus disease 2019 (COVID-19) reported hemolytic anemia and thrombosis; however, the clinical significance of cold agglutinins (CA) in patients with COVID-19 is unclear,” the authors wrote.

The first case involved a 64-year-old male with a 5-day history of fever admitted to a hospital due to hypoxia and bilateral pulmonary infiltrates in chest X-Ray. After reverse transcription polymerase chain reaction (rRT-PCR) of a nasopharyngeal swab, he was diagnosed with COVID-19. Due to worsening hypoxia, the patient was intubated on the 6th day of admission.

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Due to an incidental finding of mean corpuscular hemoglobin concentration (MCHC) and macrocytic anemia, the attending physicians performed a peripheral blood smear that revealed red blood cell (RBC) agglutination with no evidence of hemolytic anemia, which led them to perform a CA titer. Results revealed a CA titer of 1:512 (reference range 0–1:63). A bone marrow biopsy was unremarkable. 

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Following 38 days in the hospital, he was discharged after clinical improvement, and hemoglobin levels improved after zinc supplementation. CA titer at the moment of discharge descended to 1:64.

The second case involved a 72-year-old woman admitted for hypoxia due to COVID-19 pneumonia, which, despite showing clinical improvement after corticosteroid treatment, presented with a urinary tract infection. An incidental finding of RBC agglutination with a normal hemoglobin level led to the performance of CA titers, which turned out to be elevated (1:2048). The patient was discharged after clinical improvement; CA titers performed in an outpatient visit were 1:512.

The authors hypothesize that although elevated CA titers have been reported in the context of viral and bacterial infection, clinical manifestation could be absent due to no exposure to cold. The literature suggests that infection-associated CAD tends to be polyclonal and therefore less pathogenic. 

“Further studies are required to clarify the pathophysiology of CA in COVID-19,” the authors concluded. 


Imoto H, Yoshioka S, Nakagawa D, et al. Cold agglutinin anti-I antibodies in two patients with COVID-19. J Clin Lab. Published online August 02,  2022. doi:10.1002/jcla.24629