A positive direct antiglobulin test is associated with enhanced anemia and the HLA-DR12 allele in patients from Japan, according to a new study published in Annals of Hematology.

A positive direct antiglobulin test is also known to be related to SARS-CoV-2 infection, so a SARS-CoV-2 infection may cause the body to produce antiglobulins that attack the red blood cells and lead to the development of autoimmune hemolytic anemia including cold agglutinin disease (CAD), which commonly occurs in the early stages of the infection and seems to correlate with the cytokine storm.

To elucidate the significance of a positive direct antiglobulin test for anemia and inflammation in patients with COVID-19, a team of researchers from Japan analyzed 40 patients with COVID-19 between December 2020 and September 2021.

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They found that patients who were aged 70 years and older were more likely to have a positive direct antiglobulin test result and that this was related to a decrease in the levels of hemoglobin. Patients with COVID-19 with a positive direct antiglobulin test exclusively had the HLA-DRB1*12:01 and DRB1*12:02 alleles.

The researchers speculated that patients with COVID-19 might have a positive direct antiglobulin test because the hyperinflammatory state induced by the cytokine storm that occurs following a SARS-CoV-2 infection may enhance the binding of immunoglobulin g (IgG) and/or may modify the membrane of red blood cells. Alternatively, there may be molecular mimicry between SARS-CoV-2 and red blood cell proteins, they said.

The researchers then identified a peptide sequence within SARS-CoV-2 Spike protein, which could strongly bind to HLA-DR12 and be a B cell epitope. This led them to conclude that the particular peptide portion of the spike protein may act as an epitope for IgG binding to red blood cells in patients with COVID-19 who are positive for the direct antiglobulin test.


Matsuura H, Fujii S, Matsui Y, Sugiura Y, Akiyama H, Miura Y. An association between a positive direct antiglobulin test and HLA-DR12 in COVID-19. Ann Hematol. Published online July 14, 2022. doi:10.1007/s00277-022-04921-9