A patient was diagnosed with cold agglutinin syndrome (CAS) after the discovery of cold-antibody autoimmune hemolytic anemia (cAIHA) and splenic marginal zone lymphoma (MZL), as published in Hematology, Transfusion and Cell Therapy. CAS was recently described as a separate but similar entity to cold agglutinin disease (CAD).

“In [CAD], patients may have a B-cell clonal [lymphoproliferative disorder] detectable in blood or marrow, but no clinical or radiological evidence of malignancy. On the other hand, [CAS] is associated with the presence of a clinical disease, such as infection, autoimmune disease or lymphoma,” the authors said.

In the case report, a 61-year-old male patient was referred for consultation after an incidental finding of splenomegaly on preoperative evaluation for hernia repair surgery.

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Blood analysis revealed a diagnosis of cAIHA, and an analysis of samples from bone marrow biopsy and aspiration found hypercellular marrow with lymphocyte infiltration, and immunohistochemistry indicated a diagnosis of MZL. Based on the combination of cAIHA and MZL, a diagnosis of CAS secondary to splenic MZL was given.

Read more about CAD clinical features

“cAIHA is an uncommon disease that, when diagnosed, should always trigger the investigation for hematological malignancies,” the authors said. With the diagnosis of CAS, it was decided to treat the underlying MZL, so the patient received 6 cycles of rituximab plus cyclophosphamide, vincristine, and prednisone.

After treatment, there was a partial reduction in spleen volume and normalization of its metabolic activity along with the resolution of anemia. Upon initial investigation after referral, a complete blood count showed that hematimetric levels were weakened by erythrocyte agglutination. He also had aggregated platelets that were morphologically normal from the investigation.

Investigation into the splenomegaly found that liver and renal tests were found to be normal and hepatitis and HIV tests were negative. Direct antiglobulin tests for C3d and immunoglobulin M 3+ were strongly positive, and cold agglutinin screening reinforced a diagnosis of cAIHA.

After a diagnosis of cAIHA and further questioning, the patient also recalled observing Reynaud’s phenomenon in his hands and feet previously, especially in colder temperatures.

“Besides its rarity and anecdotal clinical and laboratory findings, this case emphasizes the importance of the mutual exchange between the clinical and the immunohematology laboratory teams, providing a correct, fast and efficient diagnosis to support the patient’s need,” the authors concluded.


Portich JP, Blos B, Sekine L, Franz JPM. Cold agglutinin syndrome secondary to splenic marginal zone lymphoma: a case report. Hematol Transfus Cell Ther. Published online November 12, 2021. doi:10.1016/j.htct.2021.07.009

Berentsen S. New insights in the pathogenesis and therapy of cold agglutinin-mediated autoimmune hemolytic anemia. Front Immunol. 2020;11. doi:10.3389/fimmu.2020.00590