A team from the Sapporo Medical University School of Medicine, Japan, reported the case of a woman aged 74 years with systemic lupus erythematosus who developed cold agglutinin disease (CAD). The case report, recently published in Clinical Rheumatology, stresses the importance of differentiating CAD from spurious macrocytic anemia, a possible misdiagnosis as erythrocyte agglutination may lead to errors in cell counting.

The patient presented to the hospital with increased fatigue upon exertion in early winter. She had been experiencing Raynaud phenomenon for 4 years and was taking prednisolone for recurrent pleurisy.

Physical examination revealed acrocyanosis in the patient’s fingers. Moreover, she had disproportionately low red blood cell count, decreased hemoglobin, hematocrit, and haptoglobin, and increased mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration.

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She showed no evidence of vitamin B12 and folic acid deficiencies or hypothyroidism. Furthermore, the analyses of antiphospholipid antibodies and paraprotein returned negative.

Read about CAD differential diagnosis

“In the absence of folate and vitamin B12 deficiency, liver disease, hypothyroidism, or [vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic] syndrome, which causes macrocytic anemia in older men, clinicians should consider CAD as a differential diagnosis,” the team explained.

The patient’s peripheral blood smear at room temperature showed significant red blood cell agglutination and her direct antiglobulin test was positive. She had a cold agglutinin titer of 1:2048. These findings confirmed the diagnosis of CAD.

The patient received a blood transfusion to manage her condition. In addition, treatment included rapid warming and recommendations to protect from cold to prevent recurrent hemolytic attacks.

CAD is occasionally associated with systemic lupus erythematosus. Symptoms of CAD include acrocyanosis or Raynaud sign, livedo reticularis, fatigue, dizziness, headaches, cold hands and feet, pale skin color, and heart palpitations, among many others.


Nagahata K, Suzuki C, Takahashi H. Spurious macrocytic anaemia in a patient with systemic lupus erythematosus: cold agglutinin disease. Clin Rheumatol. Published online February 9, 2023. doi:10.1007/s10067-023-06536-5