Clinicians presented the case of a 71-year-old woman who was diagnosed with refractory hemolytic anemia in The New England Journal of Medicine. 

The patient had a 7-month history of fatigue and dyspnea, which worsened on exertion. She was on breast cancer follow-up and had diffuse cutaneous systemic sclerosis. 

Blood investigations revealed anemia, and a peripheral blood smear showed schistocytes. There was no evidence of COVID-19 infection or paroxysmal nocturnal hemoglobinuria. A direct antiglobulin test was negative; complement levels were low and a low titer of cold agglutinins was present. She was then treated on a working diagnosis of Coombs-negative autoimmune hemolytic anemia (cold agglutinin disease). 

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The patient was given a packed red cell infusion and glucocorticoids. On day 3 of admission, her blood pressure rose from 118/62 to 150/60 mm Hg; this prompted her physicians to stop glucocorticoids and initiate captopril on a working diagnosis of scleroderma renal crisis. On day 6, plasmapheresis treatment was initiated for possible thrombotic thrombocytopenic purpura. 

Read more about cold agglutinin disease etiology 

During week 2, the patient was started on eculizumab. Packed red cell transfusions were continued every few days due to ongoing anemia. The ADAMTS13 investigation initiated the week before returned with an activity level of 65%; plasmapheresis treatment was then stopped. During week 3, rituximab was added on, and blood transfusions were continued at the same frequency. In addition, her physicians initiated a 3-day course of intravenous immunoglobulin. 

The patient developed thrombocytopenia during week 5. This prompted her physicians to resume glucocorticoid treatment and twice-weekly injections of epoetin alfa. A bone marrow biopsy revealed hypercellular marrow with maturing trilineage hematopoiesis and erythroid predominance. 

At week 6 of admission, cyclophosphamide was added on, and the captopril dose was raised. At week 7, she developed acute kidney injury; captopril and glucocorticoids were stopped. On day 50, she was transferred to a different hospital for further treatment. 

Read more about cold agglutinin disease diagnosis

Upon further evaluation, Dr. Alfred I. Lee was of the opinion that the patient had microangiopathic hemolytic anemia, which is a form of anemia characterized by red-cell fragmentation due to direct trauma. Multiple blood-smear fields at high magnification revealing 2 or more schistocytes were highly suggestive of this diagnosis. 

After being started on chemotherapy, the patient experienced myelosuppression, fatigue, and drowsiness. Upon discussions with her medical team, she opted for home hospice services and died 1 month later. 

“Despite major strides in the field of cancer therapeutics, the outcome of this case was similar to that of a case reported nearly 40 years ago in the paper, ‘Case Records of the Massachusetts General Hospital’,” the authors of the study wrote. “The management of cancer-associated [thrombotic microangiopathy] remains a major problem.”


Lee AI, Heidari P, Fenves AZ, Bardia A, Ta R. Case 8-2023: a 71-year-old woman with refractory hemolytic anemia. N Engl J Med. 2023;388(11):1032-1041. doi:10.1056/NEJMcpc2211370