Researchers recommended that a frontline clone-directed approach, such as rituximab-based therapy, should be used to treat cold agglutinin disease (CAD), even if complete eradication is rarely achieved, as published in Haematologica.

CAD is characterized by monoclonal IgMκ in over 90% of cases. These antibodies are produced in the bone marrow and bind to erythrocyte antigens optimally at low temperatures, causing agglutination and activating the classic complement pathway.

“Less frequently there is initiation of the terminal pathway, assembly of the membrane attack complex (C5b-C9) and intravascular hemolysis, which can lead to acute life-threatening anemia,” the authors of the study wrote.

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Patients with CAD often present with symptoms of anemia and/or symptoms associated with cold-induced circulation. Around 50% of patients have acrocyanosis or Raynaud’s phenomenon, and 38% of patients require blood transfusions for anemia upon diagnosis; 47% require blood transfusions during follow-up. In addition, there is an increased risk of thrombosis in patients with CAD.

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In approximately 80% of cases, clonality is demonstrated. An adequate diagnostic workup includes laboratory tests investigating hemolysis, as well as the direct antiglobulin test, which usually reveals a strong positivity for C3d. A cold agglutinin titer of >1:64 at 4 ̊C is commonly observed.

Treatment should focus on alleviating anemia and cold-induced symptoms, the authors said. Red blood cell transfusions should take place via a blood warmer, and symptomatic patients should be prescribed folic acid as thromboprophylaxis. Rituximab is one of the most established therapies for CAD, with studies revealing that it improves clinical outcomes. Splenectomy and steroids are ineffective in treating CAD.

If acute intravascular hemolysis occurs, plasma exchange may be prescribed once all priming fluids and replacement products have been warmed. Erythropoietin support should be offered if erythropoietin falls to abnormally low levels. 

“Clinical trials should be considered in relapsed disease,” the authors said. “Promising studies have examined proximal complement inhibition to inhibit extravascular haemolysis.”


Khwaja J, D’Sa S, Minnema MC, Kersten MJ, Wechalekar A, Vos JM. IgM monoclonal gammopathies of clinical significance: diagnosis and managementHaematologica. Published online June 30, 2022. doi:10.3324/haematol.2022.280953