Cold Agglutinin Disease (CAD)

Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA) in which the body’s immune system attacks the red blood cells at low temperatures (32ºF-50ºF). The premature destruction of red blood cells (hemolysis) causes symptoms and signs of anemia.1

CAD can develop without a specific cause (primary disease) or can be associated with other medical conditions, such as bacterial, parasitic, or viral infections, certain types of cancer, and other autoimmune diseases. CAD can be also multifactorial, in which case the interaction of various environmental factors and genes contributes to the development of the disease.1 Even though it is not an inherited disease, recurrent mutations in specific genes have been identified in patients with CAD.2

Patients with a diagnosis of CAD should be followed by a multidisciplinary team of healthcare professionals for optimal care, including primary care physicians, hematologists, immunologists, and oncologists. 

Cold Agglutinin Disease Specialists


Hematologists specialize in the treatment of blood disorders and are familiar with CAD. They can guide the diagnostic process and treat affected patients to maintain their red blood cells at optimal levels. Other blood disorders may be identified during the diagnostic process that also require treatment. Patients with CAD can facilitate their care by discussing currently available treatments with their physicians and, if possible, enrolling in a clinical trial.3


CAD may be secondary to an underlying disease, such as cancer. certain types of cancer (eg, lymphoma, chronic lymphocytic leukemia, multiple myeloma, Waldenström macroglobulinemia, Kaposi sarcoma) may be associated with CAD.1 Patients who have CAD may benefit by consulting an oncologist to rule out any of these conditions and receive adequate treatment if necessary.


In CAD, the body’s immune system reacts against its own red blood cells. Because CAD is an autoimmune disease, patients may benefit from consulting an immunology specialist. Secondary CAD can be associated with other autoimmune disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis.1,4 Immunologists can help patients with CAD through the diagnostic process and the course of treatment with antibodies. Those who have severe symptoms of hemolytic anemia may require medical intervention, and treatment with rituximab may be recommended. Rituximab is an antibody that promotes the reduction of specific immune cells in the body. A response to treatment with rituximab generally occurs within 1 to 2 months1 


Supplementation with folic acid may be recommended for patients with CAD.5 Nutritionists can help patients plan a balanced diet that includes fresh fruits and vegetables as important sources of folic acid. 


Patients with CAD are at increased risk for venous thromboembolism (VTE).6 Other cardiac symptoms of the disease include chest pain and an irregular, fast heartbeat (arrhythmia).1,3 A cardiologist can identify the cause of any cardiac symptoms and establish a treatment plan. 

Preparing for a Specialist Appointment

Preparing beforehand for a visit with a specialist can help patients derive the greatest benefit from the consultation. Preparing a list of questions or concerns that should be discussed can guide the patient through the conversation. Taking all available medical records to the consult and even bringing a family member to join in the discussion may also contribute to a fruitful conversation and a successful appointment.

Patients living with a chronic disease must often adjust their lifestyle or working conditions, which may exacerbate symptoms of anxiety and depression.7 The need to avoid cold environments and regularly monitor one’s temperature can provoke anxiety.3 Several organizations are available to support patients with CAD by providing information about the disease and available treatments; they also facilitate connecting with other patients, Talking to and connecting with people who are living with the same disease and experiencing similar feelings of anxiety, and who understand the personal or professional adjustments that may be required, can reduce stress and help patients and their families cope with their feelings of frustration.


1. Cold agglutinin disease. Genetic and Rare Diseases Information Center (GARD). Accessed September 17, 2021.

2. Małecka A, Trøen G, Tierens A, et al. Frequent somatic mutations of KMT2D (MLL2) and CARD11 genes in primary cold agglutinin disease. Br J Haematol. 2018;183(5):838-842. doi:10.1111/bjh.15063

3. Info for medical professionals. Cold Agglutinin Disease Foundation. Accessed September 17, 2021.

4. Berentsen S, Ulvestad E, Langholm R, et al. Primary chronic cold agglutinin disease: a population-based clinical study of 86 patients. Haematologica. 2006;91(4):460-466.

5. Berentsen S. How I manage patients with cold agglutinin disease. Br J Haematol. 2018;181(3):320-330. doi:10.1111/bjh.15109

6. Broome CM, Cunningham JM, Mullins M, et al. Increased risk of thrombotic events in cold agglutinin disease: a 10‐year retrospective analysis. Res Pract Thromb Haemost. 2020;4(4):628-635. doi:10.1002/rth2.12333

7. Turner J, Kelly B. Emotional dimensions of chronic disease. West J Med. 2000;172(2):124-128. doi:10.1136/ewjm.172.2.124

Reviewed by Debjyoti Talukdar, MD, on 9/20/2021.