Cold Agglutinin Disease (CAD)

Cold agglutinin disease (CAD) is a rare autoimmune disease in which exposure to cold temperatures (usually 3-4 °C or 37-39 °F) causes the body’s immune system to attack its own red blood cells (RBCs), leading to their premature lysis. In affected individuals, B-cells produce autoantibodies, also known as cold agglutinins (CAs), which are usually of the immunoglobulin (Ig) M class that specifically target the carbohydrate antigens I/i on the surface of RBCs at cold temperatures. This self-attack of CAs causes RBC clumping or agglutination, resulting in complement activation via the classical pathway. This leads to hemolysis, causing anemia and other associated signs and symptoms.1


CAD occurs mainly in elderly and middle-aged people, but it has also been found in patients as young as 30 years of age.2

CAD is a rare disease; the prevalence in Norway has been estimated to be 16 cases per 1 million inhabitants, and the incidence rate has been estimated to be 1 case per 1 million people per year.2,3

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CAD has 2 types – primary and secondary. While the cause of primary CAD is not known, affected individuals often produce a monoclonal CA, indicating a clonal proliferation of cells from a lymphoproliferative disorder.

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Secondary CAD is caused by an underlying condition such as bacterial infection (Mycoplasma, E. coli, listeriosis), viral infection (Epstein-Barr virus, cytomegalovirus, influenza), parasitic infection (malaria, trypanosomiasis), autoimmune disease (systemic lupus erythematosus), and certain types of cancer (lymphoma, multiple myeloma).4

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Symptoms of CAD include fatigue, dizziness, headaches, cold hands and feet, pale skin color, heart palpitations, shortness of breath, dark urine, jaundice, chest pain, back pain, leg pain, muscle weakness, vomiting, diarrhea, and heart problems such as arrhythmia, heart murmur, cardiomegaly, and heart failure.

Other symptoms include a painful bluish coloration of hands and feet (acrocyanosis or Raynaud sign), mottled discoloration of the skin (livedo reticularis), splenomegaly, respiratory problems (in CAD secondary to Mycoplasma pneumoniae), and swollen lymph nodes, among others.4


A diagnosis is suspected based on the patient’s history, clinical evaluation, presence of characteristic signs and symptoms, and various tests including blood tests.

A blood smear can identify abnormal clumping of the RBCs. Blood tests that measure hemoglobin levels, complete blood count (CBC), and absolute reticulocyte count help determine hemolytic anemia.

Biochemical tests that determine the levels of lactate dehydrogenase (LDH), bilirubin, and haptoglobin can also help diagnose hemolysis, which leads to elevated LDH and bilirubin levels and reduced haptoglobin levels.1

Physical examination for spleen or liver enlargement can also be performed.

A CA titer should be measured in all suspected individuals; a titer of 64 or higher at 4 °C is suggestive of CAD.

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Individuals suspected to have CAD should undergo a direct antiglobulin test (DAT), also called a direct Coombs test, which can detect autoantibodies (IgM) or complement components (particularly C3d) bound to the surface of RBCs.5

The Coombs test is followed by a thermal amplitude test, which measures the reactivity of CAs at different temperatures.1

Confirmed diagnosis is made with the detection of monoclonal IgM𝛋 in serum and a bone marrow biopsy showing CAD-associated lymphoproliferative disorder in histological specimens.5

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The treatment of CAD depends on the symptoms, disease severity, and underlying cause. Individuals with mild symptoms do not require specific treatment, and management often involves avoidance of cold temperatures and thermal protection. Management of severe cases includes avoiding cold, keeping warm, treating anemia and hemolysis, and taking medications that reduce the production of autoantibodies. Management of secondary CAD involves treating the underlying cause, such as an infection (bacterial, viral, or parasitic) or a certain cancer.

Plasmapheresis, which involves filtering the blood to remove antibodies, is a temporary treatment for critical cases in which waiting for the effect of a specific therapy is not appropriate. However, its effects are short-lived, and drug therapy should be initiated simultaneously.4

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In severe cases, rituximab, an antibody that selectively binds to B-cells and leads to cell death, is used as a first-line therapy. Although rituximab is not approved, it has been shown to have an acceptable response within 1 to 2 months, and the effect of treatment lasts for 1 to 2 years. The combination of rituximab and bendamustine has shown a higher response rate (71%) with a longer response duration, and it should be considered as a first-line treatment.

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Novel treatment options targeting the classical complement pathway, such as the C1s inhibitor sutimlimab (BIVV009, TNT009), are under development and are being investigated in clinical trials.5,6


The prognosis of individuals with CAD is variable based on the disease severity and underlying cause. Those with CAD secondary to bacterial or viral infections usually have an excellent prognosis since CAD symptoms disappear when the infection resolves. Those with mild to moderate primary CAD also have a good prognosis if exposure to cold is avoided. However, patients with CAD caused by HIV (human immunodeficiency virus) infection or certain types of cancer generally have a poor prognosis due to their underlying condition.4

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  1. Cold agglutinin disease. National Organization for Rare Disorders. Accessed September 3, 2021.
  2. 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.
  3. Berentsen S, Röth A, Randen U, Jilma B, Tjønnfjord GE. Cold agglutinin disease: current challenges and future prospects. J Blood Med. 2019;10:93-103. doi:10.2147/JBM.S177621
  4. Cold agglutinin disease. Genetic and Rare Diseases Information Center. Accessed September 3, 2021.
  5. Berentsen S. New insights in the pathogenesis and therapy of cold agglutinin-mediated autoimmune hemolytic anemia. Front Immunol. 2020;11:590. doi:10.3389/fimmu.2020.00590
  6. Röth A, Barcellini W, D’Sa S, et al. Inhibition of complement C1s with sutimlimab in patients with cold agglutinin disease (CAD): results from the phase 3 cardinal study. Blood. 2019;134(Supplement_2):LBA-2. doi:10.1182/BLOOD-2019-132490

Reviewed by Debjyoti Talukdar, MD, on 9/7/2021.