Cold agglutinin disease (CAD) is a rare acquired autoimmune disorder in which exposure to cold temperatures between 32o to 50o (Fahrenheit) causes autoantibodies, also called cold agglutinins, to bind tightly to red blood cells (RBCs) and inducing their lysis (disintegration), resulting in anemia.

Signs and symptoms of CAD

The characteristic clinical signs and symptoms of CAD include:

  • Acrocyanosis: dark purple to grayish discoloration in the fingertips, nose, toes, and ears;
  • Livido reticularis: patchy, reticulated (spider web-like) vascular pattern on the skin with a red-blue or violet coloration;
  • Raynaud’s phenomenon: cold intolerance such as pain and a bluish coloration in the fingertips and toes;
  • Pain or discomfort in swallowing cold foods and liquids;
  • Skin ulceration or necrosis (in severe cases);
  • Typical symptoms of hemolytic anemia, which include weakness, weight loss, pale skin, cold hands and feet, tiredness or fatigue, dizziness, headaches, pain in the back or legs, vomiting or diarrhea, chest pain, and jaundice;
  • In some cases, heart problems, such as irregular heartbeat (arrhythmia), heart murmurs, enlarged heart or heart failure, that occur because the heart works overtime to compensate for the deficiency in RBCs;
  • In some cases, enlarged liver and spleen (hepatosplenomegaly).

Causes of CAD

CAD is caused by autoantibodies called cold agglutinins, which cling to RBCs at low temperatures. This causes the RBCs to clump together and prompts the immune system to destroy them, leading to severe depletion of RBCs in the blood and resulting in anemia.

CAD, which commonly affects adults who are of middle age and older, may manifest as a primary disease, in which the underlying mechanism is not known, or as a secondary disease caused by other underlying medical issues such as:

  • Bacterial infections;
  • Viral infections;
  • Parasitic infections;
  • Other autoimmune diseases such as systemic lupus erythematosus;
  • Certain types of cancer.

Diagnosis of CAD

CAD is suspected when individuals show signs and symptoms typical of the disease only during cold temperatures. It also is suspected when there are  unexplained reasons for hemolytic anemia or the observation of RBC clumping in a cooled blood collection tube or a blood smear.

There are several diagnostic tests to confirm CAD. These include:

  • Blood tests such as a complete blood count (CBC) to detect anemia, the estimation of hemoglobin levels to analyze the extent of anemia, tests to identify and quantify reticulocytes, which are immature red blood cells that are normally not present in the blood, but are found in conditions of hemolytic anemia while the body tries to compensate for low RBC counts;
  • A blood smear that can reveal the abnormal clumping (agglutination) of the RBCs;
  • Biochemical tests on blood samples to identify the levels of the lactate dehydrogenase (LDH) enzyme, haptoglobin protein, and the liver metabolite, bilirubin, which is produced by the breakdown of hemoglobin. In general, hemolysis is accompanied by a significant increase in LDH and bilirubin levels and a decrease in haptoglobin levels;
  • A physical examination that can detect hepatosplenomegaly;
  • A direct Coombs test or antiglobulin test that can detect the presence of autoantibodies (immunoglobulin M (IgM) or cold agglutinins) or the complement proteins that are attached to the surface of the RBCs.

CAD Treatments

In cases where the disease symptoms are not severe, drug therapy is not required, and CAD can be resolved by avoiding exposure to cold, keeping warm, or moving to a warmer climate.

In more severe cases, monotherapy with Rituximab, an antibody that selectively binds to and induces the destruction of immune cells called B-cells that produce the autoantibodies, can be used. This is effective in about 60% of cases. The response is generally observed within one to two months of treatment, and the effect of the treatment can last one to two years. However, Rituximab is now recommended as the first-line treatment of CAD.

Combined treatment with rituximab and fludarabine results in higher response rates (76% of cases) and longer periods of remissions (on average, 6.5 years). However, the combined treatment can have serious side effects. That is why it is recommended only when rituximab has not worked alone.

Rituximab combined with oral Cytoxan (cyclophosphamide), prednisone or other immunosuppressive medications may be used for cases of CAD that do not resolve with other treatments.

In more severe cases, plasma exchange or plasmapheresis may be performed to remove the IgM or cold agglutinin antibodies from the blood to reduce or alleviate disease symptoms. However, the effect of plasmapheresis is temporary because the B-cells that generate these antibodies are not removed by this procedure. It is useful to overcome acute hemolytic crisis and before surgery-requiring hypothermia.

Previously, corticosteroid treatment has been prescribed for CAD patients. However, patients usually require very high doses of corticosteroids to alleviate symptoms (at levels not considered safe). Hence, corticosteroid treatment is no longer recommended.

In extreme cases, a blood transfusion may be required. Care has to be taken to transfuse warm blood. Moreover, transfusion of blood products with high plasma content should be avoided because elevated levels of complement proteins can cause hemolysis, which exacerbates the condition.

There are several other experimental therapies for CAD being tested in clinical trials. One such approach is bendamustine-rituximab combination therapy that has shown promise in some case studies. Other therapeutic strategies being tested include those that can block complement proteins, such as the monoclonal anti-C5 antibody eculizumab and anti-C1s monoclonal antibody TNT009, which are responsible for hemolysis of autoantibody-bound RBCs.

 

Last updated: July 28, 2019

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