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Cold Agglutinin Disease

Information About Cold Agglutinin Disease

Cold Agglutinin Disease, a rare blood disorder, is a type of Autoimmune Hemolytic Anemia. Cold agglutinin antibodies are made in your bone marrow and high levels can occur when your immune system malfunctions. The body mistakenly perceives, as foreign, the very antibodies that it produces and sets up an autoimmune response thereby prematurely killing the red blood cells (hemolysis).


The antibodies called cold agglutinins, are activated by cold temperatures and react by causing a sticking together or clumping of the red blood cells to which they are attached.  The temperature, at which the agglutination (clumping) takes place, varies from patient to patient.  A thermal study may be done to determine the level.


PLEASE NOTE: According to Dr. Sigbjørn Berentsen et. al., the thermal amplitude, defined as the highest temperature at which the antibody will react with the antigen, appears to be more important than the titer with respect to the pathogenicity of (capacity to cause) CAD.


Cold agglutinins or cold antibodies occur naturally in nearly everyone.  These natural cold auto antibodies occur at low titers, less than 1:64 measured at 4º C. and have no activity at higher temperatures.  Pathologic cold agglutinins (such as with CAD) occur at titers of 1:64-100,000 and react at 28-31ºC and sometimes near or at 37ºC.  Those individuals with antibodies reacting higher than 37ºC are said to have Warm Antibody Disease.


The cold agglutinin antibodies, usually of the IgM variety, (much less frequently IgG or IgA) combine with complement and attack the antigen on the surface of red blood cells causing the cells to burst open and release hemoglobin (hemolysis).  When the rate of destruction exceeds the ability of the bone marrow to produce an adequate number of oxygen-carrying red cells, then anemia occurs.  The greater the hemolysis, the more severe the anemia unless the body is compensating on its own or due to help from treatments such as Rituxan, Mabthera, Procrit, folic acid or others.  (See Medical Terms Page)


Normal red blood cells live about 120 days and become smaller in size as they approach maturity.  New young cells are larger and individuals with Cold Agglutinin Autoimmune Hemolytic Anemia have a greater number of large, younger cells than older, smaller ones. These can be measured by a CBC (complete blood count) which also tests for hemoglobin, the number of oxygenated red cells circulating in the blood, and many other blood components.  The normal range for women is 12-16 and for men 14-18. In some countries the units of measurement are different and these become 120-160 and 140-180.

Additional Information about CAD:


  • Cold Agglutinin Disease can be caused by an underlying infectious disease (mycoplasma pneumonia, mumps, mononucleosis), lymphoproliferative disease (lymphoma, chronic lymphocytic leukemia), or connective tissue disorder (lupus). This form, accounting for about 50% of CAD patients, is referred to as Secondary CAD, and tends to resolve if there is improvement in the underlying condition.
  • In the early 2000s, Primary CAD was considered idiopathic (no known cause). We presently know otherwise.  In an article, Cold agglutinin disease: current challenges and future prospects” by CAD researcher, Dr.  Sigbjørn  Berentsen et al, Journal of Blood Medicine 2019:10 93-103 wrote that “…..Primary CAD, is a clonal B-cell Lymphoproliferative Disorder (LPD).”   
  • Both Primary and Secondary Cold Agglutinin Disease are acquired conditions, not inherited.     One can have “warm agglutinins” and both warm and cold agglutinins at the same time.  Warm antibody disease is easier to treat.
  • Exposure to cold may significantly worsen anemia.
  • Many people with CAD also can be affected by two conditions called Raynaud’s phenomenon and acrocyanosis.


Raynaud’s phenomenon is triggered when cold constricts small arteries usually in the fingers and toes but can also affect other parts of the body such as the nose, ears, and face.  The digits become pale or bluish and can be numb, tingle, or have a burning sensation.  As re-warming takes place, the skin may be reddish then return to normal.  (See Links Page)


Acrocyanosis is a painless disorder caused by constriction or spasms of small blood vessels due to cold.  People with the disease tend to be uncomfortable with sometimes swollen, sweaty, cold, bluish colored fingers, hands and feet.  Warming decreases the bluishness.


  • Young people can develop CAD as a result of some other disease.  It is generally self-limiting.
  • The onset of CAD can occur suddenly or gradually and typically first appears in individuals in their 50’s, 60’s or 70’s.  Some studies suggest that it affects slightly more women than men and this may be due to the fact that women comprise a greater proportion of the senior population.
  • Some signs of anemia are fatigue, headache, lack of energy and stamina, a yellow pallor and perhaps a yellowing of the eyes, dark urine, irritability, mental confusion, and an enlarged spleen.
  • Some individuals with CAD have low levels of cold antibodies and may not have overt symptoms while others having a very high antibody titer and low hemoglobin, may require blood transfusions as a temporary measure.  (See Treatment Options Page)
  • This was forwarded by a CADdy and its origin is unknown:
    Certain disease states are marked by the appearance of antibodies capable of agglutinating red blood cells at cold temperatures. These cold agglutinins are usually IgM class auto-antibodies which recognize specific sites on red blood cells. They can be transiently associated with infections such as mycoplasma pneumonia and infectious mononucleosis, or be persistently present in diseases such as Waldenstrom’s macroglobulinemia, chronic lymphocytic leukemias, and idiopathic cold agglutinin disease. Post-infectious cold agglutinins are usually polyclonal, whereas cold agglutinins associated with B-cell neoplasms are generally monoclonal. The effects of cold agglutinins can range from minimal to severe hemolytic anemia. The degree of red blood cell destruction depends upon complex factors, including the titer of the antibody (greatest serum dilution able to agglutinate red cells) and the thermal amplitude (maximum temperature at which agglutination of red cells still occurs.) Generally, high titers occur with high thermal amplitudes. However, there are cases in which even low titers can be clinically significant if the reactive temperature is very high. If a cold agglutinin has a high thermal amplitude, special measures must be taken to keep the patient’s body temperature above the reaction temperature. In such cases, ordinary room temperature may trigger agglutination. Blood transfusions pose special problems unless the cross matching has been done at 37°C. and the transfused cells have been washed to minimize the amount of complement in the transfusion.


When one is diagnosed with Cold Agglutinins, in addition to a CBC (complete blood count), doctors customarily do a battery of tests to determine what is causing the Autoimmune Hemolytic Anemia.  Often, a bone marrow biopsy is performed to rule out any underlying lymphoproliferative disease such as lymphoma or leukemia.

MORE INFORMATION ON MANAGING COLD AGGLUTININ DISEASE

Medical Terms

Treatment Options

Treatment Options

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Treatment Options

Treatment Options

Treatment Options

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