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Cold Agglutinins


At a Glance

Why Get Tested?

To help determine the cause of hemolytic anemia; to help diagnose cold agglutinin disease

When to Get Tested?

When you have symptoms associated with anemia and/or pain, paleness, and bluing in the fingers, toes and tips of the ears that occurs after exposure to cold temperatures; when you have been diagnosed with hemolytic anemia and your health practitioner is investigating the cause

Sample Required?

A blood sample drawn from a vein in your arm

Test Preparation Needed?

None

The Test Sample

What is being tested?

Cold agglutinins are autoantibodies produced by a person's immune system that mistakenly target red blood cells (RBCs). They cause RBCs to clump together when a person is exposed to cold temperatures and increase the likelihood that the affected RBCs will be destroyed by the body. This test detects and measures the amount of cold agglutinins in the blood.

When the presence of cold agglutinins in a person's blood leads to significant RBC destruction, it can cause hemolytic anemia and lead to a low RBC count and hemoglobin. This rare form of autoimmune hemolytic anemia is known as cold agglutinin disease. Cold agglutinin disease may be primary or secondary, induced by some other disease or condition.

Primary cold agglutinin disease typically affects those who are middle age to elderly, and it tends to continue over time (chronic). Secondary cold agglutinin disease may affect anyone and may be acute or chronic, temporary or persistent. It may cause hemolytic anemia to a greater or lesser degree and is associated with a variety of conditions, such as:

  • infectionsMycoplasma pneumoniae—up to 75% of those affected will have increased cold agglutinins.
  • Infectious mononucleosis—more than 60% of those affected will have increased cold agglutinins, but anemia is rare with this infection.
  • Some cancers, including lymphoma, leukemia, and multiple myeloma
  • Some other bacterial infections, such as Legionnaires disease and syphilis
  • Some parasitic infections, such as malaria
  • Other viral infections such as HIV, influenza, CMV, EBV, hepatitis C

The cold agglutinin test is not routinely ordered. It is a test that has been available for a long time, but it has become less commonly used as more specific tests for secondary causes, such as Mycoplasma pneumoniae infection, have become available.

How is the sample collected for testing?

A blood sample is obtained by inserting a needle into a vein in the arm. The sample requires special handling and must be kept within a specific temperature range (not refrigerated) during transport to the laboratory and prior to testing.

Is any test preparation needed to ensure the quality of the sample?

No test preparation is needed.

The Test

How is it used?

A cold agglutinin test may be used to help detect cold agglutinin disease and determine the cause of a person's hemolytic anemia. It may be used as a follow-up test after a complete blood count (CBC) shows a decrease in a person's red blood cell (RBC) count and hemoglobin, especially if these findings are linked to an exposure to cold temperatures.

Cold agglutinin disease is a rare autoimmune disorder in which autoantibodies produced by a person's immune system mistakenly target and destroy RBCs, causing hemolytic anemia. These autoantibodies are cold-reacting and can cause signs and symptoms related to anemia after an affected person is exposed to cold temperatures. This disease may be classified as either primary or secondary, triggered by an infection or other condition.

This test is performed on a series of dilutions of a blood sample that are prepared in test tubes and then cooled to a low temperature, typically 4°C (39.2°F). Each dilution is then evaluated for clumped RBCs, with the results reported as a titer – the highest dilution that shows detectable clumping. When cold agglutinins are present, RBC clumping is visible while the sample is cold and disappears when the sample is warmed. The exact temperature at which this will occur will vary as some cold agglutinins will react over a wider temperature range than others.

When is it ordered?

This test may be ordered when a person has reactions to cold temperature exposures and has signs of hemolytic anemia that may be due to cold agglutinin disease. Symptoms may include:

  • Fatigue, weakness, lack of energy, pale skin (pallor), dizziness and/or headaches from anemia
  • In some cases, painful bluish fingers, toes, ears, and the tip of the nose that occur with exposure to cold temperatures

What does the test result mean?

The result of a cold agglutinin test is typically reported as a titer, such as 1:64 or 1:512. A higher number means that there are more autoantibodies present. Higher titers of autoantibodies and those that react at warmer temperatures are associated with hemolytic anemia and worse symptoms.

The degree of red blood cell (RBC) hemolysis and hemolytic anemia will vary from person to person and with each episode of cold exposure. Some conditions, such as infectious mononucleosis, are frequently associated with elevated cold agglutinins but rarely associated with anemia.

Sometimes a cold agglutinin test may be run at one or more additional temperatures that are lower than body temperature but warmer than 4°C, such as performed at 30°C (86°F) to determine the point at which the RBCs start to clump. This information may be important for someone who has chronically elevated cold agglutinins and is being considered for a surgery that involves body cooling.

Is there anything else I should know?

A cold agglutinin test may rarely be ordered to identify increased cold agglutinins if someone has a condition that has been linked to secondary cold agglutinin disease, such as infectious mononucleosis or a Mycoplasma pneumoniae infection. Since the test is not specific for these conditions, it is not typically ordered to diagnose or monitor them.



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