What Is Cold Agglutinin Disease?

Understanding the Rare Form of Anemia

Dressing warmly
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Cold agglutinin disease (CAD) is a rare type of autoimmune hemolytic anemia—an anemia that develops when your immune system attacks and destroys your red blood cells. The most common cause of AIHA is due to a warm autoantibody. This means that the antibody attaches to the red blood cell at warm (body) temperature. As the name suggests, CAD occurs secondary to a cold autoantibody, meaning that the antibody attaches when the red blood cell is exposed to colder temperatures, typically in the hands, feet, and nose.

These antibodies cause your red blood cells to stick together, called agglutination. CAD occurs more commonly in females, particularly at older ages.  

What Are the Symptoms of CAD? 

  • Fatigue or weakness
  • Shortness of breath, particularly with activity
  • Acrocyanosis: purple discoloration of the fingers, toes, nose, or ears. This discoloration disappears when the area is heated. This may be associated with pain. It should not be confused with Raynaud's phenomenon
  • Rash: CAD may cause livedo reticularis, the development of a purple, lace-like rash.  Sometimes this is called mottled skin.  

What Causes CAD?

  • Idiopathic: no cause is identified
  • Infection: The two most common causes are mycoplasma pneumonia (a respiratory infection) and Epstein-Barr Virus (EBV, the virus that causes mononucleosis). It can also be caused by other viral illnesses, such as cytomegalovirus (CMV), measles, mumps, or rubella. These cases of CAD are self-limited and typically resolve within one to three weeks.  

How Is CAD Diagnosed?

If the anemia is mild, it may be discovered incidentally on complete blood count (CBC) drawn for other reasons. In addition to anemia, the CBC may also reveal macrocytosis, enlarged size of red blood cells.  The red blood cells are not actually large, but when the red blood cells stick together, the machine reads it as one large red blood cells.

A review of the peripheral blood smear (microscope slide of blood) can help determine if agglutinated (stuck together) cells are present. Similar to other hemolytic anemias, the reticulocyte count (immature red blood cell) is elevated as the bone marrow tries to replace the red blood cells that have been destroyed.  

Because CAD is an immune hemolytic anemia, the direct antiglobulin test (DAT, or direct Coomb's test) will be positive, indicating the presence of red blood cell antibodies. There is specialty testing to look for the presence of cold agglutinins to confirm the diagnosis.  

Because the majority of CAD is secondary to another problem, additional testing may be sent to determine the cause, so that it may be treated appropriately.  

What Are the Treatments for Cold Agglutinin Disease?

If the anemia is mild, no specific treatment is needed. If your anemia is severe and/or you are symptomatic from the anemia (rapid heart rate, fatigue, dizziness) you will likely need a red blood cell transfusion.

Because the blood transfusion does not eliminate the cold autoantibody, the transfusion needs to be given through a warmer, so that the antibody does not attach to the transfused red blood cells.  

A very important part of treatment of CAD is avoidance of cold temperatures. This sounds simpler than it is in real life. This means people suffering with CAD often wear hats, gloves, and socks even in warm weather, as you may be exposed to cold rooms or environments. In addition to warm clothing, drinking cold liquids, or immersing body parts in cold water should be avoided.  

Rituximab is an intravenous (IV) medication that helps to destroy the white blood cells that produce the antibodies against red blood cells, called B-cells. The hope is that when your B-cells regenerate, they will no longer make the antibody. This is typically used for patients with severe disease.

Medications like steroids and intravenous immunoglobulin (IVIG), which are used for other immune blood disorders are less effective in CAD. Splenectomy (surgical removal of the spleen) can be very effective treatment for warm autoimmune hemolytic anemia, but in CAD the majority of the red blood cell destruction occurs in the liver, making it ineffective.  

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