Cold Agglutinin Disease: Symptoms, Causes, Treatment

Understanding the Rare Form of Anemia

Cold agglutinin disease (CAD) is a rare type of autoimmune hemolytic anemia (AIHA) 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 risk goes up after the age of 55 and affects both males and females.

Woman reading dressed warmly
Diane Labombarbe / Creative RF / Getty Images

Symptoms

The National Institute of Health (NIH) reports several CAD symptoms, some of which are more likely to occur than others. According to the NIH, up 80-99% of CAD patients have the following symptoms:

Some patients with CAD suffer from acrocyanosis (purple discoloration of the fingers, toes, nose, or ears) or Raynaud's phenomenon.

Causes

The causes of CAD are either primary, considered unknown, or secondary, caused by another underlying condition. Secondary causes are linked to the following conditions:

  • Bacterial Infections
  • Viral infections
  • Parasitic infections
  • Autoimmune diseases 
  • Certain types of cancers 

Diagnosis

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 cell. 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.

Treatments

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 living with CAD often wear hats, gloves, and socks even in warm weather, as they may still be exposed to cold rooms or environments. Additionally, drinking cold liquids or immersing body parts in cold water should be avoided.

In early 2022, the Food and Drug Administration (FDA) approved the intravenous (IV) treatment Enjaymo (sutimlimab-jome) to decrease the need for red blood cell transfusion due to the destruction of red blood cells (hemolysis) in adults with CAD. Following two weekly starter doses, Enjaymo is given every two weeks in doses that are based on the person's body weight.

Rituxan (rituximab) is another intravenous medication used to treat CAD; it 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 a very effective treatment for warm autoimmune hemolytic anemia, but given that the majority of the red blood cell destruction in CAD occurs in the liver, the treatment is ineffective for CAD.

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5 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. The National Organization for Rare Disorders. Warm Autoimmune Hemolytic Anemia.

  2. Mullins M, Jiang X, Bylsma LC, et al. Cold agglutinin disease burden: a longitudinal analysis of anemia, medications, transfusions, and health care utilizationBlood Adv. 2017;1(13):839-848. Published 2017 May 19. doi:10.1182/bloodadvances.2017004390

  3. The National Institute of Health. Cold Agglutinin Disease.

  4. Cold agglutinin disease. UpToDate.

  5. United States Food and Drug Administration. FDA approves treatment for adults with rare type of anemia.