Cold Agglutinin Disease

What is cold agglutinin disease?

Cold agglutinin disease (CAD) is a rare blood condition that occurs when your immune system attacks your red blood cells. Your immune system makes proteins called antibodies that destroy harmful germs that enter your body. With CAD, your immune system releases an autoantibody, or “cold agglutinin,” that attacks healthy red blood cells.

CAD causes you to have too few red blood cells. Having enough red blood cells is essential because these cells carry oxygen throughout your body. The oxygen powers your cells to make the energy your body needs to function.

Cold agglutinin disease is a type of hemolytic anemia. Hemolytic anemia involves not having enough red blood cells because they break down or die faster than your body can replace them.

Who does cold agglutinin disease affect?

Cold agglutinin disease is most common in people assigned female at birth (AFAB) between the ages of 40 and 80. Most diagnoses occur in people in their mid to late 60s.

How common is cold agglutinin disease?

Cold agglutinin disease is rare. Approximately one in a million people get diagnosed each year. In the United States, people living with CAD range from 300 to 3,000.

How does cold agglutinin disease affect my body?

Cold agglutinin disease can cause you to experience the symptoms of anemia. Anemia is a condition that involves not having enough red blood cells. Depending on what’s causing your anemia, it may be a life-long condition (chronic) or short-lived. Its impacts on your body can range from mild to severe.

For instance, with mild cases of CAD, symptoms may set in so slowly that you may have the condition for several years before receiving a diagnosis. CAD can lead to severe and even life-threatening heart conditions in emergency scenarios.

Related to its name — “cold” agglutinin disease — CAD causes most intense symptoms in cold climates or chilly weather.

What are the symptoms of cold agglutinin disease?

The symptoms of CAD are often related to anemia and problems with blood circulation throughout your body. Symptoms of CAD that are related to anemia and poor circulation include:

• Fatigue.
• Weakness.
• Dizziness.
• Sweating.
• Shortness of breath (dyspnea).
• Fast heartbeat (tachycardia).
• Skin that appears pale or drained of blood (pallor).
• Bluish fingers, toes or ears after spending time in the cold (Raynaud’s phenomenon).

You may also experience the symptoms of jaundice. As your red blood cells get destroyed, they release a yellowish substance called bilirubin. Bilirubin build-up leads to jaundice. Symptoms of jaundice include:

• Dark brown-colored urine.
• A yellowish color in your skin and the whites of your eyes.

What causes cold agglutinin disease?

Cold agglutinin disease is a type of autoimmune hemolytic anemia. With CAD, cold conditions activate your immune system to make an autoantibody that flags your red blood cells for destruction. Your red blood cells clump together (agglutinate) in response. The clumped cells make an easy target for another part of your immune system, called macrophages, to destroy.

The process begins when temperatures are approximately less than 37 degrees Fahrenheit to 39 degrees Fahrenheit (3 degrees Celsius to 4 degrees Celsius).

CAD disrupts the regular timeline that your body needs to make healthy red blood cells. Red blood cells typically live for about 120 days. This period allows your bone marrow enough time to make new red blood cells to replace the dying ones.

Researchers aren’t sure what causes your immune system to attack healthy cells. It’s possible that CAD results from an underlying condition. This is called secondary CAD. When there doesn’t seem to be a relationship between CAD and another disease, CAD is called primary, or idiopathic.

What conditions are associated with cold agglutinin disease?

Secondary CAD is associated with infections, autoimmune disorders and lymphoproliferative disorders, including:

• Infectious mononucleosis.
• Mycoplasma pneumonia.
• Cytomegalovirus.
• Lupus.
• Rheumatoid arthritis.
• Non-Hodgkin lymphoma.
• Chronic lymphocytic leukemia.
• Waldenstrom macroglobulinemia.

How is cold agglutinin disease diagnosed?

Your healthcare provider will review your medical history and symptoms. They’ll run blood tests to determine whether you have hemolytic anemia and the autoantibodies associated with CAD.

Blood tests for diagnosing hemolytic anemia include:

• A complete blood count (CBC): A CBC provides detailed information about your red blood cells that can be used to diagnose hemolytic anemia. It shows how many red blood cells you have, their size and your hemoglobin level. Hemoglobin is an important protein that allows your red blood cells to transport oxygen.
• A reticulocyte count: A reticulocyte count measures how many immature red blood cells (reticulocytes) you have. Your body may produce a higher-than-normal amount of reticulocytes if your immune system destroys mature red blood cells.
• Serum levels tests: High levels of lactate dehydrogenase (LDH) and bilirubin and low levels of haptoglobin are signs of hemolytic anemia.

Your healthcare provider will check for the autoantibody that attacks your red blood cells to determine if your hemolytic anemia is CAD. Tests include:

• Direct Coombs test (DAT): The Coombs test checks for autoantibodies associated with CAD. During the test, your red blood cells are separated from the other parts of your blood and placed in a controlled environment. A special solution is added. If the cells clump together (agglutinate) with the solution, the test is positive for the autoantibody.
• Cold agglutinin titer test: This test checks how concentrated the autoantibodies are, or how many of them you have. A high concentration of autoantibodies is a sign of CAD.

Once your healthcare provider confirms your diagnosis, they’ll explore whether your CAD is related to an underlying condition (secondary cold agglutinin disease).

How is cold agglutinin disease treated?

Treatment may involve managing CAD with lifestyle changes and medications, depending on how severe your symptoms are. Emergencies may require blood transfusions.

• Lifestyle: Your healthcare provider will advise you to avoid cold temperatures if you have CAD.
• Medications: The most commonly used medication to treat CAD is Rituximab. It works by preventing your immune system from making the autoantibodies that attack your red blood cells. A new medication called sutimlimab was recently approved. It works by blocking your immune system from attacking the red blood cells.
• Blood transfusions: If your CAD is severe (acute), your healthcare provider may need to perform a blood transfusion or plasma exchange to stabilize your condition. Plasma exchange works by reducing the number of autoantibodies circulating in your blood.

Your healthcare provider will treat your underlying condition if you have secondary CAD.

How can I prevent CAD?

CAD isn’t a preventable condition.

How long can you live with cold agglutinin disease?

People diagnosed with CAD, on average, live as long as people their same age without CAD. According to a recent study, on average, people diagnosed at 68 are alive in their 80s.

What questions should I ask my doctor?

• Is my CAD related to an underlying condition?
• What symptoms will let me know if my condition is improving or worsening?
• Will I need medications for my condition?
• What’s the ideal climate for a person living with CAD?
• What temperature ranges should I avoid to keep my symptoms in check?

A note from Cleveland Clinic

Your experience of cold agglutinin disease (CAD) depends on whether it occurs independently or is related to an underlying condition. The severity of your symptoms will also play an important role in how aggressive your treatments may be. Your healthcare provider may be able to cure your CAD by treating any related underlying conditions. Even if you have long-term CAD, avoiding cold temperatures and taking medicines as prescribed can help you manage anemia symptoms.