Autoimmune hemolytic anemia (AIHA) comes in two main forms — warm and cold. Each type can affect symptoms and treatments in unique ways. In this article, we’ll discuss what sets these types of AIHA apart and the most common treatments for each.

What Is Autoimmune Hemolytic Anemia?

AIHA is an autoimmune disease, meaning your immune system mistakenly attacks healthy parts of your body instead of targeting damaged cells or harmful invaders such as bacteria. The tools the immune system uses to attack its cells are known as autoantibodies.

In AIHA, autoantibodies attack red blood cells, leading to their destruction in a process known as hemolysis. The resulting loss of red blood cells causes anemia, a condition in which there aren’t enough red blood cells to deliver sufficient oxygen to the body’s tissues.

The two distinct types of AIHA, warm and cold, differ in their causes, primary symptoms, and treatments. AIHA can also be classified based on whether it’s linked to another condition. When AIHA is caused by an underlying disease, it’s known as secondary autoimmune hemolytic anemia. AIHA with no identifiable cause is known as primary or idiopathic autoimmune hemolytic anemia.

The wide range of AIHA symptoms includes:

• Fatigue (tiredness)
• Dizziness
• Fever
• Jaundice (yellowing of the skin and whites of the eyes)
• Irregular heartbeat
• Shortness of breath and difficulty breathing
• Headaches
• Muscle aches
• Paleness
• Abdominal pain due to an enlarged spleen

Warm Autoimmune Hemolytic Anemia

The most common form of the disease, warm AIHA, accounts for 60 percent to 70 percent of all AIHA cases. The disorder affects 1 to 3 people per every 100,000 each year and can start at any age. However, it’s more common in adults than children and usually occurs between ages 50 and 70.

Autoantibodies in Warm AIHA

Warm AIHA occurs when autoantibodies attach to red blood cells, leading to the cells’ destruction. Although there are multiple antibody types, the main one involved in warm AIHA is called Immunoglobulin G (IgG). These autoantibodies are known as “warm antibodies” because they’re most active at the core body temperature — hence the name warm AIHA.

Symptoms of Warm AIHA

Some symptoms of AIHA are more commonly found in people with the warm form of the disease. Symptoms of warm AIHA include:

• Fatigue
• Dizziness
• Jaundice
• Irregular heartbeat

Cold Autoimmune Hemolytic Anemia

Cold AIHA accounts for 10 percent to 20 percent of cases. There are two types of cold-induced AIHA — cold agglutinin disease (CAD) and paroxysmal cold hemoglobinuria (PCH). The antibodies responsible for these disorders differ from those for warm AIHA. They’re called cold antibodies because they bind to red blood cells at colder temperatures.

Cold temperatures trigger many CAD and PCH symptoms. Beyond the general AIHA symptoms, people with cold AIHA may also experience:

• Cold extremities (hands and feet)
• Chest pain
• Leg pain
• Raynaud’s phenomenon (numbness and discoloration of hands and feet when exposed to the cold)

Cold Agglutinin Disease

Each year, cold agglutinin disease affects about 1 out of every million people, with onset most often occurring between ages 40 and 80. People with certain diseases have a higher risk of developing secondary CAD. These conditions include:

• Infectious diseases such as measles, mumps, cytomegalovirus, mononucleosis, and mycoplasma pneumoniae
• Blood cancers such as non-Hodgkin lymphoma and chronic lymphocytic leukemia
• Autoimmune conditions such as rheumatoid arthritis and lupus

CAD involves immunoglobulin M (IgM) antibodies, which cause red blood cells to clump up. This clumping triggers immune responses that end up destroying the red blood cells.

Paroxysmal Cold Hemoglobinuria

Unlike warm AIHA and cold agglutinin disease, paroxysmal cold hemoglobinuria is most often seen in children. Historically, PCH has been classified as a cold AIHA, but recent cases have shown that antibody binding and red blood cell death can also occur in warmer temperatures.

In children, PCH is strongly associated with viral infections and often resolves on its own after the virus clears. A specific IgG antibody, the Donath-Landsteiner autoantibody, is produced in response to a viral infection. This “biphasic” antibody binds to red blood cells in the cold and triggers hemolysis when the temperature warms again.

Because of the viral infection, children who experience PCH often have flu-like symptoms — but no signs of anemia — for one to two weeks. After that, symptoms of anemia typical for AIHA start to appear.

Related Disorders: Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease with symptoms similar to those of PCH, although it’s not a form of AIHA. People living with PNH have abnormal stem cells — precursor cells that can become other types of cells, including red blood cells. In PNH, these abnormal stem cells lead to abnormal red blood cells, which are more vulnerable to destruction by the immune system.

PNH is not a type of AIHA — it’s caused by a specific genetic mutation (variant), whereas AIHA is typically triggered by immune system malfunction. The genetic mutation in PNH changes the instructions for cell development, resulting in the production of abnormal stem cells and, consequently, red blood cells that are more prone to immune attack.

PNH often starts in people between ages 30 to 40. In the U.S., an estimated 400 to 500 new cases are diagnosed each year.

People with PNH often experience only some of a wide range of possible symptoms, which include:

• Dark-colored urine (especially in the morning)
• Fatigue
• Blood clots
• Rapid heartbeat
• Headaches
• Chest pain
• Breathing difficulty
• Stomach pain
• Squeezing or pressure behind the breastbone
• Jaundice

Treatment Options for AIHA

AIHA is a highly manageable disorder. Treatment may include medications, surgery, blood transfusions, or — in the case of secondary AIHA — treatment of the underlying condition.

The precise regimen depends on the type of AIHA you have. For people with warm AIHA, first-line treatments include medications that aim to suppress the immune system or reduce the body’s production of autoantibodies. Surgery is recommended when these treatments don’t work. Suggested treatments include:

• Corticosteroids such as prednisone
• Rituximab (Rituxan)
• Spleen removal (splenectomy)

Similar to people with warm AIHA, those who have cold agglutinin disease may find relief using immunosuppressive drugs such as rituximab (but not corticosteroids).

One treatment specific to CAD is sutimlimab-jome (Enjaymo), which helps reduce the breakdown of red blood cells. Avoiding the cold can also help manage CAD, and this approach is similarly beneficial for paroxysmal cold hemoglobinuria. Unlike CAD, PCH often clears up on its own and may require only supportive measures such as bed rest and warmth. However, red blood cell transfusions may be necessary in cases of severe anemia.

For PNH, treatments include medications that help slow the breakdown of red blood cells, such as eculizumab (Soliris). In severe cases of anemia caused by PNH, blood transfusions may be needed. Blood thinners also may be prescribed because PNH is associated with a higher risk of blood clots. Additionally, clinical trials are exploring new drugs for PNH.

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Have you been diagnosed with AIHA? What type of AIHA do you have? Share your experiences and thoughts in the comments below or by posting on your Activities page.