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What Causes AIHA?

Posted on June 13, 2022
Medically reviewed by
Todd Gersten, M.D.
Article written by
Brian Niemeyer, Ph.D.

Autoimmune hemolytic anemia (AIHA) is a rare blood disorder that can have many causes, including viral infections, autoimmune diseases, and cancer.

What Is AIHA?

AIHA occurs when your immune system mistakenly targets your red blood cells (RBCs). Your immune system produces antibodies that misinterprets your cells as foreign cells that need to be destroyed. When these self-targeting antibodies (autoantibodies) attach to your red blood cells, it triggers their death — a process known as hemolysis.

Red blood cell death results in anemia — a disorder in which your blood can no longer carry enough oxygen throughout your body. Symptoms of AIHA include:

  • Fatigue
  • Paleness
  • Shortness of breath
  • Chest pain
  • Dark urine

Once diagnosed through blood tests, AIHA is highly manageable. Treatment options include medications like corticosteroids and immunosuppressants, removal of your spleen (splenectomy), and blood transfusion if needed.

AIHA can be broken down into two types of the disease — warm autoimmune hemolytic anemia and cold autoimmune hemolytic anemia. These two forms of AIHA have unique causes, symptoms, and treatments. With warm AIHA, your antibodies attach and kill your RBCs at your core body temperature. With cold AIHA, cell death occurs at colder temperatures.

Causes of Warm AIHA

Your immune system produces five types of antibodies — immunoglobulin (Ig) A, D, E, G, and M. Warm AIHA is caused by IgG antibodies binding to your red blood cells at your normal body temperature.

Because the antibodies involved in wAIHA bind at normal body temperature, they are sometimes referred to as warm antibodies. After the warm antibodies bind to the red blood cells, the cells make their way back to the spleen. Once in the spleen, a variety of immune cells recognize the IgG antibodies on the RBCs and respond by killing the antibody-coated cell.

Causes of Cold AIHA

Unlike warm AIHA, cold AIHA results when antibodies and other immune proteins bind to red blood cells at colder temperatures, such as 37 degrees to 39 degrees Fahrenheit. These autoantibodies are often referred to as cold antibodies. There are two subtypes of cold AIHA — cold agglutinin disease and paroxysmal cold hemoglobinuria.

Cold Agglutinin Disease

With cold agglutinin disease, a different subset of antibodies and immune proteins causes hemolytic anemia. Instead of IgG, IgM antibodies are the primary antibody type attacking the red blood cells.

Because IgM antibodies are so bulky, they cause the affected red blood cells to clump (agglutinate). These cell clumps are then coated with special immune proteins known as complement proteins.

Paroxysmal Cold Hemoglobinuria

The other type of cold AIHA — paroxysmal cold hemoglobinuria — is a unique form of AIHA that is indirectly caused by respiratory infection, mostly in children. The primary antibody responsible for red blood cell death is a specific IgG antibody known as the Donath-Landsteiner autoantibody. Viral and bacterial infections trigger the production of this autoantibody.

Secondary AIHA and Its Causes

Most of the forms of AIHA described above can occur by themselves or can be caused by other underlying diseases. When AIHA is the only obvious disease, it is considered primary or idiopathic AIHA. In these cases, it’s not clear why the body is producing autoantibodies.

When another disease is contributing to the development of AIHA, the condition is called secondary AIHA. The underlying disease is linked to the production of autoantibodies. The following conditions are linked with the development of secondary AIHA, making them risk factors for AIHA.

Genetic Mutations

Some genetic mutations can lead to a type of AIHA known as paroxysmal nocturnal hemoglobinuria (PNH). Your bone marrow is an organ that houses special cells known as stem cells, which make your red blood cells. With PNH, a mutation in a gene within your stem cells leads to production of defective red blood cells.

Infections

Numerous infections have been linked to the development of both warm and cold AIHA. Although it’s not known how exactly this happens, one hypothesis is called molecular mimicry. This occurs when the virus or bacteria have a protein or sugar that looks very similar to proteins or sugars on your blood cells. Once your body clears the infection, your immune system continues to attack your RBCs because of the similar protein. Below are some of the viruses linked to AIHA:

  • Cytomegalovirus
  • Epstein-Barr virus
  • Hepatitis
  • HIV
  • Measles
  • Mumps
  • Rubella
  • Varicella (chickenpox and shingles)

Cancer

Cancers such as lymphoma, leukemia, and colon cancer have been linked to AIHA. How cancer drives AIHA isn’t entirely clear, but some evidence suggests that chronic activation of the cells that ultimately produce antibodies can lead to autoantibody formation.

Autoimmune Disorders

Some people with autoimmune disorders go on to develop AIHA. Autoimmune disorders that have been linked to AIHA include:

  • Hashimoto’s disease
  • Rheumatoid arthritis
  • Sjögren’s syndrome
  • Systemic lupus erythematosus (commonly called lupus)
  • Thyroid disease
  • Ulcerative colitis

Drug-Induced Immune Hemolytic Anemia

AIHA can be caused by medications, which is referred to as drug-induced immune hemolytic anemia (DIIHA). DIIHA is rare, with an estimated 1 to 4 cases per million people occurring each year. The most common drugs associated with DIIHA are antibiotics, anti-inflammatories, and certain anti-cancer therapeutics.

If you are currently taking any medications associated with DIIHA, do not make any changes without consulting your doctor. DIIHA is a rare complication and can be managed with proper treatment.

Condition Guide

All updates must be accompanied by text or a picture.
Todd Gersten, M.D. is a hematologist-oncologist at the Florida Cancer Specialists & Research Institute in Wellington, Florida. Review provided by VeriMed Healthcare Network. Learn more about him here.
Brian Niemeyer, Ph.D. received his doctorate in immunology from University of Colorado Anschutz Medical Campus.. Learn more about him here.

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