Autoimmune Hemolytic Anemia (AIHA) is a disorder where the immune system produces autoantibodies that attach to the surface of red blood cells, marking them for destruction. To understand this, let’s break down the term:

• Anemia: A condition in which you lack enough healthy red blood cells to carry adequate oxygen to your body’s tissues.
• Hemolytic: This means the anemia is caused by hemolysis, the premature destruction of red blood cells, faster than the bone marrow can replace them.
• Autoimmune: This indicates that destruction is caused by the body’s own immune system.

To visualize this process, it is helpful to use an analogy. Think of your red blood cells as a massive fleet of delivery trucks, and your immune system as the city’s security force. In AIHA, this security force malfunctions. It starts producing “faulty parking tickets” (autoantibodies) and slapping them onto your own healthy delivery trucks. Other immune cells, particularly in the spleen and liver, act like tow trucks. They see these ticketed vehicles, identify them as unauthorized, and haul them away to the scrap yard to be destroyed. This leads to two main problems: a severe shortage of delivery trucks (anemia) and a buildup of scrap metal (bilirubin, a byproduct of red blood cell breakdown), which causes jaundice.

AIHA is broadly classified into two main types, based on the temperature at which the autoantibodies are most active:

• Warm Agglutinin AIHA: This is the most common type, accounting for about 80% of adult cases. The autoantibodies (typically IgG antibodies) are most active and cause the most destruction at normal core body temperature.
• Cold Agglutinin Disease (CAD): A rarer type where the autoantibodies (typically IgM antibodies) become highly active and cause red blood cells to clump together (agglutinate) at colder temperatures, usually in the more exposed parts of the body like the fingers, toes, ears, and nose.

I’ve seen AIHA catch both patients and physicians off guard because its symptoms can mimic common anemia. But when standard iron or vitamin therapies don’t help, and lab results show signs of hemolysis, that’s when AIHA should be considered.

AIHA is caused by the production of autoantibodies that bind to antigens (proteins) on the surface of red blood cells. These antibodies act as tags that signal to other parts of the immune system, primarily macrophages in the spleen and liver, that these red blood cells should be eliminated.

The fundamental cause is a profound immune dysregulation, where the immune system loses its normal state of self-tolerance. The complex checks and balances that are supposed to prevent the immune system from attacking “self” tissues fail. Why this loss of tolerance occurs is not fully understood, but it is believed to be a combination of genetic predisposition and environmental or medical triggers.

In practice, I always look for underlying autoimmune or blood cancers in new AIHA cases. In some patients, it’s the first sign of a more serious systemic disease that hasn’t been diagnosed yet.

A person develops AIHA spontaneously or as a complication of another underlying disease. The exact trigger is often unknown, but it can be:

Primary (or Idiopathic) AIHA

In approximately 50% of cases, the condition occurs on its own without any other identifiable underlying disease. The immune system dysregulation appears to arise spontaneously for reasons that are not yet known.

Secondary AIHA

In the other 50% of cases, AIHA development is associated with or triggered by another medical condition. Common secondary causes include:

• Other Autoimmune Diseases: AIHA is frequently seen in individuals with other autoimmune disorders, most notably Systemic Lupus Erythematosus (SLE). It can also be associated with rheumatoid arthritis and ulcerative colitis.
• Cancers of the Lymphatic System: Certain blood cancers are a major cause of secondary AIHA, especially in older adults. These include Chronic Lymphocytic Leukemia (CLL) and lymphomas.
• Infections: Some infections can cause temporary or persistent AIHA. Mycoplasma pneumoniae (a cause of “walking pneumonia”) is a classic trigger for Cold Agglutinin Disease. Other triggers include viruses like Epstein-Barr virus (the cause of infectious mononucleosis), cytomegalovirus (CMV), and HIV.
• Medications: In rare cases, certain drugs can induce the immune system to produce antibodies against red blood cells. This is known as drug-induced hemolytic anemia.

I often ask patients if they recently had a bad cold or took new medication, because many cases of AIHA seem to follow those events. Sometimes the immune system just gets confused and doesn’t switch off after fighting an infection.

The signs and symptoms of AIHA can develop gradually over weeks or months, or they can appear very suddenly and severely. The symptoms are a direct result of the anemia (lack of oxygen-carrying cells) and the hemolysis (the process of red blood cell destruction).

The most common symptoms are those related to anemia:

• Fatigue and Weakness is often the most prominent and debilitating symptom. It is a profound sense of exhaustion and lack of energy that is not relieved by rest.
• Shortness of Breath (Dyspnea), especially with physical activity.
• Dizziness or Lightheadedness.
• Pale Skin (pallor).
• Rapid Heartbeat (Tachycardia) or palpitations, as the heart works harder to pump the limited number of red blood cells around the body to deliver oxygen.
• Headaches.

Symptoms related to the rapid hemolysis include:

• Jaundice: A yellowing of the skin and the whites of the eyes (the sclera). This is caused by the buildup of bilirubin, a yellow pigment created when the liver breaks down hemoglobin from destroyed red blood cells.
• Dark, Tea-Colored Urine: The excess bilirubin and free hemoglobin from destroyed red cells can be filtered by the kidneys, making the urine appear dark brown or cola-colored.
• Enlarged Spleen (Splenomegaly): The spleen can become enlarged as it works overtime to filter out the antibody-coated red blood cells. This can sometimes cause a feeling of fullness or discomfort in the upper left side of the abdomen.

In Cold Agglutinin Disease, exposure to cold temperatures can trigger specific symptoms in the extremities, such as acrocyanosis, a dusky, purplish discoloration of the fingers, toes, ears, and nose.

When someone describes feeling wiped out, with yellowish eyes and dark urine, I start thinking about hemolysis. Those are clues that the red blood cells are breaking down rapidly and spilling their contents.

Diagnosing AIHA requires a combination of blood tests and sometimes bone marrow evaluation to rule out other causes of anemia.

• Initial Blood Tests:
  • A Complete Blood Count (CBC) will confirm the presence of anemia (a low hemoglobin level and red blood cell count).
  • A Peripheral Blood Smear involves looking at the blood under a microscope. It may show spherocytes, which are small, spherical red blood cells that are the remnants of cells partially destroyed by the immune system.
  • Tests for Hemolysis will show a characteristic pattern: a high reticulocyte count (as the bone marrow works hard to produce new red cells), high levels of indirect bilirubin, and high levels of an enzyme called lactate dehydrogenase (LDH). The level of a protein called haptoglobin will be low, as it gets used up binding to the free hemoglobin released from the destroyed cells.
• The Direct Antiglobulin Test (DAT) or Coombs Test: This is the most important and definitive test for diagnosing AIHA. The DAT is a blood test specifically designed to detect the presence of antibodies or complement proteins that are physically attached to the surface of a patient’s red blood cells. A positive DAT result confirms that the hemolysis is being caused by an autoimmune process.
• Investigating the Cause: Once a diagnosis of AIHA is confirmed, a doctor will conduct further tests to determine if it is primary or secondary to an underlying condition. This may involve screening for autoimmune diseases like lupus, or imaging tests to look for cancers like lymphoma.

I always rely on the Coombs test to confirm AIHA. When combined with high LDH, low haptoglobin, and signs of anemia, it paints a clear picture of the body attacking its own red cells.

The goal of treatment is to stop the immune system from destroying RBCs and restore healthy oxygen levels.

1. First-Line Therapy

• Corticosteroids: For warm agglutinin AIHA, the cornerstone and first-line treatment is high-dose oral corticosteroids, such as prednisone. Steroids are powerful drugs that work by broadly suppressing the immune system, which reduces the production of autoantibodies and decreases the destruction of red blood cells by the spleen.
• Avoiding Cold: For Cold Agglutinin Disease, the most important treatment is strict avoidance of cold exposure. Steroids are generally not very effective for this type.

2. Second-Line Therapies

If a patient does not respond to steroids, or if their disease relapses as the steroid dose is lowered, second-line treatments are used.

• Rituximab: This is a modern, highly effective second-line therapy. It is a biologic medication (a monoclonal antibody) that targets and eliminates a specific type of immune cell called the B-cell. Since B-cells are the factories that produce the harmful autoantibodies, depleting them can lead to a long-lasting remission.
• Other Immunosuppressants: Other drugs that suppress the immune system, such as azathioprine, mycophenolate mofetil, or cyclosporine, may also be used.

3. Other Treatment Options

• Splenectomy: This is surgical removal of spleen. Since the spleen is the primary site where antibody-coated red cells are destroyed in warm AIHA, removing it can be a very effective treatment for people who fail medical therapy.
• Blood Transfusion: In cases of life-threateningly severe anemia, a blood transfusion can be a life-saving measure. However, it can be very difficult and complex in AIHA patients due to risk of reactions.

Steroids usually turn things around quickly, but I always counsel patients about tapering carefully. In stubborn cases, rituximab has been a game-changer in reducing relapses and minimizing long-term steroid use.

Autoimmune Hemolytic Anemia is a serious blood disorder where the body’s own defense system turns against its vital, oxygen-carrying red blood cells, leading to hemolytic anemia. Characterized by the debilitating fatigue of anemia and the tell-tale signs of hemolysis like jaundice, the condition requires a prompt and accurate diagnosis confirmed by a positive Coombs test. While diagnosing a chronic autoimmune disease can be frightening, the outlook for most patients is good. With a range of effective immunosuppressive therapies, from corticosteroids to targeted biologics like rituximab and other options like splenectomy, most people can achieve remission and effectively manage their disease.

American Society of Hematology (ASH). (n.d.). Autoimmune Hemolytic Anemia. Retrieved from https://www.hematology.org/education/patients/anemia/autoimmune-hemolytic-anemia

National Institutes of Health, Genetic and Rare Diseases Information Center (GARD). (2023). Autoimmune hemolytic anemia. Retrieved from https://rarediseases.info.nih.gov/diseases/5869/autoimmune-hemolytic-anemia

National Organization for Rare Disorders (NORD). (2022). Anemia, Autoimmune Hemolytic. Retrieved from https://rarediseases.org/rare-diseases/anemia-autoimmune-hemolytic/