November 10, 2022
Years published: 1990, 2000, 2008, 2012, 2016, 2020
NORD gratefully acknowledges Etienne Leveille, MD Candidate, McGill University School of Medicine and Carlo Brugnara, MD, Professor of Pathology, Harvard Medical School; Medical Director of the Hematology Laboratory, Department of Laboratory Medicine, Boston Children’s Hospital, for assistance in the preparation of this report.
Warm autoimmune hemolytic anemia (wAIHA) is an autoimmune disorder characterized by the premature destruction of healthy red blood cells (hemolysis). Autoimmune diseases occur when one’s own immune system attacks healthy tissue. In the case of wAIHA and other types of autoimmune hemolytic anemia, red blood cells are “tagged” by antibodies and are then destroyed by other types of immune cells. wAIHA is the most common type of autoimmune hemolytic anemia; it affects approximately 1 to 3 per 100,000 people every year and can occur at any age. The disease is termed “warm” because the antibodies are active and cause hemolysis at body temperature, which is not necessarily the case in other types of autoimmune hemolytic anemia. Normally, the red blood cells have a life span of approximately 120 days before they are destroyed by the spleen. In individuals with wAIHA, the red blood cells are destroyed prematurely and the rate of production of new cells in the bone marrow can no longer compensate for their loss. A decreased number of red blood cells (anemia) may cause fatigue, weakness, a pale skin color (pallor), dizziness, palpitations, and shortness of breath (dyspnea). Hemolysis leads to an increased release from the red blood cells of hemoglobin, a protein responsible for carrying oxygen in the blood. Degradation of hemoglobin into bilirubin can result in yellowing of the skin and whites of the eyes (jaundice). Hemoglobin can also pass in the urine and give it a dark brown color. The treatment of wAIHA is supportive and can also include corticosteroids and/or rituximab. Individuals that do not respond to usual treatment of have more severe disease might require drugs that suppress the immune system (immunosuppressive agents), blood transfusions, or surgical removal of the spleen (splenectomy).
wAIHA can develop at any age, but the median age of onset is 52 years. This means that one half of affected individuals will be younger than 52 years of age when the disease begins and that the other half will be above this age. The symptoms of wAIHA usually develop slowly over a period of several weeks to months, but in some people can develop suddenly over a few days. Specific symptoms that occur may vary from one person to another and depend on the rate of onset, the degree of hemolysis, and the presence of an underlying disorder. Some individuals, especially those with a gradual onset of anemia, may not have any obvious symptoms (asymptomatic). Symptoms of anemia include paleness of the skin (pallor), fatigue, shortness of breath (dyspnea), dizziness and palpitations. In cases of brisk and severe hemolysis, chest pain, decreased alertness (lethargy), confusion, transient loss of consciousness (syncope), and deregulation of heart rate and blood pressure (hemodynamic instability) might occur. Hemolysis also leads to increased release of hemoglobin (an oxygen-carrying protein) in the blood and urine, which can result in darkly pigmented urine. Hemoglobin is degraded into a yellow compound called bilirubin, which can accumulate and lead to yellowing of the skin and whites of the eyes (jaundice). An enlarged spleen (splenomegaly) can also be seen. Splenomegaly may cause an affected individual to have a bloated or full feeling in the abdomen. wAIHA is also associated with an increased risk of blood clots in the veins (venous thromboembolism). These clots can notably develop in the legs (deep vein thrombosis) and have the potential to detach, circulate in the blood, and occlude the veins of the lungs (pulmonary embolism). Thromboembolisms typically occur in the weeks after diagnosis and are more common in patients with more severe hemolysis and in those that are treated with surgical removal of the spleen (splenectomy). Rarely, clots can form in the arteries feeding the heart (coronary arteries) and lead to a heart attack (myocardial infarction) or in the arteries of the brain (cerebral arteries) and lead to a stroke. Patients that require a splenectomy are also at a higher rate of developing infections. After being treated, 30% of patients will be cured, and the rest are at risk of developing recurrent episodes of hemolysis. The majority of people with wAIHA survive, although a mortality rate of about 5% is seen. Mortality is mainly attributed to thromboembolisms and infections, and the risk depends on many factors, notably the cause of wAIHA and the overall health of the affected individual.
wAIHA occurs when antibodies produced by the immune system bind to red blood cells and identify them as targets to be attacked. Most of the “tagged” red blood cells are transported to the spleen, where they are destroyed by different types of immune cells. Antibodies are specialized proteins that usually bind to invading organisms and lead to their destruction. There are five main classes of antibodies: IgA, IgD, IgE, IgG, and IgM. Most cases of wAIHA are due to IgG antibodies. Less often, IgM or IgA antibodies cause the disorder. When antibodies attack healthy tissue, they may be referred to as autoantibodies. In the case of wAIHA, these autoantibodies are active and can trigger hemolysis when they are at body temperature.
The trigger leading to the development of autoantibodies against red blood cells is usually unknown. These cases may be referred to as primary or idiopathic wAIHA. The disorder may also have a clear trigger in the case of secondary wAIHA. The list of causes of secondary wAIHA is extensive but notably includes medications, autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, deficiency of the immune system (immunodeficiency), leukemias and lymphomas, infections, and pregnancy. Identifying the cause of secondary wAIHA is important, as it might influence treatment and management of the underlying condition.
wAIHA affects 1 to 3 people per 100,000 each year in the general population. A total of about 1 in 8,000 individuals live with this condition. People of any age, including children, may develop wAIHA, but it is more common among adults, with a peak incidence between 50-70 years. The median age at onset is 52 years. It is possibly slightly more common in women compared to men. Secondary wAIHA is more common in people with predisposing conditions, such as those with lymphomas and leukemias or those with a disease affecting the immune system.
A diagnosis of hemolytic anemia may be suspected based on a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms and a variety of tests such as blood tests that measure values of hemoglobin and the percentage of the total blood volume occupied by red blood cells (hematocrit). Blood tests may also show an elevated value of immature red blood cells (reticulocytes), which occurs when the body is forced to produce extra red blood cells to make up for those that are destroyed prematurely. Some individuals with hemolytic anemia have elevated values of bilirubin in the blood (hyperbilirubinemia). Hemolytic anemia also leads to increased values of lactate dehydrogenase (LDH) in the blood, as it is released from destroyed red blood cells. Haptoglobin is a hemoglobin scavenger that gets consumed when increased values of hemoglobin are released in the blood due to hemolysis. Haptoglobin values are therefore low in hemolytic anemia. When hemolytic anemia is suspected to be autoimmune in origin, specialized tests such as a Coombs test may be performed. This test is used to detect antibodies that act against red blood cells. A sample of blood is taken and then exposed to the Coombs reagent. A positive test is indicated when the red blood cells clump in the presence of the reagent. The autoantibodies seen in wAIHA are notable for being of the IgG subtype in most cases and being active at body temperature. Depending on the case, further testing might be performed to attempt to identify a cause of secondary wAIHA. In summary, the following sequence allows the diagnosis of wAIHA: 1) detection of anemia with increased reticulocyte counts, 2) determination that the anemia is caused by hemolysis, based on elevated bilirubin and LDH and low haptoglobin, 3) determination that wAIHA is the cause of hemolytic anemia with a Coombs test and 4) possible investigation for a secondary cause of wAIHA.
The treatment of warm antibody hemolytic anemia is symptomatic and supportive. Affected individuals are usually treated with corticosteroid drugs such as prednisone and can usually be well controlled with proper treatment. A high-dose of these drugs may be recommended initially followed by a gradual reduction (tapering) of the dose over the next few weeks or months. Rituximab is an artificially-created antibody (monoclonal antibody) that targets certain white blood cells that create the antibodies which prematurely destroy red blood cells. Rituximab might be initiated alongside or instead of corticosteroids, or might be given if there is no response to initial treatment. It is sometimes combined with mycophenolate mofetil (MMF), a medication that suppresses the immune system (immunosuppressive agent). Individuals that do not respond to these medications might be given other immunosuppressive agents, such as azathioprine and cyclophosphamide. Another treatment option for patients that do not respond to treatment is surgical removal of the spleen (splenectomy). Splenectomy is also used for people with severe cases that require continual prednisone for control, as this medication is associated with numerous side effects if it is used for an extended period of time. In affected individuals with an underlying disorder, treatment of the disorder usually brings marked improvement of the anemia. Red blood cell transfusions may be necessary to maintain proper red blood cell values in people with severe cases. This supportive technique provides temporary relief, but does not treat the underlying cause of the disorder.
Most patients respond to corticosteroids, rituximab, or splenectomy. Successful use of several drugs has been reported, including azathioprine, danazol, cyclophosphamide, alemtuzumab, cyclosporine and mycophenolate mofetil. The risks and benefits of these drugs in autoimmune hemolytic anemia have not been defined, nor do we know the exact response rates. However, cures are not expected with these treatments. Other medications that target different parts of the immune system are currently being studied for refractory wAIHA. These include fostamatinib, ixazomib, ibrutinib, daratumab and complement inhibitors.
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