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Last updated: 7/30/2024
Years published: 1990, 2000, 2008, 2012, 2016, 2020, 2024
NORD gratefully acknowledges Etienne Leveille, MD, Yale School of Medicine and Carlo Brugnara, MD, Professor of Pathology, Harvard Medical School; Medical Director of the Hematology Laboratory, Department of Laboratory Medicine, Boston Childrenโs 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 someoneโs own immune system attacks healthy tissue. In the case of wAIHA and other types of autoimmune hemolytic anemia, red blood cells are โtaggedโ 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 โwarmโ 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, 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 or 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). 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. Most 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 โtaggedโ 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.
According to medical literature, AIHA affects between 0.8 and 3 people per 100,000 each year in the general population. A multi-database analysis in the U.S. estimated that the point prevalence for AIHA ranged from 6 to 21 per 100,000. According to Orphanet, the European database for rare diseases, warm autoantibodies are responsible for 60%-70% of autoimmune hemolytic anemia, with an annual incidence estimated to be between 1/35,000-1/80,000 in North America and Western Europe. It also have been reported that a total of about 1 in 8,000 individuals live with wAIHA.
People of any age, including children, may develop wAIHA, but it is more common in adults, with a peak incidence between 50-70 years. The median age at onset is 52 years. It is possibly slightly more common in females than males. Secondary wAIHA is more common in people with predisposing conditions, such as people with lymphomas and leukemias or people 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 or absent 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
4) Possible investigation for a secondary cause of wAIHA.
Treatment involves managing symptoms and providing supportive care. Usually, corticosteroids like prednisone are used, starting with a high dose and gradually tapering off.
A medication known as rituximab, a monoclonal antibody, can be used alongside or instead of steroids, or if initial treatments fail.
Immunosuppressant medication like mycophenolate mofetil (MMF), azathioprine and cyclophosphamide may also be used.
For severe cases, surgical removal of the spleen (splenectomy) is an option. In some patients, red blood cell transfusions are necessary for immediate relief.
Most patients respond to corticosteroids, rituximab or splenectomy. Other medications, like azathioprine, danazol, cyclophosphamide, alemtuzumab, cyclosporine and MMF, have shown varying degrees of success, though none offer a cure. New drugs targeting different immune system components are being studied, including fostamatinib, alemtuzumab, bortezomib, daratumumab, eculizumab, ibrutinib and complement inhibitors.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Packman, CH. Hemolytic Anemia Resulting from Immune Injury. In Kaushansky K; Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, Caligiuri MA, eds. Williams Hematology, 9th ed. New York, NY: McGraw Hill; 2016:823-845.
Petz LD. Warm Antibody Hemolytic Anemia. In: NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:371-372.
Berkow R., ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003:991-992.
JOURNAL ARTICLES
Bozzi S, Umarje S, Hawaldar K & cols. Prevalence and incidence of primary autoimmune hemolytic anemia and cold agglutinin disease in the United States, 2016-2022: a retrospective study in administrative claims. Blood. November 2023. 142(1,2): 5202. https://www.sciencedirect.com/science/article/abs/pii/S0006497123118039
Tranekรฆr S, Hansen DL, Frederiksen H. Epidemiology of secondary warm autoimmune haemolytic anaemia-a systematic review and meta-analysis. J Clin Med. 2021 Mar 17;10(6):1244. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002719/
Brodsky RA. Warm autoimmune hemolytic anemia. N Engl J Med. 2019;381(7):647-654.
Go RS, Winters JL, Kay NE. How I treat autoimmune hemolytic anemia. Blood. 2017;129(22):2971-2979.
Sudulagunta SR, Kumbhat M, Sodalagunta MB, Settikere Nataraju A, Bangalore Raja SK, Thejaswi KC, Deepak R, Mohammed AH, Sunny SP, Visweswar A, Suvarna M, Nanjappa R. Warm autoimmune hemolytic anemia: clinical profile and management. J Hematol. 2017 Mar;6(1):12-20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155818/
Barcellini W, Fattizzo B, Zaninoni A, et al. Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients. Blood. 2014;124(19):2930-2936.
Lechner K, Jรคger U. How I treat autoimmune hemolytic anemias in adults. Blood. 2010;116(11):1831-8.
Packman CH. Hemolytic anemia due to warm autoantibodies. Blood Rev. 2008;22:17-31.
DโArena G, Califano C, Annunziata M, et al. Rituximab warm-type idiopathic autoimmune hemolytic anemia: a retrospective study of 11 adult patients. Eur J Haematol. 2007;79:53-58.
King KE, Ness PM. Treatment of autoimmune hemolytic anemia. Semin Hematol. 2005;42:131-136.
Ramanathan S, Koutts J, Hertzberg MS. Two cases of refractory warm autoimmune hemolytic anemia treated with rituximab. Am J Hematol. 2005;78:123-126.
INTERNET
Brugnara C, Brodsky RA, Warm autoimmune hemolytic anemia (AIHA) in adults, UpTodate. Last updated: Feb 21, 2024. https://www.uptodate.com/contents/warm-autoimmune-hemolytic-anemia-aiha-in-adults Accessed May 28, 2024.
Brugnara C, Barcellini W, Paroxysmal cold hemoglobinuria, UpToDate. Last updated: Apr 05, 2023. https://www.uptodate.com/contents/paroxysmal-cold-hemoglobinuria Accessed May 28, 2024.
Nagalia S. Hemolytic Anemia. Medscape. Last updated:Nov 10, 2022. https://emedicine.medscape.com/article/201066-overview Accessed May 28, 2024.
Autoimmune hemolytic anemia, warm type. Orphanet. 2010. https://www.orpha.net/en/disease/detail/90033 Accessed July 30, 2024.
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