NORD gratefully acknowledges Charles H. Packman, MD, Professor of Medicine, University of North Carolina School of Medicine; Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Carolinas Healthcare System, for assistance in the preparation of this report.
The symptoms of warm antibody hemolytic anemia usually develop slowly over a period of several weeks to months, but in some cases can develop suddenly over a few days.
Specific symptoms that occur may vary from one person to another and may depend upon the rate of onset, the rate of destruction of healthy red blood cells and the presence of an underlying disorder. Some individuals, especially those with a gradual onset of anemia, may not have any obvious symptoms (asymptomatic). Affected individuals may eventually develop abnormal paleness of the skin (pallor), fatigue, difficulty breathing upon exertion, dizziness and palpitations. Yellowing of the skin and whites of the eyes (jaundice) and enlargement of the spleen (splenomegaly) are also common findings in individuals with warm antibody hemolytic anemia. Splenomegaly may cause an affected individual to have a bloated or full feeling in the abdomen. Occasionally enlargement of the liver (hepatomegaly) may also occur in some people.
In individuals with severe cases, especially those with rapid (acute) onset more serious complications may develop including loss of consciousness (syncope), chest pain (angina), abnormally rapid heartbeats (tachycardia), and heart failure.
The cause of warm antibody hemolytic anemia is usually unknown (idiopathic). These cases may be referred to as primary warm antibody hemolytic anemia or idiopathic warm antibody hemolytic anemia. The disorder may also occur as part of a larger disorder, these cases are known as secondary warm antibody hemolytic anemia.
Warm antibody hemolytic anemia is an autoimmune disorder – a disorder in which the body’s natural defenses against invading organisms (e.g., lymphocytes, antibodies) destroy healthy tissue for unknown reasons. Antibodies mistakenly attack healthy red blood cells causing the cells to breakdown prematurely, a condition called hemolysis.
Antibodies (which are also known as immunoglobulins) are specialized proteins that bind to invading organisms and bring about their destruction. There are five main classes of antibodies -IgA, IgD, IgE, IgG, and IgM. Most cases of warm antibody hemolytic anemia are due to IgG antibodies that mistakenly attack healthy red blood cells. Less often, IgM or IgA antibodies cause the disorder. When antibodies attack healthy tissue, they may be referred to as autoantibodies.
Several underlying disorders are associated with warm antibody hemolytic anemia including other autoimmune disorders such as systemic lupus erythematosus and disorders characterized by the overproduction of white blood cells (lymphoproliferative disorders) such as leukemia or lymphoma. Secondary warm antibody hemolytic anemia may also occur as a side effect of certain drugs.
Warm antibody hemolytic anemia affects males and females in equal numbers. Autoimmune hemolytic anemias as a group are estimated to affect 1-3 people per 100,000 in the general population. People of any age, including children, may develop warm antibody hemolytic anemia, but it is more common among adults with a peak incidence between 50-70 years.
A diagnosis of hemolytic anemia may be suspected based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms and a variety of tests such as blood tests that measure hemoglobin and hematocrit. Hemoglobin is the protein within red blood cells that carries oxygen. Hematocrit is the percentage of the total blood volume occupied by red blood cells. Blood tests may also show an elevated level 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 levels of bilirubin in the blood (hyperbilirubinemia). Bilirubin is a yellowish waste product that is formed when the liver metabolizes hemoglobin.
When anemia is suspected to be caused by immune system dysfunction (autoimmune hemolytic anemia), 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. Warm antibody hemolytic anemia and cold antibody hemolytic anemia are distinguished from one another by the temperature at which autoantibodies bind most efficiently to red blood cells.
A specific chemical compound called dithiothreitol (DTT) may be used to distinguish warm antibody hemolytic anemia caused by IgM autoantibodies from the more common form caused by IgG autoantibodies. DTT reacts with IgM, but not with IgG.
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 initially recommended followed by a gradual reduction (tapering) of the dose over the next few weeks or months.
For individuals who do not respond to corticosteroid therapy or develop intolerable side effects, immunosuppressive drugs may be administered or surgical removal of the spleen (splenectomy) may be performed. Immunosuppressive drugs such as cyclophosphamide are drugs that suppress or block the immune system and have benefited some individuals with warm antibody hemolytic anemia who fail to respond to prednisone or splenectomy. Splenectomy is usually used for people with severe cases that require continual prednisone for control. In affected individuals with an underlying disorder, treatment of the disorder usually brings marked improvement of the anemia.
Rituximab is a monoclonal antibody, an artificially-created antibody that targets certain white blood cells that create the antibodies which prematurely destroy red blood cells. Rituximab has proven beneficial in some individuals with warm antibody hemolytic anemia who did not respond to prednisone (refractory disease). The response rate may be as high as 80% in adults and 60% in children. Rituximab may be used before splenectomy or may be used in individuals who relapse after splenectomy.
Red blood cell transfusions may be necessary to maintain proper red blood cell levels 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, splenectomy or rituximab. There are no randomized trials to guide therapy of those who do not respond. Successful use of several drugs has been reported, including azathioprine, danazol, cyclophosphamide, alemtuzumab, cyclosporine and mycophenylate mofetil. The risks and benefits of these drugs in autoimmune hemolytic anemia have not been defined, nor do we know the response rates. However, cures are not expected with these treatments.
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