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Warm Antibody Hemolytic Anemia

NORD is very grateful to Charles H. Packman, MD, Clinical Professor of Medicine, University of North Carolina School of Medicine, Chief, Hematology-Oncology Section, Carolinas Medical Center, for assistance in the preparation of this report.

Synonyms of Warm Antibody Hemolytic Anemia

  • idiopathic warm antibody hemolytic anemia
  • primary warm antibody hemolytic anemia
  • warm antibody autoimmune hemolytic anemia
  • warm reacting antibody disease

Disorder Subdivisions

  • warm autoimmune hemolytic anemia secondary to IgM autoantibodies
  • warm-reactive AIHA secondary to IgM

General Discussion

Warm antibody hemolytic anemia is an autoimmune disorder characterized by the premature destruction of healthy red blood cells by autoantibodies. Autoimmune diseases occur when the body's natural defenses against foreign organisms (e.g., lymphocytes, antibodies) destroy healthy tissue for unknown reasons. Normally, red blood cells have a life span of approximately 120 days before they are removed by the spleen. The medical term for low levels of circulating red blood cells is anemia. Anemia may cause fatigue, a pale skin color (pallor), yellowing of the skin and whites of the eyes (jaundice) and the passage of blood in the urine (hemoglobinuria), which gives the urine a dark brown color. Warm antibody hemolytic anemia is classified as an autoimmune hemolytic anemia (AIHA), an uncommon group of disorders in which the immune system mistakenly attacks healthy red blood cells.

Symptoms

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 (hepatolmegaly) may also occur in some cases.

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.

Some individuals have a rare form of the warm antibody hemolytic anemia caused by IgM antibodies (as opposed to the more common form caused by IgG antibodies.

Causes

In most cases, the cause of warm antibody hemolytic anemia is 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.

Affected Populations

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.

Related Disorders

Symptoms of the following disorders can be similar to those of warm antibody hemolytic anemia. Comparisons may be useful for a differential diagnosis.

Cold antibody hemolytic anemia (CAHA) is a rare autoimmune disorder characterized by the premature destruction of red blood cells (RBCs) by the body's natural defenses against invading organisms (antibodies). Normally, the red blood cells have a life span of approximately 120 days before they are destroyed by the spleen. In individuals with CAHA, 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. The severity of the anemia is determined by the length of time that the red blood cells survive and by the rate at which the bone marrow continues to create new red blood cell production. In most cases, CAHA is a primary disorder that typically becomes apparent at 50 to 60 years of age. Symptoms and findings associated with the disorder may include fatigue; low levels of circulating red blood cells (anemia); persistent yellowing of the skin, mucous membranes, and whites of the eyes (jaundice); and/or sweating and coldness of the fingers and/or toes (digits) and uneven bluish or reddish discoloration of the skin of the digits, ankles, and wrists (acrocyanosis or Raynaud's sign). Although CAHA is known to be an autoimmune disorder, its exact underlying cause is not fully understood. (For more information on this disorder, choose "cold antibody hemolytic anemia" as your search term in the Rare Disease Database.)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired stem cell disorder. The classic finding is the premature destruction of red blood cells (hemolysis), resulting in repeated episodes of hemoglobin in the urine (hemoglobinuria). Hemoglobin is the red, iron-rich pigment of blood. Individuals with hemoglobinuria may exhibit dark-colored or bloody urine. This finding is most prominent in the morning, after the urine has concentrated overnight during sleep. In addition to hemolysis, individuals with PNH are also susceptible to developing repeated, potentially life-threatening blood clots (thromboses). Affected individuals also have some degree of underlying bone marrow dysfunction. Severe bone marrow dysfunction potentially results in low levels of red and white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary great and affected individuals usually do not exhibit all of the symptoms potentially associated with the disorder. Two factors are necessary for the development of PNH: an acquired somatic (not passed on to children) mutation of the PIG-A gene, which affects hematopoietic stem cells creating defective "PNH" blood cells, and a predisposition to the multiplication and expansion of these defective stem cells. Most likely, PNH arises in the setting of autoimmune bone marrow failure, as occurs in most cases of acquired aplastic anemia. Researchers believe that defective PNH stem cells survive the misguided attack by the immune system and multiply, while the healthy stem cells are destroyed, resulting in the development of PNH. (For more information on this disorder, choose "paroxysmal nocturnal hemoglobinuria" as your search term in the Rare Disease Database.)

Thrombotic thrombocytopenia purpura (TTP) is a rare, serious blood disease. Major symptoms may include a severe decrease in the number of blood platelets (thrombocytopenia), abnormal destruction of red blood cells (hemolytic anemia), and disturbances in the nervous system. Affected individuals also exhibit red rash-like areas of skin or patches of purplish discoloration (purpura) resulting from abnormal bleeding into the mucous membranes (the thin, moist layer lining the body's cavities) and into the skin similar to ITP. The exact cause of thrombotic thrombocytopenia purpura is unknown. (For more information on this disorder, choose "thrombotic thrombocytopenia purpura" as your search term in the Rare Disease Database).

Standard Therapies

Diagnosis
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 hemoglobulin 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 elevated levels of immature red blood cells (reticulocytes), which occurs when the body is forced too 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.

Treatment
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. Surgical removal of the spleen (splenectomy) is usually used for 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.

Red blood cell transfusions may be necessary to maintain proper red blood cell levels in severe cases. This supportive technique provides temporary relief, but does not treat the underlying cause of the disorder.

Investigational Therapies

Researchers are studying a specific immunosuppressive drug known as rituximab as a potential treatment for individuals with warm antibody hemolytic anemia. Rituximab is a monoclonal antibody, an artificially-created antibody that targets certain white blood cells that create the antibodies which prematurely breakdown red blood cells. Rituximab has proven beneficial in some individuals with warm antibody hemolytic anemia who did not respond to other treatments (refractory disease). More research is necessary to determine the long-term safety and effectiveness of this potential therapy for individuals with warm antibody hemolytic anemia.

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:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Warm Antibody Hemolytic Anemia Resources

Organizations:

References

TEXTBOOKS
Packman, CH. Hemolytic Anemia Resulting from Immune Injury. In Kaushansky K; Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, Prchal JT eds. Williams Hematology, 8th ed. New York, NY: McGraw Hill; 2010:777-798.

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
Lechner K, J├Ąger 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.

D'Arena 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
Schick P. Hemolytic Anemia. Emedicine. http://emedicine.medscape.com/article/201066-overview. Updated August 8, 2011. Accessed March 14, 2012.

National Heart, Lung and Blood Institute. What is Hemolytic Anemia? http://www.nhlbi.nih.gov/health/health-topics/topics/ha/. Updated April 1, 2011. Accessed March 14, 2012.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2012/03/16 00:00:00 GMT+0

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