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Autoimmune hemolytic anemia

autoimmune hemolytic anemia, autoimmune hemolytic anemia in dogs
Autoimmune hemolytic anemia or autoimmune haemolytic anaemia; AIHA occurs when antibodies directed against the person's own red blood cells RBCs cause them to burst lyse, leading to an insufficient number of oxygen-carrying red blood cells in the circulation The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases12 The intracellular components of the RBCs are released into the circulating blood and into tissues, leading to some of the characteristic symptoms of this condition The antibodies are usually directed against high-incidence antigens, therefore they also commonly act on allogenic RBCs RBCs originating from outside the person themselves, eg in the case of a blood transfusion3 AIHA is a relatively rare condition, affecting one to three people per 100,000 per year4

The terminology used in this disease is somewhat ambiguous Although MeSH uses the term "autoimmune hemolytic anemia",5 some sources prefer the term "immunohemolytic anemia" so drug reactions can be included in this category67 The National Cancer Institute considers "immunohemolytic anemia", "autoimmune hemolytic anemia", and "immune complex hemolytic anemia" to all be synonyms8


  • 1 Classification
  • 2 Causes
  • 3 Pathophysiology
  • 4 Diagnosis
    • 41 Evidence for hemolysis
  • 5 Treatment
  • 6 History
  • 7 In children
  • 8 See also
  • 9 References
  • 10 External links


AIHA is classified as either warm autoimmune hemolytic anemia or cold autoimmune hemolytic anemia, which includes cold agglutinin disease and paroxysmal cold hemoglobinuria These classifications are based on the characteristics of the autoantibodies involved in the pathogenesis of the disease Each has a different underlying cause, management, and prognosis, making classification important when treating a patient with AIHA


The causes of AIHA are poorly understood The disease may be primary, or secondary to another underlying illness The primary illness is idiopathic the two terms used synonymously Idiopathic AIHA accounts for approximately 50% of cases9 Secondary AIHA can result from many other illnesses Warm and cold type AIHA each have their own more common secondary causes The most common causes of secondary warm-type AIHA include lymphoproliferative disorders eg, chronic lymphocytic leukemia, lymphoma and other autoimmune disorders eg, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, crohn's disease, ulcerative colitis Less common causes of warm-type AIHA include neoplasms other than lymphoid, and infection Secondary cold type AIHA is also caused primarily by lymphoproliferative disorders, but is also commonly caused by infection, especially by mycoplasma, viral pneumonia, infectious mononucleosis, and other respiratory infections Less commonly, it can be caused by concomitant autoimmune disorders10

Drug-induced AIHA, though rare, can be caused by a number of drugs, including α-methyldopa and penicillin This is a type II immune response in which the drug binds to macromolecules on the surface of the RBCs and acts as an antigen Antibodies are produced against the RBCs, which leads to complement activation Complement fragments, such as C3a, C4a and C5a, activate granular leukocytes eg, neutrophils, while other components of the system C6, C7, C8, C9 either can form the membrane attack complex MAC or can bind the antibody, aiding phagocytosis by macrophages C3b This is one type of "penicillin allergy"


AIHA can be caused by a number of different classes of antibody, with IgG and IgM antibodies being the main causative classes Depending on which is involved, the pathology will differ IgG is not very effective at activating complement and effectively binds the Fc receptor FcR of phagocytic cells,11 AIHA involving IgG is generally characterized by phagocytosis of RBCs IgM is a potent activator of the classical complement pathway, thus, AIHA involving IgM is characterized by complement mediated lysis of RBCs IgM also leads to phagocytosis of RBCs however, because phagocytic cells have receptors for the bound complement rather than FcRs as in IgG AIHA In general, IgG AIHA takes place in the spleen, whereas IgM AIHA takes place in Kupffer cells – phagocytic cells of the liver Phagocytic AIHA is termed extravascular, whereas complement-mediated lysis of RBCs is termed intravascular AIHA In order for intravascular AIHA to be recognizable, it requires overwhelming complement activation, therefore most AIHA is extravascular – be it IgG- or IgM-mediated3

AIHA cannot be attributed to any single autoantibody To determine the autoantibody or autoantibodies present in a patient, the Coombs test, also known as the antiglobulin test, is performed There are two types of Coombs tests, direct and indirect; more commonly, the direct antiglobulin test DAT is used Classification of the antibodies is based on their activity at different temperatures and their etiology Antibodies with high activity at physiological temperature approximately 37 °C are termed warm autoantibodies Cold autoantibodies act best at temperatures of 0–4 °C Patients with cold-type AIHA, therefore, have higher disease activity when body temperature falls into a hypothermic state Usually, the antibody becomes active when it reaches the limbs, at which point it opsonizes RBCs When these RBCs return to central regions, they are damaged by complement Patients may present with one or both types of autoantibodies; if both are present, the disease is termed "mixed-type" AIHA

When DAT is performed, the typical presentations of AIHA are as follows Warm-type AIHA shows a positive reaction with antisera to IgG antibodies with or without complement activation Cases may also arise with complement alone or with IgA, IgM or a combination of these three antibody classes and complement Cold-type AIHA usually reacts with antisera to complement and occasionally to the above antibodies This is the case in both cold agglutinin disease and cold paroxysmal hematuria In general, mixed warm and cold AIHA shows a positive reaction to IgG and complement, sometimes IgG alone, and sometimes complement alone Mixed-type can, like the others, present unusually with positive reactions to other antisera10


Diagnosis is made by first ruling out other causes of hemolytic anemia, such as G6PD, thalassemia, sickle-cell disease, etc Clinical history is also important to elucidate any underlying illness or medications that may have led to the disease

Following this, laboratory investigations are carried out to determine the etiology of the disease A positive DAT test has poor specificity for AIHA having many differential diagnoses; so supplemental serological testing is required to ascertain the cause of the positive reaction Hemolysis must also be demonstrated in the lab The typical tests used for this are a complete blood count CBC with peripheral smear, bilirubin, lactate dehydrogenase LDH in particular with isoenzyme 1, haptoglobin and urine hemoglobin3

Evidence for hemolysisedit

The following findings may be present:12full citation needed

  • Increased red cell breakdown
    • Elevated serum bilirubin unconjugated
    • Excess urinary urobilinogen
    • Reduced plasma haptoglobin
    • Raised serum lactic dehydrogenase LDH
    • Hemosiderinuria
    • Methemalbuminemia
    • Spherocytosis
  • Increased red cell production:
    • Reticulocytosis
    • Erythroid hyperplasia of the bone marrow
Specific investigations
  • Positive direct Coombs test


Much literature exists regarding the treatment of AIHA Efficacy of treatment depends on the correct diagnosis of either warm- or cold-type AIHA

Warm-type AIHA is usually a more insidious disease, not treatable by simply removing the underlying cause Corticosteroids are first-line therapy For those who fail to respond or have recurrent disease, splenectomy may be considered Other options for recurrent or relapsed disease include immunosuppressants such as rituximab, danazol, cyclophosphamide, azathioprine, or cyclosporine

Cold agglutinin disease is treated with avoidance of cold exposure Patients with more severe disease symptomatic anemia, transfusion dependence may be treated with rituximab Steroids and splenectomy are less efficacious in cold agglutinin disease13

Paroxysmal cold hemoglobinuria is treated by removing the underlying cause, such as infection14


"Blood-induced icterus" produced by the release of massive amounts of a coloring material from blood cells followed by the formation of bile was recognized and described by Vanlair and Voltaire Masius' in 1871 About 20 years later, Hayem distinguished between congenital hemolytic anemia and an acquired type of infectious icterus associated with chronic splenomegaly In 1904, Donath and Landsteiner suggested a serum factor was responsible for hemolysis in paroxysmal cold hemoglobinuria French investigators led by Chauffard stressed the importance of red-cell autoagglutination in patients with acquired hemolytic anemia In 1930, Lederer and Brill described cases of acute hemolysis with rapid onset of anemia and rapid recovery after transfusion therapy These hemolytic episodes were thought to be due to infectious agents A clear distinction between congenital and acquired hemolytic anemia was not drawn, however, until Dameshek and Schwartz in 1938, and, in 1940, they demonstrated the presence of abnormal hemolysins in the sera of patients with acquired hemolytic anemia and postulated an immune mechanism

During the past three decades, studies defining red-cell blood groups and serum antibodies have produced diagnostic methods that have laid the basis for immunologic concepts relevant to many of the acquired hemolytic states Of these developments, the antiglobulin test described by Coombs, Mourant, and Race in 1945 has proved to be one of the more important, useful tools now available for the detection of immune hemolytic states This technique demonstrated that a rabbit antibody against human globulin would induce agglutination of human red cells "coated with an incomplete variety of rhesus antibody" C Moreschlit had used the same method in 1908 in a goat antirabbit-red-cell system The test was premature and was forgotten In 1946, Boorman, Dodd, and Loutit applied the direct antiglobulin test to a variety of hemolytic anemias, and laid the foundation for the clear distinction of autoimmune from congenital hemolytic anemia

A hemolytic state exists whenever the red cell survival time is shortened from the normal average of 120 days Hemolytic anemia is the hemolytic state in which anemia is present, and bone marrow function is inferentially unable to compensate for the shortened life-span of the red cell Immune hemolytic states are those, both anemic and nonanemic, which involve immune mechanisms consisting of antigen-antibody reactions These reactions may result from unrelated antigen-antibody complexes that fix to an innocent-bystander erythrocyte, or from related antigen-antibody combinations in which the host red cell or some part of its structure is or has become antigenic The latter type of antigen-antibody reaction may be termed "autoimmune", and hemolytic anemias so produced are autoimmune hemolytic anemias2

In childrenedit

In general, AIHA in children has a good prognosis and is self-limiting However, if it presents within the first two years of life or in the teenage years, the disease often follows a more chronic course, requiring long-term immunosuppression, with serious developmental consequences The aim of therapy may sometimes be to lower the use of steroids in the control of the disease In this case, splenectomy may be considered, as well as other immunosuppressive drugs Infection is a serious concern in patients on long-term immunosuppressant therapy, especially in very young children less than two years15

See alsoedit

  • Hematology
  • Hemolytic anemia
  • List of circulatory system conditions
  • List of hematologic conditions


  1. ^ Shoenfield, Y; et al 2008 Diagnostic Criteria in Autoimmune Disease Humana Press 
  2. ^ a b Sawitsky A, Ozaeta PB June 1970 "Disease-associated autoimmune hemolytic anemia" Bull N Y Acad Med 46 6: 411–26 PMC 1749710  PMID 5267234 
  3. ^ a b c Gehrs BC, Friedberg RC April 2002 "Autoimmune hemolytic anemia" Am J Hematol 69 4: 258–71 PMID 11921020 doi:101002/ajh10062 
  4. ^ Böttiger LE, Westerholm B March 1973 "Acquired haemolytic anaemia I Incidence and aetiology" Acta Med Scand 193 3: 223–6 PMID 4739592 doi:101111/j0954-68201973tb10567x 
  5. ^ Autoimmune hemolytic anemia at the US National Library of Medicine Medical Subject Headings MeSH
  6. ^ Wright MS 1999 "Drug-induced hemolytic anemias: increasing complications to therapeutic interventions" Clin Lab Sci 12 2: 115–8 PMID 10387489 
  7. ^ Cotran, Ramzi S; Kumar, Vinay; Fausto, Nelson; Nelso Fausto; Robbins, Stanley L; Abbas, Abul K 2005 Robbins and Cotran pathologic basis of disease St Louis, Mo: Elsevier Saunders p 636 ISBN 0-7216-0187-1 
  8. ^ "Definition of immunohemolytic anemia" NCI Dictionary of Cancer Terms Archived from the original on 15 January 2009 Retrieved 2009-02-07 
  9. ^ Gupta S, Szerszen A, Nakhl F, et al 2011 "Severe refractory autoimmune hemolytic anemia with both warm and cold autoantibodies that responded completely to a single cycle of rituximab: a case report" J Med Case Reports 5: 156 PMC 3096571  PMID 21504611 doi:101186/1752-1947-5-156 
  10. ^ a b Sokol RJ, Hewitt S, Stamps BK June 1981 "Autoimmune haemolysis: an 18-year study of 865 cases referred to a regional transfusion centre" Br Med J Clin Res Ed 282 6281: 2023–7 PMC 1505955  PMID 6788179 doi:101136/bmj28262812023 
  11. ^ Abramson N, Gelfand EW, Jandl JH, Rosen FS December 1970 "The interaction between human monocytes and red cells Specificity for IgG subclasses and IgG fragments" J Exp Med 132 6: 1207–15 PMC 2180500  PMID 5511570 doi:101084/jem13261207 
  12. ^ Kumar P, Clark M 2005 Clinical Medicine 6th ed Elsevier Saunders p 437 
  13. ^ Go, R S, Winters, J L, & Kay, N E 2017 How I treat autoimmune hemolytic anemia Blood, , blood-2016-11-693689 Accessed April 28, 2017 doi:101182/blood-2016-11-693689
  14. ^ Bradencarter 21 January 2017 "Hemolytic Anemia Treatment" hemolyticanemiaorg Retrieved 21 January 2017 
  15. ^ Zecca M, Nobili B, Ramenghi U, et al May 2003 "Rituximab for the treatment of refractory autoimmune hemolytic anemia in children" Blood 101 10: 3857–61 PMID 12531800 doi:101182/blood-2002-11-3547 

External linksedit

  • Case report of Autoimmune Hemolytic Anemia with typical laboratory findings Clinical Cases and Images

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