Autoimmune hemolytic anemia (AIHA) is caused by autoantibodies that bind to and destroy a person's own red blood cells. There are several subtypes depending on the temperature sensitivity of the autoantibodies. Warm AIHA is the most common type and involves IgG autoantibodies that bind to red blood cells at 37°C, leading to their destruction. Cold AIHA involves IgM autoantibodies that agglutinate red blood cells at 4°C and activate the complement system. Symptoms are typically slow in onset and include anemia, jaundice, and splenomegaly. Diagnosis involves detection of antibody-coated red blood cells via the direct antiglobulin

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Autoimmune Hemolytic
Anemia (AIHA)
Becca Greenstein and Rebekah Wood
Immunology
2 December 2014
What is AIHA?
• Increased destruction of erythrocytes due to the
presence of anti-erythrocyte autoantibodies (AEA)
• Decreased life span
• Multiple types
• Primary, Secondary, Warm, Cold, Mixed, and Drug
induced

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Symptoms
 Onset typically slow
 Referable to anemia
 In secondary AIHA,
symptoms of primary
illness may overshadow
 Jaundice
 Splenomegaly ~20%
Erythrophagocytosis
Figure 1 Hematological Diseases http://www.medvet.umontreal.ca/clinpath/banq-im/cytology/erythophagieE.htm

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Epidemiology
• Annual incidence is approximately 1-3 cases per
100,000 people
• Primarily found in adults – More severe
• Children with primary immunodeficiency
• Major is idiopathic
• Secondary-Malignant lymphoproliferative diseases,
drugs, and viral infections
• No known predisposition
AIHA Subtypes
• Classification based on optimal RBC-autoantibody
reactivity temperatures
• Warm and Cold AIHA more predominant
• Warm is IgG (Opsinization) autoantibodies that bind
optimally at 37°C
• Cold is IgM (Complement) that strongly agglutinates at
4°C
• Glucocorticoids
• Pathogenesis, diagnosis, and treatment vary greatly
between subtypes

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Warm AIHA (wAIHA)
• 1 in 80,000
• Predominant type found in children
• Secondary wAIHA – mononucleosis, HIV, and chronic
lymphocytic lymphoma
• Optimal temperature of 37°C
• Usually associated with IgG (Also IgA and IgM)
• The etiology underlying the pathogenesis of such
autoantibodies is still unclear
wAIHA Continued
 Binding of self AB (Polyclonal) to Rh proteins, causing
Fcγ receptors to mediate removal of RBCs within the
spleen
 Imbalances in IL-10 and IL-12 believed to play a role
 Molecular mimicry
 Exogenous antigens mimic an autoantigen (Influenza
Virus)
 Autoantibodies induced nonspecifically and transiently
during microbial infections

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wAIHA Mechanism
Cold AIHA (cAIHA)
 Caused by cold agglutinin syndrome (CAS) or paroxysmal
cold hemoglobinuria (PCH)
 Less prevalent than wAIHA
 Mainly affects middle-aged or elderly
 Complement-dependent manner
 I/i - Blood type that contains specific carbohydrates C3
proteins
 Most are IgM (Formation of MAC)
 Optimal temperature of 4°C
 Presence of cold stress increases AEA activity, facilitating RBC
lysis
 Occurs often in extremities

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cAIHA Mechanism
Drug induced (diAIHA) and
Mixed (mAIHA)
 Both rare
 diAIHA – associated with ~150 drugs
 Hapten-type
 Drug-autoantibody immune complexes
 Methyldopa
 mAIHA – presence of warm and cold
 IgM and IgG

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Diagnosis
 Recognition of hemolysis and anemia
 Jaundice and abnormally dark urine
 Direct antiglobulin test (DAT) or Coombs test
 Anti-human globulins are used to assess the presence of
antibody coated RBCs via agglutination
 Polyclonal and monoclonal
 Possibly flow cytometry
 Increased sensitivity for RBC-bound Ig detection
Diagnosis
http://emedicine.medscape.com/article/1731264-overview

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Treatments
 Based on type of antibody involved (IgG, IgM, or IgA)
and whether primary or secondary
 Fc receptor-competition – Intravenous infusion of IgG
 The mechanism of the IVIG effect in AIHA appears to
be related to the saturation of Fc phagocyte
receptors in reticuloendothelial system that is
amplified in AIHA patients
Treatments Continued
 Immunotherapy – the treatment of disease by inducing,
enhancing, or suppressing an immune response
 Classified as suppression immunotherapy if the
immunotherapy reduces or suppresses the immune
response
 Corticosteroids or Rituximab
 Rituximab is a humanized monoclonal antibody directed
against CD20 on pre-B cells and mature B lymphocytes
 Severe anemia/ Other drugs will not work
 High Dose immunosuppressive drugs and stem cell
transplantation

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Future Treatments
 More efficacious and less toxic
 Soluble receptors, monoclonal antibodies, and molecular
mimetics
 Possibly gene therapy
 Multigenetic control
 Aia-1 allele (chromosome 4)
 Suppressive genes Aem-1, Aem-2, Aem-3
 Down-regulate production of AEA
Study Questions
1. Describe Autoimmune Hemolytic Anemia and the mechanism for
the warm subtype.
2. Which of the following correctly describes the mechanism of
Cold AIHA?
a. The binding of warm IgG AEA to erythrocytes does not itself damage
the erythrocytes
b. Surface bound IgG is usually recognized by Fcγ receptors of cells of
the monocyte-macrophage phagocytic system, preferentially in the
spleen and liver, resulting in uptake and destruction of IgG-
opsonized erythrocytes
c. IgM autoantibodies bind to I/i carbohydrate on RBCs and form
multivalent complex. Upon returning to the central part of the body
the IgM complex detaches, leaving C3b, an opsonizing complement
molecule. C3b then allows trapping and phagocytosis of RBC by
kupffer cells.

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Study Questions
3. Which is not a treatment or potential treatment for AIHA?
a. The treatment of the disease using the drug Rituximab, which contains
humanized monoclonal antibody directed against CD20 on pre-B cells
and mature B lymphocytes and results in apoptosis of CD20 positive
cells.
b. The treatment of the disease using the drug Imiquimod, which activates
the innate immune system through TLR-7 and can lead to the activation
of B-cells through cell migration to the lymph nodes.
c. Removal of the spleen to eliminate a large portion of potential
autoerythrocyte antibody producing B-cells
d. Gene therapy that utilizes suppressive genes to downregulate the
production of anti-erythrocyte auto-antibodies
Study Questions
4. Which type of AIHA is the most common?
a. Cold
b. Mixed
c. Warm
d. Drug Induced

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Study Questions
5. Which of the following statements about AIHA is
false?
a. Mixed AIHA involves the formation of hapten molecules that
activate an immune response.
b. The onset of symptoms of AIHA is typically slow, but can
include dizziness, jaundice, and rapid heart beat.
c. There is no race or gender component, no age pre-
selection, and no identified genetic background for AIHA.
d. The most common test for AIHA is the direct antiglobulin test
(DAT), which utilizes anti-human globulins to detect the
presence of antibody coated RBCs via agglutination.
Answers
1. Autoimmune Hemolytic Anemia is the increased destruction of
erythrocytes due to the presence of anti-erythrocyte
autoantibodies (AEA).
1. Binding of self AB (Polyclonal) to Rh proteins, causing Fcγ
receptors to mediate removal of RBCs within the spleen
2. Imbalances in IL-10 and IL-12 believed to play a role
2. C
3. B
4. C
5. A

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References
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Oncology: Children’s Hospital & Research Center Oakland, Second Edition. 10-17.
Lambert J, Nydegger UE. 2010. Geoepidemiology of autoimmune diseases. Autoimmunity Reviews 9: 350-354.
Liu B, Gu W. 2013. Immunotherapy treatments of warm autoimmune hemolytic anemia. Clinical and developmental
Immunology. 1-6.
Olsson M, Hagnerud S, Hedelius DUR, Oldenborg P. 2006. Hematologic diseases: Autoimmune hemolytic anemia
and immune thrombocytopenic purpura. Immunogenetics of Autoimmune Disease. 135-143.
Petz L. Cold antibody autoimmune hemolytic anemias. Blood reviews. 2008. 22. 1-15.
Stahl D, Sibrowski W. Warm autoimmune hemolytic anemia is an IgM-IgG immune complex disease. Journal of
Autoimmunity. 2005. 25. 272-282.