Autoimmune hemolytic anemia

Autoimmune hemolytic anemia

Classification and external resources
ICD-10

D59.0-D59.1

ICD-9

283.0

MeSH

D000744

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 insufficient plasma concentration. The lifetime of the RBCs is reduced from the
normal 100120 days to just a few days in serious cases.[1][2] 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 highincidence antigens, therefore they also commonly act on allogenic RBCs (RBCs originating from
outside the person themselves, e.g. in the case of a blood transfusion)[3] AIHA is a relatively rare
condition, affecting one to three people per 100,000 per year.[4]
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 category.[6][7]The National Cancer Institute considers
"immunohemolytic anemia", "autoimmune hemolytic anemia", and "immune complex hemolytic
anemia" to all be synonyms.[8]
Contents
[hide]

1 Classification

2 Causes

3 Pathophysiology

4 Diagnosis

o 4.1 Evidence for hemolysis[12]

5 Treatment

6 History

7 In children

8 See also

9 References

10 External links

Classification[edit]
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.
Causes[edit]
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 cases.[9] 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 (e.g., chronic lymphocytic leukemia, lymphoma) and other autoimmune disorders
(e.g., systemic lupus erythematosus,rheumatoid arthritis, scleroderma, 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 disorders.[10]
Drug-induced AIHA, though rare, can be caused by a number of drugs, including 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 (e.g., 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".

Pathophysiology[edit]
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-mediated.[3]
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 test, 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 04 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 withantisera 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 antisera.[10]
Diagnosis[edit]
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
CBC with peripheral smear, bilirubin, LDH (in particular with isoenzyme 1), haptoglobin and
urine hemoglobin.[3]
Evidence for hemolysis[12][edit]

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

Treatment[edit]
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. First-line therapy for this is usually with corticosteroids, such as prednisolone.
Following this, other immunosuppressants are considered, such
as rituximab, danazol, cyclophosphamide, azathioprine, or cyclosporine.

Cold agglutinin disease is treated by avoiding the cold or sometimes with rituximab. Removal of
the underlying cause is also important.
Paroxysmal cold hemoglobinuria is treated by removing the underlying cause, such as infection.
History[edit]
"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
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 redcell 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 anemias.[2]

In children[edit]
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 years).[13]
See also[edit]

Hematology

Hemolytic anemia

List of circulatory system conditions

List of hematologic conditions

References[edit]
1. Jump up^ Shoenfield, Y et al. (2008). Diagnostic Criteria in Autoimmune
Disease. Humana Press.
2. ^ Jump up to: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. ^ Jump up to:a b c Gehrs BC, Friedberg RC (April 2002). "Autoimmune hemolytic
anemia". Am. J. Hematol. 69 (4): 258
71.doi:10.1002/ajh.10062. PMID 11921020.
4. Jump up^ Bttiger LE, Westerholm B (March 1973). "Acquired haemolytic
anaemia. I. Incidence and aetiology". Acta Med Scand 193 (3): 223
6. doi:10.1111/j.0954-6820.1973.tb10567.x. PMID 4739592.
5. Jump up^ Autoimmune hemolytic anemia at the US National Library of
Medicine Medical Subject Headings (MeSH)
6. Jump up^ Wright MS (1999). "Drug-induced hemolytic anemias: increasing
complications to therapeutic interventions". Clin Lab Sci 12 (2): 115
8. PMID 10387489.

7. Jump up^ 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. Jump up^ "Definition of immunohemolytic anemia". NCI Dictionary of Cancer
Terms. Archived from the original on 15 January 2009. Retrieved 2009-02-07.
9. Jump up^ 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.doi:10.1186/1752-1947-5-156. PMC 3096571. PMID 21504611.
10. ^ Jump up to: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. doi:10.1136/bmj.282.6281.2023. PMC 1505955.PMID 6788179.
11. Jump up^ 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. doi:10.1084/jem.132.6.1207.PMC 2180500. PMID 5511570.
12. Jump up^ Kumar P, Clark M (2005). Clinical Medicine (6th ed.). Elsevier
Saunders. p. 437.
13. Jump up^ Zecca M, Nobili B, Ramenghi U et al. (May 2003). "Rituximab for the
treatment of refractory autoimmune hemolytic anemia in
children". Blood 101 (10): 385761. doi:10.1182/blood-2002-113547. PMID 12531800.