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C H A P T E R 46

AUTOIMMUNE HEMOLYTIC ANEMIA

Marc Michel and Ulrich Jäger

Autoimmune hemolytic anemia (AIHA) is caused by autoimmune- alone are destroyed in the spleen and liver, IgG-coated cells in the
mediated destruction of red blood cells (RBCs) by autoantibodies spleen, and IgM-coated cells in the liver. 11,12 This has major implica-
with various properties and target specificities. Exact laboratory tions for treatment, particularly for the effect of steroids and
diagnosis is often difficult; therefore, experienced diagnostic reference splenectomy.
centers play an important role. The disease can be primary (idio-
pathic) or caused by an underlying condition (secondary), including
autoimmune diseases, infections, drugs, or neoplasms. The clinical Warm Antibody Hemolytic Anemia
course of the disease as well as treatment decisions are influenced by
the type of antibody involved. Success in treatment and the evalua- About 70% to 80% of cases of AIHA are caused by WAIHAs. The
tion of therapies have lagged behind the achievements in laboratory RBC antibodies in WAIHAs are mostly polyclonal IgG (IgG 1–4),
diagnosis but will hopefully improve with the introduction of new which have a low capacity to activate the complement system (Table
effective drugs. Currently, almost all treatments in AIHA are based on 46.1). The direct antiglobulin test (DAT) in WAIHAs is positive
experience and opinion but not on evidence. There are no established either with IgG (37%) or IgG + C3d (43%). Rarely, the DAT is only
guidelines. Thus, management of the disease requires general hema- positive with C3d (when the amount of IgG on the RBCs is very
tologic skills and critical evaluation of treatment recommendations. small). Patients with IgG antibodies may have also IgA antibodies,
but IgA antibodies without IgG antibodies are a very rare cause of
WAIHAs. WAIHAs are often directed against Rh antigens but also
HISTORY against other blood group antigens (non–Rh-related autoantibod-
ies) such as band 3 protein or glycophorin A. The antibodies fix
The history of diagnostic and therapeutic progress in AIHA has been complement and bind tightly to the RBCs at 37°C. Therefore, there
1
described by Dacie, one of the great pioneers in this field. Milestones is only a small amount of antibody detectable in the serum. The
were the discovery of the first RBC autoantibody (Donath–Landsteiner antibody-coated RBCs are removed from the circulation by splenic
antibody) in 1904, the introduction of the Coombs test in 1945, the (to a lesser degree also by hepatic) macrophages via F cγ RIII receptors.
establishment of splenectomy as effective treatment of AIHA in the IgG 3 and IgG 1 have the highest affinity for the Fc receptors of mac-
1950s, and the finding that rituximab is an effective treatment in rophages. Erythrocytes that are only partially phagocytosed by the
the past decade. The diagnosis and treatment of patients with AIHA macrophages become spherocytes, which are removed in the splenic
were recently reviewed by several authors. 2–8 cords because of their rigid structure. Destruction of RBCs may also
be caused by other mechanisms such as antibody-dependent cellular
cytotoxicity. 13
EPIDEMIOLOGY IgM WAIHAs are a very rare cause of AIHA. This type of AIHA
can be suspected if RBC autoagglutination occurs at room tempera-
Because only a low proportion of patients have spontaneous or ture. The DAT result is positive with C3d alone (65%) or with IgG
treatment-induced long-term remissions and the death rate is low, (24%). Using sensitive methods, IgM on the RBCs can be detected
14
the prevalence of AIHA is relatively high and has been estimated as in 71%. Non-Hodgkin lymphoma (NHL) is the underlying disease
17 in 100,000 (in Denmark). The incidence of AIHA in children in some of these cases. This AIHA is severe, often fatal, and refractory
9
and teenagers is 0.2–1.0 per million per year. There is some evidence to steroids and splenectomy.
of a familial clustering of AIHA in children, but no hereditary genetic
background has been identified.
Primary AIHA and Evans syndrome are slightly more prevalent Cold Antibody Hemolytic Anemia
10
in women and in children. In secondary AIHA, the female-to-male
ratio is very high in systemic lupus erythematosus (SLE), but low in CAIHAs in primary or secondary CAIHA are usually monoclonal
chronic lymphocytic leukemia (CLL)-associated AIHA. The inci- IgM. The IgM has two binding sites for C1q and fixes complement
T
dence of chronic cold agglutinin disease (CAD) is estimated to be easily. The targets are polysaccharides (I, I , I, or Pr antigens). The
one per million per year, with a female prevalence. Geographical “i” antigen is a nonbranched polysaccharide in the cord blood, and
differences have been suggested, with a higher incidence of CAD in the “I” antigen is a similar but branched molecule expressed in the
Northern climates. RBCs of adults. The CAIHAs bind to the RBCs at low temperatures
and cause their lysis at temperatures above 22°C. The DAT is typi-
cally positive with C3d alone. When CAIHAs are present at high
PATHOBIOLOGY titers, they may activate the complement system directly and produce
a membrane attack complex and intravascular hemolysis with hemo-
Hemolysis is initiated when an autoantibody binds to the RBC globinuria. Usually the complement-coated RBCs are sequestered by
membranes and recruits complement. Destruction of the RBC can liver macrophages.
occur directly in the circulation (intravascular hemolysis) or by Paroxysmal cold hemoglobinuria (PCH) is caused by the Donath–
removal of the cell by macrophages in the spleen, liver, or both Landsteiner (DL) antibody. This is a rare, usually polyclonal IgG cold
(extravascular hemolysis) (Fig. 46.1). Several immunoglobulin (Ig) antibody to P antigen (glycosphingolipid globoside), which binds to
subclasses can fix complement: IgG, IgA, and IgM. Macrophages the RBCs at 4°C. The cells are lysed at higher temperatures. The
recognize opsonized erythrocytes via receptors specific for the Fc DAT is positive with C3d, and the diagnosis is made by the DL test.
fragment of IgG and for C3d. RBCs coated with IgG or complement In this test, normal RBCs and patient and normal serum are

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