Autoimmune haemolytic anaemia

Autoimmune hemolytic anemia is caused by autoantibodies that react with RBCs at temperatures ≥ 37°
C (warm antibody hemolytic anemia) or < 37° C (cold agglutinin disease). Hemolysis is usually
extravascular.

Etiology

 Warm antibody hemolytic anemia

Warm antibody hemolytic anemia is the most common form of autoimmune hemolytic anemia
(AIHA); it is more common among women. They may occur spontaneously or in association with
certain disorders (SLE, lymphoma, chronic lymphocytic leukemia). Some drugs (eg, α-methyldopa,
levodopa) stimulate production of autoantibodies against Rh antigens (α-methyldopa-type of AIHA).
Other drugs stimulate production of autoantibodies against the antibiotic–RBC-membrane complex
as part of a transient hapten mechanism; the hapten may be stable (eg, high-dose penicillin,
cephalosporins) or unstable (eg, quinidine, sulfonamides).
In warm antibody hemolytic anemia, hemolysis occurs primarily in the spleen. It is often severe and
can be fatal. Most of the autoantibodies in warm antibody hemolytic anemia are IgG. Most are
panagglutinins and have limited specificity.
 Cold agglutinin disease
Cold agglutinin disease sometimes occurs with infections (especially mycoplasmal pneumonias or
infectious mononucleosis) and lymphoproliferative states; about ½ of cases are idiopathic, which is
the common form in older adults. Infections tend to cause acute disease, whereas idiopathic disease
tends to be chronic. The hemolysis occurs largely in the extravascular mononuclear phagocyte
system of the liver. The anemia is usually mild (Hb > 7.5 g/dL). Autoantibodies in cold agglutinin
disease are usually IgM. The higher the temperature (ie, the closer to normal body temperature) at
which these antibodies react with the RBC, the greater the hemolysis.
 Paroxysmal cold hemoglobinuria
Paroxysmal cold hemoglobinuria (PCH; Donath-Landsteiner syndrome) is a rare type of cold
agglutinin disease. Hemolysis results from exposure to cold which may even be localized (eg, from
drinking cold water, from washing hands in cold water). An IgG autohemolysin binds to RBCs at low
temperatures and causes intravascular hemolysis after warming. It occurs most often after a
nonspecific viral illness or in otherwise healthy patients, although it occurs in some patients with
congenital or acquired syphilis.
 Symptoms

If the disorder is severe, fever, chest pain, syncope, or heart failure may occur. Mild splenomegaly is
typical.

Cold agglutinin disease manifests as an acute or chronic hemolytic anemia. Other cryopathic symptoms
or signs may be present (eg, acrocyanoses, Raynaud’s syndrome, cold-associated occlusive changes).
Symptoms of PCH may include severe pain in the back and legs, headache, vomiting, diarrhea, and
passage of dark brown urine; hepatosplenomegaly may be present.

Diagnosis
 Assays for hemolytic anemia (eg, peripheral smear, reticulocyte count; sometimes urinary
hemosiderin, serum haptoglobin)
 Direct antiglobulin test
Routine laboratory tests generally suggest extravascular hemolysis (eg, hemosiderinuria is absent;
haptoglobin levels are near normal) unless anemia is sudden and severe or PCH is the cause.
Spherocytosis and a high MCHC are typical. AIHA is diagnosed by detection of autoantibodies with the
direct antiglobulin (direct Coombs’) test, agglutination indicates the presence of immunoglobulin or
complement (C) bound to the RBCs. Generally IgG is present in warm antibody hemolytic anemia, and C3
(C3b and C3d) in cold antibody disease. Once AIHA has been identified by the Coombs’ test, testing
should differentiate between warm antibody hemolytic anemia and cold agglutinin disease. This is
achieved by observing the pattern of the direct antiglobulin reaction. Three patterns are possible;
 The reaction is positive with anti-IgG and negative with anti-C3. This pattern is common in
idiopathic AIHA and in the drug-associated or α-methyldopa-type of AIHA, usually warm antibody
hemolytic anemia.
 The reaction is positive with anti-IgG and anti-C3. This pattern is common in patients with SLE
and idiopathic AIHA, usually warm antibody hemolytic anemia, and is rare in drug-associated cases.
 The reaction is positive with anti-C3 but negative with anti-IgG. This pattern occurs in cold
agglutinin disease. It is uncommon in idiopathic AIHA, warm antibody hemolytic anemia

Treatment
 For drug-induced warm antibody hemolytic anemia, drug withdrawal, sometimes IV immune
globulin
 For idiopathic warm antibody hemolytic anemia, corticosteroids
 For cold agglutinin disease, avoidance of cold