Transcript Autoimmune Hemolytic Anemias Associated With *Warm* Antibodies

By
Dr.AMEER E. AL-AASAM
In the autoimmune hemolytic anemias, abnormal antibodies are directed
against RBC membrane antigens, but the pathogenesis of antibody induction
is uncertain. The autoantibody may be produced as an inappropriate immune
response to an RBC antigen or to another antigenic epitope similar to an RBC
antigen, known as molecular mimicry. Alternatively, an infectious agent may
alter the RBC membrane so that it becomes “foreign” or antigenic to the host.
The antibodies usually react to epitopes (antigens) that are “public” or
common to all human RBCs, such as Rh proteins.
In most instances of warm antibody hemolysis, no underlying cause can be
found; this is the primary or idiopathic type (see Table 458-1). If the
autoimmune hemolysis is associated with an underlying disease, such as a
lymphoproliferative disorder, SLE, or immunodeficiency, it is secondary. In as
many as 20% of cases of immune hemolysis, drugs may be implicated (Table
458-2).
SELECTED DRUGS THAT CAUSE IMMUNE-MEDIATED HEMOLYSIS -- 2-458Table
MECHANISM
DRUG
ADSORPTION
(HAPTEN)
TERNARY
(IMMUNE)
COMPLEX
AUTOANTIBODY
INDUCTION
Direct antiglobulin test
Positive (anti-IgG)
Positive (anti-C3)
Site of hemolysis
Extravascular
Penicillin
Ampicillin
Methicillin
Intravascular
Extravascular
Quinidine
α-Methyldopa
Phenacetin
Mefenamic acid
Hydrochlorothiazide (Ponstel)
Carbenicillin
Cephalothin
(Keflin)*
Rifampin (Rifadin)
l-Dopa
Sulfonamides
Procainamide
Isoniazid
Ibuprofen
Diclofenac
(Voltaren)
Quinine
Medications
Cephaloridine
(Loridine)
Positive (anti-IgG)
Insulin
Tetracycline
Melphalan (Alkeran)
Acetaminophen
Hydralazine
(Apresoline)
Interferon alfa
Probenecid
Chlorpromazine
(Thorazine)
Streptomycin
Drugs (penicillin or sometimes cephalosporins) that cause
hemolysis via the “hapten” mechanism (immune but not
autoimmune) bind tightly to the RBC membrane (see Table
458-1). Antibodies to the drug, either newly or previously
formed, bind to the drug molecules on RBCs, mediating their
destruction in the spleen. In other cases, certain drugs, such
as quinine and quinidine, do not bind to RBCs but, rather,
form part of a “ternary complex,” consisting of the drug, an
RBC membrane antigen, and an antibody that recognizes both
(see Table 458-1). Methyldopa and sometimes cephalosporins
may, by unknown mechanisms, incite true autoantibodies to
RBC membrane antigens, so that the presence of the drug is
not required to cause hemolysis.
Clinical Manifestations
Autoimmune hemolytic anemias may occur in either of 2 general
clinical patterns. The first, an acute transient type lasting 3-6 mo
and occurring predominantly in children ages 2-12 yr, accounts
for 70-80% of patients. It is frequently preceded by an infection,
usually respiratory. Onset may be acute, with prostration, pallor,
jaundice, fever, and hemoglobinuria, or more gradual, with
primarily fatigue and pallor. The spleen is usually enlarged and is
the primary site of destruction of immunoglobulin G (IgG)–
coated RBCs. Underlying systemic disorders are unusual. A
consistent response to glucocorticoid therapy, a low mortality
rate, and full recovery are characteristic of the acute form. The
other clinical pattern involves a prolonged and chronic course,
which is more frequent in infants and in children >12 yr old.
Hemolysis may continue for many months or years.
Abnormalities involving other blood elements are common, and
the response to glucocorticoids is variable and inconsistent. The
mortality rate is approximately 10%, and death is often
attributable to an underlying systemic disease.
Laboratory Findings
In many cases, anemia is profound, with hemoglobin levels <6 g/dL. Considerable
spherocytosis and polychromasia (reflecting the reticulocyte response) are present. More
than 50% of the circulating RBCs may be reticulocytes, and nucleated RBCs usually are
present. In some cases, a low reticulocyte count may be found, particularly early in the
episode. Leukocytosis is common. The platelet count is usually normal, but concomitant
immune thrombocytopenic purpura sometimes occurs (Evans syndrome). The
prognosis for patients with Evans syndrome is guarded, because many have or eventually
have a chronic disease, including SLE, an immunodeficiency syndrome, or an
autoimmune lymphoproliferative disorder.
Results of the direct antiglobulin test are strongly positive, and free antibody can
sometimes be demonstrated in the serum (indirect Coombs test). These antibodies are
active at 35-40?C (“warm” antibodies) and most often belong to the IgG class.
They do not require complement for activity and are usually incomplete antibodies
that do not produce agglutination in vitro. Antibodies from the serum and those
eluted from the RBCs react with the RBCs of many persons in addition to those of the
patient. They often have been regarded as nonspecific panagglutinins, but careful
studies have revealed specificity for RBC antigens of the Rh system in 70% of patients
(≈50% of adult patients). Complement, particularly fragments of C3b, may be
detected on the RBCs in conjunction with IgG. The Coombs test result is rarely
negative because of the limited sensitivity of the Coombs reaction. A minimum of
260-400 molecules of IgG per cell is necessary on the RBC membrane to produce a
positive reaction. Special tests are required to detect the antibody in cases of
“Coombs-negative” autoimmune hemolytic anemia. In warm antibody hemolytic
anemia, the direct Coombs test may detect IgG alone, both IgG− and complement
fragments, or solely complement fragments if the level of RBC-bound IgG is below the
detection limit of the anti-IgG Coombs reagent
Treatment
Transfusions may provide only transient benefit but may be lifesaving
in cases of severe anemia by providing delivery of oxygen until the effect
of other treatment is observed. In general, all tested units for
transfusion are serologically incompatible. It is important to identify
the patient's ABO blood group in order to avoid a hemolytic transfusion
reaction mediated by anti-A or anti-B. The blood bank should also test
for the presence of an underlying allo-antibody, which could cause
rapid hemolysis of transfused red cells. Patients who have neither been
previously transfused nor pregnant are unlikely to harbor an
alloantibody. Early consultation between the clinician and the blood
bank physician is essential. Failure to transfuse a profoundly anemic
infant or child may lead to serious morbidity and even death.
Patients with mild disease and compensated hemolysis may not
require any treatment. If the hemolysis is severe and results in
significant anemia or symptoms, treatment with glucocorticoids is
initiated. Glucocorticoids decrease the rate of hemolysis by blocking
macrophage function by down regulating Fcγ receptor expression,
decreasing the production of the autoantibody, and perhaps
enhancing the elution of antibody from the RBCs. Prednisone or its
equivalent is administered at a dose of 2 mg/kg/24 hr. In some
patients with severe hemolysis, doses of prednisone of up to
6 mg/kg/24 hr may be required to reduce the rate of hemolysis.
Treatment should be continued until the rate of hemolysis decreases,
and then the dose gradually reduced. If relapse occurs, resumption of
the full dosage may be necessary. The disease tends to remit
spontaneously within a few weeks or months. The Coombs test result
may remain positive even after the hemoglobin level returns to
normal,
In general
it is safe to discontinue prednisone once the direct Coombs
test result becomes negative. When hemolytic anemia
remains severe despite glucocorticoid therapy, or if very large
doses are necessary to maintain a reasonable hemoglobin
level, IV immunoglobulin may be tried. Rituximab, a
monoclonal antibody that targets B lymphocytes, the source
of antibody production, has been useful in chronic cases
refractory to conventional therapy. Plasmapheresis has been
used in refractory cases but generally is not helpful.
Splenectomy may be beneficial but is complicated by a
heightened risk of infection with encapsulated organisms,
particularly in patients <6 yr. Prophylaxis is indicated with
appropriate vaccines (pneumococcal, meningococcal, and
Haemophilus influenzae type b) before splenectomy and with
oral penicillin after splenectomy.
Course and Prognosis
Acute idiopathic autoimmune hemolytic disease in childhood varies in severity
but is self-limited; death from untreatable anemia is rare. Approximately 30% of
patients have chronic hemolysis, often associated with an underlying disease, such
as SLE, lymphoma, or leukemia. The presence of antiphospholipid antibodies in
adult patients with immune hemolysis predisposes to thrombosis. Mortality in
chronic cases depends on the primary disorder.