Download Immne Hemolytic Aanemia

Immne Hemolytic Aanemia
Majid vafaie
• A number of extrinsic agents and disorders
may lead to premature destruction of red
blood cells (RBCs) (Table 458-1)
• Among the most clearly defined are
antibodies associated with immune hemolytic
anemias.
• The hallmark of this group of diseases is the
positive result of the direct antiglobulin
(Coombs) test
• The most important immune hemolytic
disorder in pediatric practice is hemolytic
disease of the newborn(erythroblastosis fetalis)
• caused by transplacental transfer of maternal
antibody active against the RBCs of the fetus,
that is,isoimmune hemolytic anemia
• Various other immune hemolytic anemias are autoimmune
(see Table 458-1)
• may be idiopathic or related to various infections (Epstein• Barr virus, rarely HIV, cytomegalovirus, and mycoplasma),
• immunologic diseases (systemic lupus erythematosus [SLE],
• rheumatoid arthritis)
• immunodeficiency diseases
(agammaglobulinemia,autoimmune lymphoproliferative
disorder, dysgammaglobulinemias)
• neoplasms (lymphoma, leukemia, and Hodgkin disease)
• drugs (methyldopa, L-dopa)
• Other drugs (penicillins,cephalosporins) cause
hemolysis by means of "drug-dependent
antibodies-that is antibodies directed toward
the drug and in some cases toward an RBC
membrane antigen as well
AUTOIMMUNE HEMOLYTIC
ANEMIAS ASSOCIATED WITH
"WARM" ANTIBODIES
• 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 (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).
• 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 4581)
• 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
• 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
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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 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
Iymphoproliferative disorder.
• Results of the direct antiglobulin test are
strongly positive
• 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-lgG 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
• Failure to transfuse a profoundly anemic
infant or child may lead to serious morbidity
and even death.
• 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 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 Fey 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.
AUTOIMMUNE HEMOLYTIC
ANEMIAS ASSOCIATED WITH
"COLD" ANTIBODIES
• "Cold" antibodies agglutinate RBCs at
temperatures <37°C.
• They are primarily of the IgM class and require
complement for hemolytic activity.
• The highest temperature at which RBC
agglutination occurs is called the thermal
amplitude.
• A higher thermal amplitude antibody-that isone that can bind to RBCs at temperatures
achievable in the body, results in hemolysis
with exposure to a cold environment.
• High antibody titers are associated with a high
thermal amplitude.
Cold Agglutinin Disease
• Cold antibodies usually have specificity for the
oligosaccharide antigens of the IIi system.
• They may occur in primary or idiopathic cold
agglutinin disease, secondary to infections
such as those from Mycoplasma pneumoniae
and Epstein-Barr virus, or secondary to
Iymphoproliferative disorders.
• After M. pneumoniae infection, the anti-I
levels may increase considerably, and
occasionally, enormous increases may occur to
titers >1/30,000.
• The antibody has specificity for the I antigen
and thus reacts poorly with human cord RBCs,
which possess the i antigen but exhibit low
levels of I.
• Patients with infectious mononucleosis
occasionally have cold agglutinin disease, and
the antibodies in these patients often have
anti-i specificity.
• This antibody causes less hemolysis in adults
than in children because adults have fewer i
molecules on their RBCs.
• Spontaneous RBC agglutination is observed in
the cold and in vitro, and RBC aggregates are
seen on the blood film.
• Mean corpuscular volume may be spuriously
elevated because of RBC agglutination.
• The severity of the hemolysis is related to the
thermal amplitude of the antibody, which
itself partly depends on the IgM antibody titer
• When very high titers of cold antibodies are
present and active near body temperature,
severe intravascular hemolysis with
hemoglobinemia and hemoglobinuria may
occur and may be heightened on a patient's
exposure to cold (external temperature or
ingested foods)
• Each IgM molecule has the potential to
activate a C1molecule so that large amounts
of complement are found on the RBCs in cold
agglutinin disease.
• These sensitized RBCs may undergo
intravascular complement-mediated lysis or
may be destroyed in the liver and spleen
• Cold agglutinin disease is less common in
children than in adults and more frequently
results in an acute, self-limited episode of
hemolysis
• Glucocorticoids are much less effective in cold
agglutinin disease than in disease with warm
antibodies.
•
• Patients should avoid exposure to cold and
should be treated for underlying disease
• In the uncommon patients with severe
hemolytic disease, treatment includes
immunosuppression and plasmapheresis.
• Successful treatment has been reported with
rituximab
• Splenectomy is not useful
Paroxysmal Cold Hemoglobinuria
• P C H is mediated by the Donath-Landsteiner
hemolysin, which is an IgG cold-reactive
autoantibody with anti-P specificity.
• This antibody fixes large amounts of
complement in the cold, and the RBCs are
lysed as the temperature is increased.
• Most reported cases are self-limited and
• are usually associated with nonspecific viral
infections
• They are now rarely found in association with
congenital or acquired syphilis
• This disorder may account for 30% of immune
hemolytic episodes among children
• Treatment includes transfusion
for severe anemia
• avoidance of cold ambient temperatures
FRAGMENTATION HEMOLYSIS
• RBC destruction may occur in hemolytic
anemias because of mechanical injury as the
cells traverse a damaged vascular bed.
• Damage may be microvascular when RBCs are
sheared by fibrin in the capillaries during
intravascular coagulation or when
renovascular disease accompanies the HUS or
TTP
• Larger vessels may be involved in KasabachMerritt syndrome (giant hemangioma and
thrombocytopenia
• or when a replacement heart valve is poorly
epithelialized.
• The blood film shows many "schistocytes," or
• fragmented cells, as well as
polychromatophilia, reflecting the
• reticulocytosis
• Secondary iron deficiency may complicate the
intravascular hemolysis because of urinary
hemoglobin and hemosiderin iron loss
• Treatment should be directed toward the
underlying condition
• the prognosis depends on the effectiveness of
this treatment.
• The benefit of transfusion is transient
because the transfused cells are destroyed as
quickly as those produced by the patient