C h a p t e r 1 3
Disorders of Red Blood Cells
287
body’s principal means of preventing oxidative damage.
Abnormalities of glutathione metabolism resulting from
impaired enzyme function reduce the ability of red cells
to protect against oxidative stress. The most common
inherited enzyme defect that results in hemolytic anemia
is a deficiency of glucose-6-phosphate dehydrogenase
(G6PD). The gene that determines this enzyme is located
on the X chromosome, and the defect is expressed only
in males and homozygous females. There are several
hundred variants of this gene, but only the G6PD A-
variant, found in 10% to 15% of African Americans,
and the G6PD Mediterranean variant are known to
cause clinically significant hemolytic anemia.
5,6
The
disorders are also associated with favism, a disorder of
hemolysis due to consumption of fava beans.
Glucose-6-phosphate dehydrogenase deficiencymakes
red cells more vulnerable to oxidants. The disorder fea-
tures direct oxidation of hemoglobin to methemoglobin,
which cannot transport oxygen, and denaturing of the
hemoglobin molecule to form Heinz bodies, which are
precipitated in the red blood cell. Hemolysis usually
occurs as the damaged red blood cells move through the
narrow vessels of the spleen, causing hemoglobinemia,
hemoglobinuria, and jaundice. The hemolysis is short-
lived, occurring 2 to 3 days after the triggering event. In
African Americans, the defect is mildly expressed and
is not associated with chronic hemolytic anemia unless
triggered by oxidant drugs, acidosis, or infection. In
affected persons, the hemolysis can be triggered by expo-
sure to oxidant drugs such as the antimalarial drug pri-
maquine, quinine, the sulfonamides, and nitrofurantoin.
Severe G6PD deficiency (as in Mediterranean variants)
may produce a chronic hemolytic anemia. The disorder
can be diagnosed through the use of a G6PD assay and
other screening blood tests (complete blood count, bili-
rubin, and reticulocyte count). No treatment is necessary
except to avoid known oxidant drugs.
Acquired Hemolytic Anemias
Several acquired factors exogenous to the red blood
cell produce hemolysis by direct membrane destruction
or antibody-mediated lysis. Various drugs, chemicals,
toxins, venoms, and infections such as malaria destroy
red cell membranes. Hemolysis can also be caused by
mechanical factors such as prosthetic heart valves, vas-
culitis, and severe burns. Obstructions in the microcir-
culation, as in disseminated intravascular coagulation,
thrombotic thrombocytopenic purpura, and renal dis-
ease, may traumatize the red cells by producing turbu-
lence and changing pressure gradients.
Although commonly referred to as autoantibody ane-
mia, the currently preferred designation is immunohe-
molytic anemia, since it may be initiated by an ingested
drug. The antibodies that cause hemolysis are of two
types: warm-reacting antibodies of the immunoglobu-
lin G (IgG) class, which are maximally active at 37°C,
and cold-reacting antibodies of the IgM type, which are
optimally active at about 4°C.
In the warm-reacting antibody type, the most com-
mon form of immunohemolytic anemia, the antibodies
react with antigens on the red cell membrane, causing
destructive changes that lead to spherocytosis, with sub-
sequent phagocytic destruction in the spleen or reticulo-
endothelial system. The antibodies lack specificity for the
ABO antigens but may react with the Rh antigens. The
hemolytic reactions usually have a rapid onset and may
be severe and life-threatening. There are varied causes
for this anemia: approximately 50% are idiopathic, and
50% are related to predisposing conditions such as lym-
phoid neoplasms, autoimmune disorders (particularly
systemic lupus erythematosus), and exposure to drugs
such as penicillin and the cephalosporins.
5,6
Some drugs,
of which the antihypertensive drug
α
-methyldopa is the
prototype, induce the production of antibodies against
red cell antigens, particularly Rh antigens. About 10%
of persons taking
α
-methyldopa develop antibodies, and
about 10% develop clinically significant hemolysis.
5
In the cold-reacting agglutinin type of hemolytic ane-
mia, which is less common than the warm-reacting type,
IgM antibodies bind red cells and cause agglutination
and activate complement. Cold agglutinin antibodies
sometimes appear transiently following certain infec-
tions (e.g., Epstein-Barr, influenza), in which case the
condition is relatively benign. The condition may also
develop as a chronic complication of B-cell neoplasms
and as an idiopathic entity. Symptoms are variable and
occur in parts of the body, such as the ears, fingers, and
toes, where the temperature may fall below 30°C. They
manifest due to vascular obstruction caused by aggluti-
nated red cells resulting in pallor, cyanosis, and Raynaud
phenomenon.
The diagnosis of immunohemolytic anemia requires
use of the Coombs test to detect the presence of antibody
or complement on the surface of red blood cells. The
direct Coombs test
uses antibodies specific for human
immunoglobulins or complement to detect antibodies
on red blood cells. It is positive in cases of autoimmune
hemolytic anemia, Rh disease of the newborn, transfu-
sion reactions, and drug-induced hemolysis. The
indi-
rect Coombs test
uses commercially available red cells
with known antigens to characterize the antigen target
and temperature dependence of the responsible antigen.
Anemias of Deficient Red Cell
Production
Anemia may result from the decreased production of
erythrocytes by the bone marrow. This category includes
anemias caused by a deficiency of substances that are
needed for hematopoiesis, particularly iron, vitamin B
12
,
and folic acid. Other disorders that suppress erythropoi-
esis include those associated with bone marrow failure
or replacement of the bone marrow by tumor or inflam-
matory cells.
Iron-Deficiency Anemia
Iron deficiency is a common worldwide cause of ane-
mia affecting persons of all ages.
16
The anemia results
from dietary deficiency, loss of iron through bleeding,
