1304 MNOQ 14 • THE BLOOD AND HEMATOPOIETIC SYSTEM

decreased erythropoietin production, the reticulocyte TABLE 88-9 Prevalence of Rh-Negative

count may be inappropriately low for the degree of Genotype (CDE/CDE)
anemia present. With maximal response, the bone
marrow can compensate for RBC survival of 20 to 30 days
by Population
without anemia. The bone marrow may show hyperplasia šXØPUW±Xœ YXPØ Percent Affected
and a reversal of the usual myeloid-to-erythroid ratio of European whites 11-21
3 : 1. Because optimal conditions for bone marrow US whites 14.4
response are not present in the newborn, hemolysis with Indians (India) 8
anemia and hyperbilirubinemia may be evident in the US African Americans 5.5
neonate. In chronic hemolytic states, compensatory Native Americans 0
hypertrophy of the bone marrow may result in bony Chinese 0
changes and other evidence of extramedullary hematohemato- Japanese 0
poiesis. Intrinsic hemolytic anemias are caused by inher
inher- Adapted from Prokop O, et al. Human blood and serum groups. Barking, UK:
ited abnormalities of the RBC membrane, hemoglobin, Elsevier; 1969.
or RBC intracellular enzymes. Some intrinsic hemolytic
anemias also result in extrinsic damage to the RBC
membrane. Extrinsic factors cause hemolytic anemia by
damaging the RBC chemically, physically, or immunoimmuno- when indicated, lack of identification of a large FMH, and
logically. Extrinsic hemolysis can be divided into immune chronic transplacental hemorrhage.
and nonimmune etiologies (see Ç~È 88-1lv the most The Rh antigens are inherited as a linked group of two
common causes of immune hemolytic anemia are dis- genes, RHD and RHCE, located on chromosome 1.
cussed first. Persons are typed as Rh negative or positive based on the
expression of the major D antigen on the RBC, and their
Alloimmune Hemolytic Anemia. See Chapter 24. Allo- RBCs will also express C or c and E or e antigens. Rarely,
immune hemolytic disease of the newborn (HDN) is Rh deletions of D, C/c, and E/e loci can occur. Anti-c and
caused by the destruction of fetal or neonatal RBCs by anti-E are emerging as the most frequent causes of HDN
maternal immunoglobulin G (IgG) antibodies. Alloim- as the incidence of Rh(D) disease decreases. The inci-
mune HDN involves the major blood group antigens of dence of Rh disease depends on the prevalence of
the Rhesus (Rh) and the A, B, AB, and O systems, but Rh-negative antigens in the population studied (nopqk
minor blood group incompatibilities (Kell, Duffy, MNS, rrs8lm Even in white populations, only a small percentage
and P systems) can also be associated with clinically sig- of pregnancies are affected because not all women who
nificant disease. Particularly for Rh (D), anti-c, anti-E, and are Rh negative develop antibodies, Rh immunization of
anti-K (Kell) antibodies, intrauterine or direct fetal trans- the mother does not usually occur during the first preg-
fusion may be indicated prenatally, and exchange transfu- nancy, and some of the second infants will be Rh
sion may be necessary postnatally. Maternal IgG negative.
antibodies can cross the placenta, enter the fetal circula- Because the interaction of the anti-D IgG with a
tion and cause hemolysis, anemia, hyperbilirubinemia, D-positive RBC does not usually involve complement,
and hydrops fetalis. In utero, the process is called eryth- hemolysis is extravascular. Hyperbilirubinemia and jaun-
roblastosis fetalis, whereas postnatally it is called hemolytic dice can occur in the first day of life when the placenta is
disease of the newborn (HDN). Maternal sensitization no longer available to clear bilirubin from hemolyzed
occurs through a prior transfusion of incompatible RBCs, RBCs. The peripheral blood smear may show anemia,
after fetal-maternal hemorrhage of incompatible fetal reticulocytosis, and macrocytosis. Microspherocytes are
RBCs, or from production of a pre-existing antibody usually not seen in Rh disease. A direct antiglobulin
developed against antigens from bacteria, viruses, or (Coombs) test should demonstrate anti-D IgG. Partial or
food. Transfer of antibodies across the placenta depends total exchange transfusions may be necessary to reduce
on the Fc component of the IgG molecule. Because both the load of antibody and remove the antibody-coated
IgM and IgA antibodies lack this component, only IgG cells. Management of hyperbilirubinemia is discussed in
antibodies cause hemolytic disease of the newborn. Chapter 100.
Immunoglobulin G1 antibodies cross the placenta earlier ABO Hemolytic Disease. Although the incidence of
and are responsible for more prenatal hemolysis. Immu- blood group O mothers delivering babies of blood group
noglobulin G3 antibodies cross the placenta later in gesta- A or B is about 15%, ABO hemolytic disease is estimated
tion and are responsible for more severe hemolysis to occur in only 3% of pregnancies and requires treat-
postnatally. ment with exchange transfusion in less than 0.1% of
Rh Hemolytic Disease. The original description of pregnancies. In contrast to Rh hemolytic disease, ABO
HDN was caused by Rh D incompatibility, and it remains hemolytic disease tends to be less severe, and the severity
the most severe cause. The spectrum of clinical problems does not depend on birth order. Most anti-A and anti-B
caused by Rh HDN ranges from mild, self-limited hemo- antibodies are IgM molecules, which do not cross the
lytic anemia to hydrops fetalis. With the widespread use placenta. However, maternal anti-A or anti-B IgG anti-
of antenatal and postpartum Rh immunoglobulin admin- bodies, which may have been raised against A or B sub-
istration, Rh D sensitization is less common in pregnan- stances occurring in food or on bacteria or in response to
cies when prenatal care is received. Most cases today are fetal-maternal hemorrhage, can cross the placenta and
caused by failure to administer Rh immunoglobulin react with the sparsely distributed A or B antigens on the
 // • HEMATOLOGIC AND ONCOLOGIC PROBLEMS IN THE FETUS AND NEONATE 1305

neonatal RBCs. Hemolysis is primarily extravascular. Other Immune Hemolytic Anemias. The other immune
Infants may develop anemia, reticulocytosis, and hyper- hemolytic diseases of early childhood are relatively rare.
bilirubinemia within the first 24 hours of life. The hall- Autoimmune hemolytic anemia occurs, as do anemias
mark of ABO hemolytic disease (in contrast to Rh disease) associated with infections, drugs, and immunodeficiency
is the presence of microspherocytes on the peripheral syndromes. IgG antibodies, with or without complement,
blood smear. The direct antiglobulin test (DAT), or are often directed against one of the Rh erythrocyte anti-
Coombs test, should be at least weakly positive for anti-A gens. These antibodies are most active at 37° C and often
or anti-B; however, because of the sparse distribution of are called warm autoantibodies. The IgG-coated cells, with
antigenic sites on a newborn’s RBCs, ABO hemolytic or without the assistance of complement, are cleared by
disease may be present even without a positive result on the spleen and, to a lesser extent, by the liver. Congenital
the DAT. The maternal serum should have high titers of infections (syphilis, cytomegalovirus, rubella, toxoplas-
IgG directed against A or B (positive indirect antiglobulin mosis, herpes, HIV, hepatitis) and acquired infections can
test or IAT, which is the indirect Coombs test). In the cause hemolytic anemia and bone marrow suppression
absence of clinical hemolytic disease, laboratory evidence with reticulocytopenia (see Chapters 55, 56, and 57).
of erythrocyte sensitization should not be considered Immunoglobulin M autoantibodies can cause disease
HDN. and are usually are referred to as cold agglutinins because
Minor Blood Group Hemolytic Diseases. The incidence they are most active at between 0° and 30° C. These
of HDN for minor blood group antigens is related to the antibodies, with complement, coat RBCs and are usually
antigenicity of the particular blood group antigen and the cleared in the liver. Intravascular hemolysis is less
expression of that antigen on fetal RBCs. Maternal anti- common. The best-known causes of cold hemagglutinin
bodies against minor blood group antigens develop after disease are Mycoplasma pneumoniae, adenovirus, and
exposure from a transfusion or prior pregnancy, or from Epstein-Barr virus. Immunoglobulin A-mediated hemoly-
contact with bacteria or viruses that express the antigen. sis is quite rare but is remarkable for its severity
Hemolytic disease of the newborn has been associated (nopqk rrsƒTlm
with the minor group antigens Kell, Duffy, MNS system, The natural history of autoimmune hemolytic disease
and P system. Most clinically significant HDN not attrib- in infancy is that of a rapid onset of anemia with hyper-
uted to ABO or Rh incompatibility is caused by anti-Kell, bilirubinemia, splenomegaly or hepatomegaly, and
anti-E, and anti-c. Kell HDN may require intrauterine hemoglobinuria (with intravascular hemolysis). Initially,
intervention. The severity of anti-Kell HDN is owing both reticulocytopenia may be noted, especially if antibodies
to hemolysis and suppression of erythropoiesis in pro- are directed against RBC progenitors in the bone marrow,
genitor cells. Screening for minor group antibodies is but a brisk reticulocytosis usually follows. Resolution
recommended for all women in the 34th week of preg- within 3 to 6 months is common. Anemia with reticulo-
nancy: Routine screening with cells containing only high- cytosis and spherocytosis may be seen on the peripheral
frequency antigens would not detect antibodies to blood smear, but the diagnosis depends on demonstra-
low-frequency antigens. The diagnosis and treatment of tion of antibody-coated cells, with or without comple-
hemolytic disease are identical to those for Rh hemolytic ment, in the DAT and antibodies in the serum by the
disease. Identification of low-frequency antibodies asso- IAT. Therapy includes treatment of underlying infection,
ciated with HDN is especially important for mothers who
plan additional pregnancies. The role of IVIG in treat-
ment of neonatal hemolytic disease, especially ABO TABLE 88-10 Acute Hemolytic Anemia:
incompatibility, is discussed in Chapter 100. Causative Mechanisms
Natural History of Hemolytic Diseases of the And Representative
Newborn. Hydrops fetalis is the most severe consequence Infectious Agents
of hemolysis, but anemia generally is less problematic
than hyperbilirubinemia in the acute phase of illness. ×[VÙUœ±›\ Infectious Agent
Hyperbilirubinemia may be evident within the first 24 Hemolysin production Clostridium perfringens
hours of life. Anemia can occur in the first few weeks in Direct invasion of RBCs Malaria
both those who received exchange transfusions and those Alteration of RBC surface:
who required only phototherapy for management of Adherence to RBCs Bartonella organisms
hyperbilirubinemia. The anemia can be caused by Neuramidase alters Influenza virus
antigenic phenotype
ongoing hemolysis, hypersplenism, inadequate replace-
Cold agglutinin Epstein-Barr virus
ment by transfused red blood cells, and shortened sur- Absorption of capsular Haemophilus influenzae
vival of transfused red blood cells. Because the half-life polysaccharide
of IgG molecules is about 28 days, hemolysis should Microangiopathy Any agent causing disseminated
resolve within the first 3 or 4 months. Resolution often intravascular coagulation or
occurs sooner if the antibodies are cleared by adhering to hemolytic-uremic syndrome
RBCs or by exchange transfusion. Thrombocytopenia and Enhanced oxidative stress Campylobacter jejuni enteritis in
bleeding can complicate hemolytic disease. Usually, neonates with a diminished
thrombocytopenia without other laboratory evidence of cytochrome-b5 reductase system
disseminated intravascular coagulation (DIC) is noted, From Ritchey AK, et al. Hematologic manifestations of childhood illness. In:
but DIC can be triggered by massive hemolysis or shock Hoffman R, et al, eds. Hematology: basic principles and practice. 2nd ed.
and acidosis. New York: Churchill Livingstone; 1995:1722.
 1306 MNOQ 14 • THE BLOOD AND HEMATOPOIETIC SYSTEM

S
  Spectrin 4.1-GP
Spectrin lipid  
 Spectrin lipid interaction
interaction interaction
%#
$
! Band
 GP Lipid bilayer
# 3
"
! 2.1 4.1
 β α
V Actin
α b spectrin
Spectrin dimer- Spectrin 4.1-
dimer interaction actin interaction

Horizontal interactions
Hypothesis

Vertical defect 
  

Lipid bilayer destabilization Skeletal destabilization

Loss of membrane material MILD SEVERE

Defective shape Fragmentation
recovery

HS

HE HE/HPP
Figure 88-6 Molecular origins of hereditary spherocytosis (HS) and hereditary
her elliptocytosis-pyropoikilocytosis (HE/HPP) based on the hypothesis
of vertical and horizontal defects. Vertical interactions are those needed to stabilize the attachment of the spectrin lattice to the lipid bilayer. Abnor-
malities in this attachment result in destabilization of the lipid bilayer, membrane loss during splenic conditioning, and HS. Horizontal interactions
reversibly hold spectrin dimers and tetramers together, allowing stretching and distortion of the red blood cell membrane during circulation. Weak-
ening of these interactions results in loss of elasticity. GP, Glycoproteins. (Adapted from Palek J. Red cell membrane disorders. In: Hoffman R, et al, eds.
Hematology: basic principles and practice. New York: Churchill Livingstone; 1991:472.)

removal of the offending drug, and supportive measures osmotic pressure. The lipid bilayer that forms the cell
to limit hyperbilirubinemia. Response to corticosteroids membrane is the site of numerous biologic functions
is common, as is complete recovery. Steroids are less mediated by integral proteins. It also is the attachment
effective in IgM-mediated disease. A subset of patients site for the proteins of the cytoskeleton, which confer the
younger than 2 years, and with a slower onset of disease shape and stability necessary for proper membrane func func-
at presentation, develops chronic hemolytic anemia. Dif- tion. Some abnormalities in the membrane-cytoskeleton
ficulties with identifying compatible blood during a (fghijk 88-6).
unit result in morphologic defects of RBCs (Figure 88-6lm
hemolytic crisis, as well as the usually self-limited nature Because abnormally shaped RBCs are removed from the
of the disease, restrict blood transfusions to cases in circulation by the reticuloendothelial system, many of
which severe anemia impairs tissue oxygenation. these defects cause some degree of hemolytic anemia.
Analysis of these congenital defects has led to an under-
Nonimmune Hemolytic Anemia standing of the erythrocyte membrane and cytoskeleton.
Erythrocyte Structural Defects. During its lifetime, a The more common erythrocyte cytoskeletal defects origi-
normal RBC traverses the circulation thousands of times, nally were described by morphologic and clinical criteria.
enduring tremendous mechanical and metabolic stress With better understanding of the cytoskeleton at a molec-
molec
with each passage. The smallest capillaries have an inter-
inter ular level, it became clear that various mutations in genes
nal diameter that is smaller than the diameter of the RBC; coding for a few structural proteins are responsible for a
thus the blood cells must deform to squeeze through the family of inherited hemolytic anemias with overlapping
capillaries and then return to their normal shape as they morphologic, clinical, and genetic features.
features Mutations
enter distal venules. During their rapid transit, the RBCs -spectrin, β-spectrin,
in the genes encoding α-spectrin, -spectrin, ankyrin,
must endure tremendous fluctuations in pH, PO2, and protein 4.1, glycophorin C, protein 4.2, and band 3 have
 // • HEMATOLOGIC AND ONCOLOGIC PROBLEMS IN THE FETUS AND NEONATE 1307

been reported in patients with hereditary defects of the dominant inheritance with reduced penetrance also have
red blood cell membrane/cytoskeleton.6x been reported. Spontaneous mutations account for about
Mk¥pjok defects associated with hemolytic anemia one fourth of HS. The defects alter the vertical stability of
may present in the neonate with hepatosplenomegaly, the cytoskeletal attachment to the lipid bilayer so that
hyperbilirubinemia, and hemolytic anemia. Often, the pieces of untethered membrane are removed in the
specific diagnosis depends on evaluation of family spleen. Defects or deficiency in ankyrin are the most
members and serial examinations of the infant’s blood common, although defects in spectrin, band 3, and
smear over time. Aplastic crisis, attributed to drugs or an protein 4.2 also occur. Nondeformable spherocytes with
infectious agent such as parvovirus B19, or splenic seques- a decrease in the surface area are more susceptible to lysis
tration, may cause life-threatening anemia in patients with exposure to the metabolic and deformation stresses
with hemolytic anemia. The more severe cases of hemo- of the splenic sinuses or with incubation in hyposmolar
lytic anemia can require splenectomy, although surgery solutions. The osmotic fragility test exposes the suspected
generally is delayed
yed beyond the first few years of life. cells and normal control cells to progressively more
Hereditary Spherocytosis. Hereditary spherocytosis hypotonic solutions and compares their ability to resist
(HS) is characterized by the appearance of spherocytes lysis.6„
on the peripheral blood smear, accompanied by a hemo hemo- &'(editary Elliptocytosis and Hereditary Pyropoikilocy-
lytic anemia of varying severity and splenomegaly. Hered
Hered- tosis. The findings on the peripheral blood smears in
itary spherocytosis occurs predominantly in those of hereditary elliptocytosis and hereditary pyropoikilocyto-
Northern European ancestry. Inheritance usually is auto
auto- sis are distinct (fghijk 88-7lm Hereditary elliptocytosis
somal dominant, but autosomal recessive and autosomal (HE) is an autosomal dominant condition characterized

A B

C D

E F

Figure 88-7 Peripheral blood smears. A, Pre-

mature newborn of 26 weeks’ gestation. B, Iron
deficiency. C, Hemoglobin SS. D, Hemoglobin
SC. E, Hemoglobin CC. F, Hereditary spherocyto-
sis. G, Hereditary elliptocytosis. H, Hereditary G H
pyropoikilocytosis.
1308 MNOQ 14 • THE BLOOD AND HEMATOPOIETIC SYSTEM

by elliptical RBCs called ovalocytes, which is more BOX 88-3 RED BLOOD CELL ENZYMATIC
common in people of African and Mediterranean origin.
In hereditary pyropoikilocytosis (HPP), the RBC mor-
DEFECTS ASSOCIATED WITH
phology is bizarre, marked by fragments, elliptocytes, and HEMOLYSIS
spiculated cells. The disorders are caused by defects in 7ÌÖÏOSE PHOSPHATE PATHWAY
cytoskeletal proteins, most commonly α- or β-spectrin, • Glucose-6-phosphate dehydrogenase9
which weaken the horizontal interactions necessary for
cytoskeletal stability and reversible deformability (see GÍÔËÑÍÔÏÕË 7ÊÏ:;ÊÔ
fghijk 88-6lm The deformed RBCs are prematurely cleared • Pyruvate kinase²
by the reticuloendothelial system. Hemolysis in HE gen- • Hexokinase
erally is milder than in hereditary spherocytosis. The • Glucose phosphate isomerase
majority of those with HE are symptomatic. Hereditary • Phosphofructokinase
pyropoikilocytosis is caused by homozygous or com-
pound heterozygous defects.6„ ~¥k k~ozk} gz{ )*
• Aldolase
may exhibit hemolysis with HPP morphology on blood • Triose phosphate isomerase
smear, but later in life their red blood cells will appear as • Glyceraldehyde-3-phosphate dehydrogenase
typical elliptocytes. Hereditary pyropoikilocytosis is asso- • Phosphoglycerate kinase
ciated with more severe hemolysis and hyperbilirubine- • 2,3-Diphosphoglycerate mutase
mia, often requiring exchange transfusion or phototherapy • Enolase
in the neonatal period. Examination of blood smears HEXOSE MONOPHOSPHATE PATHWAY
from each parent may be helpful in making this
diagnosis. • Glutathione synthetase
Southeast Asian Ovalocytosis (SAO) or stomatic ellipto- • γ-Glutamyl cysteine synthetase
cytosis is a mild hemolytic variant of HE, which is • Glutathione reductase
common in Southeast Asia, likely because it confers • Glutathione S-transferase
malaria resistance. Defects in band 3 are the most • Glutathione peroxidase
common.6„
ERYTHROCYTE NUCLEOTIDE METABOLISM
+,-./ocytic elliptocytosis, characterized by spherocytes
and elliptocytes and a mild hemolysis, occurs in those of • Elevated adenosine deaminase levels
European ancestry.6„ • Pyrimidine 5′-nucleotidase
• Adenylate kinase
012345þ1 Lipid Defects. Membrane lipid abnormali-
ties can be inherited but most often are acquired. Their *Most common defect worldwide.
†
presence, detected by morphologic abnormalities on the Second most common defect.
peripheral blood smear, is most important as the signal of
an underlying disease. Target cells form when the surface-
to-volume ratio of the red blood cell increases, either z{k enzyme deficiencies cause abnormalities in other
because of poorly hemoglobinated cells (iron deficiency, tissues. The end result of these defects is hemolytic anemia
thalassemias, Hb C) or because lipids are added to the of varying severity, sometimes called hereditary nonsphero
nonsphero-
RBC membrane (liver disease with intrahepatic cholesta- cytic anemia. The RBCs may be morphologically normal
sis, lecithin-cholesterol acyltransferase deficiency). Acan- and usually produce normal results on osmotic fragility
thocytes form when the membrane lipid composition testing, but they have a shorter life span. The milder cases
between the inner and outer leaflets of the bilayer is cause little difficulty in the neonatal period. Some defects
altered, as in liver disease and abetalipoproteinemia. are associated with chronic and/or severe hemolysis,
necessitating intermittent or chronic blood transfusions.
Inherited Enzymatic Defects. The mature RBC, lacking Glucose-6-phosphate dehydrogenase deficiency is the
a nucleus, polyribosomes, and mitochondria with which only common defect of RBC enzymes and can be associ associ-
to carry out protein synthesis, must circulate through ated with severe hemolysis, anemia, and hyperbilirubi
hyperbilirubi-
extremes of pH, PO2, and osmotic gradients while nemia in the neonate, although many are asymptomatic.
maintaining deformability and integrity
integrity. Red blood cells This enzymatic defect is common in infants with bili bili-
metabolize glucose through the Embden-Meyerhof rubin encephalopathy. Occasionally, the hyperbiliru
hyperbiliru-
pathway and hexose monophosphate shunt to provide binemia is severe, because of an interaction of G6PD
energy for maintaining ionic pumps, to reduce methe methe- deficiency with the (TA)7 promoter polymorphism of the
moglobin, and to synthesize small molecules such as UDP-glucuronosyltransferase 1A1 (UGT1A1) bilirubin-
adenine, guanine, pyrimidine nucleotides, glutathione, conjugating enzyme.„„ n{k ‚jk¬oqk|k o¥~h }~¥k kz{g|
and lipids. The most commonly defective enzyme, glucose-6- groups suggests a selective advantage because deficient
phosphate dehydrogenase (G6PD), has been extensively cells are resistant to malaria. As an enzyme in the pentose
evaluated at the clinical, biochemical, and molecular phosphate pathway, G6PD supplies NADPH, and by pro pro-
level. Man
Many other enzymatic defects have been reported, ducing hydrogen ions, promotes reduction of glutathiglutathi-
but the rarity of the disorders has hindered investigation. one. Deficiency limits the cell’s ability to recover from
Enzymatic defects of the RBC known to be associated oxidative stress. The gene is inherited as an X-linked reces
reces-
with hemolytic anemia are listed in Ç~È 88-3m ­ k ~ sive. Males are affected most commonly. Females may
 // • HEMATOLOGIC AND ONCOLOGIC PROBLEMS IN THE FETUS AND NEONATE 1309

also be affected, either because of homozygosity or com- deficiency. A deficiency state in preterm infants and those
pound heterozygosity, or in cases in which X-inactivation with very low birth weight has been described, character-
is unbalanced. In the United States, African-American ized by hemolytic anemia, reticulocytosis, thrombocyto-
males are the most commonly affected. The A-minus sis, chronic lung disease, intracranial hemorrhage, and
variant, common in Africans, results in a mild reduc- retinopathy of prematurity. However, present evidence
tion in both catalytic activity and stability. The B variant, does not support routine supplementation with intrave-
common among Mediterranean, some Asian, and Ashke- nous or high-dose vitamin E in neonates.
nazi Jewish populations, involves a severe reduction of
enzyme activity, resulting in chronic, moderate-to-severe The Thalassemias
hemolytic anemia that could prove fatal in the face of The thalassemias are a group of hereditary anemias that
severe oxidant challenge. In affected patients, the oldest arise from quantitative defects in the synthesis of globin
RBCs are most deficient, resulting in a normal or mini- chains. In their milder forms, thalassemias are among the
mally shortened erythrocyte life span, but exposure to most common heritable disorders. The α-thalassemias
oxidant drugs and toxins or a febrile episode can pre- are most common in the Chinese subcontinent, Malaysia,
cipitate severe hemolysis. Hemolysis occurs within 24 to Indochina, and Africa. β-Thalassemia is common in Med-
48 hours of exposure and is accompanied by abdominal iterranean and African populations but also has a higher
pain, vomiting, diarrhea, low-grade fever, jaundice, sple- incidence in China, Pakistan, India, and the Middle East.
nomegaly, hemoglobinuria, and anemia. Hemoglobin E is common in Southeast Asia. The four
Neonates may present with hemolytic anemia and α-thalassemia syndromes (silent carrier, α-thalassemia
hyperbilirubinemia within 24 hours of life and are trait, Hb H disease, and hydrops fetalis) are caused by
susceptible to developing methemoglobinemia. Manage Manage- diminished production of α-globin protein due to dele-
ment involves avoidance of precipitating agents, hydrahydra- tion in one, two, three, or four of the α-globin genes,
tion, phototherapy and, if needed, transfusion (partial respectively. Although only two genes for β-globin pro-
volume exchange or simple). Common drugs to be duction are inherited, there are four clinical classifica-
avoided or used with caution in this disorder include tions for β-thalassemia: silent carrier, β-thalassemia trait,
antimalarials, sulfonamides and sulfones, nitrofurans, thalassemia intermedia, and thalassemia major. The
anthelminthics, ciprofloxacin, methylene blue, acetamin
acetamin- blood smear shows hypochromic microcytes, target cells,
ophen, aspirin, and vitamin K analogues. An excellent and nucleated RBCs. Bizarre RBC shapes and fragments
resource for complete food and drug lists, as well as are seen in more severe disease. The clinical outcome in
family education, is at .G6PD.org
o||k}}k€ y|z~pkj this disease is a result of complex interactions involving
24, 2013). Enzyme levels are highest in younger cells. the type of genetic defect, the degree of β-globin produc-
Evaluation immediately after a hemolytic episode could tion, and the ratio of α-globin chains produced relative
be inconclusive because the older, abnormal cells have to the number of β-globin chains (nopqk rrsƒƒlm Abnor-
been destroyed. Repeat quantitative testing at a later time, mal hemoglobin tetramers can accumulate in the bone
as well as evaluation of maternal enzyme levels, can be marrow and reticuloendothelial system, resulting in
useful. Some states and countries include G6PD defi- ineffective erythropoiesis. Mutant hemoglobins can pre-
ciency screening as part of their newborn screening cipitate to form inclusion bodies that adhere to cell mem-
program, using biochemical qualitation, biochemical branes, promote oxidative damage to the membrane,
quantitative assays, and DNA-based PCR screening for diminish cell deformability, and shorten RBC survival.
common mutations.„„†…ú¨ Coinheritance of α- and β-globin defects may result in a
<ý=52ýþ E Deficiency. Vitamin E is a fat-soluble anti- less severe thalassemia because the ratio of α- to β-globin
oxidant that reduces the peroxidation of polyunsaturated chains is rebalanced.
fatty acids by reactive oxygen species during oxidative Prenatal diagnosis strategies are available for both α-
enzyme activity. Preterm infants and infants with low and β-thalassemia. If evaluation of the parents’ RBCs pro-
birth weight have low serum and tissue levels of this vides evidence of thalassemia, molecular detection
vitamin. Patients who have chronic fat malabsorption strategies can be used. Fetal tissue from chorionic villus
are the most likely to develop symptomatic vitamin E sampling (10-12 weeks’ gestation) or amniocentesis

TABLE 88-11 Effects of Thalassemia Mutations

>ÙUU››[\±U Defect Product Result Outcome
Absent or reduced globin production α :β Globins ratio altered Precipitation of excess globins Abnormal hemoglobin pattern
RBC membrane damage Hemolysis
Thrombosis
Ineffective erythropoiesis Basophilic stippling
Hypochromia
Microcytosis
Reticulocytosis
Anemia Bone marrow expansion
Extramedullary hematopoiesis
Iron hyperabsorption
1310 MNOQ 14 • THE BLOOD AND HEMATOPOIETIC SYSTEM

(15-20 weeks) can be analyzed by a number of DNA- failure in utero secondary to severe anemia and, in the
based methodologies (see Chapter 11). After 18 to 20 absence of fetal transfusion, becomes grossly hydropic
weeks’ gestation, fetal reticulocytes may be tested for (hydrops fetalis). There is evidence of extensive extramed-
globin chain biosynthetic ratios, although sampling ullary hematopoiesis and placental hypertrophy. Most are
carries higher risks. stillborn at 30 to 40 weeks’ gestation or die shortly after
delivery. Infants with hepatosplenomegaly, jaundice, and
α-Thalassemia. Because the production of α-globin a moderate hypochromic, microcytic hemolytic anemia
chains predominates from midgestation onward, defects should be evaluated for deletion of three α-globin genes,
in synthesis can be detected at birth. Before the debut of Hb H disease. At birth, large amounts of Hb Barts may
molecular analysis, the various α-thalassemia syndromes be seen as well as some Hb H. Incubation of the RBCs
were assigned according to clinical criteria (nopqk rrsƒ?lm with brilliant cresyl blue reveals many small inclusions.
Hydrops fetalis, the most severe and rarest form of Treatment is supportive and includes supplementation
α-thalassemia, occurs when an infant inherits deletions with folic acid, avoidance of oxidant drugs, transfusion
of both α-globin genes from each of the parents (see of RBCs, and attention to iron hyperabsorption and
Chapter 24). Such an infant produces small quantities of transfusional iron overload. Hypersplenism, character-
Hb Portland to maintain in utero viability. The excess γ ized by leukopenia, thrombocytopenia, and worsening
and β chains form tetramers with themselves, resulting in anemia, may necessitate splenectomy, although this
functionally useless Hb Barts (γ4) present in the newborn usually is deferred beyond the first few years of life and
and Hb H (β4) present in the older infant. The fetus with is associated with infectious risk as well as increased
four α-globin gene defects experiences congestive heart thrombosis.

TABLE 88-12 The Thalassemias

@-Thalassemia Genotype Number of α Genes Deleted Phenotype
αα/αα 0 Normal
αα/α− 1 Silent carrier
α−/α− 2 Alpha thalassemia trait, trans
αα/− − Alpha thalassemia trait, cis
α−/− − 3 Hemoglobin H
− −/αcsα Hemoglobin H-Constant Spring
− −/− − 4 Hydrops fetalis
β-Thalassemia Genotype Phenotype Clinical Implications
β/β Normal Normal
β/β+ β-Thalassemia minor (trait) Microcytosis
β/β0 Hypochromia
Increased Hb F, Hb A2
Basophilic stippling
Occasional target cells
β+/β+ β-Thalassemia intermedia Moderate microcytosis
β+/β0 Moderate-severe anemia
βE/β+ Moderate hypochromia
βE/β0 Basophilic stippling
Target cells
Increased Hb F, Hb A2
Variable transfusion dependence
Hepatosplenomegaly variable
Iron hyperabsorption
β0/β0 β-Thalassemia major Severe microcytosis, hypochromia, target cells
Increased Hb F, Hb A2
Transfusion dependence
Hepatosplenomegaly
Iron hyperabsorption
Transfusional iron overload
Hemoglobin E Genotype Phenotype Clinical Features
β/ε Hb E Trait Microcytosis
ε/ε Hb E Disease Microcytosis
Mild anemia
ε/β+ Hb E/β+-Thalassemia Moderate microcytosis
Moderate anemia
ε/β0 Hb E/β0-Thalassemia Moderate-severe microcytosis
β-Thalassemia intermedia
 // • HEMATOLOGIC AND ONCOLOGIC PROBLEMS IN THE FETUS AND NEONATE 1311

α-Thalassemia trait is characterized by a mild ane- α-globin proteins to form a functional hemoglobin tet-
mia with microcytosis, hypochromia and erythrocytosis. ramer with essentially normal stability and oxygen-
Hemoglobin Barts is mildly elevated at birth. After the dissociation characteristics. Persons with Hb E are anemic
neonatal period, there is no simple laboratory evaluation because the mutation creates a cryptic splice site in the
that is diagnostic for α-thalassemia trait. Alpha globin β-globin message. During RNA processing, a portion of
gene analysis can be ordered to confirm clinical suspicion. the message is spliced into an abnormal, unstable tran-
The diagnosis usually is made in an iron-replete patient script. Consequently, the total level of β-globin messen-
with a normal hemoglobin electrophoresis and appropri- ger RNA is reduced, resulting in a thalassemia phenotype.
ate family history for α-thalassemia. As the name implies, Hemoglobin E trait results in mild microcytosis. Those
silent carriers of α-thalassemia could have slightly micro- who are homozygous for Hb E have chronic, mild to
cytic RBCs but usually are asymptomatic. Several states moderate, microcytic anemia but are otherwise well;
now use molecular testing for HBA1 and HBA2, the genes however, co-inheritance of a Hb E allele from one parent
coding for α1- and α2-globin, respectively. and a β-thalassemia allele from the other produces a
moderate to severe anemia that can be transfusion depen-
β-Thalassemia. β-Thalassemia is not usually diagnosed dent. Hemoglobin levels in these patients range from 2
at birth unless blood loss or RBC destruction has created to 7 g/dL, and children with this condition can develop
an unusually high demand for replacement of fetal RBCs hepatosplenomegaly and growth failure. Hemoglobin
with adult. The disease generally manifests after 6 months E-β0 thalassemia disease now is the most common form
of age, when a microcytic anemia persists beyond the of transfusion-dependent thalassemia in the United
time course for physiologic anemia. The more severe States and other parts of the world. Hemoglobin E
manifestations of the disease traditionally were called co-inherited with Hb S results in a sickle phenotype.
Cooley anemia, but these have been separated into thalas-
semia major and thalassemia intermedia (see nopqk rrsƒ?lm Qualitative Defects in Hemoglobin:
Affected patients exhibit splenomegaly, poor growth, Hemoglobin Variants
microcytic hemolytic anemia with ineffective erythropoi- In the fetus, switching from one type of globin chain
esis, target cells on the peripheral blood smear, and extra- expression to another occurs several times (see fghijk
medullary expansion of erythropoiesis. An abnormal rrs?lu and during the first few months of the postnatal
hemoglobin analysis reveals elevations of Hb F and Hb period, the final switch to the adult-type hemoglobin
A2 and a decrease in Hb A. occurs. Some hereditary defects in fetal globin gene prod-
Patients are categorized as having thalassemia interme- ucts can produce a hemolytic anemia that resolves as
dia if they are able to maintain a hemoglobin level greater β-globin gene expression predominates. Similarly, a
than 7 g/dL without routine transfusion. Thalassemia neonate who is asymptomatic at birth can develop a
major patients require regular transfusions and iron che- hemolytic anemia over the subsequent months as pro-
lation therapy to maintain a hemoglobin value adequate duction of β-globin–containing hemoglobin assumes
for growth and development. Iron overload is a signifi- major importance. Because α chains are produced from
cant cause of morbidity and mortality starting in the the fetal period onward, defects in α-globin are present
second decade of life. Evidence of hypersplenism may at birth. If the combination of the mutant α- and the
necessitate splenectomy. Bony deformities from expan- γ-globin is more unstable than that of α- and β-globin or
sion of extramedullary hematopoiesis occur in incom- α- and δ-globin, the infant experiences a transient hemo-
pletely transfused patients. lytic anemia that resolves as Hb A predominates.
β-Thalassemia trait is characterized by abnormalities More than 500 structurally different hemoglobin vari-
on the blood smear: microcytosis, hypochromia, erythro- ants have been reported. The clinically important variants
cytosis, and the appearance of elliptocytes and target are listed in Ç~È 88-4m M~}z g¬~q¬k o }ghqk o¥g~ o|g€
cells. Hemoglobin analysis reveals a mild elevation of Hb substitution in one of the globin polypeptide chains
A2 and Hb F, although this is not observed if the genetic owing to a single nucleotide change in DNA. Other vari-
mutation also interferes with production of δ- or γ-globin ants are the result of gene deletions or duplications
or if Hb A2 and Hb F production are depressed because caused by unequal crossover.
of coexistent iron deficiency anemia. The silent carrier
state of β-thalassemia is associated with normal findings Unstable Hemoglobins. Most mutations causing unsta-
on the peripheral blood smear and hemoglobin electro- ble hemoglobin affect β-globin and involve amino acid
phoresis and usually is identified through family studies
of patients with a more severe β-thalassemia syndrome.

Hemoglobin E. Hemoglobin E causes one of the most BOX 88-4 QUALITATIVE HEMOGLOBIN
common hemoglobinopathies in the world. This thalas- (HB) VARIANTS
semia syndrome, characterized as a qualitative and quan-
ÊBCDEFCIJK in Hb Function Example
titative hemoglobinopathy, is particularly abundant
Increased oxygen affinity Hb F, Hb Syracuse
among people of Southeast Asian ancestry, especially Decreased oxygen affinity Hb Kansas
individuals from Laos, Cambodia, and Thailand. Hemo- Increased heme iron oxidation Hb M, methemoglobin
globin E is generated by a single nucleotide substitution, Unstable Hb Hasharon
Glu26Lys, in the coding region of the β-globin gene. The Decreased solubility Hb S, Hb C
β-globin monomers associate normally with a pair of
 1312 MNOQ 14 • THE BLOOD AND HEMATOPOIETIC SYSTEM

Hemoglobin separation
(cellulose acetate electrophoresis pH 8.6, isoelectric focusing, HPLC)

Abnormal

Confirmatory testing: Electrophoresis

(citrate agar pH 6.1 and cellulose acetate pH 8.6) or HPLC

LNO QRUWXYZ WZYY [\]U[^ FSA (sickle cell anemia bthal+) Any other abnormal pattern
FAC (hemoglobin C trait) FSC (hemoglobin SC disease)
FAE (heterozygote hemoglobin E) FC (homozygous hemoglobin C) Repeat electrophoresis at age
FE (homozygous hemoglobin E) 6 months
Usually clinically asymptomatic FCA (hemoglobin C bthal+)
Provide genetic family counseling FS (sickle cell anemia)

Refer to hematologist for counseling and long-term care

Confirmatory electrophoresis at age 6 months
Figure 88-8 Algorithm for investigating abnormal results on hemoglobinopathy screening tests in newborns. FAC, FAE, FAS, FC, FCA, FE, FS, FSA,
FSC, Sickle-cell traits; HPLC, high-performance liquid chromatography.

substitutions in hydrophobic residues around the heme BOX 88-5 COMMON NEWBORN SCREEN
pocket. These amino acid replacements alter the hydro- HEMOGLOBIN PATTERNS
phobic interior of the molecule, predisposing the hemo-
globin to instability and precipitation as small round :D_J`BJaIK Interpretation
inclusions known as Heinz bodies. Because the amino Pattern
acid substitutions often involve replacing one neutral FA Normal
amino acid with another, the hemoglobin electrophoretic FAS Sickle cell trait
mobility may not change. Patients usually develop anemia FSC Sickle C disease (Hb SC)
and jaundice in late infancy as β-globin synthesis FS Sickle cell disease or Sickle β0-thalassemia
increases. Mutations in fetal or embryonic globins can FSA Sickle β+-thalassemia
cause symptoms at birth but not later in life. The diagno- FVA Hb variant with β+-thalassemia
FAV Heterozygous or trait variant
sis is confirmed by supravital staining for Heinz bodies, 2%-8% Barts—α-thalassemia trait
which are usually present, and hemoglobin analysis after 25%-50% Hb Barts—Hemoglobin H
isopropanol precipitation. disease
FV Hb variant with β0-thalassemia
Sickle Cell Anemia. Sickle cell disease is a common FVV Double heterozygous variant
medical problem in the United States, where 1 in 400 FSV Sickle Hb and variant
newborns is affected. By definition, sickle cell anemia Hb SOarab and Hb SD are sickle
refers to the doubly heterozygous inheritance of abnor-
abnor hemoglobinopathies
mal genes that code for the substitution of valine in place FS and Hb Barts—sickle cell disease with
of glutamic acid at position 6 in the β chain of hemoglo-
hemoglo α-thalassemia
F Very premature infant
bin (Hb SS). There are also a number of sickle hemoglo-
Absence of β globin production
binopathies in which one gene coding for Hb S is
inherited along with a second abnormal β-globin gene
coding for other hemoglobins, such as Hb C, D, OArab, or
β-thalassemia. The clinical course of affected patients
may be indistinguishable from, or milder than, those of The clinical hallmark of Hb SS disease is hemolytic
Hb SS disease.. As with the thalassemias, prenatal diag
diag- anemia with reticulocytosis and the appearance of irreirre-
nostic techniques are available. Newborn screening pro pro- versibly sickled cells on the peripheral blood smear. The
grams have been instituted in many parts of the world, onset of signs and symptoms correlates with the decrease
including most of the United States. Samples of cord or in Hb F levels and increasing expression of the mutant
capillary blood are subjected to testing, usually hemoglo
hemoglo- β-globin
-globin gene products during the first year of life. Neo
Neo-
bin electrophoresis, high pressure liquid chromatography nates generally are asymptomatic, although older infants
or isoelectric focusing. Infants with abnormal results on are at risk for several disease-related complications.
the newborn screen are referred for confirmatory testing Because of splenic dysfunction, infections with certain
and disease counseling (fghijk 88-8v Ç~È 88-5lm bacteria such as pneumococcus are a major cause of
 // • HEMATOLOGIC AND ONCOLOGIC PROBLEMS IN THE FETUS AND NEONATE 1313

mortality and morbidity in infants and young children. of infants receiving breast milk, the use of standard iron-
A suddenly pale, listless infant may be experiencing supplemented infant formulas and iron-supplemented
life-threatening anemia caused by hepatic or splenic baby cereals during the first year of life, and the delay of
sequestration. Aplastic crisis, triggered by infection or the introduction of cow milk into the infant diet until
drugs, also may occur. Vaso-occlusive crisis of the infant’s after 1 year of age.
hands and feet, the hand-foot syndrome (dactylitis), Iron is an essential nutrient. Most iron is bound to the
manifests with pain, warmth, and swelling of the hands heme proteins, hemoglobin, and myoglobin. The storage
and/or feet. proteins ferritin and hemosiderin contain most of the rest
Identification of affected newborns through newborn of the iron. A small percentage is bound in enzyme
screening programs with enhancements in parent educa educa- systems such as cytochromes and catalase. In healthy
tion and supportive care such as penicillin prophylaxis, adults, most of the body’s iron is recycled from the break-
immunization against S. pneumoniae and H. influenzae,
influenzae down of RBCs. Little iron needs to be absorbed from the
and early identification of hepatic or splenic sequestra
sequestra- intestines and little is lost through fecal or urinary excre-
tion have decreased the death rate for infants and chil- tion. Because neonates must rapidly expand muscle mass
dren. The natural history of sickle cell anemia includes and blood volume, they require a much higher percent-
painful vaso-occlusive events, acute and chronic lung age of dietary iron intake. The amount of iron stored in
disease, stroke, overwhelming sepsis from splenic dys- the neonate’s body is proportional to birth weight. Eighty
function, avascular necrosis of joints, retinopathy, and percent of a term infant’s iron is acquired during the third
transfusion-related iron overload. The National Heart, trimester.c f~j o iqqszkj¥ gozu z{g} }{~iq€ pk }id|gkz
Lung and Blood Institute (NHLBI) issued manage- for the first 4 to 6 months of life. Preterm infants and
ment guidelines for sickle cell disease in 2002, which those born small for gestational age have a much faster
are available at .nhlbi.nih.gov/health/prof/blood/ rate of postnatal growth and are at risk for iron deficiency
sickle/sc_mngt.pdf
o||k}}k€ y|z~pkj ?wu ?Tƒtlm ­ within the first 3 months of life (Ç~È 88-6lm Infants born
updated version of these guidelines was released in anemic and those who have accelerated iron losses from
2013 at .nhlbi.nih.gov/guidelines/scd/progress.htm repeated laboratory testing, trauma, surgery, or anatomic
(accessed October 24, 2013). Treatment of the sickle abnormalities may also become deficient. Although both
hemoglobinopathies has been largely supportive using breast milk and cow milk contain iron, the bioavailability
penicillin prophylaxis, vaccinations, blood transfusions of the iron in breast milk is much superior. The American
with extended RBC phenotyping, and cross-matching to Academy of Pediatrics (AAP) Committee on Nutrition
decrease the incidence of transfusion-associated alloim- updated its recommendations for diagnosing and pre-
munization, and hydration, narcotics, and nonsteroidal venting iron deficiency and iron deficiency anemia in
anti-inflammatory drugs for painful crises. Hydroxyurea 2010 (nopqk rrsƒtlmc fiqqszkj¥ goz} {~ ojk pjko}zk€
decreased the number and severity of vaso-occlusive pain should not require iron supplementation until 4 to 6
events in infants and young children with Hb SS and Hb months of age. At 4 months of age, human milk-fed
SB0 thalassemia in the randomized, placebo-controlled infants should receive iron supplementation until they
Baby HUG study.‡x zk¥ |kqq zjo}‚qozozg~u z{k ~q¡ are eating iron-containing foods. Two daily servings of an
established cure for sickle cell anemia, has been limited iron-fortified cereal will meet this requirement. Infant
by the availability of suitable donors and the uncertainty cereal fortified with iron should be one of the earliest
in predicting which children will express a more severe solid foods introduced. After 6 months of age, one daily
phenotype. Ongoing studies using reduced intensity con- serving of a vitamin C–rich food should be introduced.
ditioning regimens and alternative donor options, as well Because the protein in cow milk can cause occult
as risk stratification of sickle cell patients, may allow
larger number of patients to undergo stem cell transplan-
tation in the future.

Sickle Cell Trait. Heterozygotes for Hb S (sickle cell

trait) were thought to be clinically unaffected, but there
BOX 88-6 RISK FACTORS FOR IRON
are reports of hematuria, decreased urinary concentrating DEFICIENCY ANEMIA
ability, and occasional reports of sudden death related to IN INFANTS
high altitude and extreme exercise. Associations have • Prematurity
been made between sickle cell trait and venous thrombo- • Small for gestational age
sis, renal medullary carcinoma, and a more severe course • Anemia at birth
of diabetes mellitus.
• Fetal-maternal hemorrhage
Anemia Caused by Inefficient Production of • Twin-twin transfusion
Red Blood Cells • Perinatal hemorrhage
Iron Deficiency Anemia. Although the prevalence of • Iatrogenic or other ongoing blood loss
iron deficiency anemia is decreasing in the United States, • Insufficient dietary intake or malabsorption
it remains a major cause of anemia in infants and chil- • Early introduction of cow milk
dren, and it has been associated with adverse neurocogni- • Erythropoietin use
tive outcomes. Factors associated with the declining rates • Maternal conditions: severe iron deficiency, diabetes
of iron deficiency anemia include the increasing number
 1314 MNOQ 14 • THE BLOOD AND HEMATOPOIETIC SYSTEM

TABLE 88-13 Guidelines for Iron Supplementation for Infants in the First Year of Life
f±Yth Status Intake Minimum Daily Recommendation How Supplied
Term, Healthy Human milk 1 mg/kg per day after 4 mo of age until Iron supplement until addition of complementary
addition of complementary iron-rich foods iron-rich foods
Term, Healthy >Half human milk 1 mg/kg per day after 4 mo of age until Iron supplement until addition of complementary
addition of complementary iron-rich foods iron-rich foods
Term, Healthy Standard infant 1 mg/kg per day after 4 mo of age Supplied by standard infant formula and/or addition
formula of complementary iron-rich foods
Preterm Human milk 2 mg/kg per day beginning at 1 mo of age Supplement added to human milk or given separately
and until 12 mo of age until addition of complementary iron-rich foods
Preterm Standard infant 2 mg/kg per day beginning at 1 mo of age Supplied by full feeds of standard infant formula and/
formula and until 12 mo of age or complementary iron-rich foods

Adapted from Baker RD, Greer FR, Committee on Nutrition American Academy of Pediatrics. Clinical report—diagnosis and prevention of iron deficiency and iron-
deficiency anemia in infants and young children (0-3 years of age). Pediatrics. 2010;125:1040-1050.

BOX 88-7 CHALLENGES IN THE chronic or acute illness. The AAP recommends that testing
for anemia by hemoglobin estimation should occur at
DIAGNOSIS AND TREATMENT approximately 12 months of age. In addition, there
OF IRON DEFICIENCY AND should be an assessment of risk factors for iron deficiency/
IRON DEFICIENCY ANEMIA iron deficiency anemia at that time. Earlier and/or more
IN NEONATES frequent assessments should occur in situations of high
• Optimal lab testing for premature infants concern. A careful dietary history should be taken, and
• Optimal formulation of iron supplementation
consideration should be given to special circumstances
such as ongoing blood loss, malabsorption, early or
• Optimal iron preparation
excessive cow milk intake, and birth history. In early iron
• Optimal dose and interval of supplementation deficiency, the bone marrow stores are depleted and the
• Duration of iron supplementation RBC distribution width increases. Subsequently, the iron
• Incidence and proper management of adverse effects of transporter levels fall, resulting in lower serum levels of
iron supplementation iron, ferritin, and transferrin in the term infant. Finally,
erythrocyte production is affected. A hypochromic, micro-
Adapted from Buchanan GR. Paucity of clinical trials in iron deficiency:
lessons learned from study of VLBW infants. Pediatrics. 2013;131:
cytic anemia becomes apparent. Screening test results
e582-e584. such as serum iron, total iron-binding capacity, ferritin,
and transferrin saturation may be inconclusive because
of acute or chronic illness. It is unclear what testing is
optimal in the premature infant. The AAP favors the retic-
gastrointestinal bleeding in the neonate and because of ulocyte Hb concentration (CHr) and the serum transfer-
the poor bioavailability of iron in cow milk, it is recom- rin receptor 1 (TfR1) because these tests are not affected
mended that babies avoid cow milk until after 1 year of by inflammation or infection, but these tests are not
age. In general, preterm infants who are fed human milk widely available. A therapeutic trial of iron for presump-
require iron supplementation after 1 month of age, either tive iron deficiency anemia is a cost-effective strategy.
by a supplement added to the breast milk or iron given Ferrous sulfate, in a dose of 2 to 6 mg/kg per day of
directly to the infant. An exception may be made for elemental iron, may be given for 1 month. If the hemo-
infants who have received multiple blood transfusions globin rises by at least 1 g/dL (in the absence of ongoing
and are thus at risk for iron overload, rather than defi- blood loss), the diagnosis of iron deficiency is made, and
ciency. A thought-provoking, recently published random- the iron supplementation is usually continued for 2 to 3
ized, placebo-controlled trial of daily oral iron more months or until 1 to 2 months after the hemoglo-
supplementation in very low birth weight infants bin is in the normal range. Screening for lead exposure
(<1500 g) of less than 32 weeks’ gestational age, who should be done as part of routine well-baby care and
were managed on a liberal transfusion strategy, did not particularly considered if a hypochromia and microcyto-
demonstrate an increase in the hematocrit, reticulocyte sis are detected.
count, or transfusion requirements at week 36 postmen-
strual age.ˆˆ Hepcidin and Iron Homeostasis. The hepatically pro-
egz{ improved survival in the smallest patients, addi- duced peptide, hepcidin, is an important regulator of iron
tional knowledge gaps and opportunities for investiga- homeostasis. It inhibits the transport of iron across
tion are identified in diagnosing, treating, and preventing the gut mucosa as well as the transport of iron out of
iron deficiency and iron deficiency anemia (Ç~È 88-7lm macrophages. Hepcidin is an acute-phase reactant: in
Although severe iron deficiency in children is fairly simple inflammation, increased hepcidin results in decreased
to diagnose, milder deficiency may not yet have caused iron absorption. Overexpression of hepcidin in geneti-
anemia or may be difficult to distinguish from other cally modified mice results in iron deficiency anemia.
causes of microcytic anemia, especially in patients with This has led to interest in human defects of hepcidin
 // • HEMATOLOGIC AND ONCOLOGIC PROBLEMS IN THE FETUS AND NEONATE 1315

overexpression that may result in the inability to absorb with Diamond-Blackfan anemia and parvovirus-induced
iron (i.e., refractoriness to oral iron).„g h~¬kj}kq¡u z{k anemias.
intestinal hyperabsorption of iron in thalassemias is asso-
ciated with low hepcidin levels. Parvovirus-Induced Anemia. Parvovirus B19, which
proliferates in human erythroid precursors, causes several
Physiologic Anemia of Infancy and Physiologic diseases. The majority of adults in the United States have
Anemia of Prematurity: The Role of Erythropoietin. antibody to the virus. The virus produces fifth disease.
The physiologic anemia of infancy can be exaggerated The rash and joint symptoms associated with this gener-
in the sick or premature infant by frequent blood sam sam- ally minor illness are caused by vascular deposition of
pling: the smaller the infant, the proportionally greater antibody complexes generated in response to the infec-
the volume of blood that is withdrawn for laboratory tion. In patients with underlying hemolytic anemias, par-
testing. Most RBC transfusions in neonates occur within vovirus infection can cause a transient, severe aplastic
the first 3 to 4 weeks of life, with the majority being in crisis. It can also cause chronic anemia from a persistent
the first 2 weeks. Physiologically lower levels of EPO in infection in erythroblasts in immunocompromised hosts.
neonates provided the rationale for the pharmacologic Chronic parvovirus anemia responds to administration
use of erythropoietin to reduce the volume and risks of of intravenous immunoglobulin. The virus binds to
blood transfusions. Recombinant erythropoietin prod prod- blood group P-antigen on the surface of erythroid precur-
ucts are commercially available and are used to treat the sors, is internalized, and then replicates, disrupting
anemia of renal failure. Erythropoietin has also been used normal erythroid differentiation. Endothelial cell
for the anemia of cancer treatment. Recently, the Food P-antigen is postulated to participate in placental trans-
and Drug Administration (FDA) mandated black box mission of the virus. This antigen is also found on fetal
warnings for EPO because of increased risks of death, cardiomyocytes, a finding consistent with the fact that the
myocardial infarction, stroke, venous thrombosis, and fetus infected with parvovirus can develop myocarditis.
cancer progression in adult patients. Two approaches to Infection rate during pregnancy is estimated to be in the
EPO therapy have been systematically reviewed in neo- 3% range. Parvovirus infection during pregnancy can
nates and reported in a 2012 Cochrane database system
system- result in anemia, hydrops fetalis, fetal loss, or congenital
atic review.x n{k
The kojq¡ o‚‚j~o|{u €k
early approach, dk€ p¡
defined by z{k
the i}k
use ~
of infection. The rate of transplacental transmission of the
EPO before day 8 of life, has been shown to reduce (but virus has been estimated at 33%. Initial reports of high
not eliminate) RBC transfusions and donor exposures, rates of stillbirth and fetal loss have been modified; it is
but did not impact morbidity and mortality measures, recognized that most of the mortality occurs during the
except that EPO was associated with increased risk for first 20 weeks of gestation.x‡ 27
k¬kjk z{j~¥p~|¡z~‚kgo
Severe thrombocytopenia
retinopathyy of prematurity. The later use of EPO (on day occurs in more than one third of cases and can compli
compli-
8 of life or after) resulted in a reduction in the number cate intrauterine transfusion. Parvovirus-induced hydrops
of blood transfusions, but not the total volume of blood, can be detected by ultrasound, and treatment of sus sus-
per infant, so that meaningful clinical outcomes were not pected hydropic infants includes intrauterine RBC trans
trans-
affected by the use of EPO. Because most infants received fusion. Parvovirus infection of the fetus may persist after
RBC transfusions very early and before being enrolled in birth as a cause of congenital RBC aplasia.
the clinical trials evaluating this question, the authors
concluded that the critical effort should be aimed at pre- Diamond-Blackfan Anemia. Diamond-Blackfan anemia
venting donor exposures in the very first few days of life.x (DBA) is a rare, autosomal dominant bone marrow
zopqk and larger preterm infants have a better response failure syndrome of congenital macrocytic anemia with
to EPO therapy when compared with ELBW infants. reticulocytopenia. Bone marrow examination reveals
Erythropoiesis requires iron. Even though EPO adminis- normal cellularity with decreased numbers of erythroid
tration has been shown to reduce hepcidin levels, thereby precursors and abnormal erythroid maturation. Serum
increasing intestinal iron absorption, ferritin levels have EPO levels are elevated as a compensatory response to
been reported to drop with EPO use. Supplementation inefficient RBC production by the marrow. Erythrocyte
of between 1 mg/kg per day and 10 mg/kg per day ele- adenosine deaminase (eADA) levels are elevated, as is
mental iron has been used to lessen the risk of iron fetal hemoglobin. Patients with DBA often have one or
deficiency.x more physical anomalies, such as low birth weight, short
stature, abnormal facies, skeletal abnormalities (includ-
û45þiý1þ= Erythroblastopenia of Childhood. Tran- ing abnormal thumbs) and visceral anomalies. The
sient erythroblastopenia of childhood (TEC) is an median age of diagnosis is 2 months. Although the phe-
acquired, transient, normocytic, hypoplastic anemia with notypes of DBA and Fanconi anemia overlap, several fea-
a peak incidence at ages 2 to 3 years. It is exceedingly rare tures distinguish these syndromes. Patients with DBA are
in neonates. The etiology of TEC is unknown but may be usually anemic from birth, whereas those with Fanconi
the result of viral injury to erythroid precursors. Familial anemia generally develop reticulocytopenia later in life.
cases have been reported. The degree of anemia can range Laboratory evaluation reveals increased chromosome fra-
from moderate to severe. Transient erythroblastopenia gility in Fanconi lymphocytes, but not in DBA. The other
of childhood is a diagnosis of retrospect. Treatment con- macrocytic bone marrow failure syndrome that presents
sists of supportive measures, including RBC transfusion at birth is Pearson syndrome (nopqk rrsƒwlm Several genes
if needed, until bone marrow recovery. Most patients have been identified whose mutations together account
recover in 1 to 2 months. The condition may be confused for about 45% of patients with DBA. All mutations