Core Concepts: The Biology of Hemoglobin

Robin K. Ohls
NeoReviews 2011;12;e29-e38
DOI: 10.1542/neo.12-1-e29

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 Article core concepts

Core Concepts: The Biology of Hemoglobin

Robin K. Ohls, MD*
Abstract
A consistent and organized transition from embryonic to fetal to adult hemoglobin
Author Disclosure (Hgb) occurs during human fetal development. Hgb concentrations gradually in-
Dr Ohls has disclosed crease, averaging 18 g/dL (180 g/L) by 40 weeks’ gestation. The ability to deliver
no financial oxygen to tissues in the fetus and neonate is primarily determined by the percentage of
fetal versus adult Hgb and the concentration of 2,3 diphosphoglycerate (2,3-DPG).
relationships relevant
Studies continue to evaluate the relationship between Hgb concentrations and oxygen
to this article. This
delivery in neonates to determine what Hgb concentrations best meet the needs of a
commentary does not wide variety of clinical situations from the critically ill extremely low-birthweight
contain a discussion infant to the stable growing preterm infant. Biochemical interactions between nitric
of an unapproved/ oxide (NO) and Hgb beyond the production of methemoglobin do occur and may be
investigative use of a a source of deliverable NO to the microcirculation under hypoxic conditions.
commercial
product/device.
Objectives After completing the article, readers should be able to:

1. Describe the development of globin gene synthesis and Hgb formation.

2. Explain fetal to neonatal transition of Hgb F to Hgb A.
3. Review the development and function of 2,3-DPG.
4. Describe the relationship between NO and Hgb.

Hemoglobin Concentration During Development

Red blood cell indices such as Hgb, hematocrit, mean cell volume, and red cell distribution
width change during gestation and continue to change through the first postnatal year. (1)
Hgb concentrations gradually rise during gestation. At 10 weeks’ gestation, the average
concentration is approximately 9 g/dL (90 g/L); (1)(2) by the start of the third trimester,
values in the developing fetus reach 11 to 12 g/dL (110 to 120 g/L); and by 30 weeks,
Hgb concentrations are 13 to 14 g/dL (130 to 140 g/L). (1) Jopling and associates (3)
have identified reference ranges based on approximately 25,000 preterm and term infants.
From 22 to 40 weeks’ gestation, there is a consistent increase in Hgb of 0.21 g/dL
(2.1 g/L) per week (Fig. 1). (3) In this large cross-sectional study, no sex differences were
noted in Hgb concentrations, but some studies have reported a slight difference in Hgb
concentrations between white and African American preterm infants. (4) At delivery, a 1-
to 2-g/dL (10- to 20-g/L) rise in Hgb may result from transfusion of placental blood into
the infant. In term and late preterm infants, Hgb concentrations increase by approximately
4% at 4 hours of postnatal age, resulting from a decrease in plasma volume. (5) By 8 to
12 hours of age, Hgb concentrations achieve a relatively constant level. In contrast, in an
evaluation of more than 20,000 preterm infants (29 to 34 weeks’ gestation), a decrease of
approximately 6% was measured at 4 hours of age. (3) This decrease might be due to a lack
of placental transfusion because the umbilical cord in preterm infants is rapidly clamped to
expedite resuscitation.
Red blood cell production decreases significantly after birth, primarily as a result of the
increased availability of oxygen, which greatly reduces erythropoietin (Epo) production
and endogenous erythropoiesis. By the end of the first postnatal week, Hgb concentrations
begin to decline (3) and continue to decrease over the next several weeks as a result of
decreased erythrocyte production, a shortened erythrocyte life span, and an increase in

*Professor of Pediatrics, University of New Mexico, Albuquerque, NM.

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core concepts hemoglobin
Figure 1. Reference ranges for blood hemoglobin concentrations at birth in 24,416
patients at 22 to 42 weeks’ gestation. The solid line represents the mean value and the
dashed lines represent the 5% to 95% reference range. Reprinted with permission from
Jopling. (3)
blood volume related to growth (Fig. 2). Term infants
reach their Hgb nadir at approximately 8 weeks, with
an average Hgb concentration of 11.2 g/dL (112 g/L).
(6) Hgb concentrations subsequently rise so that by
6 months, the concentration averages 12.1 g/dL
(121 g/L). (7)
The decline in Hgb in very low-birthweight infants is
greater than that in term infants, in part because of
phlebotomy losses and in part because of the suppressive
impact of transfusions on endogenous erythropoiesis.
Such infants reach the Hgb nadir of 8 g/dL (80 g/L)
at 4 to 8 weeks of age. (8) Figure 2 demonstrates
relationships among birthweight, chronologic age, and
Hgb in term and preterm infants. (3)
Maternal conditions can influence fetal Hgb concen-
trations. Infants born small for gestational age can have
higher Hgb concentrations due to placental insufficiency
and secondary polycythemia. (9)(10) Infants of dia-
betic mothers, infants of smoking mothers, and infants
born at higher altitudes also tend to have higher Hgb
concentrations at birth (11)(12)(13)(14) In all of these
conditions, accelerated erythropoiesis is believed to be
part of a compensating mechanism designed to raise
oxygen-carrying capacity to maintain an adequate oxy-
gen supply to the fetus. In the case of the fetus of a
mother who has diabetes, increased metabolic demands
of the fetus (as evidenced by a positive correlation be-
tween maternal Hgb A1c and neonatal Hgb) may ac-
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count for the higher oxygen needs
and the compensatory increase in
erythropoiesis and Hgb concentra-
tion. (15)
Hemoglobin Synthesis
During fetal erythropoiesis, an or-
derly evolution of the production
of various Hgbs occurs. Eight glo-
bin genes direct the synthesis of six
different polypeptide chains, desig-
nated alpha (␣), beta (␤), gamma
(␥), delta (␦), epsilon (␧), and zeta
(␨). These globin chains combine
in the developing erythroblast to
form seven different Hgb tetramers:
Gower 1 (␨2-␧2), Gower 2 (␣2-␧2),
Portland (␨2-␥2), fetal hemoglobin
(Hgb F: ␣2-␥2), and two types of
adult hemoglobin: ␣2-␤2, known as
Hgb A, and ␣2-␦2, known as Hgb
A2 (Table 1).
Globin Genes
The globin genes are organized into two clusters
(Fig. 3). The ␣-like genes are located along a 20-kb distal
segment of the short arm of chromosome 16. The cluster
contains three functional genes (␣1, ␣2, and ␨2), three
pseudogenes (evolutionary remnants of genes that are
not expressed because of inactivating mutations that
prevent production of a functional globin protein), and
one gene of undetermined function (a globin-like gene
without inactivating mutations). The ␤-like gene cluster
is located along a 60-kb segment of the short arm of
chromosome 11, and it contains five functional genes
(␤, ␦, A␥, G␥, and ␧) and one pseudogene. Within each
complex, the genes are all in the same 5⬘ to 3⬘ orienta-
tion, and they are arranged in the order in which they are
expressed during development. (16)
Timing of Globin Chain Synthesis
Globin chain production has been determined at each
stage of development, from initial yolk sac (primitive) to
hepatic (definitive) and marrow erythropoiesis. It is not
clear why or how primitive erythroid progenitors pro-
grammed to produce embryonic Hgb transition to de-
finitive progenitors programmed to produce Hgb F.
Because quantification of globin gene expression using
real time polymerase chain reaction methods reflects
production by a heterogeneous source of erythrocytes,
production of a specific Hgb is usually reported as a
 core concepts hemoglobin

During the sixth to seventh week of

gestation, primitive erythroblasts
continue to produce ␣, ␨, and ␧
chains, while definitive erythrocytes
produce ␣, ␧, G␥, and A␥ chains. By
the seventh to eighth week, ␧- and
␨-chain synthesis is no longer de-
tectable, and the primary globin
chains produced are ␣, G␥, and A␥.
␤-chain production is just barely
detectable at this time and gradu-
ally increases, comprising up to 10%
of total non–␣-chain production by
10 weeks of gestation. (18) Genetic
disorders associated with ␤-chain
synthetic or structural abnormali-
ties may be detected in utero as
soon as ␤-chain production occurs
but are often not clinically apparent
until after birth.
From 10 to 33 weeks of gesta-
tion, the primary globin chains syn-
thesized are ␣, G␥, A␥, and ␤. As-
sessment of the output of the two
linked ␣-globin genes by mRNA
analysis suggests that they are ex-
pressed in the ratio (␣2:␣1) rang-
ing from 1.5 to 3.0:1 throughout
fetal life, and this ratio continues
through normal adulthood. The
relative rates of G␥-chain and A␥-
chain production are also constant
throughout fetal life at a G␥:A␥ ratio
of approximately 3:1. (19) During
the transition from 32 to 36 weeks
of gestation, the relative rate of
␤-chain synthesis increases and that
of ␥-chain production declines, so
at birth, ␤-chain synthesis makes
Figure 2. Reference ranges for blood hemoglobin concentrations in 39,559 patients
during the 28 days after birth in late preterm and term infants 35 to 42 weeks’ gestation up approximately 50% of non–␣-
(panel A) and in preterm infants 29 to 34 weeks’ gestation (panel B). The solid line chain synthesis. There is consider-
represents the mean value and the dashed lines represent the 5% to 95% reference range. able variation among infants, how-
Reprinted with permission from Jopling. (3) ever, with many infants showing
prolonged dependence on Hgb F.
After birth, the level of ␤-chain pro-
percentage of the total Hgb measured. Studies measur- duction increases, while the level of ␥-chain production
ing Hgb production by erythroid colonies in culture steadily declines, so by the end of the first year, ␥-chain
show that individual cells in a colony produce predomi- synthesis reaches the low concentration that is character-
nantly one type of Hgb. (17) istic of adult life (⬍2%). Over the first few months after
During the fourth to fifth week of gestation, ␣, ␨, and birth, the G␥:A␥ ratio changes from 3:1 to 2:3, although
␧ chains are the primary globin chains produced (Fig. 4). this ratio varies in adults. (20)(21)(22)

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core concepts hemoglobin

Globin Chain Composition

Table 1. ing in the presence of ␧4. (23) Soon thereafter, ␣- and
␨-chain production begins, and Hgb Gower 1 (␨2-␧2),
of Common Hemoglobin Gower 2 (␣2-␧2), and Portland (␨2-␥2) are formed. (24)
By 5 to 6 weeks’ gestation, Hgb Gower 1 and Gower 2
Type of Hemoglobin Composition
constitute 42% and 24% of the total Hgb, respectively,
Embryonic Hemoglobin: with Hgb F (␣2-␥2) making up the remainder. By 14 to
Gower 1 ␨2-␧2 16 weeks, Hgb F constitutes 50% of the total Hgb, and
Gower 2 ␣2-␧2
Portland ␨2-␥2 by 20 weeks, it forms more than 90% of the Hgb. (25)
Fetal Hemoglobin: Small quantities of Hgb A (␣2-␤2) are found beginning
F ␣2-␥2 at 6 to 8 weeks’ gestation. The increase in ␤-chain
Adult Hemoglobin: production occurring between 12 and 20 weeks’ gesta-
A ␣2-␤2 tion accounts for the sudden rise in Hgb A found at
A2 ␣2-␦2
the end of the first trimester of pregnancy. Tetramers of
␥-chains (␥4 or Hgb Barts) and ␤-chains (␤4 or Hgb H)
Delta-chain production has been observed as early as can be found in conditions in which ␣-chain synthesis is
32 weeks’ gestation. Delta-gene production lags behind impaired or absent, such as ␣-thalassemia syndromes.
␤-gene production, so the adult ␤/␦ synthesis ratio is not Hgb F is easily distinguished immunologically and bio-
reached until 4 to 6 months after birth. chemically from Hgb A. The primary differentiating physi-
ologic characteristic of Hgb F is its decreased interaction
with 2,3-DPG (also known as 2, 3 bisphosphoglycerate).
Hemoglobin Production During Development 2,3-DPG binds to deoxyhemoglobin in a cavity between
Developmental changes in the production of Hgb can be the ␤-chains and stabilizes the deoxy form of Hgb, resulting
seen in Figure 5. Before the onset of other chain forma- in reduced Hgb-oxygen affinity. 2,3-DPG binds less effec-
tion, unpaired globin chains may form tetramers, result- tively to ␥-globin chains because of the differing amino acid
sequence in the non–␣-chain. Con-
sequently, 2,3-DPG does not reduce
the oxygen affinity of Hgb F as much
as that of Hgb A.
Fetal and adult Hgb also differ in
solubility. Hgb F is more soluble in
strong phosphate buffers than Hgb A
and is oxidized to methemoglobin
more easily than Hgb A. Hgb F has a
considerably greater affinity for oxy-
gen as a result of differences in bind-
ing to 2,3-DPG mentioned previ-
ously. Hgb F is resistant to acid
elution, which allows differentiation
of cells containing Hgb F from cells
containing Hgb A. (26) This prop-
erty forms the basis of differentiating
fetal from maternal red cells using the
Kleihauer Betke stain.
Figure 3. Organization of the globin genes. Transcription takes place from the 5ⴕ to the 3ⴕ G
␥-chains represent 70% to 80%
end; for both chromosomes, the genes are arranged in order of their developmental activation.
of the total ␥-chains in the blood of
The upper part of the figure represents the beta-like globin genes on the short arm of
the fetus and newborn. The percent
chromosome 11, and the lower part of the figure represents the alpha-like genes on the distal
short arm of chromosome 16. Regions of the gene that code for primary globin proteins are of ␥-chains made up of ␥ falls to
G

shown as shaded ovals. Regions that code for pseudogenes (y-nonexpressed remnants that about 40% by 5 months of age. This
have a number of inactivating mutations that prevent transcription and translation into unique difference in ␥-chain pro-
G

functional globin protein) are shown as open ovals. ␪-1 is a globin-like gene without duction found in the fetus helps to
inactivating mutations. The locus control region (LCR) is shown as a hatched segment. distinguish fetal hematopoiesis from

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Figure 4. Production of globin chains during the fetal and neonatal period.
that found in later life. Under stress, the older infant and
adult increase production of Hgb F. Increased Hgb F
production often occurs in leukemic states and in other
conditions. (27)(28) The delay in the switch of Hgb F to
Hgb A has been noted in conditions of maternal hypoxia, in
infants who are small for gestational age, (29) and in infants
Figure 5. Hemoglobin production during the fetal and neonatal period.
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core concepts hemoglobin
of diabetic mothers. (30)(31) Ele-
vated concentrations of Hgb F may
have protective effects in some dis-
ease states. For example, a high con-
centration of fetal Hgb F in patients
who have sickle cell disease may be a
predictor of increased adult life ex-
pectancy. (32)(33)
On a body weight basis, red blood
cell production during the latter
months of gestation is significantly
greater compared with that in adult
life. Immediately after birth, erythro-
poiesis is considerably reduced, asso-
ciated with a steady and linear decline
in ␥-chain synthesis during the pe-
riod of reduced neonatal erythropoi-
esis. Newly synthesized red blood cells
appearing in the circulation when
erythropoiesis resumes contain pre-
dominantly Hgb A. The postpartum
decline of Hgb F production and of
the intercellular distribution of fetal and adult Hgb over
the first postnatal months has been extensively examined.
Immediately after birth, there is a brief rise in Hgb F,
followed by a steady decline. Studies of the intercellular
distribution of Hgb F (using an acid-elution technique)
have shown that the distribution of Hgb F is heterogeneous
over the first few months after birth.
At 3 months, the distribution of
Hgb F becomes bimodal, with pop-
ulations of cells that contain acid-
resistant Hgb F and populations of
cells containing Hgb A. These obser-
vations have suggested that Hgb
F-containing cells are replaced by a
population of cells containing Hgb A
during the early postnatal period.
Studies show that the type of
globin chains produced at different
stages of development are not closely
related to the site of erythropoiesis.
It appears that ␨- and ␧-chains are
synthesized in both primitive and
definitive cell lines. Moreover, dur-
ing the later stages of fetal develop-
ment, the switch from ␥- to ␤-chain
production occurs synchronously
throughout the liver and bone
marrow. The transition from ␥- to
␤-chain synthesis is most closely re-
NeoReviews Vol.12 No.1 January 2011 e33
core concepts hemoglobin
lated to postconceptional age and not chronologic age.
(27) Thus, infants born preterm continue to synthesize
significant amounts of ␥-globin (and fetal Hgb) until
40 weeks’ gestation.
2,3-DPG Metabolism
The affinity of Hgb for oxygen can be decreased by
interaction with certain organic phosphates, such as
2,3-DPG and adenosine triphosphate. (34) The highly
charged anion 2,3-DPG binds to deoxyhemoglobin but
not to oxyhemoglobin. Deoxyhemoglobin F does not
possess as great an affinity for 2,3-DPG as does deoxy-
hemoglobin A and, therefore, cannot bind 2,3-DPG to
the same degree as Hgb A. Thus, the fetal leftward-
shifted Hgb oxygen dissociation curve (Fig. 6) is not
easily modulated in the presence of 2,3-DPG.
The P50 (partial pressure of oxygen at which half of
Hgb is saturated) of fetal blood is 19 to 21 mm Hg, some
6 to 8 mm Hg lower than that of adult blood. As Hgb F
concentration declines after birth, however, there is a
marked rightward shift in the postnatal Hgb oxygen
equilibrium curve. The percentage of Hgb A and the red
cell 2,3-DPG content play the greatest roles in altering
the position of the Hgb oxygen dissociation curve. As a
result, preterm infants who have a greater proportion of
Hgb A but less 2,3-DPG (which occurs following packed
red blood cell transfusion) may have a similar P50 as those
who have increased quantities of Hgb F.
Figure 6. Hemoglobin-oxygen dissociation curve. The curve representing fetal hemoglo- controlling blood flow via hypoxic
bin is on the left, and the curve representing adult hemoglobin is on the right. The P50 is vasodilatation. These mechanisms
shown as a hatched line for each curve.
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Certain factors are known to alter the affinity of Hgb for
oxygen (Table 2). The most important of these are the Hgb
F concentration and the red cell 2,3-DPG content. The
concentration of red blood cell 2,3-DPG gradually in-
creases with gestation. At term, the concentration is similar
to that of adults. By the end of the first postnatal week, the
2,3-DPG concentrations are considerably higher than they
are at birth. After the first week, red blood cell 2,3-DPG
concentrations remain relatively unchanged for the next
6 months. In term infants, the Hgb-oxygen dissociation
curve gradually shifts to the right, and by 4 to 6 months of
age, the P50 values approximate those of the adult.
The situation is somewhat different in preterm in-
fants. Because Hgb F synthesis is still active, increases in
P50 seen in term infants as a result of the switch from
Hgb F to Hgb A do not occur as rapidly. The red blood
cell 2,3-DPG concentrations also are slightly lower in
preterm infants. (35) These concentrations are increased
with the use of human recombinant Epo, which shifts the
oxygen dissociation curve to the right. (36)(37)
Nitric Oxide-hemoglobin Interactions
NO plays a significant role in vasoactive regulation.
Under baseline conditions, NO is produced by endo-
thelial NO synthase and diffuses into surrounding smooth
muscle cells, activating soluble guanylyl cyclase to produce
cyclic guanosine 5⬘-monophosphate, and regulates vascular
tone. NO reacts with oxyhemoglobin to form methemo-
globin, which is reversed by erythro-
cytic methemoglobin reductase. A
second reaction also can occur, in
which NO reacts with deoxyhemo-
globin to form nitrosyl hemoglobin
(NO-Hgb). There is some evidence
that erythrocytes containing NO-
Hgb may be able to release NO into
the circulation, thus causing vasodi-
latation in the microvasculature. A
third reaction has been studied that
involves the binding of NO to the
␤-chain cysteine amino acid to form
S-nitrosyl-hemoglobin (SNO-Hgb).
It has been postulated that nitrite
ions within erythrocytes can be re-
duced to NO by deoxyhemoglobin,
so NO is generated as erythrocytes
enter hypoxic regions. All of these
potential mechanisms result in NO
are especially important in preterm

Factors Affecting
Table 2.
Hemoglobin-Oxygen Affinity
Increased P50, increased red blood cell 2,3-DPG:
● Adaptation to high altitude
● Hypoxemia associated with chronic pulmonary disease
● Hypoxemia associated with cyanotic heart disease
● Anemia
● Decreased red blood cell mass
● Hyperthyroidism
● Red cell pyruvate kinase deficiency
Increased P50, no consistent alteration in red blood cell
DPG:
● Abnormal hemoglobins (Kansas, Seattle,
Hammersmith, Tacoma, E)
● Vigorous exercise
Decreased P50, decreased red blood cell 2,3-DPG:
● Septic shock
● Severe acidosis
● Following massive transfusions of stored blood
● Neonatal respiratory distress syndrome
Decreased P50, no consistent alteration in red blood cell
DPG:
● Abnormal hemoglobins (Kempsey, Chesapeake,
Capetown, Yakima, Rainier)
2,3-DPG⫽2,3 diphosphoglycerate, P50⫽partial pressure of oxygen at
which half of hemoglobin is saturated
infants because vulnerable vascular beds such as the splanch-
nic system are at risk for hypoxic injury via shunting of
blood to the brain and heart. Blood that is collected for
transfusion loses its SNO-Hgb within hours, so transfused
packed red blood cells (PRBCs) lack NO. Transfusing
PRBCs that cannot deliver NO to the microvasculature
may, in fact, reduce local oxygen delivery to tissues through
vasoconstriction. Studies are in progress to evaluate the
renitrosylization of Hgb before transfusion.
Oxygen Transport
The mechanisms controlling oxygen transport in utero
and immediately postpartum are complex. During pre-
natal life, the fetal arterial oxygen tension (PO2) is ap-
proximately 30 mm Hg, and the venous PO2 is approxi-
mately 15 mm Hg (Fig. 6). These low PO2s contribute to
the development of relative polycythemia in the fetus.
After birth, numerous factors affect oxygenation, includ-
ing the inspired gas mixture, pulmonary function, the
arterial oxygen dissociation curve, and the ability to
extract oxygen at the tissue level. (38) It has been spec-
ulated that the actual amount of oxygen released to
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core concepts hemoglobin
tissues may be greater in utero because of the character-
istics of the Hgb-oxygen dissociation curve.
If pulmonary function is normal, the PO2 of pulmo-
nary blood rises from the 40 mm Hg of pulmonary
arterial blood to the 100 mm Hg of pulmonary venous
blood. Because of the shape of the Hgb-oxygen dissoci-
ation curve, these PO2 values permit 95% saturation of
Hgb by oxygen. Further increases in PO2 produce little
additional increase in saturation. In the healthy adult,
approximately 50% of Hgb is saturated with oxygen
when the PO2 falls to 27 mm Hg (P50⫽27 mm Hg). In
situations in which the Hgb-oxygen dissociation curve
has shifted to the right, the affinity of Hgb for oxygen is
reduced. Thus, at any given PO2, more oxygen is released
to tissues. Conversely, if the curve is shifted to the left,
the affinity of Hgb for oxygen is increased. Therefore, at
any given PO2, less oxygen is released to the tissues.
A precise relationship does not exist between the decline
in Hgb F and the decrease in oxygen affinity of a neonate’s
blood. (38) Rather, changes in P50 reflect the interaction
between red blood cell 2,3-DPG, the increase in Hgb A
that occurs after birth, and the decline in Hgb F. Although
oxygen-carrying capacity (Hgb concentration ⫻ oxygen
saturation ⫻ 1.36 mL oxygen/g of Hgb) decreases over
the first few postnatal months as Hgb concentration de-
clines, the amount of oxygen delivery can remain similar or
even increase. (35) For example, a preterm infant born with
a Hgb concentration of 15 g/dL (150 g/L) delivers 1 mL
of oxygen to the tissues for every 100 mL of circulating
blood (based on a P50 of 19 and a central venous PO2 of
40 mm Hg). As the percent of Hgb A increases over time,
the P50 shifts to the right. The infant can now deliver
2.1 mL of oxygen per 100 mL of blood, despite a decrease
in total Hgb to 8 g/dL (80 g/L) (based on a P50 of 24 mm
Hg and a central venous PO2 of 40 mm Hg). (35)
After intrauterine transfusion, infants have oxygen-
unloading properties characteristic of adult blood. Despite
the decrease in oxygen affinity that accompanies intrauter-
ine transfusion, no deleterious effects of this procedure with
respect to oxygen uptake by the fetus have been docu-
mented. (39) The physiologic significance of manipulating
the Hgb-oxygen affinity of extremely preterm infants via
PRBC transfusions continues to be studied. It is important
to understand an infant’s ability to deliver oxygen to tissues
when determining whether to administer an erythrocyte
transfusion. The decision to transfuse should not be based
on Hgb concentration alone. Transfusions significantly af-
fect an infant’s endogenous erythropoiesis: for infants who
undergo exchange transfusion or multiple transfusions,
both Epo concentrations and reticulocyte counts are lower
at any given Hgb concentration. (8)(40) The search con-
NeoReviews Vol.12 No.1 January 2011 e35
core concepts hemoglobin
tinues for a specific marker that reflects the need for im-
proved oxygen delivery to tissues (via red blood cell trans-
fusion). Currently, no ideal marker that is simple, requires
little or no blood, is reproducible, and can be applied to
preterm infants exists for clinical use in neonates.
Summary
The organized transition from embryonic to fetal to adult
Hgb has been extensively studied, providing significant
understanding of the molecular basis of Hgb development.
Studies continue to evaluate the relationship between Hgb
concentrations and oxygen delivery in neonates to best
determine what Hgb concentrations best meet the needs of
a wide variety of clinical situations from the critically ill
extremely low-birthweight infant to the stable growing
preterm infant. Studies are underway to explore the mech-
anisms linking Hgb metabolism and the transfer of NO by
erythrocytes, and these studies have the potential to add
greatly to the body of evidence regarding transfusion guide-
lines in various neonatal populations.
American Board of Pediatrics Neonatal-Perinatal
Medicine Content Specifications
• Know the biochemical characteristics of
fetal hemoglobin.
• Know the developmental biology of
hemoglobin types.
• Know normal erythropoiesis in the fetus
and neonate.
ACKNOWLEDGMENTS. I wish to thank Rebecca Mo-
ran, MD, and Andrea Duncan, MD, for their thoughtful
review and comments and Ann Chavez for her assistance
in completing the manuscript.
References
1. Forestier F, Daffos F, Catherine N, Renard M, Andreux JP.
Developmental hematopoiesis in normal human fetal blood. Blood.
1991;77:2360
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NeoReviews Vol.12 No.1 January 2011 e37
core concepts hemoglobin

NeoReviews Quiz
9. Red blood cell production decreases after birth, primarily as a result of increased availability of oxygen,
which greatly reduces erythropoietin production and endogenous erythropoiesis. A decrease in hemoglobin
concentration follows this reduced red blood cell production. Of the following, the hemoglobin nadir in
healthy term infants is reached at a postnatal age closest to:
A. 8 weeks.
B. 12 weeks.
C. 16 weeks.
D. 20 weeks.
E. 24 weeks.

10. Hemoglobin consists of heme, an iron-containing protoporphyrin, and globin, a polypeptide. Eight globin
genes direct the synthesis of six different polypeptide chains, designated as alpha (␣), beta (␤), gamma
(␥), delta (␦), epsilon (␧), and zeta (␨). These globin chains combine in the developing erythroblast to
form seven different hemoglobin tetramers: Gower 1 (␨2-␧2), Gower 2 (␣2-␧2), Portland (␨2-␥2), fetal
hemoglobin (Hgb F: ␣2-␥2), adult hemoglobin (Hgb A: ␣2-␤2), and adult hemoglobin A2 (Hgb A2: ␣2-␦2).
Of the following, the most prevalent hemoglobin tetramer in the fetus at 18 weeks of gestational age is:
A. Gower 1.
B. Hgb A.
C. Hgb A2.
D. Hgb F.
E. Portland.

11. A term infant is born with severe anemia. A Kleihauer Betke test is performed on maternal blood to
determine whether fetomaternal hemorrhage is the cause. Of the following, the property of fetal
hemoglobin that best differentiates fetal from maternal red blood cells using the Kleihauer Betke test is
that the fetal hemoglobin, relative to adult hemoglobin, is/has:
A. Decreased interaction with 2,3-diphosphoglycerate.
B. Greater affinity for oxygen.
C. Greater solubility in strong phosphate buffer.
D. Readily oxidized to methemoglobin.
E. Resistant to acid elution.

e38 NeoReviews Vol.12 No.1 January 2011

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 Core Concepts: The Biology of Hemoglobin
Robin K. Ohls
NeoReviews 2011;12;e29-e38
DOI: 10.1542/neo.12-1-e29

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