Chapter 05

Part 2
Erythrocytes
Chapter 5: Erythrocyte
Maturation, Physiology, and
Lifecycle
Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Erythropoiesis
The mature erythrocyte is a biconcave disc with a central
pallor that occupies the middle one third of the cell.
In the mature cell, the respiratory protein, hemoglobin,
performs the function of oxygencarbon dioxide
transport.
Throughout the life span of the mature cell, an average
of 120 days, this soft and pliable cell moves with ease
through the tissue capillaries and splenic circulation.
As the cell ages, cytoplasmic enzymes are catabolized,
leading to increased membrane rigidity (density),
phagocytosis, and destruction.

Erythropoiesis (cont.)
The term used to describe the process of erythrocyte
production is erythropoiesis.
Erythropoiesis encompasses differentiation from the
hematopoietic stem cell (HSC) through the mature
erythrocyte.

Erythropoiesis (cont.)
Transport of oxygen to the tissues and transport of
carbon dioxide from the tissues is accomplished by the
heme pigment in hemoglobin, which is synthesized as
the erythrocyte matures.
The basic substances needed for normal erythrocyte and
hemoglobin production are amino acids (proteins), iron,
vitamin B12, vitamin B6, folic acid (a member of the
vitamin B2 complex), and the trace minerals cobalt and
nickel.
Abnormal erythropoiesis can result from deficiencies of
any of these necessary substances.

Erythropoietin
Erythropoietin is produced primarily by the kidneys.
Blood levels of erythropoietin are inversely related to
tissue oxygenation.
Erythropoietin produces an increase in the production
of several types of ribonucleic acid (RNA) followed by an
increase in deoxyribonucleic acid (DNA) activity and
protein synthesis.

General Characteristics of Maturation and
Development
Once the stem cell differentiates into the erythroid cell
line, a cell matures through the nucleated cell stages in 4
or 5 days.
Bone marrow reticulocytes have an average maturation
period of 2.5 days.
Once young reticulocytes enter the circulating blood,
they remain in the reticulocyte stage for an average of 1
day.
Reticulocytes represent approximately 0.5% to 1.5% of
the circulating erythrocytes.

Development (cont.)
Figure 5.1 Erythrocyte maturation. (Reprinted with permission from Anderson SC. Anderson's Atlas of
Hematology, Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins, Copyright 2003.)
Development (cont.)
Figure 5.2 Erythrocyte morphology. The morphological development of the erythrocyte is typical of blood cell
maturation. The unique difference is that the erythrocyte loses its nucleus. If the erythrocyte is stained
with a supravital stain, such as new methylene blue, reticulocytes, as depicted on the right, will be
visible.
Development (cont.)
Figure 5.3 Pronormoblast (rubriblasts). (Reprinted with permission from Anderson SC. Anderson's Atlas of

Development (cont.)
Figure 5.4 Basophilic normoblast (prorubricyte). (Reprinted with permission from Anderson SC. Anderson's
Atlas of Hematology, Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins, Copyright
2003.)

Development (cont.)
Figure 5.5 Polychromatophilic normoblast (rubricyte). (Reprinted with permission from Anderson SC.
Anderson's Atlas of Hematology, Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins,
Copyright 2003.)

Development (cont.)
Figure 5.6 Orthochromatic normoblast (metarubricyte). (Reprinted with permission from Anderson SC.
Anderson's Atlas of Hematology, Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins,
Copyright 2003.)

Development (cont.)
Figure 5.7 Erythroid maturation. (Reprinted with permission from (Handin RI, Lux SE, Stossel TP. Blood:
Principles and Practice of Hematology, 2nd ed, Philadelphia, PA: Lippincott Williams & Wilkins, 2003.)

Development (cont.)
Figure 5.8 Erythroid maturation. (Reprinted with permission from Greer JP (ed). Wintrobe's Clinical
Hematology, 11th ed, Philadelphia, PA: Lippincott Williams & Wilkins, 2004.)
Development (cont.)
Figure 5.9 Changes in total body hemoglobin blood hemoglobin concentration reticulocyte count and body
weight in a representative premature infant. The vertical bars represent the infants body weight.
(Reprinted with permission from Mhairi G, et al. Averys Neonatology Pathophysiology and Management
of the Newborn, 6th ed, Philadelphia, PA: Lippincott Williams & Wilkins, 2005.)

Development (cont.)
Figure 5.10 Polychromatophilia. (Reprinted with permission from Anderson SC. Anderson's Atlas of

Mature Erythrocyte
After the reticulocyte stage, the mature erythrocyte (RBC
red blood cell) is formed.
An RBC has an average diameter of 6 to 8 mm.

Reticulocytes
A supravital stain, such as new methylene blue,
precipitates the ribosomal RNA in these cells to form a
deep-blue, mesh-like network.
The reticulocyte count procedure (see Chapter 26) is
frequently performed in the clinical laboratory as an
indicator of the rate of erythrocyte production.

Reticulocytes (cont.)
Usually, the count is expressed as a percentage of total
erythrocytes. The normal range is 0.5% to 1.5% in
adults. In newborn infants, the range is 2.5% to 6.5%,
but this value falls to the adult range by the end of the
second week of life.
The corrected reticulocyte count be made
mathematically by correcting the observed reticulocyte
count to a normal packed red blood cell volume.

Reticulocyte production index
A simple percentage calculation of reticulocytes does not
account for the fact that prematurely released reticulocytes
require from 0.5 to 1.5 days longer in the circulating blood
to mature and lose their net-like reticulum.
The RPI measures erythropoietic activity when stress
reticulocytes are present. The rationale for obtaining this
value is that the life span of the circulating stress
reticulocytes is 2 days instead of the normal 1 day.
To compensate for the increased maturation time and
consequent retention of residual RNA of the prematurely
released reticulocytes, the corrected reticulocyte count is
divided by a correction factor derived from the maturation
timetable.
Reticulocyte production index (RPI)
RPI = corrected reticulocyte count in %
maturation time in days

Disorders Related to Erythrocyte
Maturation and Production
Disorders of erythropoietin
Polycythemia is the term used to refer to an increased
concentration of erythrocytes (erythrocytosis) in the circulating
blood that is above normal for gender and age.
Secondary, or absolute, polycythemias reflect an increase in
erythropoietin production and should not be confused with
polycythemia vera (see Chapter 21) or relative polycythemias.

Disorders Related to Erythrocyte
Maturation and Production (cont.)
Red cell increases
Increases in erythrocytes can result from conditions
that are not related to increased erythropoietin
production. These conditions include the relative
polycythemias.

Defective Nuclear Maturation
A defect in maturation known as megaloblastic maturation
can be seen in certain anemias, such as vitamin B12 or folate
deficiencies.
The most noticeable characteristic of this type of defect is that
nuclear maturation lags behind cytoplasmic maturation.
Because of an impaired ability of the cells to synthesize DNA,
both the interphase and the phases of mitotic division are
prolonged.
This asynchronous pattern of maturation can be confusing
because the nuclear development of the cell is much younger
looking than the actual developmental age, which is expressed
by the cytoplasmic development.

Defective Nuclear Maturation (cont.)
Figure 5.11 Megaloblastic anemia. A bone marrow aspirate from a patient with vitamin B 12 deficiency
(pernicious anemia) shows prominent megaloblastic erythroid precursors. (Reprinted with permission
from Rubin E, Farber JL. Pathology, 3rd ed, Philadelphia, PA: Lippincott Williams & Wilkins, 1999.)

Characteristics and Biosynthesis of
Hemoglobin
Genetic inheritance of hemoglobin
Normal adult hemoglobin A is inherited in simple
mendelian fashion.

Chemical Composition and Configuration
of Hemoglobin
Figure 5.12 Structure of the hemoglobin. (Reprinted with permission from Porth CM. Pathophysiology
Concepts of Altered Health States, 7th ed, Philadelphia, PA: Lippincott Williams & Wilkins, 2005.)

of Hemoglobin (cont.)
Figure 5.13 The heme portion of the hemoglobin molecule consists of one iron (Fe 2+) atom and four pyrrole
rings that are joined to each other. A complete hemoglobin molecule consists of four heme molecules,
each of which is attached to one molecule of the protein globin.

The role of 2,3-diphosphoglycerate
The oxygen affinity of the hemoglobin molecule is
associated with the spatial rearrangement of the
molecule and is regulated by the concentration of
phosphates, particularly 2,3-diphosphoglycerate (2,3-
DPG) in the erythrocyte.
The manner in which 2,3-DPG binding to reduced
hemoglobin (deoxyhemoglobin) affects oxygen affinity
is complex. Basically, 2,3-DPG combines with the beta
chains of deoxyhemoglobin and diminishes the
molecules affinity for oxygen.

Figure 5.14 Hemoglobin molecular changes.

Oxygen Dissociation and Alterations
Figure 5.15 The oxygen dissociation curve of normal adult blood. (Reprinted with permission from Mhairi G,
et al. Averys Neonatology Pathophysiology and Management of the Newborn, 6th ed, Philadelphia, PA:
Lippincott Williams & Wilkins, 2005.)

Carbon Dioxide Transport
In the predominant indirect erythrocyte mechanism,
approximately three fourths of the activity for removing carbon
dioxide, carbon dioxide diffuses into the erythrocytes, is
catalyzed by the enzyme carbonic anhydrase, and is
transformed into carbonic acid.
H2O + CO2 --------- H2CO3
The hydrogen ion of carbonic acid is accepted by the alkaline

deoxyhemoglobin, and the bicarbonate ion diffuses back into
the plasma.
H2CO3 ----------- H+ + HCO3 -

Biosynthesis of Hemoglobin
Formation of heme from
porphyrin
Figure 5.16 Heme biosynthetic pathway. Ac, acetate; ALA, -aminolevulinic acid; CoA, coenzyme A; CoAS,
succinyl-CoA; CoASH, uncombined coenzyme A; COPROGEN, coproporphyrinphyrinogen; UROGEN,
uroporphyrinogen; Vi, vinyl. (Reprinted with permission from Greer, JP (ed). Wintrobes Clinical Hematology,
12th ed, Philadelphia, PA: Lippincott Williams & Wilkins, 2009, p. 114.)

Biosynthesis of Hemoglobin (cont.)
Figure 5.17 Sites of heme synthesis.

The Role of Iron in Hemoglobin Synthesis
Figure 5.18 Intestinal absorption of iron. (Reprinted with permission from Andrews NC. Understanding heme
transport, NEJM, 353:2508. Copyright 2005 Massachusetts Medical Society. All rights reserved.)

Hepcidin
Figure 5.19 Pathways of iron exchange. (Reprinted with permission from Swinkels DW, et al. Hereditary
hemochromatosis: genetic complexity and new diagnostic Approaches, Cl Chem, 52(6):951, 2006; Figure
1.)

Globin Structure and Synthesis
Figure 5.20 The globin gene loci.

Disorders Related to Hemoglobin
Biosynthesis
Disorders of heme (porphyrin) synthesis
Figure 5.21 The heme biosynthetic pathway. Inherited defects of each of the heme biosynthetic enzymes
except -aminolevulinic acid synthase have been described and lead to the clinical disorders known as
the porphyrias. (Reprinted with permission from Mulholland MW, et al. Greenfields Surgery Scientific
Principles and Practice, 4th ed, Philadelphia, PA: Lippincott Williams & Wilkins, 2006.)
Disorders of Heme (Porphyrin) Synthesis
Porphyrias are disorders in the synthesis of porphyrin.
Porphyrias can be classified based on various
characteristics:
Clinical presentation (acute versus chronic)
Source of enzyme deficiency
Site of enzyme deficiency in the heme biosynthetic
pathway

Disorders of Iron Metabolism
Genetic defect of iron
Iron overload
Sideroblastic anemia

Disorders of Iron Metabolism (cont.)
Causes of sideroblastic anemia include the following:
Congenital defect: hereditary sex-linked (primarily males);
autosomal
Acquired defect: primary (one of the myelodysplastic
syndromes); may evolve into acute myelogenous leukemia
Association with malignant marrow disorders: acute
myelogenous leukemia, polycythemia vera, myeloma,
myelodysplastic syndromes
Secondary to drugs: isoniazid (INH), chloramphenicol; after
chemotherapy
Toxins, including alcohol, and chronic lead poisoning

Disorders of Iron Metabolism (cont.)
Hereditary hemochromatosis
HFE-gene related (type 1)
Different mutations of the HJV gene are responsible
for juvenile hemochromatosis (or type 2
hemochromatosis).
Type 3 hemochromatosis is a different form of the
disease that usually appears in midlife.
Type 4 is related to the SLC40A1 gene that encodes
for ferroportin.

Disorders of Globulin Synthesis
Globin synthesis is highly coordinated with porphyrin
synthesis. When globin synthesis is impaired,
protoporphyrin synthesis is correspondingly reduced.
Similarly, when porphyrin synthesis is impaired, excess
globin is not produced.
There is no such fine regulation of iron uptake with
impairment of either protoporphyrin or globin synthesis.
When globin production is deficient, iron accumulates in
the cytoplasm of cells as ferritin aggregates.
Defects of globulin synthesis are manifested in the
thalassemias.

Ontogeny of Hemoglobin
Embryonic hemoglobins
Embryonic hemoglobins are primitive hemoglobins
formed by immature erythrocytes in the yolk sac.
These hemoglobins include Gower I, Gower II, and
Portland types.
They are found in the human embryo and persist until
approximately 12 weeks of gestation.

Ontogeny of Hemoglobin (cont.)
Fetal hemoglobin
Fetal hemoglobin (hemoglobin F) is the predominant
hemoglobin variety in the fetus and the newborn.
This hemoglobin type has two alpha and two gamma
chains.
Fetal hemoglobin appears by the fifth week of
gestation and persists for several months after birth.

Ontogeny of Hemoglobin (cont.)
Hemoglobin A
Although adult hemoglobin is predominantly of the A
variety (95% to 97%), the A2 type is also found in
small quantities (2% to 3%).

Glycosylated Hemoglobin (Hemoglobin A1)
A subfraction of normal hemoglobin A is hemoglobin A1.

This subfraction can be termed glycosylated
hemoglobin and includes the separate hemoglobin
fractions A1a, A1b, and A1c.

(cont.)
This type of hemoglobin is formed during the maturation
of the erythrocyte. Because proteins are vulnerable to
modification after being synthesized by the ribosomes,
this modification takes the form of glycosylation of
hemoglobin in hyperglycemic persons.
The concentration of glycosylated hemoglobin accurately
reflects the patients blood glucose level over the
preceding weeks and has been recently used to monitor
the control of diabetes.

(cont.)
Glycosylated hemoglobin is a stable hemoglobin and is
structurally the same as hemoglobin A except for the
addition of a carbohydrate group at the terminal valine of
the beta chain.
The concentration of hemoglobin A1 is 3% to 6% in
normal persons and 6% to 12% in both insulin-
dependent and noninsulin-dependent diabetics.

Ontogeny of Hemoglobin
Variant forms of normal hemoglobin
Carboxyhemoglobin
Sulfhemoglobin
Methemoglobin

Abnormal Hemoglobin Molecules
Abnormal hemoglobin molecules such as those seen in
sickle cell anemia result from mutant, codominant genes.

Abnormal Hemoglobin Molecules (cont.)
Figure 5.24 Comparison of normal and sickle hemoglobin molecules. Glu, glutamic acid; Val, valine.

Analysis of Hemoglobin
A method for the preliminary identification of abnormal
hemoglobin is electrophoresis.

Analysis of Hemoglobin (cont.)
Figure 5.25 Examples of common hemoglobin variants on both cellulose acetate and citrate agar
electrophoresis. (Reprinted with permission from McClatchey KD. Clinical Laboratory Medicine, 2nd ed,
Philadelphia, PA: Lippincott Williams & Wilkins, 2002.)

Figure 5.26 Cellulose acetate electrophoresis. (Reprinted with permission from McClatchey KD. Clinical
Laboratory Medicine, 2nd ed, Philadelphia, PA: Lippincott Williams & Wilkins, 2002.)

Citrate agar electrophoresis
In this method, hemoglobins are separated on the
basis of a complex interaction between hemoglobin,
agar, and citrate buffer ions.
Citrate agar separates hemoglobin fractions that
migrate together on cellulose acetatehemoglobins
S, D, G, C, E, and O.
All hemoglobin specimens that show an abnormal
electrophoretic pattern in alkaline media should
undergo electrophoresis on acid citrate agar.

A procedure commonly used to determine the amount of
fetal blood that has mixed with maternal blood following
delivery is the Kleihauer-Betke.

Figure 5.27 Kleihauer-Betke acid elution for fetal hemoglobin (Hb). Red blood cells containing HbF are deeply
stained red; red cells containing HbA appear as pale pink ghosts. (Reprinted with permission from Greer,
JP (ed). Wintrobe's Clinical Hematology, 11th ed, Philadelphia, PA: Lippincott Williams & Wilkins, 2004.)

Chromatography
Quantitation of hemoglobin A1 can be accomplished
by cation exchange minicolumn chromatography.
However, the results of this technique can be affected
by several types of hemoglobin in addition to
hemoglobin A1. Cellulose acetate and citrate agar
electrophoresis should be used in conjunction with
cation exchange chromatography to eliminate the
possibility of interference by hemoglobin variants.
Other assay methods for glycosylated hemoglobin
include high-pressure liquid chromatography (HPLC)
and colorimetric methods.

Membrane Characteristics and Metabolic
Activities of Erythrocytes
The mature erythrocyte has no nucleus or other
organelles but is capable of existing in the blood
circulation for an average of 120 days.
An erythrocyte has a limited ability to metabolize fatty
acids and amino acids and lacks mitochondria for
oxidative metabolism.

Activities of Erythrocytes (cont.)
Energy for metabolic processes is generated almost
exclusively through the breakdown of glucose and acts in
different ways to maintain the function of hemoglobin. All
these processes are essential for the erythrocyte to
transport oxygen and to maintain the physical
characteristics required for survival in the blood
circulation.

The overall pathway of erythrocyte glycolysis may be
subdivided into the following:
The major anaerobic Embden-Meyerhof glycolytic
pathway that generates ATP and maintains the
function of hemoglobin
Three supplementary pathways
The methemoglobin reductase pathway
The Luebering-Rapoport pathway
The phosphogluconate pathway

Figure 5.28 Energy metabolism in the erythrocyte. (Reprinted with permission from Greer JP (ed). Wintrobes
Clinical Hematology, 12th ed, p. 150.)

Membrane characteristics
The shape of the erythrocyte constantly changes as it
moves through the circulation and performs extremely
complex maneuvers.
The cellular membrane is composed of a protein-lipid
bilayer with associated antigens.
The cell membrane is deformable and tolerant against
mechanical stress and various pH and salt concentrations in
vivo and in vitro.
Cell shape changes reversibly depending on ATP level in the
cell and intracellular calcium ion concentration.

Cytoplasmic characteristics
In addition to hemoglobin, the cytoplasmic contents
of the erythrocyte include potassium ions in excess of
the concentration of sodium ions, glucose, the
intermediate products of glycolysis, and enzymes.

Cytoplasmic characteristics
In addition to hemoglobin, the enzymes synthesized during early
cell development have to be sufficient to provide the energy
needed for these processes:
Maintaining hemoglobin iron in an active ferrous (Fe 2+) state
Driving the cation pump needed to maintain intracellular
sodium ion (Na+) and potassium ion (K+) concentrations
despite the presence of a concentration gradient
Maintaining the sulfhydryl groups of globins, enzymes, and
membranes in an active reduced state
Preserving the integrity of the membrane

If metabolic pathways are blocked or inadequate, the life
span of the erythrocyte is reduced and hemolysis results.
Defects in metabolism can include the following:
Failure to provide sufficient reduced glutathione,
which protects other elements in the cell from
oxidation
Insufficient energy-providing coenzymes such as
reduced nicotinamide-adenine dinucleotide (NADH),
nicotinamide-adenine dinucleotide phosphate
hydrogenase (NADPH), and ATP

The most common erythrocytic enzyme deficiency, which
involves the Embden-Meyerhof glycolytic pathway, is a
deficiency of pyruvate kinase.

Metabolic Activities
Embden-Meyerhof pathway
Oxidative pathway or hexose monophosphate shunt
Methemoglobin reductase pathway
Luebering-Rapaport pathway

Catabolism of Erythrocytes
Exceptions to the normal erythrocytic life span occur in
premature infants, whose erythrocytes have a mean life
span of only 35 to 50 days, and in fetuses, in which case
erythrocytes have an average life span of 60 to 70 days.

Catabolism of Erythrocytes (cont.)
As an erythrocyte ages, the following processes occur:
The membrane becomes less flexible.
The concentration of cellular hemoglobin increases.
Enzyme activity, particularly glycolysis, diminishes.

Extravascular Catabolism of Erythrocytes
When an erythrocyte is phagocytized and digested by the
macrophages of the mononuclear phagocytic system, the
hemoglobin molecule is disassembled.
The resulting components are as follows:
Iron
Protoporphyrin
Globin

(cont.)
Iron is transported in the plasma by transferrin to be
recycled by the red bone marrow in the manufacture of
new hemoglobin.
Globin is catabolized in the liver into its constituent
amino acids and enters the circulating amino acid pool.

(cont.)
Figure 5.29 Extravascular catabolism of erythrocytes.

Intravascular Catabolism
Intravascular destruction is an alternate pathway for
erythrocyte breakdown.
This process normally accounts for less than 10% of
erythrocytic destruction.
As the result of intravascular destruction, hemoglobin is
released directly into the bloodstream and undergoes
dissociation into alpha and beta dimers, which are
quickly bound to the plasma globulin haptoglobin.

Intravascular Catabolism of Erythrocytes
Figure 5.30 Intravascular catabolism of erythrocytes.

Measurement of Erythrocytes
The erythrocyte indices are used to mathematically
define cell size and the concentration of hemoglobin
within the cell. They are as follows:
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin (MCH)
Mean corpuscular hemoglobin concentration (MCHC)

Measurement of Erythrocytes (cont.)
Mean corpuscular volume (MCV)
The MCV expresses the average volume of an
erythrocyte.
MCV = femtoliters (fL)
The reference value of MCV is 80 to 96 fL.

Mean corpuscular hemoglobin (MCH)
The MCH expresses the average weight (content) of
hemoglobin in an average erythrocyte. It is directly
proportional to the amount of hemoglobin and the
size of the erythrocyte.
MCH = picograms (pg)
The reference value of MCH is 27 to 32 pg.

Mean corpuscular hemoglobin concentration
(MCHC)
The MCHC expresses the average concentration of
hemoglobin per unit volume of erythrocytes. It is also
defined as the ratio of the weight of hemoglobin to
the volume of erythrocytes.
MCHC = g/dL
The normal value of MCHC is 32% to 36%.

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Figure 5.14 Hemoglobin molecular changes.

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The hydrogen ion of carbonic acid is accepted by the alkaline

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Figure 5.17 Sites of heme synthesis.

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Figure 5.20 The globin gene loci.

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A subfraction of normal hemoglobin A is hemoglobin A1.

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