Structure and function of red

and white blood cells

Ted Gordon-Smith
Abstract
Red blood cells (RBCs) carry oxygen bound reversibly to the ferrous Fe
2
atoms of the four haem groups of the haemoglobin (Hb) tetramer. In order
to transport the Hb around the body in a functional state, the RBC re-
quires a exible membrane and contents to pass passively through the
capillary bed and a source of energy to maintain the internal milieu. Aden-
osine triphosphate is provided by anaerobic glycolysis. Reducing power is
provided as NADH and NADPH, via the pentose phosphate pathway. Ge-
netic abnormalities that affect the membrane deformability lead to shape
changes and haemolysis; defects in the glycolytic pathway cause non-
spherocytic haemolytic anaemia and failure of reducing power to intravas-
cular haemolysis in response to oxidative stress. RBCs may also control
local blood ow through vasodilatation produced by the nitriteenitic
oxide pathway. White blood cells provide the basis for the innate immune
system as well as interacting with specic immune processes. They need
to pass from the circulation, through the vessel wall into the extravascular
tissues in order to carry out these functions. Inherited defects of the
migratory process also lead to susceptibility to infection. The phagocytic
neutrophils and macrophages have specialized systems for rapid recogni-
tion of pathogens, and systems for killing and antigen presentation.
Keywords allosteric; cell adhesion; erythrocytes; glycolysis; gran-
ulocytes; migration; monocytes; oxygen carriage; phagocytosis; red
blood cells
Values for the numbers of circulating blood cells for normal in-
dividuals at different ages are given in Table 1.
1,2
Numbers are
maintained within fairly close limits under steady conditions but
can be increased rapidly and appropriately in response to stress.
The value for each cell type is a reection of the rates of release
into and escape from the circulation. Red cells and platelets have
a nite life span within the circulation. Granulocytes and
monocytes may be marginated on vessel walls and can leave the
circulation rapidly in response to inammatory signals.
Red blood cells (erythrocytes)
Red blood cells (RBCs) are released into the circulation as re-
ticulocytes. Reticulocytes are enucleate cells that contain residual
RNA, which gives them a faintly basophilic appearance in blood
lms and provides the reticulate material in supravitally stained
preparations (Figure 1). They are about 20% larger than mature
RBCs, contain some mitochondria capable of oxidative respira-
tion and make up 1e2% of the circulating red cells. Values are
usually expressed in absolute numbers (Table 1). As re-
ticulocytes pass through the splenic vessels they lose their or-
ganelles and RNA is degraded. About half the reticulocyte
population resides in the spleen. Although splenectomy increases
the number of circulating reticulocytes it does not hinder matu-
ration, nor does it increase the overall RBC count.
The function of RBCs is to carry haemoglobin (Hb) around the
body in sufciently high concentration to allow effective trans-
port of oxygen from the lungs to the tissues, and to facilitate the
return of carbon dioxide, produced during oxidative phosphor-
ylation, back to the lungs. To achieve this, RBCs have a suitably
large surface area for rapid gas exchange (the biconcave disc
shape), a readily deformable structure to pass through the
capillary bed, and a source of energy to maintain this structure
and provide the internal milieu necessary for functioning
haemoglobin.
The red cell membrane
The RBC membrane (Figure 2)
3
is a phospholipid bilayer, stabi-
lized with equimolar amounts of cholesterol. The main phos-
pholipids are phosphatidyl groups linked to ethanolamine,
inositol, serine or choline (lecithin) and sphingomyelin. The lipid
bilayer provides a stable milieu for the membrane proteins. The
proteins determine the shape and exibility of the RBC. Mem-
brane proteins may be attached to the outer surface of the
membrane through integral membrane domains or by the gly-
cophosphatidyl inositol (GPI) anchor. Transmembrane proteins,
for example band 3 protein, have both plasma and cytoplasmic
domains. External domains include blood groups, binding sites
for immune complexes, and the external parts of transmembrane
channels and signalling proteins. They are mostly heavily gly-
cosylated, which gives the RBC a strong negative surface charge.
Two important complement-inactivating proteins, decay accel-
erating factor (CD55) and membrane inhibitor of reactive lysis
(CD58), are attached via the GPI anchor. Deciency of these
proteins in paroxysmal nocturnal haemoglobinuria is responsible
for haemolysis in this condition.
The main proteins of the cytoskeleton are spectrin, actin,
protein 4.1 and ankyrin The two chains of spectrin (a and b)
wind round each other to form heterodimers, which are linked
end to end by actin, protein 4.1 and other proteins to form a
network of tetramers on the inner membrane surface (Figure 2).
The spectrin is also linked to transmembrane proteins, band 3
and glycophorin C via ankyrin and actin. Together these proteins
give the RBC its biconcave disc shape. Mutations in their genes
Whats new?
C
The possible role of red blood cells and haemoglobin in local
blood ow control through the action of nitric oxide
C
The importance of specialized phagocytic pathways in neutro-
phils and macrophages in the innate immune system
C
The role of the specialized proteasome in the macrophage
family for antigen presentation
Ted Gordon-Smith MA FRCP FRCP (Ed) FRCPath FAcadMedSci is Emeritus
Professor of Haematology and Honorary Consultant Physician at
St Georges Hospital Medical School, London, UK. Competing interests:
none declared.
CLINICAL SCIENCES
MEDICINE 41:4 193 2013 Published by Elsevier Ltd.
cause haemolytic anaemias associated with abnormalities of
shape,
4
the most common being hereditary spherocytosis and
elliptocytosis.
Red cell metabolism
The mature RBC derives its energy from anaerobic respiration via
the glycolytic (EmbdeneMeyerhof) pathway, in which one
molecule of glucose is converted to two of pyruvate, providing
energy as adenosine triphosphate (ATP) and reducing power as
NADH. Gene mutations that lead to loss of activity of the en-
zymes of the pathway lead to shortened RBC survival (non-
spherocytic haemolytic anaemias).
5
The most common inherited
deciency of this pathway involves pyruvate kinase (PK). Since
reticulocytes can produce energy through oxidative phosphor-
ylation they can bypass the defect. Splenectomy in PK deciency
greatly alleviates the anaemia.
The glycolytic pathway also links to the production of 2,3-di-
phosphoglycerate (2,3-DPG), a molecule essential for the effec-
tive carriage of oxygen by Hb (see below).
The RBC needs reducing power not only to prevent the oxi-
dation of Hb to methaemoglobin, mainly provided by NADH, but
also as NADPH to prevent oxidative damage to the red cell
membrane. The RBC is subject to attack by reactive oxygen spe-
cies (ROS) in the circulation and the potentially harmful presence
of iron in the Hb. Reduced glutathione (GSH), maintained by the
production of NADPH is the main protection from ROS. Inherited
mutations of gene on the X chromosome for the enzyme that
catalyses the reaction for NADPH, glucose-6-phosphate dehy-
drogenase, leads to various intravascular haemolytic syndromes,
including favism and oxidative drug-induced haemolysis. Free Hb
in the circulation is potentially harmful because of the highly
reactive haem groups. Free Hb is tightly bound to haptoglobin in
a complex that obscures the reactive sites and promotes phag-
ocytosis through specic receptors on macrophages.
6
The path-
ways of metabolism in the mature RBC are represented in
Figure 3, which indicates the main active products.
Haemoglobin and the carriage of oxygen
Hb is a tetramer of two a and two non-a globin chains, each of
the chains enclosing one of the four haem groups which carry
oxygen in the complete tetramer (Figure 4). The a and a-like
Normal values at different ages
Unit At birth Infant Child Adult
Haemoglobin g/dl 15e24 9e13 11e15 M: 13.5e17.5, F: 11.5e15.5
Red blood cells 10
12
/litre 3.7e6.5 3e5 4e5 M: 4.5e6.5, F: 3.9e5.6
Packed cell volume % 47e75 28e38 32e43 M: 40e52, F: 36e48
Mean corpuscular volume 100e125 84e98 70e90 80e95
Mean corpuscular haemoglobin pg 31e37 30e36 25e30 27e34
Mean corpuscular haemoglobin concentration g/dl 32e36 30e35 33e36 20e35
Reticulocytes 10
9
/litre 120e400 20e60 30e100 30e100
White blood cells 10
9
/dl 9e30 5e17 6e15 4.0e11.0
Neutrophils 10
9
/dl 2.7e14.4 1.0e6.0 1.0e8.5 2.0*e7.5
Eosinophils 10
9
/dl 0.0e0.8 0.09e1.1 0.04e1.04 <0.45
Basophils 10
9
/dl <0.1
Monocytes 10
9
/dl 0.0e1.9 0.4e1.2 0.15e1.28 0.2e0.8
Lymphocytes 10
9
/dl 2.0e7.25 3.3e11.5 2.3e4.6 1.5e3.5
T (cD8) 10
9
/dl 0.8e1.5 0.33e0.67
T(cD4) 10
9
/dl 1.0e2.0 0.4e1.8
B cells 10
9
/dl 0.5e1.5 0.05e0.4
nK cells 10
9
/dl 0.2e0.4
Platelets 10
9
/dl 150e450 210e650 170e450 150e450
Figures are derived from several sources,
1,2
which should be consulted for more detailed results for specic ages. They are given here to emphasize the shifts which
occur during growth and development. People of African ethnicity may constitutionally have neutrophil counts down to 1.0 10
9
/litre.
Table 1
a Normal red blood cells with area of central pallor the result of the
biconcave disc shape. b Reticulocytes stained with supravital stain
showing reticulate precipitation of RNA.
a b
Figure 1
CLINICAL SCIENCES
MEDICINE 41:4 194 2013 Published by Elsevier Ltd.
embryonic genes are on chromosome 16, the non-a on chro-
mosome 11. In the fetus and infant the non-a chain of the main
Hb is g (HbF; a2g2), and in the adult it is b (HbA; a2b2). There
are two a genes on each chromosome 16, four in all. Mutations,
mostly deletions, in the a genes produce a wide variety of effects
on Hb synthesis, depending on whether there is complete
absence of a chain production (a
0
thalassaemias) or some
synthesis (a

), and upon the number of genes affected. Effects

vary from no appreciable loss of Hb through minor degrees of
hypochromia, to signicant anaemia with abnormal HbH (b
4
)
with the loss of three genes. When all four a genes are missing,
stillbirth at 28e40 weeks with hydrops fetalis occurs with only
HbBarts (g4) present. An extensive variety of mutations in the
b genes leads to the b thalassaemias. b Thalassaemia trait results
from the loss of one b gene and is characterized by hypochromia
and microcytosis, which has to be distinguished from iron de-
ciency but which is otherwise harmless to the carrier. Loss of
function of both b genes leads to severe anaemia starting at about
the age of 3 months as the fetal g gene is switched off (b thal-
assaemias). The minor HbA2 (a2d2) comprises less than 3.0% in
adults but is useful in the diagnosis of b thalassaemia trait. The
pocket that contains the haem group prevents its oxidation to
methaem, which cannot combine with O
2
. Mutations in the
globin genes that affect the haem pocket lead to meth-
aemoglobinaemia or instability of the Hb molecule.
7
Hb has two slightly different tertiary structures depending on
whether or not O
2
is bound:
8
in the absence of O
2
on the haem group it has a tense (T)
structure with low afnity for O
2
when O
2
attaches to a haem group it initiates a structural
change in globin so that the tetramer becomes more avid
for further O
2
molecules (high afnity, relaxed (R) form).
This allosteric transformation accounts for the sigmoid O
2
dis-
sociation curve. Various ligands, including hydrogen ions (pH)
and 2,3-DPG, affect the position of the curve and hence the
readiness of the O
2
to dissociate at different O
2
tensions (pO
2
).
2,3-DPG, which is increased in PK deciency, decreases the af-
nity of Hb for O
2
so that it is given up more readily (Figure 4d)
and the effects of anaemia are mitigated. Sickle cell Hb also has
9
.
4
4.1
4.1
Artin
The red blood cell membrane
Spectrin interacts with other proteins, some of which are transmembrane proteins, and with the lipid bilayer. Oligosaccharides on the
cytoplasmic domains of proteins determine various blood group antigens. Some proteins of the cytoskeleton are identified by numbers
corresponding to their position on electrophoresis.
Spectrin-spectrin interaction to form tetramer
-spectrin
1 . 2 1 . 2
Horizontal interactions
V
e
r
t
i
c
a
l

i
n
t
e
r
a
c
t
i
o
n
s
Glycophorins
Band 3
Sialoprotein (blood group ABH)
Phospholipid
Cholesterol
Figure 2
Outline of the metabolic pathways in the mature red
blood cell
MetHb
Reduction
Hb O
2
affinity
RapoportLuebering
shunt
Glutathione
cycle
Pentose
phosphate
pathway
Glycolysis
Glucose
NADH
2,3-DPG
ATP Metabolic
energy
Antioxidant
GSH NADPH
Reducing
power
Pyruvate/lactate
Figure 3
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MEDICINE 41:4 195 2013 Published by Elsevier Ltd.
a low O
2
afnity, so patients tolerate apparently low Hb con-
centrations well.
Red cells, haemoglobin and nitric oxide (NO)
Apart from the general carriage of O
2
from lungs to tissues in
oxyhaemoglobin, red cells may be involved in local control of O
2
delivery to hypoxic tissues. Release of ATP from RBCs may
stimulate the production of NO, a powerful vasodilator, through
the action of NO synthase (NOS). Deoxyhaemoglobin also pro-
motes the reduction of nitrite within the RBC to NO and deoxy-
genation of S-nitroso-Hb also releases NO. Whether these reactions
within the RBC directly affect tissue blood ow or merely provide
a reservoir of nitrite-NO redox reactions for other local mecha-
nisms is not certain, but it seems likely that these local pathways
do ne tune local blood ow and hence O
2
delivery.
9,10
Ageing and destruction of RBCs
RBCs have a life span in the circulation of 120 days. Senescent
RBCs are phagocytosed by macrophages of the retic-
uloendothelial system, mainly in the marrow, liver and spleen.
Iron from the haem group is available for erythropoiesis
after transfer to the marrow bound to transferrin.
The porphyrin ring is converted through a series of re-
actions to bilirubin. Excess bilirubin appears in the urine
Functioning of haemoglobin
a The haem group sits in the pocket stabilized by amino acids of the globin chains. b The haem is connected to the globin chain by histidines in the pocket which
allows reversible binding of O
2
to the Fe
2+
atom of haem. c The haemoglobin molecule consists of a helices supporting the haem group. d The tetrameric
heterodimer undergoes allosteric conformational changes during oxygenation and deoxygenation.
8
2,3-DPG occupies the central space of the deoxygenated form.
a b
c d
O
2
Fe
++
Haem
SH
Globin
2,3-DPG
1

2

1

2
H H
H H
A A
A
E7
F8
Haem
Globin
A
E7
E11
CD7
CD1 C3
F8
G5
G1
F9
FG2
F1
E18
E20
EF1
EF3
NA1
NA2
H5
A1
H1
GH4
H16
Tyr HC1
CD2
E1
E5
B5
G15
A16 B1
AB1
G19
D1
Figure 4
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MEDICINE 41:4 196 2013 Published by Elsevier Ltd.
only after conjugation to a glucuronide. In haemolytic
anaemias the bilirubin is unconjugated and there is no
bilirubin in the urine (acholuric jaundice).
RBCs are enucleate and contain no DNA or RNA, so they are
unable to synthesize proteins. The activity of some enzymes
decreases with the age of the RBC and the consequent decline in
energy production may account for increased rigidity of ageing
cells. Rearrangement of the lipid distribution in the cell mem-
brane with the replacement of the choline phospholipids, lecithin
and sphingomyelin, by phosphatidyl-serine from the inner layer
may also be a consequence that leads to phagocytosis and
apoptosis.
11
White blood cells (leucocytes)
White blood cells (WBCs) fulll the most of their functions
outside the circulation. To achieve this they have systems that
respond to specic stimuli and enable them to enter and trafc
through the extravascular milieu.
WBCs derived from the common myeloid progenitor cell,
granulocytes and monocytes, are the main components of the
innate immune system, which mediates the rst-line defence
against microbial attack. The two main functions of the phag-
ocytic cells of the innate immune system are to recognize, ingest
foreign or degraded cells or proteins either of self or on patho-
gens and kill the pathogens and to present specic pathogen
antigens to the adaptive immune system mediated by the lym-
phocyte family which produces specic immune responses.
Phagocytes have a repertoire of receptors on the cell surface that
recognize pathogen-associated molecular patterns (PAMP),
damaged self-patterns and altered self-patterns. These provide
important pathways in the removal of necrotic tissue, the
removal of aged or altered cells (the end process of apoptosis)
and have an important role in tumour surveillance.
Granulocytes
Granulocytes are recognized by the presence of specic granules
within their cytoplasm and their multi-lobed nuclei (Figure 5).
They have the capacity to change shape and migrate, via the
vessel wall,
12
through tissues in response to chemotactic signals
from infection and inammation. The granules mediate the
specic killing and signalling functions of the cells.
13
Neutrophils: they circulate in the blood for 6e10 hours. A con-
siderable fractionof the total intravascular populationis marginated
on vessel walls at any one time; the major mass is in the extrava-
scular system, where the cells eventually undergo apoptosis.
Circulating neutrophils are increased following a number of
stimuli. Exercise causes demargination and hence an increase in
the circulating count. Inammation leads to a rapid increase in
neutrophil numbers through the action of a number of cytokines,
including interleukin-1 (IL-1) and granulocyte colony-stimulating
factor (G-CSF). The primary role of neutrophils is to engulf and
kill bacteria encountered in the extravascular space and take part
in the inammatory response. The process may be divided into
migration, chemotaxis, ingestion, degranulation and oxidative
burst activity.
13
The last three comprise the process of phagocytosis.
Migration across the vascular endothelium requires engage-
ment of adhesion molecules on the neutrophils and endothelial
cells (Figure 6). There are two steps:
Rolling along the endothelium is mediated by reversible as-
sociation of molecules of the selectin family (E-selectin,
L-selectin).
Activation and adhesion: inammation activates the adhesion
system whereby the neutrophil attaches to the endothelium,
changes shape and passes between two endothelial cells to begin
the migration towards the site of inammation. The process is
regulated by adhesion molecules of the leucocyte integrins (LFA-
1 family), the immunoglobulin superfamily (ICAM-3) and the
cytoadhesins (leucocyte response integrin).
Chemotaxis e agents produced by activation complement
(C5a), breakdown of bacterial call walls (N-formyl peptides) and
cytokine-stimulated endothelial cells (leukotriene B4, IL-8),
produced at the site of inammation, provide a concentration
gradient to which the neutrophil reacts by moving towards the
higher concentration.
Ingestion e stimulation of surface receptors leads to activa-
tion of downstream pathways resulting in the formation of
phagocytic vacuoles containing the pathogenic material. This
may occur before there is a specic immune response but is
Circulating white blood cells. a Neutrophil, b eosinophil, c basophil, d monocyte, e lymphocytes.
a b c d e
Figure 5
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MEDICINE 41:4 197 2013 Published by Elsevier Ltd.
greatly enhanced by antibody and complement binding to the
microorganism. Receptors recognize complement or antibody
bound to the pathogen as well as PAMP.
Degranulation e primary granules contain a variety of bac-
tericidal toxins, including defensins, cathepsins and enzymes
such as elastase, myeloperoxidase and lysozyme. Secondary
granules contain lactoferrin, which chelates iron and is essential
for bacterial growth. The granules form packages as lysosomes
that merge with the phagocytic vacuoles to produce phag-
olysosomes or are released in to the extracellular space
(secretion).
14
Oxidative burst e degranulation activates a switch to oxida-
tive respiration and the production of high concentrations of
reactive oxygen species (including free radical O
2

, OH radicals
and H
2
O
2
), which are directly toxic to the microorganisms. NADP
oxidase is central to the generation of the ROS. Deciency causes
failure of fungal killing, in particular, and chronic granulomatous
disease. Overactivity in familial Mediterranean fever leads to
inappropriate inammatory activity. Nitric oxide (NO) genera-
tion from L-arginine by NO synthase (NOS) during inammation
is another potent reactive free radical system in phagocytes.
Once the killing process is complete the neutrophil is lysed
and forms pus, the greenish colour of which is due to myelo-
peroxidase (Figure 6).
Eosinophils: the majority of eosinophils (Figure 5B) are in the
extravascular tissue space, particularly in the subepithelium of
areas exposed to the external environment (tracheobronchial
tree, gastrointestinal tract). Their main function is protection
against parasitic organisms. They are weakly phagocytic and act
mainly by degranulating on to the surface of the parasite. The
granules have a high content of basic proteins, including major
basic protein (MBP) and an eosinophil-specic peroxidise.
Eosinophil numbers are increased in allergic reactions (e.g.
asthma) as well as in response to parasitic infection.
15
The main
mediators are IL-5, IL-3 and GM-CSF. Inappropriate increase in
numbers may lead to the hypereosinophilic syndrome (fever,
weight loss, anorexia, thromboembolic episodes, heart failure,
splenomegaly, skin lesions and central nervous system
disease).
Basophils: these (Figure 5C) and the related mast cells are also
associated with allergic and parasitic diseases.
15
They have
a high afnity immunoglobulin E (IgE) receptor: when this binds
to antigen, degranulation occurs with release of histamine. They
also synthesize and release leukotriene-D4, the slow-acting
substance of anaphylaxis. The main results are vasodilatation,
mucus secretion and smooth muscle contraction (type 1 hyper-
sensitivity reaction). Mast cells release eosinophil chemotactic
factors. The incoming eosinophils release histaminases, which
limit mast cell-mediated hypersensitivity reactions.
Monocytes and macrophages: monocytes (Figure 5D) are
released from the bone marrow into the circulation, where they
Neutrophil migration
Blood
Vessel wall
Tissue
E-Selectin
L-Selectin
Rolling Activation and
adhesion
Transendothelial
migration
Migration towards
Phagocytosis
killing
Inflammation
Phagosomes
Degranulation
Oxidative burst
Cell death
(pus)
Chemotaxis
Leukotriene-B
4
, IL-8.
LFA-1,HCAM Endothelial cells
G-CSF, IL-1
LFA-1,VLA-5
ICAM-3,LRI
CChe Chemmm
Leu LLeukkotriene-B
inflammatory site
C5a, N-formyl peptides
Figure 6
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MEDICINE 41:4 198 2013 Published by Elsevier Ltd.
comprise 5e10% of circulating white blood cells (WBCs). They
leave the circulation in about 48 hours to migrate to the
extravascular milieu forming two main classes of longer-lived
cells, xed tissue macrophages (e.g. Kupffer cells in the liver,
dendritic cells in the skin) or remaining as mobile cells able to
respond to inammatory signals.
Phagocytic role e Macrophages ingest and kill particular
microorganisms, including mycobacteria, listeria, and candida
and other fungal species; functions that are enhanced by IFNg.
16
Macrophages do not have granules but have lysosomes con-
taining cytotoxic enzymes. Activated monocytes express tissue
factor (see Haemostasis on pages 208e211 of this issue) and can
initiate coagulation. Diffuse intravascular coagulation may be an
inappropriate response in some infections.
Macrophages process foreign proteins by endocytosis and
fusion of the endosome with the lysosome. The protein is
degraded to short peptides, which are presented on the cell
surface in class II histocompatiblity molecules. The class II pre-
sentation is recognized by CD4 T cells. As well as foreign
proteins, macrophages engulf and degrade senescent cells and, in
the lungs, inhaled particulate matter. The macrophages of the
reticuloendothelial system are major antigen-presenting cells for
adaptive immunity.
Summary
Blood cells have specialized functions that depend on structural
and metabolic characteristics. Red blood cells contain haemo-
globin, carry oxygen from lungs to tissues and facilitate transport
of CO
2
back to the lungs. Inherited defects of the RBC membrane,
metabolism or haemoglobin structure lead to haemolytic anae-
mia. The white blood cells (leucocytes) comprise the cells of the
immune systems.
Cells of granulocyte/macrophage lineage provide the
innate immune system for rapid protection from microbial
pathogens, removal of foreign or damaged proteins or cells
(including tumour surveillance and end stage of apoptosis), and
antigen presentation to the adaptive immune system of
lymphocytes. A
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