5. Haematology

5. Haematology
Presented by: Prof.Mirza Anwar Baig
Anjuman-I-Islam's Kalsekar Technical Campus
School of Pharmacy,New Pavel,Navi
Mumbai,Maharashtra

Contents:
1. Composition of blood
2. Functions of blood elements
3. Erythropoiesis and life cycle of RBC.
4. Synthesis of Haemoglobin
5. Leucopoiesis
6. Immunity: Basics and Types
7. Coagulation of blood
8. Blood groups

Learning outcomes
1.Describe the chemical composition of plasma
1.Discuss the structure, function and formation of red
blood cells, including the systems used in medicine to
classify the different types
3.Discuss the functions and formation of the different
types of white blood cell
4. Outline the role of platelets in blood clotting.
3

What is Blood ?
•Blood is a connective tissue. It provides one of the
means of communication between the cells of different
parts of the body and the external environment.
•Blood makes up about 7% of body weight (about 5.6
litres in a 70 kg man).
•Blood in the blood vessels is always in motion. The
continual flow maintains a fairly constant environment
for the body cells.
4

COMPOSITION OF BLOOD
•Blood is composed of a straw-coloured transparent fluid,
plasma, in which different types of cells are suspended.
•Plasma constitutes about 55% and cells about 45% of
blood volume.
6

Figure 19.1b
Composition of Whole Blood
7

Figure 19.1c
Composition of Whole Blood
8

Erythrocytes – Red Blood Cells (RBCs)
• Oxygen-transporting cells
– 7.5 µm in diameter (diameter of capillary 8 –
10µm)
• Most numerous of the formed elements
– Females: 4.3 – 5.2 million cells/cubic millimeter
– Males: 5.2 – 5.8 million cells/cubic millimeter
• Made in the red bone marrow in long bones, cranial
bones, ribs, sternum, and vertebrae
• Average lifespan 100 – 120 days
10

RBC Structure And Function
• Have no organelles or nuclei
• Can neither reproduce nor carry extensive metabolic activities.
• Hemoglobin in cytoplasm – oxygen carrying protein
– Each RBC has about 280 million hemoglobin molecules
• Biconcave shape – 30% more surface area
11

Routine assessments in clinical practice
• Erythrocyte count.
This is the number of erythrocytes per litre or per cubic millimetre
(mm3) of blood.
• Packed cell volume or haematocrit.
This is the volume of red cells in 1 litre or 1 mm3 of whole blood.
• Mean cell volume.
This is the average volume of cells, measured in femtolitres
(fl = 10-15 litre).
• Haemoglobin.
This is the weight of haemoglobin in whole blood, measured in
grams per 100 ml.
• Mean cell haemoglobin.
This is the average amount of haemoglobin in each cell, measured
in picograms (pg = 10-12 gram).
• Mean cell haemoglobin concentration.
This is the amount of haemoglobin in 100 ml of red cells.
12

RBC Life Cycle
1. Red blood cells live only about 120 days because of the
wear and tear their plasma membranes undergo as they
squeeze through blood capillaries.
2. Without a nucleus and other organelles, RBCs cannot
synthesize new components to replace damaged ones.
3. Ruptured red blood cells are removed from circulation
and destroyed by fixed phagocytic macrophages in the
spleen and liver

Development and life span of erythrocytes
• Erythrocytes are formed in red bone marrow, which is
present in the ends of long bones and in flat and
irregular bones.
• They pass through several stages of development
before entering the blood. Their life span in the
circulation is about 120 days.
15

Erythropoiesis
• 16
The process of development of red blood
cells from pluripotent stem cells takes
about 7 days and is called erythropoiesis.
•It is characterised by two main features:
A. Maturation of the cell
B. Formation of haemoglobin inside the
cell
A. Maturation of the cell.
1.During this process the cell decreases in
size and loses its nucleus.
2.These changes depend on especially the
presence of vitamin B12 and folic acid.
These are present in sufficient quantity in
a normal diet, stored in the liver.

3. Absorption of vitamin B12 depends on a glycoprotein called
intrinsic factor secreted by parietal cells in the gastric glands.
4. Together they form the intrinsic factor-vitamin B12 complex (IF-
B12).
5. During its passage through the intestines, the bound vitamin is
protected from enzymatic digestion, and is absorbed in the
terminal ileum.
6. Folic acid is absorbed in the duodenum and jejunum
7. Deficiency of either vitamin B12 or folic acid leads to impaired
red cell production.

Formation of haemoglobin
1. Haemoglobin is synthesised inside developing erythrocytes in red
bone marrow.
2. Haemoglobin in mature erythrocytes combines with oxygen to
form oxyhaemoglobin, giving arterial blood its characteristic red
colour.
3. In this way the bulk of oxygen absorbed from the lungs is
transported around the body to maintain a continuous oxygen
supply to all cells.
4. Haemoglobin is also involved, to a lesser extent, in the transport
of carbon dioxide from the body cells to the lungs for excretion.
5. Each haemoglobin molecule contains four atoms of iron. Each
atom can carry one molecule of oxygen, therefore one
haemoglobin molecule can carry up to four molecules of oxygen.
18

Destruction of erythrocytes
Ø The life span of erythrocytes is about 120 days and their
breakdown, or haemolysis, is carried out by phagocytic
reticuloendothelial cells.
Ø These cells are found in many tissues but the main sites of
haemolysis are the spleen, bone marrow and liver.
Ø As erythrocytes age, changes in their cell membranes make
them more susceptible to haemolysis.
Ø Iron released by haemolysis is retained in the body and reused
in the bone marrow to form haemoglobin. Biliverdin is formed
from the protein part of the erythrocytes.
Ø It is almost completely reduced to the yellow pigment bilirubin,
before it is bound to plasma globulin and transported to the liver.
Ø In the liver it is changed from a fat-soluble to a water-soluble
form before it is excreted as a constituent of bile.
20

Hemostasis
1. Vasoconstriction.
i. When platelets come in contact with a damaged blood vessel,
their surface becomes sticky and they adhere to the damaged wall.
ii. They then release serotonin (5-hydroxytryptamine), which
constricts (narrows) the vessel, reducing blood flow through it.
Other chemicals that cause vasoconstriction, e.g. thromboxanes,are
released by the damaged vessel itself.
2. Platelet plug formation.
i. The adherent platelets clump to each other and release other
substances, including adenosine diphosphate (ADP), which attract
more platelets to the site.
ii. Passing platelets stick to those already at the damaged vessel and
they too release their chemicals. This is a positive feedback system
by which many platelets rapidly arrive at the site of vascular
damage and quickly form a temporary seal — the platelet plug.
21

3. Coagulation (blood clotting).
Blood coagulation refers to the process of forming a clot
to stop bleeding.
Ø This is a complex process that also involves a positive
feedback system.
Ø Their numbers represent the order in which they were
discovered and not the order of participation in the
clotting process.
Ø These factors activate each other and known as the
clotting cascade.
Ø Blood clotting results in formation of an insoluble
thread-like mesh of fibrin which traps blood cells and is
much stronger than the rapidly formed platelet plug.
Ø In the final stages of this process prothrombin activator
acts on the plasma protein prothrombin converting it to
thrombin.
22

•The clotting cascade occurs through two separate
pathways that interact, the intrinsic and the extrinsic
pathway.
1. Extrinsic Pathway:
The extrinsic pathway is activated by external trauma
that causes blood to escape from the vascular system.
This pathway is quicker than the intrinsic pathway. It
involves factor VII.
2. Intrinsic Pathway:
The intrinsic pathway is activated by trauma inside the
vascular system, and is activated by platelets, exposed
endothelium, chemicals, or collagen. This pathway is
slower than the extrinsic pathway, but more important.
It involves factors XII, XI, IX, VIII.
3. Common Pathway:
Both pathways meet and finish the pathway of clot
production in common pathway. The common pathway
involves factors I, II, V, and X.
24

Coagulation Pathway:
25
This initial pathway is independent of Factor VIII (factor missing in
hemophilia A) and Factor IX (factor missing in hemophilia B).
When the body has made a small amount of fibrin, a substance known as
Tissue Factor Pathway Inhibitor (TFPI) is released. This inhibitor binds to the
TF:FVIIa/FXa complex, preventing further formation of factor FXa. It is
thought that TFPI is released to protect against overreation of the
coagulation system. At this point, the intrinsic pathway is activated.

28
Immunity: Two Intrinsic Defense Systems
1. Innate (nonspecific) system responds quickly
and consists of:
– First line of defense – intact skin and
mucosae prevent entry of microorganisms
– Second line of defense – antimicrobial
proteins, phagocytes, and other cells
•Inhibit spread of invaders throughout the
body
•Inflammation is its hallmark and most
important mechanism
COMPILED BY: PROF.ANWAR BAIG
(AIKTC,SOP)

29
Immunity: Two Intrinsic Defense Systems
2. Adaptive (specific) defense system
– Third line of defense – mounts attack against
particular foreign substances
• Takes longer to react than the innate system
• Works in conjunction with the innate system
(AIKTC,SOP)

30
First Line of Defense
1. Surface Barriers
• Skin, mucous membranes, and their secretions make
up the first line of defense
• Keratin in the skin:
– Presents a physical barrier to most microorganisms
– Is resistant to weak acids and bases, bacterial
enzymes, and toxins
• Mucosae provide similar mechanical barriers
(AIKTC,SOP)

31
2. Epithelial Chemical Barriers
• Epithelial membranes produce protective chemicals
that destroy microorganisms
– Skin acidity (pH of 3 to 5) inhibits bacterial growth
– Sebum contains chemicals toxic to bacteria
– Stomach mucosae secrete concentrated HCl and
protein-digesting enzymes
– Saliva and lacrimal fluid contain lysozyme
– Mucus traps microorganisms that enter the digestive
and respiratory systems
(AIKTC,SOP)

32
3. Respiratory Tract Mucosae
• Mucus-coated hairs in the nose trap inhaled particles
• Mucosa of the upper respiratory tract is ciliated
– Cilia sweep dust- and bacteria-laden mucus away
from lower respiratory passages
(AIKTC,SOP)

33
Internal Defenses (Second Line of Defense)
The body uses nonspecific cellular and chemical devices to
protect itself
1. Phagocytes
2. natural killer (NK) cells
3. Inflammatory response enlists macrophages, mast
cells, WBCs, and chemicals
4. Antimicrobial proteins in blood and tissue fluid
Harmful substances are identified by surface carbohydrates
unique to infectious organisms
(AIKTC,SOP)

34
1. Phagocytes
• Macrophages are the chief phagocytic cells
• Free macrophages wander throughout a region
in search of cellular debris
• Kupffer cells (liver) and microglia (brain) are
fixed macrophages
• Neutrophils become phagocytic when
encountering infectious material
• Eosinophils are weakly phagocytic against
parasitic worms
• Mast cells bind and ingest a wide range of
bacteria
(AIKTC,SOP)

35
Mechanism of Phagocytosis
• Microbes adhere to the phagocyte
• Pseudopods engulf the particle
(antigen) into a phagosome
• Phagosomes fuse with a lysosome to
form a phagolysosome
• Invaders in the phagolysosome are
digested by proteolytic enzymes
• Indigestible and residual material is
removed by exocytosis
(AIKTC,SOP)

36
Mechanism of Phagocytosis
Figure 21.1a, bCOMPILED BY: PROF.ANWAR BAIG
(AIKTC,SOP)

37
2. Natural Killer (NK) Cells
• Cells that can lyse and kill cancer cells and
virus-infected cells
• Natural killer cells:
– Are a small, distinct group of large granular
lymphocytes
– React nonspecifically and eliminate cancerous
and virus-infected cells
– Kill their target cells by releasing perforins and
other cytolytic chemicals
– Secrete potent chemicals that enhance the
inflammatory response
(AIKTC,SOP)

38
3. Inflammation: Tissue Response to Injury
• The inflammatory response is triggered
whenever body tissues are injured
– Prevents the spread of damaging agents
to nearby tissues
– Disposes of cell debris and pathogens
– Sets the stage for repair processes
• The four cardinal signs of acute
inflammation are redness, heat,
swelling, and pain
(AIKTC,SOP)

39
Inflammation Response
• Begins with a flood of inflammatory
chemicals released into the
extracellular fluid
• Inflammatory mediators (chemicals) :
– Include kinins, prostaglandins (PGs),
complement, and cytokines
– Are released by injured tissue, phagocytes,
lymphocytes, and mast cells
– Cause local small blood vessels to dilate,
resulting in hyperemia
(AIKTC,SOP)

40
Toll-like Receptors (TLRs)
• Macrophages and cells lining the
gastrointestinal and respiratory tracts
bear TLRs
• TLRs recognize specific classes of
infecting microbes
• Activated TLRs trigger the release of
cytokines that promote inflammation
(AIKTC,SOP)

41
Inflammatory Response: Vascular Permeability
• Chemicals liberated by the
inflammatory response increase the
permeability of local capillaries
• Exudate (fluid containing proteins,
clotting factors, and antibodies):
– Seeps into tissue spaces causing local
edema (swelling), which contributes to the
sensation of pain
(AIKTC,SOP)

42
Inflammatory Response: Edema
• The surge of protein-rich fluids into
tissue spaces (edema):
– Helps to dilute harmful substances
– Brings in large quantities of oxygen and
nutrients needed for repair
– Allows entry of clotting proteins, which
prevents the spread of bacteria
(AIKTC,SOP)

43
• Occurs in four main phases:
– Leukocytosis – neutrophils are released
from the bone marrow in response to
leukocytosis-inducing factors released by
injured cells
– Margination – neutrophils cling to the walls
of capillaries in the injured area
– Diapedesis – neutrophils squeeze through
capillary walls and begin phagocytosis
– Chemotaxis – inflammatory chemicals
attract neutrophils to the injury site
Inflammatory Response: Phagocytic Mobilization
(AIKTC,SOP)

44
Neutrophils
enter blood
from bone
marrow
1
2
3
4
Marginatio
n
Diapedesis
Positive
chemotaxi
s
Capillary wall
Endothelium
Basal lamina
Inflammator
y chemicals
diffusing
from the
inflamed
site act as
chemotactic
agents
Inflammatory Response: Phagocytic Mobilization
Figure 21.3
(AIKTC,SOP)

45
Flowchart of Events in Inflammation
Figure 21.2

46
4. Antimicrobial Proteins
• Enhance the innate defenses by:
– Attacking microorganisms directly
– Hindering microorganisms’ ability to
reproduce
• The most important antimicrobial
proteins are:
– Interferon
– Complement proteins
(AIKTC,SOP)

47
• Abnormally high body temperature in
response to invading microorganisms
• The body’s thermostat is reset
upwards in response to pyrogens,
chemicals secreted by leukocytes and
macrophages exposed to bacteria and
other foreign substances
Fever
(AIKTC,SOP)

48
• High fevers are dangerous as they can
denature enzymes
• Moderate fever can be beneficial, as it
causes:
– The liver and spleen to sequester iron and
zinc (needed by microorganisms)
– An increase in the metabolic rate, which
speeds up tissue repair
Fever
(AIKTC,SOP)

49
• The adaptive immune system is a
functional system that:
– Recognizes specific foreign substances
– Acts to immobilize, neutralize, or destroy
foreign substances
– Amplifies inflammatory response and
activates complement
Adaptive (Specific) Defenses (Third Line of Defense)
(AIKTC,SOP)

50
• The adaptive immune system is
antigen-specific, systemic, and has
memory
• It has two separate but overlapping
arms
– Humoral, or antibody-mediated (B Cell)
immunity
– Cellular, or cell-mediated (T Cell) immunity
Adaptive Immune Defenses
(AIKTC,SOP)

51
• Substances that can mobilize the
immune system and provoke an
immune response
• The ultimate targets of all immune
responses are mostly large, complex
molecules not normally found in the
body (nonself)
Antigens
(AIKTC,SOP)

52
• Important functional properties:
– Immunogenicity – the ability to stimulate
proliferation of specific lymphocytes and
antibody production
– Reactivity – the ability to react with the
products of the activated lymphocytes and
the antibodies released in response to
them
• Complete antigens include foreign
protein, nucleic acid, some lipids, and
large polysaccharides
Complete Antigens
(AIKTC,SOP)

53
• Small molecules, such as peptides,
nucleotides, and many hormones,
– not immunogenic (does not stimulate a response)
– reactive when attached to protein carriers
• If they link up with the body’s proteins,
the adaptive immune system may
recognize them as foreign and mount a
harmful attack (allergy)
• Haptens are found in poison , some
detergents, and cosmetics
Haptens (Incomplete Antigens)
(AIKTC,SOP)

54
• Only certain parts of an entire antigen
are immunogenic
• Antibodies and activated lymphocytes
bind to these antigenic determinants
• Most naturally occurring antigens have
numerous antigenic determinants that:
– Mobilize several different lymphocyte
populations
– Form different kinds of antibodies against
it.
Antigenic Determinants
(AIKTC,SOP)

55
Antigenic Determinants
Figure 21.6
(AIKTC,SOP)

56
• Two types of lymphocytes
– B lymphocytes – oversee humoral
immunity
– T lymphocytes – non-antibody-producing
cells that constitute the cell-mediated arm
of immunity
• Antigen-presenting cells (APCs):
– Do not respond to specific antigens
– Play essential auxiliary roles in immunity
Cells of the Adaptive Immune System
(AIKTC,SOP)

57
• Immature lymphocytes released from
bone marrow are essentially identical
• Whether a lymphocyte matures into a B
cell or a T cell depends on where in the
body it becomes Immunocompetent
– B cells mature in the bone marrow
– T cells mature in the thymus
Lymphocytes
(AIKTC,SOP)

T-lymphocytes: (Cell-mediated immunity)
• These are processed by the thymus gland, which
lies between the heart and the sternum.
• The hormone thymosin, produced by the thymus, is
responsible for promoting the processing, which
leads to the formation of fully specialised
(differentiated), mature, functional T-lymphocytes.
• A mature T-lymphocyte has been programmed to
recognise only one type of antigen, and during its
subsequent travels through the body will react to no
other antigen, however dangerous it might be. Thus,
a T-lymphocyte manufactured to recognise the
chickenpox virus will not react to a measles
virus,a cancer cell, or a tuberculosis
bacterium.
(AIKTC,SOP)
58

B-lymphocytes.
• These are processed in the bone
marrow. Their role is in production of
antibodies (immunoglobulins), which
are proteins designed to bind to, and
cause the destruction of, an antigen.
• As with T-lymphocytes,each B-
lymphocyte targets one specific
antigen; the antibody released reacts
with one type of antigen and no other.
(AIKTC,SOP)
59

60
• Display a unique type of receptor that
responds to a distinct antigen.
• Become immunocompetent before
they encounter antigens.
• Are exported to secondary lymphoid
tissue where encounters with antigens
occur.
• Mature into fully functional antigen-
activated cells upon binding with their
recognized antigen.
Immunocompetent B or T cells
(AIKTC,SOP)

61
Red
bone marrow
1
2
3
Immunocompete
nt, but still naive,
lymphocyte
migrates via
blood
Mature (antigen-activated)
immunocompetent lymphocytes
circulate continuously in the
bloodstream and lymph and
throughout the lymphoid organs
of the body.
Key: = Site of lymphocyte origin
= Site of development of
immunocompetence as B or T cells;
primary lymphoid organs
= Site of antigen challenge and
final differentiation to activated B
and T cells
Immature
lymphocyte
s
Circulation in
blood
1
1 Lymphocytes destined to become
T cells migrate to the thymus and
develop immunocompetence
there. B cells develop
immunocompetence in red bone
marrow.
Thymus
Bone
marrow
Lymph nodes,
spleen, and
other
lymphoid
tissues
2 2 After leaving the thymus or
bone marrow as naive
immunocompetent cells,
lymphocytes “seed” the lymph
nodes, spleen, and other
lymphoid tissues where the
antigen challenge occurs.
3 3
Activated
immunocompete
nt B and T cells
recirculate in
blood and lymph
Immunocompetent B or T cells
Figure 21.8COMPILED BY: PROF.ANWAR BAIG
(AIKTC,SOP)

Clonal expansion of T-Lymphocytes
(AIKTC,SOP)
62

63
• Major roles in immunity are:
– To engulf foreign particles
– To present fragments of antigens on their
own surfaces, to be recognized by T cells
• Major APCs are dendritic cells (DCs),
macrophages, and activated B cells
• The major initiators of adaptive
immunity are DCs, which actively
migrate to the lymph nodes and
secondary lymphoid organs and
present antigens to T and B cells
Antigen-Presenting Cells (APCs)
(AIKTC,SOP)

64
• Antigen challenge – first encounter
between an antigen and a naive
immunocompetent cell
• Takes place in the spleen or other
lymphoid organ
• If the lymphocyte is a B cell:
– The challenging antigen provokes a
humoral immune response
• Antibodies are produced against the challenger
Humoral Immunity Response
(AIKTC,SOP)

Clonal expansion of B-Lymphocytes
(AIKTC,SOP)
65

Coordination of 2 immune system:
(AIKTC,SOP)
66

67
• Stimulated B cell growth forms clones
bearing the same antigen-specific
receptors
• A naive, immunocompetent B cell is
activated when antigens bind to its
surface receptors and cross-link
adjacent receptors
• Antigen binding is followed by
receptor-mediated endocytosis of the
cross-linked antigen-receptor
complexes
• These activating events, plus T cell
interactions, trigger clonal selection
Clonal Selection
(AIKTC,SOP)

68
Clonal Selection
(AIKTC,SOP)

69
• Most clone cells become antibody-
secreting plasma cells
• Plasma cells secrete specific antibody
at the rate of 2000 molecules per
second
Fate of the Clones
(AIKTC,SOP)

70
• Secreted antibodies:
– Bind to free antigens
– Mark the antigens for destruction by
specific or nonspecific mechanisms
• Clones that do not become plasma
cells become memory cells that can
mount an immediate response to
subsequent exposures of the same
antigen
Fate of the Clones
(AIKTC,SOP)

71
• Primary immune response – cellular
differentiation and proliferation, which
occurs on the first exposure to a
specific antigen
– Lag period: 3 to 6 days after antigen
challenge
– Peak levels of plasma antibody are
achieved in 10 days
– Antibody levels then decline
Immunological Memory
(AIKTC,SOP)

72
• Secondary immune response – re-
exposure to the same antigen
– Sensitized memory cells respond within
hours
– Antibody levels peak in 2 to 3 days at
much higher levels than in the primary
response
– Antibodies bind with greater affinity, and
their levels in the blood can remain high
for weeks to months
Immunological Memory
(AIKTC,SOP)

73
Primary and Secondary Humoral Responses
(AIKTC,SOP)

74
• B cells encounter antigens and
produce antibodies against them
– Naturally acquired – response to a
bacterial or viral infection
– Artificially acquired – response to a
vaccine of dead or attenuated pathogens
• Vaccines – spare us the symptoms of disease,
and their weakened antigens provide antigenic
determinants that are immunogenic and
reactive
Active Humoral Immunity
(AIKTC,SOP)

75
• Differs from active immunity in the
antibody source and the degree of
protection
– B cells are not challenged by antigens
– Immunological memory does not occur
– Protection ends when antigens naturally
degrade in the body
• Naturally acquired – from the mother
to her fetus via the placenta
• Artificially acquired – from the injection
of serum, such as gamma globulin
Passive Humoral Immunity
(AIKTC,SOP)

76
Types of Acquired Immunity
Figure 21.11
(AIKTC,SOP)

77
• Also called immunoglobulins
– Constitute the gamma globulin portion of
blood proteins
– Are soluble proteins secreted by activated
B cells and plasma cells in response to an
antigen
– Are capable of binding specifically with
that antigen
• There are five classes of antibodies:
IgD, IgM, IgG, IgA, and IgE
Antibodies
(AIKTC,SOP)

78
• IgD – monomer attached to the surface of B
cells, important in B cell activation
• IgM – pentamer released by plasma cells during
the primary immune response
• IgG – monomer that is the most abundant and
diverse antibody in primary and secondary
response; crosses the placenta and confers
passive immunity
• IgA – dimer that helps prevent attachment of
pathogens to epithelial cell surfaces
• IgE – monomer that binds to mast cells and
basophils, causing histamine release when
activated
Classes of Antibodies
(AIKTC,SOP)

79
• Consists of four looping polypeptide
chains linked together with disulfide
bonds
– Two identical heavy (H) chains and two
identical light (L) chains
• The four chains bound together form
an antibody monomer
• Each chain has a variable (V) region at
one end and a constant (C) region at
the other
• Variable regions of the heavy and light
chains combine to form the antigen-
binding site
Basic Antibody Structure
(AIKTC,SOP)

80
Basic Antibody Structure
Figure 21.12a, b
(AIKTC,SOP)

81
• Antibodies responding to different antigens
have different V regions but the C region is the
same for all antibodies in a given class
• C regions form the stem of the Y-shaped
antibody and:
– Determine the class of the antibody
– Serve common functions in all antibodies
– Dictate the cells and chemicals that the
antibody can bind to
– Determine how the antibody class will function
in elimination of antigens
Antibody Structure
(AIKTC,SOP)

82
• Plasma cells make over a billion different types
of antibodies
• Each cell, however, only contains 100,000 genes
that code for these polypeptides
• To code for this many antibodies, somatic
recombination takes place
– Gene segments are shuffled and combined in
different ways by each B cell as it becomes
immunocompetent
– Information of the newly assembled genes is
expressed as B cell receptors and as antibodies
Mechanisms of Antibody Diversity
(AIKTC,SOP)

83
• Random mixing of gene segments
makes unique antibody genes that:
– Code for H and L chains
– Account for part of the variability in
antibodies
• V gene segments, called hypervariable
regions, mutate and increase antibody
variation
• Plasma cells can switch H chains,
making two or more classes with the
same V region
Antibody Diversity
(AIKTC,SOP)

84
• Antibodies themselves do not destroy
antigen; they inactivate and tag it for
destruction
• All antibodies form an antigen-antibody
(immune) complex
• Defensive mechanisms used by
antibodies are neutralization,
agglutination, precipitation, and
complement fixation
Antibody Targets
(AIKTC,SOP)

85
• Complement fixation is the main mechanism
used against cellular antigens
• Antibodies bound to cells change shape and
expose complement binding sites
• This triggers complement fixation and cell lysis
• Complement activation:
– Enhances the inflammatory response
– Uses a positive feedback cycle to promote
phagocytosis
– Enlists more and more defensive elements
Complement Fixation and Activation
(AIKTC,SOP)

86
• Neutralization – antibodies bind to and
block specific sites on viruses or
exotoxins, thus preventing these
antigens from binding to receptors on
tissue cells
Other Mechanisms of Antibody Action
(AIKTC,SOP)

87
• Agglutination – antibodies bind the
same determinant on more than one
antigen
– Makes antigen-antibody complexes that
are cross-linked into large lattices
– Cell-bound antigens are cross-linked,
causing clumping (agglutination)
• Precipitation – soluble molecules are
cross-linked into large insoluble
complexes
Other Mechanisms of Antibody Action
(AIKTC,SOP)

88
Mechanisms of Antibody Action
(AIKTC,SOP)

89
• Commercially prepared antibodies are
used:
– To provide passive immunity
– In research, clinical testing, and treatment
of certain cancers
• Monoclonal antibodies are pure
antibody preparations
– Specific for a single antigenic determinant
– Produced from descendents of a single cell
Monoclonal Antibodies
(AIKTC,SOP)

90
• Hybridomas – cell hybrids made from a
fusion of a tumor cell and a B cell
– Have desirable properties of both parent
cells – indefinite proliferation as well as
the ability to produce a single type of
antibody
Monoclonal Antibodies
(AIKTC,SOP)

91
• Since antibodies are useless against
intracellular antigens, cell-mediated immunity is
needed
• Two major populations of T cells mediate
cellular immunity
– CD4 cells (T4 cells) are primarily helper T cells
(TH)
– CD8 cells (T8 cells) are cytotoxic T cells (TC)
that destroy cells harboring foreign antigens
• Other types of T cells are:
– Suppressor T cells (TS)
– Memory T cells
Cell-Mediated Immune Response
(AIKTC,SOP)

92
Major Types of T Cells
Figure 21.14
(AIKTC,SOP)

93
• Soluble antibodies
– The simplest ammunition of the immune
response
– Interact in extracellular environments such
as body secretions, tissue fluid, blood, and
lymph
Importance of Humoral Response
(AIKTC,SOP)

94
• T cells recognize and respond only to
processed fragments of antigen
displayed on the surface of body cells
• T cells are best suited for cell-to-cell
interactions, and target:
– Cells infected with viruses, bacteria, or
intracellular parasites
– Abnormal or cancerous cells
– Cells of infused or transplanted foreign
tissue
Importance of Cellular Response
(AIKTC,SOP)

95
• Immunocompetent T cells are
activated when the V regions of their
surface receptors bind to a recognized
antigen
• T cells must simultaneously recognize:
– Nonself (the antigen)
– Self (a MHC protein of a body cell)
Antigen Recognition and MHC Restriction
(AIKTC,SOP)

96
• Both types of MHC proteins are
important to T cell activation
• Class I MHC proteins
– Always recognized by CD8 T cells
– Display peptides from endogenous
antigens
MHC Proteins
(AIKTC,SOP)

97
• Endogenous antigens are:
– Degraded by proteases and enter the
endoplasmic reticulum
– Transported via TAP (transporter
associated with antigen processing)
– Loaded onto class I MHC molecules
– Displayed on the cell surface in
association with a class I MHC molecule
Class I MHC Proteins
(AIKTC,SOP)

98
Class I MHC Proteins
Figure 21.15a
(AIKTC,SOP)

99
• Class II MHC proteins are found only on
mature B cells, some T cells, and
antigen-presenting cells
• A phagosome containing pathogens
(with exogenous antigens) merges with
a lysosome
• Invariant protein prevents class II MHC
proteins from binding to peptides in
the endoplasmic reticulum
Class II MHC Proteins
(AIKTC,SOP)

100
• Class II MHC proteins migrate into the
phagosomes where the antigen is
degraded and the invariant chain is
removed for peptide loading
• Loaded Class II MHC molecules then
migrate to the cell membrane and
display antigenic peptide for
recognition by CD4 cells
(AIKTC,SOP)

101
Figure 21.15bCOMPILED BY: PROF.ANWAR BAIG
(AIKTC,SOP)

102
• Provides the key for the immune
system to recognize the presence of
intracellular microorganisms
• MHC proteins are ignored by T cells if
they are complexed with self protein
fragments
Antigen Recognition
(AIKTC,SOP)

103
• If MHC proteins are complexed with
endogenous or exogenous antigenic
peptides, they:
– Indicate the presence of intracellular
infectious microorganisms
– Act as antigen holders
– Form the self part of the self-antiself
complexes recognized by T cells
Antigen Recognition
(AIKTC,SOP)

104
• T cell antigen receptors (TCRs):
– Bind to an antigen-MHC protein complex
– Have variable and constant regions
consisting of two chains (alpha and beta)
T Cell Activation: Step One – Antigen Binding
(AIKTC,SOP)

105
• MHC restriction – TH and TC bind to
different classes of MHC proteins
• TH cells bind to antigen linked to class
II MHC proteins
• Mobile APCs (Langerhans’ cells) quickly
alert the body to the presence of
antigen by migrating to the lymph
nodes and presenting antigen
(AIKTC,SOP)

106
• TC cells are activated by antigen
fragments complexed with class I MHC
proteins
• APCs produce co-stimulatory molecules
that are required for TC activation
• TCR that acts to recognize the self-
antiself complex is linked to multiple
intracellular signaling pathways
• Other T cell surface proteins are
involved in antigen binding (e.g., CD4
and CD8 help maintain coupling during
antigen recognition)
(AIKTC,SOP)

107
Figure 21.16
(AIKTC,SOP)

108
• Before a T cell can undergo clonal
expansion, it must recognize one or
more co-stimulatory signals
• This recognition may require binding to
other surface receptors on an APC
– Macrophages produce surface B7 proteins
when nonspecific defenses are mobilized
– B7 binding with the CD28 receptor on the
surface of T cells is a crucial co-
stimulatory signal
• Other co-stimulatory signals include
cytokines and interleukin 1 and 2
T Cell Activation: Step Two – Co-stimulation
(AIKTC,SOP)

109
• Depending on receptor type, co-
stimulators can cause T cells to
complete their activation or abort
activation
• Without co-stimulation, T cells:
– Become tolerant to that antigen
– Are unable to divide
– Do not secrete cytokines
(AIKTC,SOP)

110
• T cells that are activated:
– Enlarge, proliferate, and form clones
– Differentiate and perform functions
according to their T cell class
(AIKTC,SOP)

111
• Primary T cell response peaks within a
week after signal exposure
• T cells then undergo apoptosis
between days 7 and 30
• Effector activity wanes as the amount
of antigen declines
• The disposal of activated effector cells
is a protective mechanism for the body
• Memory T cells remain and mediate
secondary responses to the same
antigen
(AIKTC,SOP)

112
• Mediators involved in cellular immunity,
including hormonelike glycoproteins
released by activated T cells and
macrophages
• Some are co-stimulators of T cells and
T cell proliferation
• Interleukin 1 (IL-1) released by
macrophages co-stimulates bound T
cells to:
– Release interleukin 2 (IL-2)
– Synthesize more IL-2 receptors
Cytokines
(AIKTC,SOP)

113
• IL-2 is a key growth factor, which sets
up a positive feedback cycle that
encourages activated T cells to divide
– It is used therapeutically to enhance the
body’s defenses against cancer
• Other cytokines amplify and regulate
immune and nonspecific responses
Cytokines
(AIKTC,SOP)

114
• Examples include:
– Perforin and lymphotoxin – cell toxins
– Gamma interferon – enhances the killing
power of macrophages
– Inflammatory factors
Cytokines
(AIKTC,SOP)

115
• Regulatory cells that play a central role
in the adaptive immune response
• Once primed by APC presentation of
antigen, they:
– Chemically or directly stimulate
proliferation of other T cells
– Stimulate B cells that have already
become bound to antigen
• Without TH, there is no immune
response
Helper T Cells (TH)
(AIKTC,SOP)

116
Helper T Cells (TH)
Figure 21.17a
(AIKTC,SOP)

117
• TH cells interact directly with B cells that have
antigen fragments on their surfaces bound to
MHC II receptors
• TH cells stimulate B cells to divide more rapidly
and begin antibody formation
• B cells may be activated without TH cells by
binding to T cell–independent antigens
• Most antigens, however, require TH co-
stimulation to activate B cells
• Cytokines released by TH amplify nonspecific
defenses
Helper T Cell
(AIKTC,SOP)

118
Helper T Cells
Figure 21.17b
(AIKTC,SOP)

119
• TC cells, or killer T cells, are the only T cells that
can directly attack and kill other cells
• They circulate throughout the body in search of
body cells that display the antigen to which they
have been sensitized
• Their targets include:
– Virus-infected cells
– Cells with intracellular bacteria or parasites
– Cancer cells
– Foreign cells from blood transfusions or
transplants
Cytotoxic T Cell (Tc)
(AIKTC,SOP)

120
• Bind to self-antiself complexes on all
body cells
• Infected or abnormal cells can be
destroyed as long as appropriate
antigen and co-stimulatory stimuli (e.g.,
IL-2) are present
• Natural killer cells activate their killing
machinery when they bind to MICA
receptor
• MICA receptor – MHC-related cell
surface protein in cancer cells, virus-
infected cells, and cells of transplanted
organs
Cytotoxic T Cells
(AIKTC,SOP)

121
• In some cases, TC cells:
– Bind to the target cell and release perforin
into its membrane
• In the presence of Ca2+ perforin causes cell
lysis by creating transmembrane pores
• Other TC cells induce cell death by:
– Secreting lymphotoxin, which fragments
the target cell’s DNA
– Secreting gamma interferon, which
stimulates phagocytosis by macrophages
Mechanisms of Tc Action
(AIKTC,SOP)

122
Mechanisms of Tc Action
Figure 21.18a, bCOMPILED BY: PROF.ANWAR BAIG
(AIKTC,SOP)

123
• Suppressor T cells (TS) – regulatory
cells that release cytokines, which
suppress the activity of both T cells
and B cells
• Gamma delta T cells (Tgd) – 10% of all T
cells found in the intestines that are
triggered by binding to MICA receptors
Other T Cells
(AIKTC,SOP)

124
Summary of the Primary Immune Response
Figure 21.19
(AIKTC,SOP)

Anaemias
In anaemia there is not enough haemoglobin available to
carry sufficient oxygen from the lungs to supply the needs
of the tissues. It occurs when the rate of production of
mature cells entering the blood from the red bone marrow
does not keep pace with the rate of haemolysis.
The classification of anaemia is based on the cause:
1. Impaired erythrocyte production
— iron deficiency
— megaloblastic anaemias
— hypoplastic anaemia
2. Increased erythrocyte loss
— haemolytic anaemias
— normocytic anaemia.
126

Signs and symptoms of anaemia:
Tachycardia
Palpitations (an awareness of the heartbeat)
Angina pectoris
Breathlessness on exertion
127

1. Iron deficiency anaemia
This is the most common.
The normal daily requirement of iron intake in men is
about 1 to 2 mg derived from meat and highly coloured
vegetables. The normal daily requirement in women is 3 mg.
The increase is necessary to compensate for loss of blood
during menstruation and to meet the needs of the growing
fetus during pregnancy.
Children, during their period of rapid growth, require more
than adults.
The anaemia is regarded as severe when the haemoglobin
level is below 9 g/dl blood.
It is caused by deficiency of iron in the bone marrow and
may be due to dietary deficiency,excessively high requirement
or malabsorption.
128

2. Megaloblastic anaemias
1.Maturation of erythrocytes is impaired when deficiency of vitamin B12
and/or folic acid occurs and abnormally large erythrocytes
(megaloblasts) are found in the blood.
2.During normal erythropoiesis several cell divisions occur and the
daughter cells at each stage are smaller than the parent cell because
there is not much time for cell enlargement between divisions.
3.When deficiency of vitamin B12 and/or folic acid occurs, the rate of
DNA and RNA synthesis is reduced, delaying cell division.
4.The cells can therefore grow larger than normal between divisions.
Circulating cells are immature, larger than normal and some are
nucleated (MCV >94 fl).
5.The haemoglobin content of each cell is normal or raised. The cells
are fragile and their life span is reduced to between 40 and 50 days.
6.Depressed production and early lysis cause anaemia.
129

3.Hypoplastic and aplastic anaemias
i. Due to varying degrees of bone marrow failure. Bone marrow
function is reduced in hypoplastic anaemia, and absent in
aplastic anaemia.
ii. Since the bone marrow produces leukocytes and platelets as well
as erythrocytes, leukopenia (low white cell count) and
thrombocytopenia (low platelet count) are likely to accompany
diminished red cell numbers.
iii.When all three cell types are low, the condition is called
pancytopenia, and is accompanied by anaemia, diminished
immunity and a tendency to bleed.
iv. The condition is often idiopathic.
130

Known causes include:
• Drugs, e.g. cytotoxic drugs, some anti-inflammatory and
anticonvulsant drugs, some sulphonamides and antibiotics
• Ionising radiation
• Some chemicals, e.g. benzene and its derivatives
• Diseases : Chronic nephritis,Viral disease, including
hepatitis
• Invasion of bone marrow by, e.g., malignant disease,
leukaemia or fibrosis.
131

4. Vitamin B12 deficiency anaemia
a. Pernicious anaemia
This is the most common form of vitamin B12 deficiency
anaemia.
It occurs more often in females than males, usually between 45
and 65 years of age.
It is an autoimmune disease in which auto-antibodies destroy
intrinsic factor (IF) and parietal cells in the stomach.
b. Dietary deficiency of vitamin B12
This is rare, when no animal products are included in the diet. The
store of vitamin B12 is such that deficiency takes several years to
appear.
132

Other causes of vitamin B12 deficiency
i. Gastrectomy — this leaves fewer cells available to produce IF
after partial resection of the stomach.
ii. Chronic gastritis, malignant disease and ionising radiation —
these damage the gastric mucosa including the parietal cells that
produce IF.
iii. Blind loop syndrome — this occurs when the contents of the
small intestine are slow moving or static, allowing microbes to
colonise the small intestine and use or destroy the intrinsic
factor-vitamin B12 (IF-B12) complex before it reaches the
terminal ileum where it is absorbed.
iv. Malabsorption of intrinsic factor-vitamin B12 complex —
This may follow resection of terminal ileum or inflammation of
the terminal ileum, e.g. Crohn's disease .
133

Complications of vitamin B12 deficiency
anaemia
These may appear before the signs of anaemia. They
include:
• Subacute combined degeneration of the spinal cord in
which nerve fibres in the posterior and lateral columns
of white matter become demyelinated.
(Vitamin B12 is essential for the secretion and
maintenance of myelin.)
• Ulceration of the tongue and glossitis.
134

Haemolytic anaemias
These occur when red cells are destroyed while in circulation or are removed
prematurely from the circulation because the cells are abnormal or the spleen is
overactive.
1.Congenital haemolytic anaemias:
Sickle cell anaemia
Thalassaemia
Haemolytic disease of the newborn
2. Acquired haemolytic anaemia
Chemical agents
Autoimmunity
Blood transfusion reactions
Other causes of haemolytic anaemia
eg: Parasitic diseases, e.g. malaria
Ionising radiation, e.g. X-rays, radioactive isotopes
Destruction of blood trapped in tissues in, e.g., severe
burns, crushing injuries
Physical damage to cells by, e.g., artificial heart valves, kidney
dialysis machines.
135

Normocytic normochromic anaemia
1.In this type the cells are normal but the numbers are
reduced.
2.The proportion of reticulocytes in the blood may be
increased as the body tries to restore erythrocyte numbers
to normal.
3.This occurs:
• In many chronic disease conditions, e.g. in chronic
inflammation following severe haemorrhage in
haemolytic disease.
136

Congenital haemolytic anaemias
In these diseases genetic abnormality leads to the synthesis of abnormal
haemoglobin and increased red cell membrane friability, reducing cell
oxygen-carrying capacity and life span.
The most common forms are sickle cell anaemia and thalassaemia.
a. Sickle cell anaemia:
1.The abnormal haemoglobin molecules become misshapen.
2.When deoxygenated, making the erythrocytes sickle shaped.
3.A high proportion of abnormal molecules makes the sickling permanent.
4.The life span of cells is reduced by early haemolysis.
5.Sickle cells do not move smoothly through the small blood vessels.
6.This tends to increase the viscosity of the blood, reducing the rate of
blood flow and leading to intravascular clotting,ischaemia and infarction.
7.The anaemia is due to early haemolysis of irreversibly sickled cells.
8.Blacks are more affected than other races.
9.Some affected individuals have a degree of immunity
to malaria because the life span of the sickled cells is
less than the time needed for the malaria parasite to
mature inside the cells.
137

b. Thalassaemia
There is reduced globin synthesis with resultant reduced haemoglobin
production and increased friability of the cell membrane, leading to
early haemolysis.
Severe cases may cause death in infants or young children. This
condition is most common in Mediterranean countries.
Haemolytic disease of the newborn
In this disorder, the mother's immune system makes antibodies to the
baby's red blood cells, causing haemolysis and phagocytosis of fetal
erythrocytes. The antigen system involved is usually (but not always)
the Rhesus (Rh) antigen.
138

Polycythaemia
There are an abnormally large number of erythrocytes in
the blood.
This increases blood viscosity, slows the rate of flow and
increases the risk of intravascular clotting, ischaemia and
infarction.
i. Relative increase in erythrocyte count:
This occurs when the erythrocyte count is normal but the
blood volume is reduced by fluid loss, e.g. excessive
serum exudate from extensive superficial burns.
ii. True increase in erythrocyte count Physiological.
Prolonged hypoxia stimulates erythropoiesis and the
number of cells released into the normal volume of blood
is increased.
140

Ø This occurs in people living at high altitudes where
the oxygen tension in the air is low and the partial
pressure of oxygen in the alveoli of the lungs is
correspondingly low.
Ø Each cell carries less oxygen so more cells are needed
to meet the body's oxygen needs
a. Polycythaemia Pathological.
The reason for this increase in circulating red cells,
sometimes to twice the normal number, is not known. It
may be secondary to other factors that cause
Hypoxia of the red bone marrow, e.g. cigarette
smoking,pulmonary disease, bone marrow cancer..
141

b. Polycythaemia rubra vera
In this primary condition of unknown cause there is
abnormal excessive production of the erythrocyte
precursors, i.e.myeloproliferation.
This raises the haemoglobin level and the haematocrit
(relative proportion of cells to plasma).
The blood viscosity is increased and may lead to
hypertension and cerebral, coronary or mesenteric
thrombosis.
Aplastic anaemia and leukaemia may also be present.
142

LEUKOCYTE DISORDERS
• Leukopenia --Granulocytopenia (neutropenia)
• Leukocytosis
• Leukaemia
143

1.Leukopenia
This is the name of the condition in which the total blood
leukocyte count is less than 4000/mm3.
a. Granulocytopenia (neutropenia)
i. This is a general term used to indicate an abnormal
reduction in the numbers of circulating granulocytes
(polymorphonuclear leukocytes), commonly called
neutropenia because 40 to 75% of granulocytes are
neutrophils.
ii. A reduction in the number of circulating granulocytes
occurs when production does not keep pace with the
normal removal of cells or when the life span of the cells
is reduced.
iii. Extreme shortage or the absence of granulocytes is
called agranulocytosis. A temporary reduction occurs in
response to inflammation but the numbers are usually
quickly restored.
144

Inadequate granulopoiesis may be caused by:
1. Drugs, e.g. cytotoxic drugs, phenylbutazone, phenothiazines,
some sulphonamides and antibiotics
2. Irradiation damage to granulocyte precursors in the bone marrow
by, e.g., X-rays, radioactive isotopes
3. Diseases of red bone marrow, e.g. leukaemias, some anaemias
4. Severe microbial infections.
5. In conditions where the spleen is enlarged, excessive numbers of
granulocytes are trapped, reducing the number in circulation.
Neutropenia predisposes to severe infections that can lead to
tissue necrosis, septicaemia and death.
Septicaemia is the presence of significant numbers of active
pathogens in the blood.
The pathogens are commonly commensals, i.e. microbes that are
normally present in the body but do not usually cause infection,
such as those in the bowel.
145

Leukocytosis
i. An increase in the number of circulating leukocytes
occurs as a normal protective reaction in a variety of
pathological conditions, especially in response to
infections.
ii. When the infection subsides the leukocyte count returns
to normal.
iii.Pathological leukocytosis exists when a blood leukocyte
count of more than 11000/mm3 is sustained and is not
consistent with the normal protective function.
146

Leukaemia
•Leukaemia is a malignant proliferation of white blood
cell precursors by the bone marrow.
•A malignant progressive disease in which the bone
marrow and other blood-forming organs produce increased
numbers of immature or abnormal leucocytes. These
suppress the production of normal blood cells, leading to
anaemia and other symptoms.
•It results in the uncontrolled reduction of leukocytes
and/or their precursors.
•As the tumour cells enter the blood the total leukocyte
count is usually raised but in some cases it may be normal
or even low.
•The proliferation of immature leukaemic blast cells crowds
out other blood cells formed in bone marrow, causing
anaemia,thrombocytopenia and leukopenia (pancytopenia).
147

Causes of leukaemia
Ionising radiation.
Radiation such as that produced by X-rays and radioactive
isotopes causes malignant changes in the precursors of white
blood cells. The DNA of the cells may be damaged and some
cells die while others reproduce at an abnormally rapid rate.
Leukaemia may develop at any time after irradiation, even
20 or more years later.
Chemicals.
Some chemicals encountered in the general or work
environment alter the DNA of the white cell precursors in
the bone marrow. These include benzene and its derivatives,
asbestos, cytotoxic drugs, chloramphenicol.
Viral infections.
Genetic factors. Identical twins of leukaemia sufferers have a
much higher risk than normal of developing the disease,
suggesting involvement of genetic factors.
148

Types of leukaemias
Acute leukaemias
Ø These types usually have a sudden onset and affect
the poorly differentiated and immature 'blast' cells .
Ø They are aggressive tumours that reach a climax
within a few weeks or months. The rapid progress of
bone marrow invasion impairs its function and
culminates in anaemia, haemorrhage and susceptibility
to infection.
Ø The mucous membranes of the mouth and upper
gastrointestinal tract are most commonly affected.
Acute myeloblastic leukaemia. This occurs at any
age, but most commonly between 25 and 60 years.
Acute lymphoblastic leukaemia. This disease is most
common in children under 10 years, although a number
of cases may occur up to about 40 years of age.
150

Chronic leukaemias
These conditions are less aggressive than the acute forms and the
leukocytes are more differentiated, i.e. at the 'cyte' stage.
Chronic granulocytic leukaemia. There is a gradual increase in
the number of immature granulocytes in the blood. In the later stages,
anaemia, secondary haemorrhages, infections and fever become
increasingly severe.
It is slightly more common in men than women and usually occurs
between the ages of 20 and 40 years. Although treatment may
appear to be successful, death usually occurs within about 5 years.
Chronic lymphocytic leukaemia.
There is enlargement of the lymph nodes and hyperplasia of
lymphoid tissue throughout the body. The lymphocyte count is
considerably higher than normal. Lymphocytes accumulate in the
bone marrow and there is progressive anaemia and
thrombocytopenia.
It is three times more common in males than females and it occurs
mainly between the ages of 50 and 70 years. Death is usually due to
repeated infections of increasing severity, with great variations in
survival times.
151

Thrombocytopenia
This is defined as a blood platelet count below (150 000/mm3) but
spontaneous capillary bleeding does not usually occur unless the
count falls below (30 000/mm3).
It may be due to a reduced rate of platelet production or increased
rate of destruction.
Reduced platelet production
This is usually due to bone marrow deficiencies, and therefore
production of erythrocytes and leukocytes is also reduced, giving rise
to pancytopenia. It is often due to:
Ø Platelets being crowded out of the bone marrow in bone marrow
diseases, e.g. leukaemias, pernicious anaemia, malignant tumours
Ø Ionising radiation, e.g. X-rays or radioactive isotopes,that damage
the rapidly dividing precursor cells in the bone marrow
Ø Drugs, e.g. cytotoxic drugs, chloramphenicol,chlorpromazine,
phenylbutazone, sulphonamides.
Increased platelet destruction A reduced platelet count occurs
when production of new cells does not keep pace with destruction of
damaged and worn out cells.
152

Autoimmune thrombocytopenic purpura.
• This condition, which usually affects children and young
adults,
• may be triggered by a viral infection such as measles.
• Antiplatelet antibodies are formed that coat platelets,
• leading to platelet destruction and their removal from
• the circulation.
• A significant feature of this disease is the presence of
purpura, which are haemorrhages into the skin ranging in
size from pinpoints to large blotches.
• The severity of the disease varies from mild bleeding into
• the skin to severe haemorrhage. When the platelet count
• is very low there may be severe bruising, haematuria,
• gastrointestinal or cranial haemorrhages.
153

Secondary thrombocytopenic purpura.
This may occur in association with red bone marrow
diseases,
excessive irradiation and some drugs, e.g. digoxin,
chlorthiazides, quinine, sulphonamides.
154

5. Haematology

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