Internal Medicine Al Azhar university Faculty of Oral and Dental Medicine Lama El Banna

1. Dr. Suhail S. Kishawi
Consultant in Endocrinology and DiabetesConsultant in Endocrinology and Diabetes
‫دد‬‫د‬‫د‬‫د‬‫د‬‫دد‬‫د‬‫د‬‫د‬‫دد‬‫د‬‫د‬‫د‬‫د‬‫د‬‫د‬‫د‬‫د‬
‫ييييييي‬ ‫يييييي‬ ‫ييييي‬ ‫ييييييي‬
‫يييييييي‬ ‫ييييييي‬ ‫ييييييي‬
Anemias

2. The Blood
Plasma
Red blood cell White blood cell
Platelets

3. Red Blood Cells
Contain haemoglobin, a
molecule specially
designed to hold oxygen
and carry it to cells that
need it.
Can change shape to an
amazing extent, without
breaking, as it squeezes
single file through the
capillaries.
A biconcave disc that is
round and flat without a
nucleus

4. White Blood Cells
There are many different types
and all contain a big nucleus.
The two main ones are the
lymphocytes and the
macrophages.
Some lymphocytes fight disease by making antibodies to
destroy invaders by dissolving them.
Other lymphocytes make antitoxins to break down poisons.
Macrophages ‘eat’ and digest
micro-organisms .

5. Platelets
Platelets are bits of cell
broken off larger cells.
Platelets produce
tiny fibrinogen fibres
to form a net. This
net traps other
blood cells to form
a blood clot.

6. Plasma
A straw-
coloured
liquid that
carries the
cells and the
platelets
which help
blood clot.
• Carbon dioxide
• Glucose
• Amino acids
• Proteins
• Minerals
• Vitamins
• Hormones
• Waste materials
like urea.
It also contains useful
things like;

7. | Introduction
Anaemia can be defined as a reduction in the haemoglobin in the blood below normal range
for age and sex. Essentially, anaemia is defined as haemoglobin (Hb) concentration:
For adult males < 13.5 g/dl
For adult women < 11.5 g/dl
Anaemia is a global public health problem affecting both developing and developed
countries. It has major consequences for human health as well as social and economic
development. In 2008, iron deficiency anaemia was considered to be among the most important
contributing factors to the global burden of disease.
Image above: scanning electron
microscope image of red blood cells.
Image left: Global WHO map of
anaemia in preschool age children.

8. | The Erythrocyte: An Overview
Image: scanning electron microscope of
red blood cell
To achieve these functions the red
cell has several unique properties….
Strength: it has a
strong but flexible
membrane able to
withstand the
recurrent shear forces
involved in the
circulation of blood.
Flexibility: the red cell
is 7.8 µm across and
1.7 µm thick and yet it
is able to fit through
capillaries of only 5
µm diameter. This is
in-part due to the
flexible membrane
and shedding of the
nucleus.
Biconcave shape: increases surface
area available for gaseous
exchange.
Haemoglobin content: unique to the
red cell, it is this metaloproteinmetaloprotein
molecule which is pivotal in red cell
development and Oxygen transport
due to its affinity for O2.
Function
 The primary function of the
erythrocyte is the carriage of
oxygen from the lungs to the tissues
and CO2 from the tissues to the lungs.
 The red cell also plays an important
role in pH buffering of the blood.
Lifespan: Because the fully developed
red blood cell has no nucleus the cell
cannot divide or repair itself. The
lifespan is therefore relatively short
(120 days).

9. Kidney
Bone marrow
Red blood cells in
circulationerythropoietin
Stem
cells
Erythroid
precursors
An erythrocyte is a fully developed, mature red blood cell. The adult human makes approximately
1012
new erythrocytes every day by the process of erythropoiesis. This is a complex process that
occurs within the bone marrow. Before an erythrocyte arrives fully functioning into the blood stream
it must develop from a stem cell through an important number of stages
As with much human
physiology, this system
works via a feedback
mechanism.
4. There is no store of EPO. The production of
erythropoietin is triggered by tissue hypoxia (oxygen
tension sensed within the tubules of the kidney) and
stops when oxygen levels are normal.
| Erythropoiesis
2. EPO stimulates
stem cells within the
bone marrow which
differentiate into
erythroid precursors.
3. EPO continues
to stimulate
primitive
erythroid cells
(red blood cells) in
the bone marrow
and induce
maturation.
1: Erythropoietin (EPO), a
growth factor, is synthesized
primarily (90%) from
peritubular cells of the kidneys
(renal cortex).
Macrophages surround and
supply iron to these
erythroprogenitor cells that
become erythroblastic islands.

10. | Production of erythrocyts :Erythropoiesis

11. | Erythropoiesis
Keypoint!
In chronic states of anaemia the opposite may occur. The chronic hypoxic state increases
production of EPO. This leads to an increase in the proportion of erythroblasts, expansion and
eventually fatty deposition within the bone marrow. During childhood when the growth plates are
still present, this expansion can lead to bone deformities such as frontal bossing. This is seen in
chronic haemolysis such as thalassaemia.
Keypoint!
Chronic renal disease / bilateral nephrectomy will reduce or stop the production of
EPO. It’s absence or reduction causes anaemia through reduced red cell
production. Anaemia due to EPO deficiency will be normocytic in morphology; i.e.
the red cell will be a normal shape and size but reduced in number.
Hypoxia is the major stimulant for increased EPO production
Kidney
Bone marrow
erythropoietin
Erythroid
precursors
Stem
cells
Kidney
Bone marrow
erythropoietin
Erythroid
precursors
Stem
cells

12. |Red cell precursors and the sequence of erythropoiesis
Anaemia of chronic
disease.
In individuals living
with a chronic
disease (e.g.
rheumatoid
arthritis),a complex
interaction of
inflammatory
cytokines interferes
with the red cell
lifecycle by
impairing iron
metabolism and
inhibiting red cell
precursors. The
end result is a
normocytic
anaemia.
Reticulocytes are an important cell in haematology as they increase in number following a
haemorrhage, haemolytic anaemia or from treatment of a haematinic deficiency. They provide
an excellent measure of red cell production and the age of the red cell population. In normal
blood there is usually about 1 reticulocyte : 100 erythrocytes.
Key point!
Keypoint!
marrow
3.5 Erythrocyte: after 1 week the mature
erythrocyte emerges with no organelles and high
haemoglobin content.Sequence: amplification and
maturation of the erythrocyte
Pronormoblast: This is the earliest and largest cell with
a large nucleus and no haemoglobin.
3.4. Reticulocytes: Considered the “teenagers” of the
the life cycle! This is the FINAL stage of developmentThis is the FINAL stage of development
before full maturation.before full maturation. These cells are now anucleate
and contain roughly 25% of the final haemoglobin
total. They reside mostly in the marrow but in healthy
individuals a small number can be found in the
peripheral blood. They contain some cell organelles.
Normoblasts: these cells go through a large number of
progressive changes. Fundamentally they reduce in
cell size but increase the haemoglobin concentration
in the cytoplasm. The nucleus proportionally
decreases until it is extruded before the cell is
released in to the blood.
blood

13. |Haematinics
Vitamin B12 (cobalamin) and folate (pteroylglutamic acid):
These are key building blocks for DNA synthesis and essential for cell mitosis. DNA synthesis is
reduced in all cells that are deficient in either folate or vitamin B12. The bone marrow is the
factory for blood cell production. In haematinic deficiency, DNA replication is limited and
hence the number of possible cell divisions is reduced leading to larger red cells being
discharged into the blood i.e. less DNA, less divisions and larger cells. This leads to enlarged,
misshapen cells or megaloblasts in the marrow and macrocytic red cells in the blood.
•So what exactly are the haematinics? These are the key micronutrients that must be present if a
red blood cell and its haemogoblin are to develop in a normal fashion.
• These major micronutrients, provided in a balanced diet, are iron, vitamin B12
and folate
• A deficiency in any one of these micronutrients can result in anaemia through
impaired red cell production within the bone marrow
• Assessing haematinic status is key to the investigation of the cause of anaemia
Iron:
At the centre of the haem molecule is an atom of iron which binds oxygen in a reversible
manner. Haemoglobin concentration in the developing red cell is a rate limiting step for
erythropoiesis. In iron deficiency, red cells undergo more divisions than normal and, as a
result, are smaller (microcytic) and have a reduced haemoglobin content (hypochromic).
Iron deficiency is the leading cause of anaemia worldwide.
Erthropoiesis is also regulated by the availability of haematinics
“Check the haematinics” this is a phrase
used frequently on the hospital ward!

14. |Haematinics in haemoglobin
Iron Protoporphyrin
GlobinHaem
Haemoglobin
Thalassaemia
• Iron deficiency
• Chronic
inflammation
• Malignancy
Chronic infections and
inflammatory disorders
cause chronic anaemia as
a result of;
1. Slightly shortened red
blood cell life span
2. Sequestration of iron in
inflammatory cells called
macrophages
Both procedures result in
A decrease in the amount
Of iron available to make
Red blood cells.

15. |Haematinics: the normal iron cycle
Iron deficiency can be identified best by assessing the appearances of the red cells on a
blood film. Iron indices in a blood sample are helpful to confirm a lack of iron. In order to
interpret these indices, it is vital to understand how the body handles iron …..
Erythroid bone
marrow
(normoblasts) Reticuloendothelial system;
Spleen & macrophages
Duodenum
Serum
transferrin
Fe
Red blood
cells
Liver
Iron is a key constituent of haemoglobin (60-70% of total body iron
is stored here) and it’s availability is essential for erythropoiesis. In
iron deficiency, there are more divisions of red cells during
erythropoiesis than normal. As a result the red cells are smaller
(microcytic) and have a reduced haemoglobin content
(hypochromic).
2. Iron is then attached
to a protein, transferrin
in the serum (plasma),
where it is transported
to the bone marrow for
haemoglobin synthesis.
1. Iron is absorbed from the
small intestine in the ferrous
state (Fe2+
; approx. 1mg/day).
3. Dying red cells
are recycled by
macrophages in
the spleen and
iron is recycled
into the plasma
for further use.
Soluble transferrin receptors,
sTfR are on the red cell surface.
These can be measured and
are increased in iron deficiency.
An iron deficiency
profile.
Serum Iron: Reduced
Serum total iron-
binding capacity
(TIBC): Increased- the
body works hard to bind
free iron.
Serum ferritin:
Reduced-since iron
stores are low
Serum soluble
transferrin receptors:
Increased-since red
cells attempt to absorb
more iron.
In iron deficient states, bone marrow
iron is reduced.
Some iron binds to
apoferritin to form
ferritin, a storage
compound.

16. Fe+2
Fe+2
Fe+2Fe+2
Dissociation
Passive diffusion
Fe+2
Fe+2
Fe+2
Fe+2
Fe+2
Fe+2
Gut Lumen Mucosal Cell Blood
Ferritin
Iron
salts
Fe+3
Free
Radical
Fe+2
Fe+2
Fe+2
Fe+2
Fe+2
Fe+2
Fe+2
Fe+3
Free
Radical
Transferrin
Incorporation
into Hb

17. There are a number of key steps in the absorption of Vitamin B12. The two key locations are
the stomach and the terminal ilium. Dietary vitamin B12 binds with intrinsic factor (IF) in the
stomach, a transport protein produced by gastric parietal cells. The B12-IF complex then
travels through the small intestine and is absorbed by special receptors in the distal ileum.
This pathway is important when considering possible causes of Vitamin B12 deficiency.
Vitamin B12 deficiency can
take up to two years to
develop as the body has
sufficient stores for this
period.
Distal ileum
Site of B12
absorption
Oesophagus
Stomach
IF Intrinsic factor
Vitamin B12
ingested
|Haematinics: vitamin B12
Pernicious anaemia: the
leading cause of B12
deficiency. IgG
autoantibodies target
gastric parietal cells and its
product IF causing an
atrophic gastritis. This
results in reduced secretion
of intrinsic factor and
therefore reduced B12-IF
complex for absorption in
the distal ileum.
Causes of vitamin
B12 deficiency
1.Pernicious
anaemia
2.Inadequate intake
3.Poor absorption

18. • Gives red blood cells their colour
• Can carry up to 4 molecules of O2
• Associates and dissociates with O2
• Contains iron
|Haemoglobin

19. Hemoglobin (Hb)

20. When there is a high concentration of oxygen e.g in the alveoli haemoglobin combines with oxygen to
form oxyhaemoglobin. When the blood reaches the tissue which have a low concentration of oxygen
the haemoglobin dissociates with the oxygen and the oxygen is released into body tissues
Function of Haemoglobin

21. | Haemoglobin and O2 transport
A key function of a red cell is to carry and deliver oxygen to the tissues and return CO2 from the
tissues to the lungs. As a result the red cell has developed a specialised molecule called
haemoglobin (Hb). It is important to gain a basic understanding of its synthesis, functioning and
metabolism as errors in these processes lead to a number of anaemic states. It’s waste products are
also released when a red cell is destroyed prematurely and are therefore a valuable indicator of
haemolysis.
2,3-DPG
oxyhaemoglobin deoxyhaemoglobin
A molecule called 2,3 –
Diphosphoglycerate
(2,3-DPG) sits between
the β chains and when
increased helps to
offload oxygen to the
tissues.
HAEM MOLECULE
Each individual globin
combines with one haem
molecule. This molecule
contains iron and binds
oxygen in a reversible manner.
A mature red cell.
GLOBIN CHAIN
A normal adult haemoglobin
(Hb A) molecule consists of
4 polypeptide (globin) chains:
α1α2 β1β2.
Haemoglobinopathies
Thalassaemia: reduced rate of synthesis of either α or β globin chains. Within this
group of inherited conditions there may be both ineffective erythropoiesis and
haemolysis resulting in a microcytic anaemia sometime also with hypochromia.
Sickle cell disease: an inheritance of two abnormal β-globin genes (HbSS). The
abnormality consists of a point mutation in the β globin gene. This results in Hb
insolubility in it’s deoxygenated state with crystallization within the red cell causing
sickling of the cell and vascular occlusion. A common problem that affects primarily the
Afro-Caribbean populations.
Keypoint!
Oxygen (O2)

22. |Ageing and death
Haemolytic anaemias; This is an important group of anaemias. There are
many important causes of premature red cell death resulting in anaemia and
the increased products of haemolysis within the blood circulation and beyond.
Haemolysis: any process that shortens the red blood cell lifespan to less than 120
days.
A red cell shows signs of deterioration from around 100 days of the cell’s cycle.
Without any DNA or ribosomes, the cell is unable to generate new enzymes (like
pyruvate kinase or G6PD that we have been introduced to). These ageing cells
are eventually identified by the reticuloendothelial system. This is a system of
white blood cells that are present within the spleen, liver and lymph nodes whose
main role is to phagocytose damaged or ageing cells. The tired red cells are
removed and recycled by macrophages in the spleen and liver.
Normally red cell degradation and recycling is managed by the
reticuloendothelial system on a daily basis without any problems. When a
pathological process causes premature lysis of the red cells, the ability of the
body to clear the increased number of waste products may be overloaded.

23. Haemoglobin
Haem
Unconjugated
bilirubin
Conjugated in the liver to
the diglucuronide, water-
soluble form that is
secreted in the bile and
then converted to
stercobilinogen.
Liver
Some stercobilin and stercobilogen are reabsorbed from
the intestine and excreted in the urine as urobilin and
urobilinogen. Raised levels in the urine may indicate
haemolysis.
3. Bilirubin
Heamolysis results in
excess bilirubin causing
jaundice (typically lemon
yellow colour ) and
pigment gallstones.
GlobinIron
Attaches to
transferrin
F
Is metabolized
to amino acids
Red blood cell
Investigating haemolysis
1.Lactic acid dehydrogenase
(LDH)
2.Reticulocyte count
3.Bilirubin
1. LDH is a nucleic enzyme which
is released on red cell destruction.
The concentration of LDH is
measurable from a blood sample
and provides an indicator of
haemolysis.
3. LDH
2. Reticulocyte count will be
elevated in response to the
feedback loop during anaemia.
The bone marrow increases red
cell production. Reticulocytes are
larger than mature red blood cells
causing a rise in mean cell volume
( MCV).
Flow diagram: products of red cell destruction.
The protoporphyrin of haem is
metabolised to the yellow pigment
bilirubin, which is bound to
albumin in the plasma.
Stercobilinogen is excreted in
the faeces
Haptoglobins these proteins bind
to any free haemoglobin. These
proteins can become saturated in
a haemolytic anaemia.
Haemoglobin can then pass into
the urine causing
haemoglobinuria or converted to
haemosiderinuria.

24. A red blood cell has an average lifespan of 80 days
Erythropoietin (EPO) production is reduced in chronic hypoxic states
Iron is transported in the blood bound to apoferritin.
A low pH, a high CO2 concentration in the blood and a high number of 2,3-DPG would shift the oxygen dissociation
curve to the left
Vitamin B12 is absorbed in the jejunum
Folate and vitamin B12 are key building blocks of haemoglobin
Chronic anaemia and malignancy prevent haem production
A deficiency in folate causes a macrocytic megaloblastic anaemia
Adult haemoglobin is composed of 2 alpha and 2 beta chains
Increased reticulocytes is a key feature of a haemolytic anaemia
true / false
False! A red blood cell has an average lifespan of 120 days. This is short compared to other blood cells due to the cell
having no nucleus or organelles and is thus unable to replace key enzymes and maintain cell function.
False! In chronic hypoxic states there is an increased production of EPO. This leads to an increase in the proportion of
erythroblasts, expansion and eventually fatty deposition within the bone marrow.
True! JAK 2 is a receptor for erythropoietin. A point mutation (tyrosine kinase) in this receptor is implicated in the oncogenisis
of several myeloproliferative neoplasm. (90% of Polycythemia vera patients).
False! It would shift to the right. All these factors would cause haemoglobin (Hb) to have a reduced affinity for O2 and
increase O2 release fom Hb.
False! Vitamin B12 binds to intrinsic factor in the stomach, travels through the small bowel and the complex is absorbed in
the distal ileum.
False! Vitamin B12 and folate are key building blocks of DNA.
True! Chronic anaemia and malignancy block iron from being incorporated into the haem molecule.
True! Both folate and vitamin B12 are key micronutrients for DNA synthesis. Deficiencies cause a macrocytic megaloblastic
anaemia.
True! The normal adult Hb contain 4 globin chains (often notated as α2β2).
True! The cells will be elevated in response to our feedback loop during anaemia. With excessive destruction of red cells, the bone
marrow increases production.

25. | Defining anaemia
| Dehydration |
Reduced plasma volume may
mask anaemia.
| Pregnancy or splenomegaly |
These can produce an increase in
plasma volume reducing the
apparent haemoglobin
concentration even though
circulating haemoglobin levels are
normal.
| Acute significant blood loss |
Following acute blood loss it may
take up to a day for the plasma
volume to be replaced and
anaemia to present. Therefore,
clinical features of shock and
reduced blood volume may occur
before a fall in haemoglobin
concentration.

26. |Clinical features of anemia
1. The cardiovascular system
Cardiac compensation is the major adaptation. Both stroke volume and heart
rate increase mobilizing greater volumes of oxygenated blood to the tissues.
This can present with palpitations, tachycardia and heart murmurs. Dyspnoea
which occurs in severely anaemic patients may be a sign of cardio-respiratory
failure.
Tissue hypoxia is the end result of the blood’s reduced oxygen
carrying capacity. The compensatory mechanisms in response to
hypoxia cause the clinical manifestations to develop.
An anaemic individual will have the following two key compensatory
mechanisms;
2. The skin
A common sign is generalised pallor due primarily to vasoconstriction with
redistribution of blood to key areas (brain, myocardium).

27.
1.A rapid onset: Anaemia that develops over a short period of time will cause more
symptoms than more slowly progressing anaemia because there is less time for the O2
dissociation curve of haemoglobin and the cardiovascular system to adapt.
2.Severity: Mild anaemia (Hb 9.0-11.0 g/dL) often produces no symptoms or signs. In a
young person, severe anaemia may not even present clinically. However this is notoriously
unreliable and some patients with severe anaemia may compensate well while others with
mild anaemia may present with severe symptoms.
3.Age: The elderly are less tolerable of anaemia mainly as a result of an inability to increase
cardiac output.
4. Co-existent disease - often cardiac or pulmonary disease.
|Clinical features of anemia
In general, a healthy individual may compensate well for anaemia and remain
mostly asymptomatic.
However many of the following symptoms and signs are observable when the
following occurs;

28. | Clinical features of anemia
General symptoms and signs
General Symptoms
Weakness and
lethargy
Shortness of
breath:
particularly on
exercise.
Headaches
Palpitations
Confusion and symptoms
of cardiac failure in
elderly
Some specific signsGeneral Signs

29. | Clinical features of anemia
Signs:
Pallor of mucous
membranes (most
common sign). This is a
general sign.
Beware: pallor is quite
subjective and NOT a
reliable clinical sign. Be
careful not to exclude
anaemia on the basis of
absence of pallor alone

30. | Clinical features of anemia
Signs:
Nail bed; demonstrating
koilonychia (spoon-
shaped nails). This is
specific to iron
deficiency.

31. | Clinical features of anemia
Signs
Atrophic glossitis; red
large swollen tongue.
This is seen in both
vitamin B12 and folate
deficiency.

32. | Clinical features of anemia
Signs
Angular stomitis;
fissuring at corners of
mouth. This is seen in
both vitamin B12 and
folate deficiency.

33. | clinical features of anemia
Signs
Dysphagia: pharyngeal
web (Paterson-Kelly
syndrome). This occurs
in iron deficiency.

34. | clinical features of anaemia
Signs
Peripheral
oedema. A
general sign.

35. | Clinical features of anemia
Signs
High flow murmur,
bounding pulse and/or
tachycardia: All features of
a compensatory
hyperdynamic circulation.
These are general signs!

36. An adult male will be anaemic if they have a haemoglobin of < 11.5 g/dl
on a full blood count.
Within the developing world iron deficient anaemia is the single greatest cause of anaemia
The respiratory system is the main physiological compensator in anaemia.
Koilonychia, glossitis, angular stomatitis are all general signs of anaemia.
Some key signs associated with iron deficient anaemia are koilonychia and glosso-pharyngeal
webbing.
False! An adult male is anaemic if [Hb] is < 13.5 g/dl. An adult female will be considered anaemic if [Hb] is
< 11.5 g/dl.
True!
False! The cardiovascular system is the major adaptor. Both stroke volume and heart rate increase in an attempt
to mobilize greater volumes of oxygenated blood to the tissues.
False! Koilonychia is sign of iron deficiency. Glossitis and angular stomatits are a sign of vitamin
B12 and folate deficiency.
True!
true false

37. |Classification of anaemia
Essentially there are two ways to classify anaemia, by red cell size (morphological
classification) or by cause (aetiological classification). Both have their purpose and both need
to be fully understood to gain a rounded understanding of anaemia.
Morphological classification
This is a practical and clinically useful
classification for establishing a differential
diagnosis of anaemia.
It is done by examining red cells in a blood
stained smear and by automated
measurements of red cell indices
Aetiological classification
This classification is based on cause and
illuminates the pathological process
underlying anaemia.
*Key point: In order to understand this classification it is essential to understand
red cell indices reported in the complete blood count (CBC). There is great
reward in understanding these indices as they enable one to identify some of the
underlying processes leading to anaemia and, importantly, help to formulate a
differential diagnoses.

38. MCV: Mean cell volume; the average volume of the red cells. MCV does not provide an
indicator of either haemoglobin concentration within the cells, or the number of red cells. It
enables us to categorize red cells into the following;
Microcytic (MCV <80fL) a small red blood cell.
Normocytic (MCV of 80-99fL) a normal size red blood cell.
Macrocytic (MCV > 99fL) a large red blood cell.
This is a key index that is used daily in medical settings across the world to categorize the type
of anaemia present.
It is reliable in most cases; one exception is when two pathologies occur at the same time such as vitamin B12 and
Iron deficiency. MCV reports average cell volume; further assessment of cell size and how this varies within an
individual can be ascertained from the red cell distribution width (RDW; see below).
MCH: Mean corpuscular haemoglobin ( normal range 26.7-32.5pg/cell): the average haemoglobin
content of red blood cells. Cells with a reduced haemoglobin content are termed hypochromic and
those with a normal level are termed normochromic (see below).
|Red cell indices
RDW: Red cell distribution width; an index of the variation in sizes of the red cell population within an
indiviual. This will be raised if two red cell populations are present. Occasionally useful if there is doubt
about multiple causes of anaemia. A common cause for an increased RDW is the presence of
reticulocytes.
Normochromic implies normal staining of the cells in a thin blood film. The central area of
pallor is normally about 1/3 of the cell diameter
Hypochromic indicates reduced staining with increase in the central area of pallor
These are the key measures of red cell indices. They relate to the
haemoglobin content and size of the red blood cells.

39. |Interpretation of red cell indices
Microcytosis & hypochromia Normocytosis & normochromia
Microcytic
Abnormally small red blood cells.
Microcytic anemia is not caused
by reduced DNA synthesis. It is
not fully understood but is
believed to be due reduced
erythroid regeneration.
Hypochromic
Hypochromic cells due to a
failure of haemoglobin synthesis.
Pathologies;
•Iron deficiency; iron is an essential
building block of haem.
•Failure of globin synthesis; this
occurs in the thalassemia's.
•Crystallization of haemoglobin:
sickle cell disease and
haemoglobin C.
Normocytic
Many processes causing anaemia
do not effect the cell size or
haemoglobin concentration within
cells.
Normocytic normochromic
anaemia develops when there is a
decrease in the production of
normal red blood cells.
Pathologies;
•anemia of chronic disease (some)
•aplastic anemia
•Haemolysis: a increased destruction (some)
•Hemolysis ;or loss of red blood
•pregnancy/fluid overload: an inbalance or
an increase in plasma volume compared to
red cell production
Macrocytosis & megaloblastosis
Macrocytic megaloblastic
red blood cells have an unusual misshapen
appearance, which is due to defective
synthesis of DNA. This in turn leads to delayed
maturation of the nucleus compared to that of
the cytoplasm and the cells have a reduced
survival time.
Macrocytosis:
The exact cause of the pathological
mechanisms behind these large cells is not
fully understood.. It is thought to be linked to
lipid deposition on the red cell membrane.
Alcohol is the most frequent cause of a raised
MCV!
Alcohol | Liver disease | hypothyroidism |
Hypoxia | cytotoxic drugs | pregnancy |
In clinical practice megaloblastic
anaemia is almost always caused by a
deficiency of vitamin B12 or folate which
are key building blocks in DNA synthesis.

40. Megaloblastic Anemias
• A form of anemia characterized by the presence of large,
immature, abnormal red blood cell progenitors in the bone
marrow
• 95% of cases are attributable to folic acid or vitamin B12
deficiency

41. | Morphological classification of anemia
Anaemia type
Red cell
indices
Common
examples
Microcytic
hypochromic
MCV < 80 fl
MCH < 27 pg/L
Iron deficiency
Thalassaemia
Sideroblastic
Normocytic
normochromic
Macrocytic
MCV > 98 fl
Folate deficiency
B12deficiency
Normal
Haemolysis
Chronic disease
Marrow infiltration
Megaloblastic

42. |Etiological classification of anemia
This classification is based on cause and illuminates the pathogenic process leading to anaemia.
You can look at anaemia from a production, destruction or pooling point of view.
Reduced Production
Insufficient production: If you consider the bone marrow to be the factory it must
have enough raw material (Iron, vitamin B12 and folate) to make new blood cells.
These raw material are called haematinics. If there is not enough of the raw material
(a deficiency of one or more of the haematinics), then there is insufficient production.
Inefficient production (erythropoiesis): some problem with maturation of the erythroid
in the marrow. Occurs in bone marrow infiltration (malignancy/leukaemia), aplastic
anaemia or in the macrocytic megaloblastic anaemia.
Destruction
Reduced Cell lifespan
This is either due to loss of red blood cells in a haemorrhage (a bleed) or the
excessive destruction of red blood cells in haemolysis. Haemolysis is an important
cause of red cell destruction and anaemia.

43. Reduced bone
marrow erythroid
cells
•aplastic anaemia
•Leukaemia or
malignancy
Loss of red cells
due to
bleeding
Increased
destruction of red
cells (haemolytic
anaemia
Failure of
production of
red cells by the
bone marrow
Dilution of red cells
by increased
plasma volume
(e.g.
hypersplenism)
Nutritional
(haematinic)
deficiency
•Iron
•vitamin B12
•folate
Ineffective red cell
formation
•Chronic inflam.
•Thalassaemia
•renal disease
Immune
Non-
immune
• Autoimmune
warm
• Autoimmune
cold
• Adverse drug
reaction
• Haemolytic
disease of the
newborn
• Malaria
• Burns
• Mechanical
heart valve
• Hypersplenism
• PNH
Abnormal
red cell
membrane
Abnormal
haemoglobin
Abnormal
red cell
metabolism
• Sperocytes
• Elliptocytes
Thalassaemia
•Sickle cell
anaemia
• Pyruvate
kinase
deficiency
• G6PD
deficiency
Inherited /
inside the cell
Acquired /
outside cell
Anemia
|Classification of anemia based on pathology

44. Normal CBC

45. Microcytic Anemia (IDA)

46. Macrocytic Anemia (Meg.):

47. |anaemia essential bites
iron deficieny
R.C.I.: a microcytic hypochromic anaemia
Epi: One of the most common autosomal inherited disorders.
Common in Mediterranean, Africa and middle east. Gene carriers are
protected from p.falciprum malaria.
Path: Reduced beta globin (of haemoglobin) production. Ineffective
erythropoiesis and haemolysis
IX. blood film, Hb electropheresis
Si/Sy. Heterozygotes: often asymptomatic, mild anaemia, low MCV.
Homozygote: severe anaemia, failure to thrive in first 6
months of life, splenomegaly, bone hypertrophy (secondary to
extramedullary haemopoisis).
Tx. For major Thalassaemia treat with repeated blood
transfusion and iron chelation.
Β-Thalassaemia
R.C.I.: a microcytic hypochromic anaemia
Aet: A group of autosomal recessive genetic disorders due to a
haemoglobin chain mutation. Part of the haemoglobinopathies that
primarily affect those of African origin (sickel cell trait can afford some protection
against malaria.
Path: Abnormal haemoglobin (HbS) undergo a sickling
transformation in a deoxygenated state and a permenant conformational change
of shape. The red cell looses its ability to deform becoming rigid. This can
cause occlusion of small vessels. These crises are precipitated by
hypoxia, dehydration, infection and the cold.
IX. Electropherisis, haemoglobin solubility test.
Si/Sy: Bone pain, if chronic haemolysis- jaundice and pigment
gallstones.
Txt Supportive; analgesia, fluids and antibiotics if required.
Sickle cell disease
Epi: the most common
cause of a naemia worldwide
affecting around 500million daily.
Aet: pernicious
anaemia, malabsorpion, post total
gastrectomy
Ix.  B12MCV 
platelets. IF antibodies, folate
levels
Si/Sy: Gradual
deterioration, Irritability, Loss of memory,
Painless jaundice, Loss of sensation ,
Feeling of pins and needles in
extremities. ataxic
Txt Intramuscular (IM)
of 1mg of hydroxycobalamin
(Vitamin B12). There is no oral form.
Vitamin B12 &
Folate deficiencyEpi:
Aet: increased
consumption (pregnancy),
dietary deficiency,
folate antagonist (drugs eg;
methotrexate).
Ix.  folateMCV
 transferrin saturation.
Endoscopy/ colonoscopy if
suspected blood loss.
Si/Sy: Gradual
deterioration, Irritability, Loss
of memory, Painless
jaundice, Loss of sensation ,
Feeling of pins and needles in
extremities. ataxic
Txt Intramuscular
(IM) of 1mg of
hydroxycobalamin (Vitamin B12). There is
no oral
form.
Path G6PD is a key enzyme in the hexose monophosphate shunt. An
important funtion of the shunt is maintain a health
haemoglobin by removing oxidant stresses. Wihtout the enzyme, Hb
breakdown resulting in haemolytic aneamia.
Aet: X-linked
Ix. Direct assay during haemolysis
Si/Sy: Koilonychia, sore tongue, angular stomatitis, Plummer-
Vinson syndrome (dysphagia due to
oesophageal web), painless gastritis.
Rx Avoid precipitants of oxidative stress; drugs (anti-malarials,
analgesics), fava beans.
Tx. Blood transfusion if required.
G6PD deficieny
Epi: the most common cause of anaemia worldwide affecting around
500million daily.
Aet: The most common cause of iron deficient anaemia is BLOOD loss
reduced intake (diet)
Increased demand (pregnancy)
Malabsorption (coeliac, gastrectomy)
Ix. FBC, ferritin,  serum iron, TIBC,  transferrin
saturation. Endoscopy/colonoscopy if suspected blood
loss.
Si/Sy: Koilonychia, sore tongue, angular stomatitis, Plummer-
Vinson syndrome (dysphagia due to oesophageal web),
painless gastritis.
Txt Treat underlying cause, give ferrous sulphate until Hb and MCV
normal.
Hereditary
spherocytosis;
Microcytic anaemia Macrocytic anaemia Haemolytic anaemias
Epi: the most common cause of anaemia worldwide affecting around
500million daily.
Aet: The most common cause of iron deficient anaemia is BLOOD loss
reduced intake (diet)
Increased demand (pregnancy)
Malabsorption (coeliac, gastrectomy)
Ix. FBC, ferritin,  serum iron, TIBC,  transferrin
saturation. Endoscopy/colonoscopy if suspected blood
loss.
Si/Sy: Koilonychia, sore tongue, angular stomatitis, Plummer-
Vinson syndrome (dysphagia due to oesophageal web),
painless gastritis.
Txt Treat underlying cause, give ferrous sulphate until Hb and MCV
normal.
Aquired Haemolytic
anaemias;
KEY
R.C.I. Red Cell IndicesEpi. Epidemiology
Aet. Aetiology
Ix. Investigations
Si/Sy. Signs and Symptoms Path. Pathology
Tx. Treatment

48. Iron deficient anemia; an overview
Colon cancer
microcytic hypochromic
blood film.

49. R.C.I.: a microcytic hypochromic anaemia
Epi: One of the most common inherited disorders. Common in
Mediterranean, Africa and Middle East.
Path: Reduced beta globin (of haemoglobin) production.
Ineffective erythropoiesis and haemolysis
Ix. blood film, Hb electrophoresis
Si/Sy. Heterozygotes: often asymptomatic, mild anaemia, low
MCV.
Homozygote: severe anaemia, failure to thrive in first 6
months of life, splenomegaly, bone hypertrophy
(secondary to extramedullary haemopoiesis).
Tx. β-thalassaemia major requires repeated blood transfusion
and iron chelation.
Β-Thalassaemia

50. R.C.I.: a microcytic hypochromic anaemia
Aet: Autosomal recessive genetic disorders due to mutation
of the gene for HbA. Affect primarily people of African origin.
Sickle cell trait (HbAS) affords strong protection against
malaria.
Path: Abnormal haemoglobin (HbS) undergoes a sickling
transformation when in a deoxygenated state resulting in a
permanent conformational change of shape. The red cell
looses its ability to deform becoming rigid. This can cause
occlusion of small vessels and result in sickle cell crises
precipitated by hypoxia, dehydration, infection and the cold.
IX. Electrophoresis, haemoglobin solubility test.
Si/Sy: Bone pain, jaundice, pigment gallstones, leg
ulcers, dactylitis in infants.
Txt Supportive; analgesia, fluids and antibiotics
during crises.
Sickle cell disease (HbSS); an overview
Dactylitis in a child
Blood film: sickle cells

51. path: Vitamin B12 binds to IF
intrinsic factor in the stomach
and is absorbed in the terminal
ileum
Aet: Pernicious anaemia,
malabsorpion, post total
gastrectomy
Ix.  B12MCV  platelets.
IF antibodies. Check folate
levels.
Si./Sy: Gradual deterioration,
Irritability, Loss of memory,
Painless jaundice, Loss of
sensation , Feeling of pins
and needles in extremities,
ataxic.
Txt. Intramuscular (IM) of
1mg of hydroxycobalamin
(Vitamin B12). There is no oral
form.
Vitamin B12 deficiency
Aet: increased consumption
(pregnancy), dietary
deficiency, folate
antagonist (drugs eg;
methotrexate, alcohol).
Ix. serum folate, red
cell folate. MCV
Si/Sy: Jaundice. Weight loss.
GI disturbances. Glossitis.
Txt. Folic acid
supplementation. Exclude
Vitamin B12 eficiency first.
Folate deficiency
Glossitis.
Blood film; Macrocytic hypochromic

52. Path G6PD is a key enzyme in the hexose
monophosphate shunt. An important function of the
shunt is maintain healthy haemoglobin by protection
from oxidant stress. In G6PD deficiency, haemolytic
anaemia occurs.
Aet: X-linked
Ix. Direct assay of G6PD activity
Si/Sy: None other than those of acute / chronic
anaemia
Rx Avoid precipitants of oxidative stress; drugs
(anti-malarials, analgesics), fava beans.
Tx. Blood transfusion if required.
G6PD deficient anaemia; an overview Drugs
Fava beans

53. Epi: 1 in 5000 people in Northern Europe.
Aet: Autosomal dominant
Path.Defective cell membrane protein (spectrin)
causes a loss of cell membrane, progressive
spherocytosis and eventually premature death
(haemolysis). Increased sensitivity to infections such
as parvo-virus.
IX.Blood film; spherocytes Increased osmotic
fragility. negative antiglobulin test.
Si/Sy: asymptomatic.Jaundice, splenomegaly
General features of anaemia
Txt Give ferrous sulphate , ferritin if deficiency
Hereditary spherocytosis; an overview
Blood film

54. WARM
Aet: associated with the production of
autoantibodies of IgG. They attach to the red cell at body
temp and are removed early by the reticuloendothelial
system.
Path: Idiopathic or precipitated by drugs or autoimmune
disease, leukaemia.
IX. Bloods: unconjugated haemoglobin, LDH,
Reticulocytes.
Positive direct antiglobulin test.
Si/Sy: Jaundice, general features, splenomegaly
Txt Steroids, splenectomy as 2nd
line. Vaccination
against H. Influenza, Men C and Pneumococcus.
Autoimmune haemolytic anaemia; an overview
These anaemias can be split into ‘warm’ and cold’ types. This is dependent on the temperature at
which the antibody reacts with the body.
COLD
Aet: Associated with the production of autoantibodies
of IgM and are removed early by the
reticuloendothelial system. Usually self-limiting.
Path: Idiopathic or secondary to infection or lymphoma.
IX. Bloods: unconjugated haemoglobin, LDH,
Reticulocytes.
Positive direct antiglobulin test.
Si/Sy: Worse in cold weather, acrocyanosis (purpling of
skin), Reynaud's phenomenon.
Txt Remove precipitants, keep patient warm,
consider immunosuppression.

55. Microcytosis is MCV < 90fL
The appearance of a hypochromic red blood cell is caused by reduced DNA synthesis
In vitamin B12 deficiency you would expect the MCV to be >99fL
Both sickle cell anaemia and thalassaemia have abnormal haemoglobin
A macrocytic blood film may indicate excess alcohol consumption or liver disease
False! Microcytosis is MCV < 80fL.
False! A hypochromic film is due to reduced haemoglobin content within red blood cells.
True!
True!
True!
true false

56. |Glossary
Anemia: a haemoglobin concentration in peripheral blood below normal
range for sex and age
Hemoglobin: a metalloprotien inside a red blood cell that is responsible for oxygen delivery. It is
composed of four globulin chains each containing an iron containing haem group.
Macrocytic: Red cells of average volume (MCV) above normal.
Mean cell volume: the average volume of circulating red cells
Mean Corpuscular Haemoglobin (MCH): The average haemoglobin content of red blood cells.
Microcytic: red cells of average volume (MCV) below normal
Normoblast: nucleated red cell precursor normallyy found in the bone marrow
Poikilocytosis: variation in shape of peripheral blood red cells
Reticulocyte: a non-nucleated young red blood cell still containing RNA. Can be found in the
peripheral blood and bone marrow.
Stem cell: resides in the bone marrow and by division and differentiation gives rise to all the
blood cells
Sickle cell disease: an inherited disorder of haemoglobin of varying severity. The name arises from the
deformed shape of the red blood cell takes when the abnormal haemoglobin
inside them polymerizes at low oxygen concentrations.
Thalassaemias: a spectrum of inherited disorders of haemoglobin where there is an inbalance in
globin chain production.

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