ANAEMIAS

DRFAARAH MOGEH
Erythrocytes

 Erythrocytes (red blood cells) are deformable, non-nucleated

and biconcave discs.
 They are the most abundant blood cell.
 When blood is separated, by centrifugation, into cellular and
plasma components, the red cell portion is approximately
45% of the total volume: this is the ‘packed cell volume’ or
hematocrit.
 The erythrocyte is an oxygen-carrying cell because it is rich in
hemoglobin.
 The mature erythrocyte has no nuclear material, so new
protein cannot be synthesized.
 The mature erythrocyte circulates for around 120 days
before it is removed by the reticuloendothelial system.
Morphology

 The biconcave erythrocyte shape provides a large surface

area for oxygen diffusion.
 By light microscopy, erythrocytes appear as uniform round
cells with central pallor.
 Up to 1% of cells stain with a purplish tinge and are of rather
greater diameter.
 These are polychromatic cells; this purple staining is due to
the residual ribonucleic acid (RNA) of the immature
erythrocyte.
 These young cells become indistinguishable from the mature
red cell population after 48 hours in the blood.
 When stained with a supravital stain (such as methylene blue)
polychromatic cells are more easily identified by the presence
of characteristic RNA inclusions; they are then termed
reticulocytes.
 When bone marrow production of erythrocytes is increased,
the proportion of polychromatic cells or reticulocytes, in the
peripheral blood becomes greater than 1%.
 This occurs most commonly in recovery from acute
hemorrhage or when there is an increased rate of destruction
of red cells, which is called hemolytic anemia.
 Failure to produce a reticulocyte response to anemia
suggests that the patient has bone marrow failure or
hematinic deficiency.
Changes in disease

 Anemia is present when the hemoglobin concentration is less

than approximately 13g/L in a male or 11 g/L in a female; the
hematocrit is also reduced.
 Conversely, polycythemia describes an increased red cell
concentration; it is usually accompanied by a raised
hemoglobin concentration and hematocrit.
 Anemias may be simply classified according to red cell size
(MCV) and hemoglobin content (MCH).
 This classification is of great diagnostic value in most common
types of anemia.
 Further diagnostic information is obtained by the microscopic
examination of the red cell morphology on a blood smear.
 Disease of the blood is frequently associated with increased
variation in red cells, anisocytosis and the presence of
erythrocytes of abnormal shape, poikilocytosis.
 Increased erythrocyte anisocytosis and poikilocytosis are non-
specific abnormalities present in many hematological and
systemic disorders.
 An example is the marked aniso-poikilocytosis that occurs in
the absence of a functioning spleen, due to surgical removal
or secondary to disease.
 In this situation there are also inclusions in red cells.
 They are called Howell–Jolly bodies and are remnants of
nuclear material that would normally be removed when
newly formed erythrocytes released from bone marrow
circulate for the first time through the spleen.
Key points
 Defined as when the hemoglobin is less than 13 g/L in a male
or 11 g/L in a female adult.
 Usually represent a reduction in the body red cell mass.
 Results in tissue hypoxia.
 Are due to failure of erythrocyte production or loss or
destruction of erythrocytes.
 The different lower limits of normal hemoglobin
concentration for neonates, infants and children should be
noted.
 In fact different levels of hemoglobin are observed in
individuals of the same sex but at different ages in adult life.
 The consequences of anemia are dependent upon the speed
of onset.
 Thus the rapid loss of 10% or more of the circulating blood
volume through haemorrhages will result in shock, i.e. the
failure of adequate perfusion of all tissues and organs, with
consequent hypoxia.
 In this situation the subject may not initially be anemic, as
both red cells and plasma are lost through haemorrhages.
 The plasma component is more rapidly replaced, however,
and anemia will be present after several hours have elapsed.
 Anemia that develops more gradually is better tolerated,
especially by individuals with normal cardiac and respiratory
function who can compensate by, for example, increasing
cardiac output.
 The general consequences of anemia are due to the tissue
hypoxia, which can result in fatty change, especially in the
myocardium and liver and even infarction.
 Lethargy, increased breathlessness on exertion and new or
worsened ischemic phenomena are typical clinical features.
 Breathlessness at rest implies the development of heart failure,
a result of severe anemia.
 Expansion of the red marrow is present in those anemia's
where a marrow response is possible – generally the hemolytic
anemia's.
 A low hemoglobin concentration usually reflects a reduction in
the body red cell mass.
 An important exception is pregnancy, when both red cell mass
and plasma volume increase, but the latter to a greater
degree.
 This process results in a hemoglobin concentration in blood that
is lower than in the non-pregnant state in the presence of a
relatively increased red cell mass and overall oxygen carrying
capacity; this condition is often referred to as the physiological
‘anemia’ of pregnancy.
 The increased red cell mass during pregnancy is necessary to
support the increased metabolic requirement of the mother
and fetus.
 The reason for the expansion of the plasma compartment is
obscure, but it may be explained in part by a need for
increased skin perfusion for heat loss due to the increased
metabolic rate.
 Expansion of the plasma volume, resulting in dilutional
anemia, may also occur when the spleen is pathologically
enlarged.
 Other mechanisms also operate in this situation, however, as
described under hypersplenism.
Classification

 Anemias are divided into two categories:

 those where anemia is due to failure to produce erythrocytes
and those in which erythrocyte loss is increased but
production is normal (or usually increased, in response to the
anemia).
 While useful, this categorization is an oversimplification, as
both mechanisms are present in some Anemias.
 Thus, in the megaloblastic states, cell production is defective
due to lack of vitamin B12 or folic acid for nucleic acid
synthesis but, in addition, the erythrocytes that are produced
are abnormal and have diminished survival.
 In thalassemia, cell production is not optimal due to
abnormal hemoglobin synthesis and there is also increased
erythrocyte destruction or hemolysis.
 The myeloid and megakaryocytic lines are also involved in
some processes that result in anemia due to failure of
hemopoiesis (megaloblastic anemia, hypoplastic anemia)
but not in others (iron deficiency anemia).
 Despite these qualifications, the classification described is
useful as an aid to determining the cause of the anemia.
PRODUCTION FAILURE ANAEMIAS

 The most commonly encountered Anemias are in the

production failure group.
Hematinic deficiency

 Hematinic are dietary factors essential for either hemoglobin

synthesis or erythrocyte production.
Iron deficiency

Key points
 A production failure anemia.
 The commonest cause of anemia worldwide.
 Results in a microcytic, hypochromic blood picture.
 Usually indicative of chronic blood loss.
 Frequently indicative of an occult, bleeding lesion of the
gastrointestinal tract.
 Iron deficiency is the commonest cause of anemia
worldwide.
 It is also the commonest cause of a microcytic,
hypochromic blood picture, the others being thalassemias
and (rarely) sideroblastic anemias.
Iron metabolism

 Iron is an essential requirement.

 It is also one of the commonest elements present in the
Earth’s crust.
 Excessive iron deposited in the tissues is, however, toxic,
causing damage to the myocardium, pancreas and liver in
particular.
 As the body has no active method for iron excretion, iron
status is controlled largely by its absorption; the capacity to
absorb iron is, however, limited and any tendency to
increased loss of iron, due to hemorrhage, is highly likely to
result in a negative iron balance and iron deficiency.
 These factors explain the high prevalence of iron deficiency.
 Normally, at least 60% of the body iron is in the hemoglobin of
erythroid cells.
 Approximately 30% is stored within the reticuloendothelial
system, especially in the bone marrow, as ferritin and
hemosiderin.
 A small proportion of total body iron is present in other tissues,
especially muscle and iron-containing enzymes.
 This tissue iron is relatively conserved during states of iron
deficiency.
 Only a small fraction of the total body iron is in transport,
attached to the carrier protein transferrin.
 Ferritin is a protein–iron complex.
 Ferritin is present in all tissues, but especially in the
macrophages of the bone marrow and spleen and in
hepatocytes.
 A small amount is detectable in plasma and, as it is derived
from the storage pool of body iron, its concentration is thus
an accurate indicator of body iron stores.
 Low serum ferritin concentration is a useful confirmatory test
for iron deficiency.
 However, because ferritin is an acute-phase response
protein, the concentration in plasma is not a reliable guide to
body iron stores in the presence of infection, inflammation
and neoplasia.
 In those situations serum ferritin may be normal despite tissue
iron depletion.
 Transferrin is an iron-binding beta-globulin responsible for iron
transport and delivery to receptors on immature erythroid
cells.
 Each molecule of transferrin can bind two atoms of iron, but
normally the transferrin is only one third saturated (thus the
serum iron concentration is normally one-third of the total
serum iron-binding capacity) providing readily available
excess capacity to increase iron transport from the gut, if
needed.
 Transferrin is reutilized after delivering its iron.
 A low transferrin saturation is therefore diagnostic of iron
deficiency while high levels are a feature of iron overload
with deposition of iron in tissues.
 In order to maintain iron balance, sufficient iron must be
absorbed to replace that lost from the urinary and
gastrointestinal tracts as shed cells and in sweat, together
with any extra requirements.
 A diet contains only 10–20 mg of iron per day and only a
maximum of one-third of this can be absorbed, excess losses
of iron of just a few milligrams will inevitably result in negative
iron balance and eventual depletion of iron stores.
 One milliliter of blood contains 0.5 mg iron.
 Thus, loss of 10 mL of blood daily will inevitably exceed the
capacity to absorb sufficient iron, even from a good diet.
 This explains the finding of some degree of iron depletion in
25% or more of menstruating women.
 Iron absorption takes place in the duodenum and upper
jejunum.
 Hem iron is present in meat and is readily absorbed, with
little effect from other dietary components.
 Inorganic iron in vegetables and cereals is mostly trivalent
and may be complexed to amino acids and organic acids,
from which it must be released and reduced to the divalent
state for absorption.
 HCl produced by the stomach and ascorbic acid in food,
favor its absorption.
 In contrast, phosphates and phytates in some foods form
precipitates and prevent absorption.
 Mechanisms controlling the rate of iron absorption are
becoming better understood.
 Major influences are the total body iron stores and rate of
erythropoiesis.
 Thus, if iron stores are replete a smaller proportion of
available iron is absorbed; when erythropoiesis is more
active, due to premature red cell destruction, for example,
extra iron is absorbed even though total stores may be high.
 This is a feature in thalassemia and iron overload may ensue.
 A major regulator of iron balance is the liver protein hepcidin.
 Iron loading leads to rapid production of hepcidin by the liver
which, in turn, inhibits intestinal iron absorption and
movement of iron from stores.
 This is achieved by hepcidin down-regulating the plasma
membrane transfer protein ferroportin.
 Iron is consequently trapped in iron-exporting cells, including
duodenal enterocytes.
 Plasma iron levels subsequently fall.
 Conversely, low iron levels lead to down regulation of liver
hepcidin and increased iron transfer from the gut and iron-
exporting cells so that plasma iron levels rise.
Mechanisms of iron deficiency

 In developed countries, iron deficiency in the non

menstruating and non-pregnant adult most frequently results
from chronic blood loss, often from the gastrointestinal tract.
 As it is possible to lose several millilitres of blood daily into the
gut lumen without marked change in appearance of the
stool, such blood loss is frequently occult.
 Iron deficiency anemia is thus commonly a presenting feature
of lesions within the gastrointestinal tract.
 In clinical practice, when iron deficiency anemia occurs in
the face of a reasonable diet and no excessive menstrual
loss, it is mandatory to perform a careful assessment of the
gastrointestinal tract.
 Causes of iron deficiency are:
 Chronic blood loss (e.g. peptic ulcer; carcinoma of
stomach, caecum, colon or rectum; menorrhagia).
 Increased requirements (e.g. in childhood and pregnancy).
 Malabsorption (due to gastrectomy, coeliac disease).
 Malnutrition.
 The microcytic, hypochromic anemia is a late stage in iron
deficiency; it does not occur until iron stores are severely
depleted.
 The microcyte results from an extra cell division, in addition to
the normal four, during red cell production.
 Increasing cytoplasmic hemoglobin concentration normally
acts as an inhibitor of normoblast division.
 The failure of hemoglobin synthesis that results from iron
deficiency therefore allows extra mitoses to occur, with the
production of small erythrocytes.
 The same mechanism is responsible for the microcytes in
thalassemia, another disorder of hemoglobin synthesis.
Blood and bone marrow changes

 The typical blood picture is one of microcytic, hypochromic

red cells, with increased anisocytosis and poikilocytosis;
elongated ‘pencil’ or ‘cigar’ cells are typically present.
 The proportion of reticulocytes is low for the degree of
anemia, indicating an inability of the bone marrow to
respond due to lack of iron for hemoglobin synthesis.
 The platelet count is often raised, especially if chronic
bleeding is present.
 The leucocytes are typically normal.
 Occasionally, a mixture of microcytic, hypochromic
erythrocytes and macrocytic cells is seen.
 This is termed a dimorphic picture and occurs in mixed
deficiency of iron and folic acid or vitamin B12.
 The MCV and MCH may be misleadingly normal.
 A mixture of microcytic, hypochromic cells and normocytes is
present in iron deficiency responding to iron replacement or
after transfusion of a subject with iron deficiency anemia.
 In the former circumstance, mildly increased reticulocytosis
may be present.
 Abnormalities are also present in the bone marrow.
 The nucleated red cell precursors are small in diameter and
the cytoplasm is frequently ragged – micronormoblastic
erythropoiesis.
 Staining for hemosiderin (Perls’ stain) reveals its absence from
macrophages and normoblasts.
 Important biochemical changes in the blood are a fall in
serum iron and increase in total iron-binding capacity
(representing a compensatory increased transferrin
concentration).
 Saturation of iron-binding capacity is thus reduced to 10% or
less, from the normal 33%.
 The serum ferritin is generally markedly reduced,
corresponding to severely depleted body iron content.
Changes in other organs and tissues

 In addition to the manifestations of chronic anemia, a variety

of epithelial changes may be present in chronic iron
deficiency:
 Angular cheilitis.
 Atrophic glossitis.
 Esophageal web.
 gastric achlorhydria.
 Brittle nails.
 Koilonychia.
 The cause of these phenomena is unknown.
 Angular cheilitis, painful fissuring of the mouth corners, is
common but not specific.
 Smooth tongue is also common.
 Gastric achlorhydria appears to be an occasional result, as
well as a contributory cause, of iron deficiency.
 Dysphagia (difficulty in swallowing) due to the presence of a
web or fold of mucosa in the post-cricoid region is an
uncommon association of iron deficiency.
 The combination has been termed Paterson–Kelly or
Plummer–Vinson syndrome and is important mainly because
the mucosal abnormality is pre-malignant, carcinoma
occasionally developing at the site.
 Koilonychia (spoon-shaped nails) of chronic tissue iron
depletion is typical but only rarely seen.
 The pathological changes of iron deficiency are reversed by
adequate replacement therapy by the oral route.
THANK YOUR FOR YOUR ATTENTION

12/5/2023