ANEMIA

(Clinical Features, Classification and Diagnostic Approach)

INTRODUCTION

Anaemia refers to a state in which the level of haemoglobin in the blood is

below the reference range appropriate for age and sex.
Other factors, including pregnancy and altitude, also affect haemoglobin
levels and must be taken into account when considering whether an
individual is anaemic.
Approximately 4% of men and 8% of women have values lower than
those cited. Developing countries have greater prevalence of anemia. A
significantly greater prevalence is observed in patient populations.
Subnormal level of haemoglobin causes lowered oxygen carrying capacity
of the blood. This, in turn, initiates compensatory physiologic adaptations
such as follows:

● increased release of oxygen from haemoglobin

● increased blood flow to the tissues
● maintenance of the blood volume and
● redistribution of blood flow to maintain the cerebral blood supply.

Eventually, however, tissue hypoxia develops causing impaired functions of

the affected tissues. The degree of functional impairment of individual
tissues is variable depending upon their oxygen requirements. Tissues with
high oxygen requirement such as the heart, CNS and the skeletal muscle
during exercise, bear the brunt of clinical effects of anaemia.
CLINICAL FEATURES

In symptomatic cases of anaemia, the presenting features depends on the speed

of development of anemia, age of patient, type and severity of anemia. They can
present as follows

● Tiredness, easy fatigability, generalised muscular weakness, lethargy and

headache, palpitations, anorexia, flatulence, nausea, constipation and weight
loss may occur.
● In older patients, there may be symptoms of cardiac failure, angina pectoris,
intermittent claudication, confusion and visual disturbances.
● Pallor of mucous membranes, eyes and skin.
● A hyperdynamic circulation may be present with tachycardia, collapsing pulse,
cardiomegaly, midsystolic flow murmur, dyspnoea on exertion, and in the case of
elderly, congestive heart failure.

● The older patients may develop symptoms referable to the CNS such as attacks
of faintness, giddiness, headache, tinnitus, drowsiness, numbness and tingling
sensations of the hands and feet.

● Retinal haemorrhages, rashes may occur if there is associated vascular disease

or bleeding diathesis.

● Menstrual disturbances such as amenorrhoea and menorrhagia and loss of

libido are some of the manifestations involving the reproductive system in
anaemic subjects.

● Mild proteinuria and impaired concentrating capacity of the kidney may occur in
severe anaemia.
 CLASSIFICATION
PATHOPHYSIOLOGIC

I. Anaemia due to increased blood loss

a) Acute post-haemorrhagic anaemia
b) Chronic blood loss

II. Anaemias due to impaired red cell production

a) Cytoplasmic maturation defects
1. Deficient haem synthesis: Iron deficiency anaemia
2. Deficient globin synthesis: Thalassaemic syndromes
b) Nuclear maturation defects Vitamin B12 and/or folic acid deficiency: Megaloblastic
anaemia
c) Defect in stem cell proliferation and differentiation
1. Aplastic anaemia
2. Pure red cell aplasia
 d) Anaemia of chronic disorders
e) Bone marrow infiltration
f) Congenital anaemia

III. Anaemias due to increased red cell destruction (Haemolytic anaemias)

A. Extrinsic (extracorpuscular) red cell abnormalities
B. Intrinsic (intracorpuscular) red cell abnormalities

MORPHOLOGIC

I. Microcytic, hypochromic
II. Normocytic, normochromic
III. Macrocytic, normochromic
Iron deficiency anaemia
This occurs when iron losses or physiological requirements exceed absorption.

● Blood loss
The most common explanation in men and post-menopausal women is
gastrointestinal blood loss. This may result from occult gastric or colorectal
malignancy, gastritis, peptic ulceration, inflammatory bowel disease,
diverticulitis, polyps and angiodysplastic lesions.

Worldwide, hookworm and schistosomiasis are the most common causes of gut
blood loss. Gastrointestinal blood loss may be exacerbated by the chronic use
of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs), which cause
intestinal erosions and impair platelet function.
 In women of child-bearing age, menstrual blood loss, pregnancy and
breastfeeding contribute to iron deficiency by depleting iron stores; in
developed countries, one-third of pre-menopausal women have low iron
stores but only 3% display iron-deficient haematopoiesis. Very rarely,
chronic haemoptysis or haematuria may cause iron deficiency.

● Malabsorption and malnutrition

A dietary assessment should be made in all patients to ascertain their iron

intake. Gastric acid is required to release iron from food and helps to
keep iron in the soluble ferrous state. Achlorhydria in the elderly or that
due to drugs such as proton pump inhibitors may contribute to the lack of
iron availability from the diet, as may previous gastric surgery. Iron is
absorbed actively in the upper small intestine and hence can be affected
by coeliac disease.
 Physiological demands

At times of rapid growth, such as infancy and puberty, iron requirements

increase and may outstrip absorption. In pregnancy, iron is diverted to the fetus,
the placenta and the increased maternal red cell mass, and is lost with bleeding
at parturition

INVESTIGATIONS

● Hb is reduced, MCV below 80fL, Peripheral smear shows microcytosis,

hypochromia, anisocytosis, poikilocytosis. Reticulocyte count is normal or
elevated if blood loss is the ethology and BM has enough iron stores.
● Plasma iron is reduced, TIBC raised, ferritin and transferrin saturation are
reduced.
● BM examination shows erythronium hyperplasia and reduced iron stores.
● Hepcidin is reduced.
TREATMENT

● Treating underlying cause

● Replenishment of iron by oral or parenteral formulations
Commonly used oral iron preparations include ferrous fumarole, ferrous
sulphate, ferrous gluconate, ferrous ascorbate.
Parenteral iron include ferric carboxymaltose, iron sucrose, iron dextran.
Anaemia of chronic disease (ACD)
Also known as anaemia of inflammation (AI), is a common type of anaemia, particularly
in hospital populations. It occurs in the setting of chronic infection, chronic inflammation
or neoplasia. The anaemia is not related to bleeding, haemolysis or marrow infiltration,
is mild, with haemoglobin in the range of 85–115 g/L, and is usually associated with a
normal MCV (normocytic, normochromic), though this may be reduced in long-standing
inflammation. The serum iron is low but iron stores are normal or increased, as
indicated by the ferritin or stainable marrow iron.
Megaloblastic anaemia

This results from a deficiency of vitamin B12 or folic acid, or from disturbances in
folic acid metabolism.The end result is cells with arrested nuclear maturation but
normal cytoplasmic development: so-called nucleocytoplasmic asynchrony.

Causes of vitamin B12 deficiency-

Dietary deficiency,
hypochlorhydria,
gastric surgery,
Small bowel pathology
Pernicious anaemia- is an organ-specific autoimmune disorder in which the
gastric mucosa is atrophic, with loss of parietal cells causing intrinsic factor
deficiency. In the absence of intrinsic factor, less than 1% of dietary vitamin B12
is absorbed.
Causes of folate deficiency
Poor intake of vegetables Malabsorption e.g. Coeliac disease, small bowel surgery
Increased demand like haemolysis, Pregnancy
Drugs like Certain anticonvulsants (e.g. phenytoin), Contraceptive pill, Certain
cytotoxic drugs (e.g. methotrexate)
● Vitamin B12 deficiency is treated with hydroxycobalamin. In cases of
uncomplicated deficiency, 1000 μg IM for 6 doses 2 or 3 days apart, followed by
maintenance therapy of 1000 μg every 3 months for life, is recommended. In the
presence of neurological involvement, a dose of 1000 μg on alternate days until
there is no further improvement, followed by maintenance as above, is
recommended.

● Oral folic acid (5 mg daily for 3 weeks) will treat acute deficiency and 5 mg once
weekly is adequate maintenance therapy. Prophylactic folic acid in pregnancy
prevents megaloblastosis in women at risk, and reduces the risk of fetal neural tube
defects
 HEMOLYTIC
ANEMIAS

Haemolysis indicates that there

is shortening of the normal red
cell lifespan of 120 days. There
are many causes, as shown in
Figure
Extravascular haemolysis Physiological red cell destruction occurs in the reticulo-
endothelial cells in the liver or spleen, so avoiding free haemoglobin in the plasma. In
most haemolytic states, haemolysis is predominantly extravascular.

Intravascular haemolysis Less commonly, red cell lysis occurs within the blood
stream due to membrane damage by complement (ABO transfusion reactions, PND),
infections (malaria, Clostridium perfringens), mechanical trauma (heart valves, DIC)
or oxidative damage (e.g. G6PD deficiency, which may be triggered by drugs such as
dapsone and maloprim). When intravascular red cell destruction occurs, free
haemoglobin is released into the plasma.
Red cell membrane defects
Hereditary spherocytosis

An autosomal dominant condition. The most common abnormalities are deficiencies of beta
spectrin or ankyrin. Most cases are associated with an asymptomatic compensated chronic
haemolytic state with spherocytes present on the blood film, a reticulocytosis and mild
hyperbilirubinemia. Occasional cases are associated with more severe haemolysis.

The clinical course may be complicated by crises: • A haemolytic crisis occurs when the
severity of haemolysis increases; this is rare, and usually associated with infection. • A
megaloblastic crisis follows the development of folate deficiency; this may occur as a first
presentation of the disease in pregnancy. • An aplastic crisis occurs in association with
parvovirus (erythrovirus) infection.

The blood film will show spherocytes but the direct Coombs test is negative, excluding
immune haemolysis. Osmotic fragility test may show increased sensitivity to lysis in
hypotonic saline solutions and more specific cytometry can be done. Treatment includes
folic acid supplementation, splenectomy and blood transfusion depending on severity.
Hereditary elliptocytosis

Group of disorders that produce an increase in elliptocytic red cells on the blood film and a
variable degree of haemolysis. This is due to a functional abnormality of one or more anchor
proteins in the red cell membrane. Inheritance may be autosomal dominant or recessive. The
clinical course is variable and depends on the degree of membrane dysfunction caused by the
inherited molecular defect(s); most cases present as an asymptomatic blood film abnormality but
occasional cases result in neonatal haemolysis or a chronic compensated haemolytic state.
Management of the latter is the same as for hereditary spherocytosis.

Red cell enzymopathies

The mature red cell must produce energy via ATP to maintain a normal internal environment and
cell volume while protecting itself from the oxidative stress presented by oxygen carriage. ATP is
generated by glycolysis, while the hexose monophosphate shunt produces NADPH and
glutathione to protect against oxidative stress. In general, defects in the hexose monophosphate
shunt pathway result in periodic haemolysis precipitated by episodic oxidative stress, while those
in the glycolysis pathway result in shortened red cell survival and chronic haemolysis.
Glucose-6-phosphate dehydrogenase deficiency, Pyruvate kinase deficiency, Pyrimidine 5′
nucleotidase deficiency are the common enzymatic deficiencies leading to hemolysis.
 Autoimmune haemolytic anaemia
This results from increased red cell destruction due to red cell autoantibodies. The antibodies
may be IgG or IgM, or more rarely IgE or IgA. If an antibody avidly fixes complement, it will
cause intravascular haemolysis, but if complement activation is weak, the haemolysis will be
extravascular. Antibody-coated red cells lose membrane to macrophages in the spleen and
hence spherocytes are present in the blood.

The optimum temperature at which the antibody is active (thermal specificity) is used to
classify immune haemolysis:

Warm antibodies bind best at 37°C and account for 80% of cases. The majority are IgG
and often react against Rhesus antigens.

Cold antibodies bind best at 4°C but can bind up to 37°C in some cases. They are usually
IgM and bind complement. To be clinically relevant, they must act within the range of normal
body temperatures. They account for the other 20% of cases.
Alloimmune haemolytic anaemia

Alloimmune haemolytic anaemia is caused by antibodies against non-self red

cells. It has two main causes, occurring after: • unmatched blood transfusion •
maternal sensitisation to paternal antigens on fetal cells.

Non-immune haemolytic anaemia

Endothelial damage by mechanical heart valves, thermal injury, etc

Infection like malaria
Drugs like dapsone
 Haemoglobinopathies

Sickle-cell anaemia

Sickle-cell disease results from a single glutamic acid to valine substitution at position 6 of the
beta globin polypeptide chain. It is inherited as an autosomal recessive trait.

Homozygotes only produce abnormal beta chains that make haemoglobin S (HbS, termed SS),
and this results in the clinical syndrome of sickle-cell disease.

Heterozygotes produce a mixture of normal and abnormal beta chains that make normal HbA
and HbS (termed AS), and this results in sickle-cell trait, asymptomatic but it may be associated
with an increased risk of sudden and cardiovascular death.

Clinical features- Sickling is precipitated by hypoxia, acidosis, dehydration and infection.

Irreversibly sickled cells have a shortened survival and plug vessels in the microcirculation. This
results in a number of acute syndromes, termed ‘crises’, and chronic organ damage- Painful
vaso-occlusive crisis, Sickle chest syndrome, Stroke, Sequestration crisis, Aplastic crisis
Thalassaemias It is an inherited impairment of haemoglobin production, in which there is
partial or complete failure to synthesise a specific type of globin chain. In alpha-thalassaemia,
disruption of one or both alleles on chromosome 16 may occur, with production of some or no
alpha globin chains. In beta thalassaemia, defective production usually results from disabling
point mutations causing no (β0) or reduced (β–) beta chain production.
OTHER CAUSES OF ANEMIAS

● Leukemias
● Lymphomas
● Multiple Myeloma
● Aplastic Anemia
APPROACH TO ANEMIA
HISTORY AND EXAMINATION

● The evaluation of the patient with anemia requires a careful history and physical
examination. Nutritional history related to drugs or alcohol intake and family history of
anemia should always be assessed.
● Certain geographic backgrounds and ethnic origins as Glucose-6-phosphate
dehydrogenase (G6PD) deficiency and certain hemoglobinopathies are seen more
commonly in those of Middle Eastern or African origin.
● History of exposure to certain toxic agents or drugs and symptoms related to other
disorders commonly associated with anemia. These include symptoms and signs such as
bleeding, fatigue, malaise, fever, weight loss, night sweats, and other systemic symptoms.
● Clues to the mechanisms of anemia may be provided on physical examination by findings
of infection, blood in the stool, lymphadenopathy, splenomegaly, or petechiae.

● Splenomegaly and lymphadenopathy suggest an underlying lymphoproliferative disease,

whereas petechiae suggest platelet dysfunction.
CBC The components of the CBC also help in the classification of anemia. Microcytosis is
reflected by a lower than normal MCV (<80), whereas high values (>100) reflect macrocytosis.
The MCHC reflect defects in hemoglobin synthesis (hypochromia). Automated cell counters
describe the red cell volume distribution width (RDW). The MCV (representing the peak of the
distribution curve) is insensitive to the appearance of small populations of macrocytes or
microcytes.

Peripheral Blood Smear provides important information about defects in red cell production. As
a complement to the red cell indices, the blood smear also reveals variations in cell size
(anisocytosis) and shape (poikilocytosis). Poikilocytosis suggests a defect in the maturation of red
cell precursors in the bone marrow or fragmentation of circulating red cells. The appearance of
nucleated red cells, Howell-Jolly bodies, target cells, sickle cells, and others may provide clues to
specific disorders.

Reticulocyte Count used to estimate the degree of effective erythropoiesis, which can be
reported as absolute reticulocyte count or as a reticulocyte percentage. In the latter case, if
anemia is present, the reticulocyte percentage is spuriously high and may not reflect true bone
marrow responses to anemia; therefore, the value has to be adjusted to a corrected reticulocyte
percentage based on the patient’s hematocrit.
Increased reticulocyte count reflects ongoing or recent RBC production activity, which may
result from the following:

● Post bleeding
● Post hemolysis
● Response to therapy (iron supplementation, vitamin B-12 or folic acid supplementation,
erythropoietin supplementation, bone marrow recovery following chemotherapy or bone
marrow transplantation)

A decreased reticulocyte count reflects decreased RBC production, which may result from the
following:

● Vitamin B-12, folic acid, and iron deficiency

● Decreased erythropoietin level (chronic renal failure)
● Aplastic anemia or bone marrow failure syndromes
● Post radiation therapy
● Bone marrow replacement by benign or malignant processes
Bone Marrow Examination.

● In patients with hypoproliferative anemia and normal iron status, a bone marrow is
indicated. Marrow examination can diagnose primary marrow disorders such as
myelofibrosis, a red cell maturation defect, or an infiltrative disease.

● A patient with a hypoproliferative anemia and a reticulocyte production index <2 will
demonstrate an M/E ratio of 2 or 3:1. In contrast, patients with hemolytic disease and a
production index >3 will have an M/E ratio of at least 1:1.

● Either the marrow smear or biopsy can be stained for the presence of iron stores or iron
in developing red cells. The storage iron is in the form of ferritin or hemosiderin.
THANKS