Anemia

Anemia
Hemoglobin concentration in blood below the lower
limit of the normal range for the age and sex of the
individual.
Lower extreme of normal Hb
Adult- Male 13.0 g/dl
Female 11.5 g/dl
New born Infants 15 g/dl
At 3 months 9.5 g/dl
Clinical features

The Hb level at which signs and symptoms develop depend on

1. Speed of onset of anemia- If rapid, more symptoms (less time for
physiologic adaptation)
2. Severity of anemia- rapidly developing severe anemia(Hb < 6g/dl)
produce significant clinical features
3. Age- Elderly patients develop cardiac and cerebral symptoms
more prominently due to associated CV disease.
Symptoms:
• Tiredness
• Easy fatigability
• Generalized muscle
weakness
• Lethargy
• Headache
Elderly- cardiac failure
Angina pectoris
Confusion
Visual Disturbances
Generalized Signs in all types of Anemia
• Pallor
• CVS- tachycardia, collapsing pulse, cardiomegaly, dyspnea on
exertion and in elderly CHF.
• CNS- faintness, giddiness, headache, tinnitus, drowsiness,
numbness, tingling sensation of hands and feet.
• Ocular- retinal hemorrhage
• Reproductive System- Menstrual disturbances, loss of libido.
• Renal System- mild proteinuria, impaired concentrating capacity of
kidney
• GI system- Anorexia, nausea, constipation and weight
loss.
Classification of Anemia
A. PATHOPHYSIOLOGIC
I. Anemia due to increased blood loss
a) Acute post hemorrhagic anemia
b) Chronic blood loss
II. Anemias due to impaired red cell production
a) Cytoplasmic maturation defects
1. Deficient haem synthesis: Iron deficiency anemia
2. Deficient globin synthesis: Thalassaemic syndrome
b) Nuclear maturation defects
Vitamin B12 and/or folic acid deficiency: Megaloblastic anemia
c) Defect in stem cell proliferation and differentiation
1. Aplastic anemia
2. Pure red cell aplasia
d) Anemia of chronic disorders. Eg. Anemia in renal disease, anemia in
liver disease, anemia of inflammation/infections, disseminated
malignancy, anemia due to endocrine and nutritional deficiencies
 d) Bone marrow infiltration, Eg. Leukemia, lymphomas, multiple
myeloma, myelosclerosis.
e) Congenital anemia. Eg. Sideroblastic anemia, congenital
dyserythropoietic anemia.

III. Anemias due to increased red cell destruction (Hemolytic anemias)

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

B. MORPHOLOGIC
I. Microcytic, hypochromic
II. Normocytic, normochromic
III. Macrocytic, normochromic
Anemia of Blood Loss
Acute blood loss: When the blood loss occurs
suddenly, the following events takes place:
1) Immediate threat to life due to hypovolemia
which may result in shock and death.
2) If the patient survives, shifting of interstitial fluid
to intravascular compartment with consequent
haemodilution with low haematocrit
3) Hypoxia stimulates production of erythropoietin
resulting in increased marrow erythropoiesis.
Chronic blood loss:
When the blood loss is slow and insidious, the
effects of anemia will become apparent only when
the rate of loss is more than the rate of production
and the iron stores are depleted resulting in iron
deficiency anemia.
Hypochromic anemia
• Due to iron deficiency anemia
• Occurs due to defective haemoglobin synthesis

Classified into 2:
1. Hypochromic anemia due to iron deficiency
2. Hypochromic anemia due to sideroblastic
anemia, thalassemia and anemia of chronic
disorders.
 IRON DEFICIENCY ANEMIA
• Commonest nutritional deficiency disorder.
Etiology
I. INCREASED BLOOD LOSS
1. Uterine eg. Excessive menstruation in reproductive years,
repeated miscarriages, at onset of menarche, post-menopausal
uterine bleeding.
2. Gastrointestinal eg. Peptic ulcer, haemorrhoids, hookworm
infection, cancer of stomach and large bowel, esophageal
varices, hiatus hernia, chronic aspirin ingestion, ulcerative
colitis.
3. Renal tract eg. Haematuria
4. Nose eg. Repeated epistaxis
5. Lungs eg. haemoptysis
II. INCREASED REQUIREMENTS
1. Spurts of growth in infancy, childhood and adolescence.
2. Prematurity
3. Pregnancy and lactation
III. INADEQUATE DIETARY INTAKE
1. Poor economic status
2. Anorexia eg. In pregnancy
3. Elderly individuals due to poor nutrition and financial
constraints.
IV. DECREASED ABSORPTION
1. Partial or total gastrectomy
2. Achlorhydria
3. Intestinal malabsorption such as coelic disease
Pathogenesis
• Develops when the supply of iron is inadequate for the
requirement of Hb synthesis.
• Initially the negative balance is covered by mobilisation from
tissue stores to maintain Hb synthesis.
• Once the tissue stores of iron are exhausted, the supply of iron to
the marrow becomes insufficient for Hb synthesis, thus resulting in
anemia.
• The development of iron deficiency depends on:
– Increased blood loss
– Increased requirements
– Inadequate dietary intake
– Decreased intestinal absorption
Clinical Features
• Anemia- weakness, fatigue, dyspnea on exertion,
palpitations and pallor of skin, mucous
membranes and sclera. In older patients, angina
and congestive cardiac failure.
• Epithelial tissue changes- spoon shaped nails
(koilonychia), dysphagia
 Megaloblastic Anemia
• Caused by impaired DNA synthesis and are characterized by a distinctive
abnormality in the haematopoietic precursors in the bone marrow in which the
maturation of the nucleus is delayed relative to that of cytoplasm.
• Cell division becomes slow but the cytoplasmic development progresses
normally, the nucleated red cell precursors tend to be larger termed as
megaloblasts.
• The most prominent abnormality in this is macrocytosis.
• The underlying defect for the asynchronous maturation of the nucleus is
defective DNA synthesis due to deficiency of Vitamin B12 (cobalamin) and/or
folic acid (folate).
• Less common causes are interference with DNA synthesis by congenital or
acquired abnormalities of vitamin B12 or folic acid metabolism
Etiologic Classification
I. VITAMIN B12 DEFICIENCY
A. Inadequate dietary intake eg. Strict vegetarians, breast- fed infants
B. Malabsorption
1. Gastric causes: pernicious anemia, gastrectomy
2. Intestinal causes: Crohn’s disease.
II. FOLATE DEFICIENCY
A. Inadequate dietary intake eg. in alcoholics, teenagers, infants, old
age, poverty
B. Malabsorption eg. coeliac disease, partial gastrectomy, Crohn’s
disease.
C. Excess demand
1. Physiological: pregnancy, lactation, infancy
2. Pathological: malignancy, increased haematopoiesis, chronic
exfoliative skin disorders, tuberculosis, rheumatoid arthritis
3. Excess urinary folate loss eg. In active liver disease, CHF
III. OTHER CAUSES
A. Impaired metabolism eg. Inhibitors of dihydrofolate (DHF)
reductase such as methotrexate
B. Unknown etiology eg. refractory megaloblastic anemia
Clinical Features
1. Red tongue.
2. Neurologic manifesations- Vitamin B12 deficiency is
associated with peripheral neuropathy, while folate
deficiency develop neuropathy. (numness, paraesthesia,
weakness, ataxia, poor finger coordination and diminshes
reflexes)
3. Others- mild jaundice, purpura, melanin pigmentation,
symptoms of malabsorption, weight loss and anorexia.
Biochemical basis
Methyl Tetrahydrofolate
Methionine
Methyl
vitamin B12 Homocysteine

Tetrahydrofolate
DHF Reductase
DHF Pteroyl

glutamic acid
dTMP DNA
- block due to folate deficiency
- block due to drug with normal tissue folate level
 Pernicious Anemia
• Chronic disorder of middle-aged and elderly individual of
either sex in which intrinsic factor (IF) secretion ceases
owing to atrophy of the gastric mucosa.
• Also termed as Addisonian megaloblastic anemia.
• Average presentation is 60 years.
Pathogenesis
An autoimmune reaction against gastric parietal cells
atrophy of gastric mucosa absence or low level of IF.
Clinical features
 Anemia, glossitis, neurological abnormalities, GI
manifestations(diarrhea, anorexia, weight loss, dyspepsia),
hepatosplenomegaly, CHF and haemorrhagic manifestations.
 Hemolytic Anemia
• Anemia resulting from an increase in the rate of red cell
destruction.
• The red cell lifespan is shortened in hemolytic anemia ie.
Accelerated haemolysis.
• The premature destruction occur via 2 mech:
1. The red cells undergo lysis in the circulation and release their
contents into plasma (Intravascular haemolysis). In these
cases, the plasma Hb rises substantially and a part of it is
excreted in urine (haemoglobinuria)
2. The red cells are taken up by cells of RE system where they
are destroyed and digested (extravascular haemolysis).
Plasma Hb is barely raised.
• Extravascular haemolysis is more common than other.
• Haemolytic anemias are broadly classified into 2
Acquired- caused by a variety if extrinsic environmental factors
(extracorpuscular).
Hereditary- usually the result of intrinsic red cell defects
(intracorpuscular).
Classification
I. ACQUIRED (EXTRACORPUSCULAR)
A. Antibody: Immunohaemolytic anemias
1. Autoimmune haemolyitc anemia (AIHA)
i. Warm antibody
ii. Cold antibody
2. Drug- induced immunohaemolytic anemia
3. Isoimmune haemolytic anemia
B. Mechanical trauma: microangipathic HA
C. Direct toxic effects: malaria, bacterial, infection, and
other agents.
D. Acquired red cell membrane abnormalities:
paroxysmal nocturnal haemoglobinuria (PNH)
E. Splenomegaly
II. HEREDITARY (INTRACORPUSCULAR)
A. Abnormalities of red cell membrane
B. Disorders of red cell interior
1. Red cell enzyme defects (Enzymopathies)
1) Defects in the HMP shunt: G6PD deficiency
2) Defects in the Embden-Meyerhof (or glcolytic) pathway: pyruvate
kinase deficiency
2. Disorders of Hb (haemoglobinopathies)
1) Structurally abnormal Hb: sickle cell syndromes, other
haemoglobinopathies
2) Reduced globin chain synthesis: thalassemias
I. ACQUIRED HA
A. Immunohaemolytic Anemias
• Group of anemias occurring due to antibody
production by the body against its own red cells.
• Immune haemolysis may be induced by one of the
following 3 types of antibodies:
1. Autoimmune haemolytic anemia (AIHA) characterised by the
formation of autoantibodies against patient’s own red cells.
AIHA is further divided into:
1. Warm antibody AIHA in which the autoantibodies are reactive at
body temperature (37⁰C).
2. Cold antibody AIHA in which the autoantibodies react better with
patient’s own red cells at 4⁰C.
2. Drug induced immunohaemolytic anemia
3. Isoimmune haemolytic anemia in which the antibodies are
acquired by blood transfusions, pregnancies and haemolytic
Autoimmune Haemolytic Anemia
Warm Antibody AIHA
• Warm antibodies that are reactive at body temperature
and coat the red cells are generally IgG class and
occasionally IgA.
• Human red cells coated with IgG antibodies usually
bound to surface of RE cells, esp the splenic macrophages.
• Loss of a part of coated cell membrane spherical
transformation of the red cells (acquired spherocytosis).
• Red cells coated with IgG + C3 on the surface
promote red cell- leucocyte interaction severe
haemolysis.
Etiology
• Idiopathic
• Lymphomas-leukemias
• Collagen vascular disease eg. SLE
• Drugs eg. Methyldopa, penicillin, quinidine group
• Post-viral
Clinical Features
• Chronic anemias of varying severity with remissions and relapses.
• Splenomegaly
• Occasionally hyperbilirubinemia
Cold Antibody AIHA
• Antibodies reactive in the cold climate (4⁰C) may
induce haemolysis under 2 conditions:
Cold agglutinin disease
IgM antibodies directed
I antigen on red cell surface

4⁰C
Disagglutination warming (37⁰C)
Agglutination C3 fixation

Haemolysis
Etiology- infections (mycoplasma pneumonia, infectious
mononucleosis) and in lymphomas
 SIDEROBLASTIC ANEMIA
• Group of disorders in which nucleated erythroid precursors in the bone marrow
show characteristic ‘ringed sideroblasts.’
• Siderocytes are red cells containing granules of non-haem iron.
• Sideroblasts are nucleated red cells (normoblasts) containing siderotic granules.

• Depending on the number, size and distribution of siderotic granules, sideroblasts

may be normal or abnormal.
– Normal sideroblasts contain few fine, scattered cytoplasmic granules
representing iron which has not been utilized for Hb synthesis.
– Abnormal sideroblasts are of 2 types:

One type is a sideroblast containing numerous, diffusely scattered, coarse,

cytoplasmic granules and are seen in conditions such as haemolysis.

Other type is ringed sideroblast in which haem synthesis is disturbed, containing

numerous large granules, often forming a complete or partial ring around the
Types of Sideroblastic Anemias

1. Hereditary- rare X-linked disorder associated with defective enzyme activity of

aminolevulinic acid (ALA) synthetase required for haem synthesis.

2. Acquired

A. Primary(Idiopathic or refractory)- occurs in middle aged and older individuals

of both sexes.

Pathogenesis- disturbed growth and maturation of erythroid precursors in the

haematopoietic stem cell, due to reduced activity of enzyme, ALA synthetase.

The bone marrow cells show chromosomal abnormalities, neutropenia and

thrombocytopenia with associated bleeding.

It is also regarded as myelodysplastic disorder in the French- American- British

Classification, and thus can be a preleukemic disorder.
B. Secondary- develop secondary to a variet of drugs, chemicals, toxins,
haematological and various other diseases.
• Haematological disorders- myelofibrosis, acute leukemia, myeloma, lymphoma
and haemolytic anemia.
• Miscellaneous- In association with a variety of inflammatory, neoplastic and
autoimmune diseases such as carcinoma, myxoedema, rheumatoid arthritis
and SLE.
ANEMIA OF CHRONIC DISEASE
• No invasion of the bone marrow
• Develops secondary to a disease process.
• It is usually normocytic normochromic but can have mild degree of microcytosis and
hypochromia.

ANEMIAS SECONDARY TO CHRONIC SYSTEMIC DISORDERS

1. Anemia in chronic Infections/Inflammation

a. Infections eg. Tuberculosis, lung abscess, pneumonia, subacute bacterial endocarditis,
pyelonephritis

b. Non-infectious inflammation eg. Rheumatoid arthritis, SLE, vasculitis, dermatomyositis,

scleroderma, Crohn’s disease.

c. Disseminated malignancies eg. Hodgkin’s disease, disseminated carcinomas and sarcomas.

2. Anemia of renal Disease eg. Uremia, renal failure

3. Anemia of Hypometabolic state eg. Endocrinopathies (myxoedema, hyperthyroidism,

hypopituitarism), protein malnutrition, scurvy, pregnancy, liver disease.
Pathogenesis
2 factors appear to play a significant role in the pathogenesis of anemia
are:
1. Defective red cell production
2. Reduced red cell lifespan
Defective red cell production
Though there is abundance of storage iron in these conditions, the
amount of iron available to the developing erythroid cells in the
marrow is subnormal.

Hyperplasia of mononuclear phagocyte

Suppression of erythropoietin by inflammatory cytokines and hepcidin

Inflammatory cytokines- TNF and IFN-β (released in bacterial infections
and tumors) and IL-1 and IFN-ɣ (RA and autoimmune vasculitis)
 Defective erythropoiesis
Reduced red cell lifespan
Hyperplastic mononuclear phagocyte

Decreased survival of circulating red cells