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• The main function of the red blood cells is oxygen transport. Hence
a functional definition of anaemia is 'a state in which the circulating
red-cell mass is insufficient to meet the oxygen requirements of the
tissues'.
• However, many compensatory mechanisms can be brought into
play to restore the oxygen supply to the vital centres and therefore
in clinical practice this definition is of limited value.
• For this reason anaemia is usually defined as 'a reduction of the
haemoglobin concentration, red-cell count, or hematocrit to below
normal levels'.
2. Specific signs:
– koilonychia – spoon-shaped nails seen in iron deficiency anaemia
– jaundice – haemolytic anaemia
– bone deformities – thalassaemia major
– leg ulcers – sickle cell disease
Classification:
1. Hypochromic microcytic with low mean corpuscular volume
(MCV)
2. Normochromic normocytic with a normal MCV
3. Macrocytic with a high MCV
Special investigations:
Bone marrow aspiration from the sternum or posterior iliac crest
is performed to:
– confirm a diagnosis made from peripheral blood count
– determine the cellularity of the marrow
– determine the type of erythropoiesis
– determine the proportion of the various lines
– see whether the marrow is infiltrated
– determine the size of the iron stores
MICROCYTIC ANAEMIA
}
– small cells (microcytes)
Thalassaemia
– low MCV (< 80 μL)
– normal iron content Sideroblastic anaemia
– hyperplastic BM
1. IRON-DEFICIENCY ANAEMIA
– brittle nails
– spoon–shaped nails (koilonychia)
– atrophy of the papillae of the tongue
– angular stomatitis
– brittle hair
– dysphagia and glossitis (Plummer-Vinson or Paterson-Brown-
Kelly syndrome)
– parotid gland enlargement, splenomegaly and failure to grow
Smooth, bald,
burning tongue;
Iron deficiency
anemia
Cancer of uterus
BLADDER CANCER
Gastric cancer
colonic cancer
PeptIc ulcer
investigations:
–Hct, Hb, RBC low ; reticulocyte count low
–the red cells are microcytic (MCV < 80 fL) and hypochromic
(MCH < 27 pg)
– poikilocytosis (variation in shape) and anisocytosis (variation in
size)
– target cells
– hypersegmentation of polymorphs
– serum iron falls
– iron blinding capacity ↑
– bone marrow – erythroid hyperplasia with ragged normoblasts
– ring sideroblast
other investigations:
– the G.I. tract - endoscopy
Poikilocytosis is a term which indicates that red cells of
abnormal shape are present on the blood film. Of itself it is
fairly non-specific. Some particular types of poikilocyte are
very informative, however.
Bone marrow in iron deficiency
Iron deficiency develops in stages
• The first is depletion of iron stores. At this point, there is
anemia and no change in red blood cell size. The serum
ferritin will become abnormally low. A ferritin value less
than 12 mcg/L is a highly reliable indicator of iron
deficiency. Bone marrow biopsy for evaluation of iron
stores is now rarely performed because of intraobserver
variation in its interpretation.
• After iron stores have been depleted, red blood cell
formation will continue with deficient supplies of iron.
Serum iron values decline to less than 30 mcg/dL and
transferrin levels rise, leading to transferring saturation of
less than 15%.
• In the early stages, the MCV remains normal.
Subsequently, the MCV falls and the blood
smear shows hypochromic microcytic cells (see
blood smear).
• With further progression, anisocytosis (variations
in red blood cell size) and poikilocytosis
(variation in shape of red cells) develop.
• Severe iron deficiency will produce a bizarre
peripheral blood smear, with severely
hypochromic cells, target cells, hypochromic
pencil-shaped cells and occasionally small
numbers of nucleated red blood cells. The
platelet count is commonly increased.
Differential Diagnosis
• Other causes of microcytic anemia include anemia of
chronic disease, thalassemia and sideroblastic
anemia.
• Anemia of chronic disease is characterized by normal or
increased iron stores in the bone marrow and a normal or
elevated ferritin level; the serum iron is low, often
drastically so, and the total iron-binding capacity (TIBC) is
either normal or low.
• Thalassemia produces a greater degree of microcytosis
for any given level of anemia than does iron deficiency.
Red blood cell morphology on the peripheral smear is
abnormal earlier in the course of thalassemia.
Iron Deficiency Anemia
Essentials of Diagnosis
– failure to thrive
– recurrent infections
– severe anaemia
– extramedullary haemopoiesis → hepatosplenomegaly and bone
expansion thalassaemic facies
investigation:
– blood count:
moderate to severe anaemia (↓MCV, MCH↓)
reticulocyte ↑
white cells and platelets = N
– blood film:
hypochromic and microcytic picture
Howell – Jolly bodies
– high ferritin levels
– haemoglobin electrophoresis (HbF ↑; HbA absent)
β-Thalassaemia trait (minor)
– asymptomatic
– no anaemia, red cells hypochromic and microcytic
α-Thalassaemia
– two main form:
deletion of only one alpha chain gene
deletion of both alpha chain genes → no alpha chains are
produced
Thalassemia major
Thalassemia minor
Differential Diagnosis
• Mild forms of thalassemia must be differentiated
from iron deficiency.
• Compared to iron deficiency anemia, patients
with thalassemia have a lower MCV, a more
normal red blood count and a more abnormal
peripheral blood smear at modest levels of
anemia. Iron studies are normal.
• Severe forms of thalassemia may be confused
with other hemoglobinopathies.
• The diagnosis is made by hemoglobin
electrophoresis.
The Thalassemias
Essentials of Diagnosis
• Microcytosis out of proportion to the
degree of anemia.
• Positive family history or lifelong personal
history of microcytic anemia.
• Abnormal red blood cell morphology with
microcytes, acanthocytes, and target cells.
• In beta-thalassemia, elevated levels of
hemoglobin A2 or F.
Sickle-cell Disease
• Another haemoglobinopathy
• Defective Haemoglobin (HbS) due to
chromosome 11 mutation resulting in the
beta-globin chain change
• This HbS causes a change (sickling) of the
RBC in low oxygen environment, resulting
in capillary obstruction and hypoxia
Anaemia of chronic disorders
(ACD)
• This is the rather unsatisfactory phrase used to cover the
most common of the normochromic, normocytic
anaemias, namely, those found in association with
chronic infection, all forms of inflammatory diseases, and
in malignant disease. It is very important for clinicians to
be able to identify the main features of this type of
anaemia.
• Although it may be extremely mild and asymptomatic,
the presence of this blood picture should always alert the
clinician to the possibility of there being a serious
underlying disease.
General Considerations
• Many chronic systemic diseases are associated
with mild or moderate anemia.
• Common causes include chronic infection or
inflammation, cancer and liver disease.
• The anemia of chronic renal failure is somewhat
different in pathophysiology, involving reduced
production of erythropoietin and is usually more
severe.
Pathogenesis
• The precise mechanism of the anaemia of chronic disorders is still
not understood. Several different pathological processes that occur
in response to inflammation conspire to cause a defective
proliferation of red cell progenitors. In addition, at least in some
cases, there may be a mild haemolytic component.
• The most constant feature of ACD is a low serum iron level despite
adequate iron stores in the reticuloendothelial elements of the bone
marrow. This abnormal accumulation of iron in the storage cells,
together with a low serum iron level in the blood, suggests that there
is a block in the release of iron to the developing red cell precursors.
This phenomenon may be observed within 24 h after major surgery,
for example. There is also a reduced concentration of transferrin,
and turnover studies suggest that this reflects a decreased rate of
production.
Clinical and laboratory
findings
• The anaemia of chronic disorders is usually mild. In
patients with severe inflammation the haematocrit may
fall to levels at which symptoms are experienced.
• Although the anaemia is usually normocytic and
normochromic there may be mild hypochromia with a
slight reduction in the MCH and MCV, particularly in
children.
• Occasionally there may be marked microcytosis.
Microcytosis should prompt consideration of concomitant
iron deficiency, especially in patients who might have
gastrointestinal bleeding, for example individuals with
inflammatory bowel disease or rheumatoid arthritis on
aspirin.
• The reticulocyte count is in the normal range.
• The clinical features are those of the causative
condition. The diagnosis should be suspected in
patients with known chronic diseases; it is
confirmed by the findings of low serum iron and
normal or increased serum ferritin.
• In cases of significant anaemia, coexistent iron
deficiency or folic acid deficiency should be
suspected.
• Decreased dietary intake of folate or iron is
common in these ill patients, and many will also
have ongoing gastrointestinal blood losses.
• Patients undergoing hemodialysis regularly lose
both iron and folate during dialysis.
Anemia of Chronic Disease
Essentials of Diagnosis
Occurs in:
–Vitamin B12 deficiency
–Folic acid deficiency
–Myxoedema
–Alcoholism
–Liver disease
Haematological values:
–anaemia
–MCV > 96 fL
–blood film (peripheral): macrocytes and hypersegmented
polymorphs
Pathology
• There is a gastritis in which all layers of the body and
fundus of the stomach are atrophied with loss of normal
gastric glands, mucosal architecture and absence of
parietal and chief cells, but mucous cells lining the
gastric pits are well preserved.
• An infiltrate of plasma cells and lymphocytes with an
excess of CD8 cells occurs and intestinal metaplasia
may be present.
• The antral mucosa is remarkably well preserved except
in hypogammaglobulinaemia and, like the fundus, shows
an increased number of gastrin-secreting cells.
Clinical features
• The general features of megaloblastic anaemia are
similar, whatever the underlying cause. Particular clinical
features may point to the underlying disease, whethe
pernicious anaemia or some other cause.
• In pernicious anaemia, the anaemia usually develops
gradually, perhaps over several years, and symptoms
may not occur until it is severe.
• The most common complaints are due to the anaemia,
while loss of mental and physical drive, numbness, or
difficulty in walking suggest neuropathy.
Clinical features
• Psychiatric disturbances are common and range from
mild neurosis to severe organic dementia. They may
occur in the absence of anaemia or macrocytosis.
• Mild jaundice is frequent. Loss of appetite and weight,
indigestion, and episodic diarrhoea are frequent.
• An intercurrent infection may precipitate severe anaemia
and thus symptoms.
• Older patients may present with congestive heart failure.
• In a few patients, bruising due to thrombocytopenia is
marked.
• On the other hand, many patients are diagnosed
because a routine blood test is made.
Clinical features
• The typical patient with pernicious anaemia has fair hair
(prematurely grey), with blue eyes, and wide
cheekbones.
• Physical signs, if present, are those of anaemia, perhaps
with mild jaundice, giving the patient a so-called lemon-
yellow tint.
• A few patients with either B 12 or folate deficiency
develop a widespread brown pigmentation, affecting nail
beds and skin creases particularly, but not mucous
membranes, which is reversible with the appropriate
therapy.
• The biochemical basis for this is not clear, nor for the
depigmentation that also occurs rarely.
Clinical features
• The tongue may be red, smooth, and shiny, occasionally
with ulcers.
• A mild pyrexia up to 38°C is common in patients with
moderate to severe anaemia.
• The liver may be enlarged while the cardiovascular
system shows changes due to anaemia.
• Patients with pernicious anaemia may also have features
of an associated disorder on presentation, most
commonly myxoedema. Other thyroid disorders, vitiligo,
carcinoma of the stomach, Addison's disease and
hypoparathyroidism, may precede, occur simultaneously
with or follow the onset of the anaemia.
vitamin b12 (Addison–Biermer) anaemia
– average daily diet 5 – 30 μg B12
• Macrocytic anemia.
• Macro-ovalocytes and hypersegmented
neutrophils on peripheral blood smear.
• Serum vitamin B12 level less than 100
pg/mL.
Folic acid
Daily requirement 100 μg
Causes of folate deficiency:
– poor intake:
– old age
– poor social conditions
– starvation
– alcohol excess
– poor intake due to anorexia:
– G.I. disease (partial gastrectomy, coeliac disease, Crohn’s
disease, cancer)
– excess utilization
causes
A. Physiological:
pregnancy
lactation
prematurity
B. Pathological:
haemolysis
malignant disease
inflammatory disease
metabolic disease
haemolysis
– malabsorption
– antifolate drugs
• By far the most common cause of folate deficiency is
inadequate dietary intake.
• Alcoholic or anorectic patients, persons who do not eat
fresh fruits and vegetables, and those who overcook
their food are candidates for folate deficiency.
• Reduced folate absorption is rarely seen, since
absorption occurs from the entire gastrointestinal tract.
However, drugs such as phenytoin, trimethoprim-
sulfamethoxazole, or sulfasalazine may interfere with
folate absorption.
• Folic acid requirements are increased in pregnancy,
hemolytic anemia and exfoliative skin disease, and in
these cases the increased requirements (five to ten
times normal) may not be met by a normal diet.
• Patients with increased folate requirements should
receive supplementation with 1 mg/d of folic acid.
Symptoms and Signs
• Macrocytic anemia.
• Macro-ovalocytes and hypersegmented
neutrophils on peripheral blood smear.
• Normal serum vitamin B12 levels.
• Reduced folate levels in red blood cells or
serum.
Normocytic anaemia
Stage II (2 – 4 days):
– Hb, Hct, ↓
– reticulocytosis
– ↓ white cells
Stage III (2 – 3 weeks):
– ↓ platelets
–Hb, Ht, Rc
–Wc
–Platelets
}
Normal
2. Aplastic anaemia
Aplasia of the bone marrow with peripheral blood pancytopenia.
Causes:
– congenital: Fanconi’s anaemia
– acquired:
– chemicals, drugs, insecticides
– ionizing radiation
– infections: viral hepatitis measles
– miscellaneous infection: tuberculosis
– thymoma
– pregnancy
– unknown
General Considerations
• Aplastic anemia is a condition of bone marrow
failure that arises from injury to or abnormal
expression of the stem cell.
• The bone marrow becomes hypoplastic, and
pancytopenia develops.
• The most common pathogenesis of aplastic
anemia appears to be autoimmune suppression
of hematopoiesis by a T cell-mediated cellular
mechanism.
clinical features:
– anaemia
– bleeding (ecchymoses, bleeding gums and epistaxis)
– infection (notably fungal infections, atypical)
• Pancytopenia.
• No abnormal cells seen.
• Hypocellular bone marrow.
3. Haemolytic anaemia
The red cells normally survive about 120 days, but in
haemolysis the cell survival times are considerably shortened.
Causes of haemolytic anaemia:
A. Inherited:
1. red cell membrane defect (Membranopathies):
– hereditary spherocytosis
– hereditary eliptocytosis
2. haemoglobin abnormalities (haemoglobnopathies):
– thalassaemia
– sickle cell disease
3. metabolic defects (Enzymopathies):
– glucose 6 phosphate dehydrogenize deficiency
– pyruvate kinase deficiency
(Causes of haemolytic anaemia)
B. Acquired:
1. immune:
– autoimmune
– isoimmune (Rh or ABO incompatibility)
2. non-immune:
– membrane defects: paroxysmal nocturnal
haemoglobinuria, liver disease, renal disease
– mechanical: damaged vessels, valve prosthesis, march
haemoglobinuria
3. miscellaneous:
– infections
– drugs and chemicals
– hypersplenism
site of haemolysis:
Causes of polycythaemia
Primary:
– Polycythaemia vera
Secondary:
A. due to an appropriate (Physiological) increase in
erythropoetin:
– high altitude
– lung disease
– cardiovascular disease (right left shunt)
– heavy smoking
B. due to an inappropriate increase in erithropoetin:
– renal disease, carcinoma, Wilm’s tumor
– hepatocellular carcinoma
– adrenal tumors
– cerebellar haemangioblastoma
– massive uterine fibroma
Relative:
– stress or spurious polycythaemia
– dehydration
–
PolYcYtHaemia vera
Caused by chronic sustained proliferation of the erythroid
population of the bone marrow.
↑↑red
redcell
cellvolume
volume
↑↑blood
bloodviscosity
viscosity
Hct↑↑↑↑↑↑
Hct
compensatedby
compensated byanan
increaseplasma
increase plasma
volumeand
volume and myocardial
myocardialinfarction
infarction
cardiacoutput
cardiac output stroke
stroke
Symptoms
• Most patients present with symptoms related to expanded blood
volume and increased blood viscosity.
• Common complaints include headache, dizziness, tinnitus, blurred
vision, and fatigue.
• Generalized pruritus, especially following a warm shower or bath,
may be a striking symptom and is related to histamine release from
the increased number of basophils present.
• Patients may also initially complain of epistaxis. This is probably
related to engorgement of mucosal blood vessels in combination
with abnormal hemostasis due to qualitative abnormalities in platelet
function.
• 60% of patients are men and the median age at presentation is 60
years. Polycythemia rarely occurs in persons under age 40 years.
Signs
• Physical examination reveals plethora and engorged retinal
veins. The spleen is palpable in 75% of cases but is nearly
always enlarged when imaged.
• Thrombosis is the most common complication of polycythemia
vera and the major cause of morbidity and death in this
disorder. Thrombosis appears to be related both to increased
blood viscosity and abnormal platelet function.
• Uncontrolled polycythemia leads to a very high incidence of
thrombotic complications of surgery and elective surgery
should be deferred until the condition has been treated.
• Paradoxically, in addition to thrombosis, increased bleeding
also occurs. There is a high incidence of peptic ulcer disease.
MAJOR clinical findings:
depression
vertigo
tinnitus and visual disturbance
hypertension
angina
intermitent claudication
tendency to bleed
peptic ulcerations
investigations: