Transcript THALASSAEMIA  A group of chronic, inherited anemias characterised by defective Hemoglobin (Hb) synthesis and ineffective erythropoiesis, particularly common in persons of Mediterranean, African and.

THALASSAEMIA
 A group of chronic, inherited anemias
characterised by defective Hemoglobin (Hb)
synthesis and ineffective erythropoiesis,
particularly common in persons of Mediterranean,
African and Southeast Asian ancestry.
 Thalassaemia results from unbalanced Hb
synthesis caused by production of at least one
globin polypeptide chain (α, β, γ, δ).
There are 2 forms of thalassaemia
 Thalassaemia major
 Thalassaemia minor (trait)
THALASSAEMIA MAJOR
Thalassaemia major is sometimes known
as Cooleys Anaemia, Homozygous, Bete
Thalassaemia or Mediterranean Anaemia. Is
a serious inherited childhood anaemia.
Children with Thalassaemia major cannot
make enough haemoglobin. Because of this,
their bone marrow cannot produce enough
red blood cells. The red blood cells that are
produced are nearly empty.
THALASSAEMIA MINOR
 People with Thalassaemia Minor, sometimes
known as Trait, carry Thalassaemia but they are
not ill. They are completely healthy and normal but
some of them have slight anaemia. Most people
with Thalassaemia Minor do not even know that
they have it. It is only discovered if the person has
a special blood test or if they have a child with
Thalassaemia Major. It is important to know if you
have Thalassaemia Minor later in life. The reason
for this is that it may cause some problems if the
person and their partner wants to start a family.
Thalassaemia minors red blood cell are also
different from normal blood cells.
CLINICAL FEATURES
MINOR - clinically asymptomatic
MAJOR
 Severe anemia
 Expanded marrow space
 Jaundice
 Leg ulcers
 Cholelithiasis
 Splenomegaly
 Bone changes and fractures
 Growth failure
HAEMOGLOBIN
Hb is most commonly measured to detect
anaemia. Low Hb indicates anaemia
(various types) and blood loss.
In some relatively rare genetic diseases, the
alterations in the structure of the Hb
molecule can be detected by
electrophoresis.
HAEMOGLOBIN cont..
Hb
120g/L
130-180 LOW
Hb
Normal
electrophoresis
Hb A2
4.8%
1.8-3.5 HIGH
Hb F
1.5%
0.5-0.8 HIGH
Hb inclusions not seen in red cells
HAEMOGLOBIN cont…
 HbA2 - The haemoglobin is composed of two alpha chains
and two delta chains. HbA2 is usually raised in the β
thalassaemias, and in unstable haemoglobinopathies
where the amino acid substitution is on the β chain.
 HbF - is the primary hemoglobin produced by the fetus
during gestation. The determination of fetal hemoglobin is
an aid in evaluating low concentrations of hemoglobin in
the blood (anemia). HbF may be raised in various
haematological conditions among which are the
thalassemias.
 HbH inclusions - Performed as part of a
haemoglobinopathy/thalassaemia screen. For diagnosis of
alpha thalassaemia.
Mean cell volume (MCV) - the average
volume of a single red cell.
Terms such as `microcytic' and `macrocytic'
are descriptive of low and high MCV,
respectively.
MCV
65 f/L
80-100 LOW
LOW MCV- Microcytic/hypochromic anaemia
Iron deficiency
Thalassaemia
Anaemia of chronic disease (uncommonly microcytic)
Sideroblastic anaemia (uncommon: acquired forms more
often macrocytic)
Lead Poisoning (uncommon)
Hb E trait or disease
Could The Near Normal Hb and Low
MCV be Due to Other Conditions?
- Hb 120g/L (130-180)
- MCV 65fL (80-100)
- Blood film shows mild hypochromic,
microcytic cells with occasional target cells
and basophilic stippling
Potential Causes of Anaemia
1) Blood loss
2) Reduced red cell life span (haemolytic
anaemia)
- consequent on an intrinsic abnormality of red cells either inherited or
acquired
- consequent on extrinsic factors
3) Inadequate production of red cells
- deficiency in iron, vitamin B12 or folic acid; aplastic or hypoplastic
anaemias; ineffective red cell production; bone marrow infiltration by
malignant cells; bone marrow fibrosis
4) Low-affinity haemoglobin
5) Abnormal distribution of red cells within the
vasculature
- hypersplenism
Causes of Microcytic Anaemia
-
-
-
Microcytosis is a highly prevalent finding during
blood examination and is detected in ~3% of
patients admitted to hospital
Microcytosis occurs when the number of
abnormally small RBCs in the blood is such that
the mean corpuscular volume (MCV) drops to
below the normal range
The investigation of microcytosis/microcytic
anaemia is often a challenge for the clinician and
in most cases is related to impaired hemoglobin
synthesis
Causes of Microcytic Anaemia cont…
- Non-thalassemic causes of microcytic
anaemia include
1) Iron deficiency anaemia
2) Anaemia of chronic disease /
inflammation
3) Congenital sideroblastic anaemia
Iron Deficiency Anaemia
- Iron deficiency is the primary cause of microcytosis
and therefore a complete iron-status analysis should
always be undertaken.
- In severe cases the MCV can be in the range of 5060fL
- A blood smear will typically show erythrocytes that are
microcytic and hypochromic as well as poikilocytes
and occasional target cells
Iron Deficiency Anaemia cont.
- Low serum ferritin (indication of iron stores) and
serum iron (indication of iron available for Hb
synthesis) as well as an increased TIBC are
consistent with this diagnosis
- Potential sources of blood loss should be
investigated including occult bleeding, worm
infestation and gum disease
- Once the primary cause of the deficiency has
been corrected, treatment may involve 6-12
months of oral iron supplementation to
replenish iron stores and should involve regular
Hb monitoring
Anaemia of Chronic Inflammation
- Associated with conditions such as rheumatoid arthritis
and malignancy
- is most often normochromic-normocytic with low serum
iron and adequate reticulo-endothelial stores
- May progress to become hypochromic-microcytic in
nature with MCV frequently in the range of 70-80fL
- A decrease in serum iron and TIBC is typical although
serum ferritin remains normal
- An inflammatory state should be looked for in those
patients with microcytosis and normal iron status whom
belong to ethnic groups with a low incidence of inherited
hemoglobinopathies.
- If an inflammatory state is present it should be treated
and MCV monitored.
Sideroblastic Anaemias
- Hereditary forms show a hypochromic-microcytic
picture but serum iron is raised and TIBC saturated
- In primary acquired forms the peripheral blood film is
characteristically dimorphic with some hypochromic
cells and a raised MCV
- Bone marrow examination is essential and may show
erythroid hyperplasia, excess iron and a large number
of sideroblasts
- Treatment may involve the exclusion of precipitating
drugs and toxins, pyridoxine and/or folic acid
supplementation as well as blood transfusions in
refractory cases.
- Tranfusions have the potential to increase the already
significant serum iron burden
What is basophilic stippling?
HOW DOES IT OCCUR?
 Beta thalassemia is caused by mutations in the
in haemoglobin beta gene which prevents the
production of the beta chains in haemoglobin.
 This causes an increased alpha to beta chain
ratio and precipitation of alpha ribosomal DNA
resulting coarse basophilic stippling.
 The stippling effect is aggregations of the
ribosomal DNA or protein granulations in the
cytoplasm of erythrocytes
IDENTIFICATION
The granulations are usually variable in
size and number. An identification
technique named the Ramanowsky stain
is used to confirm basophilic stippling as it
stains the particles a violet blue colour.
The RNA is not blue, it is only the stain
required for identification that causes it to
appear this way
CONDITIONS CAUSING STIPPLING
Coarse stippling is characteristic of lead
poisoning and thalassemia.
In thalassemia it is most commonly
stippling in the cytoplasm of younger cells.
 Lead poisoning often presents as stippling
in the cytoplasm of nucleated red blood
cells
LEAD POISONING
Beta Thalassemia minor
Haematological Profile
Hypochromasia
+
Anisocytosis
++(microcytes)
Polikilocytosis
Target cells +
Immature Forms
Coarse basophilic
stippling
Beta Thalassemia major
Haematological Profile:
Hypochromasia)
+++
Anisocytosis
+++ (Macrocytes, Microcytes
Poikilocytosis
Target Cells +++
Tear Drops
Schistocytes
Acanthocytes, Howell Jolly Bodies,
Target Cells (post splenectomy
Immature Forms
Polychromasia ++
Nucleated RBC +++ (bone marrow
response)
BETA THALASSEMIA MINOR
The usual haematological characteristics
of beta thalassemia minor include
-hypochromia
-microcytosis
-diminished osmotic fragility
-erythrocytes with basophilic stippling
STIPPLING IN THALASSEMIA
Basophilic stippling is not a definitive
technique to distinguish between the
different forms of thalassemia. It has been
found to occur in both beta thalassemia
minor and major, although it may be more
prevalent in minor.
TECHNIQUES
 More reliable identification techniques for the
various thalassemias include:
-Complete blood count (CBC) - a measurement
of the size, number and maturity of different
blood cells in a specific volume of blood.
-Haemoglobin electrophoresis with A2
quantitation - a lab procedure that differentiates
the types of haemoglobin present.
BLOOD SMEAR DIAGNOSIS
 Previous profiles show basophilic stippling is not
the only abnormality present on a blood smear
 Merck manual states that a blood smear is
almost diagnostic for beta thalassemia major
due to many nucleated erythroblasts, target
cells, small pale RBC and punctuate and diffuse
basophilia.
 Basophilic stippling alone is not enough to
diagnose and differentiate between the types of
thalassemias.
β-Thalassaemia
The globin part of haemoglobin A1 has 4
protein sections, two of these are alpha
and two are beta-chains.
In β-thalassaemia minor you have only
one normal β-chain instead of two.
Β-thalassaemia major occurs when you
have no functional beta chains
α-thalassaemia
The heterozygous form of α-thalassaemia
means there is only one alpha chain
whereas the homozygous form occurs when
there is no functional alpha chain.
Usually the synthesis of alpha and beta
globins is very tightly regulated to produce
equal numbers in both.
Beta Thalassaemia
In the case of beta thalassaemia with the
decrease in β-globin it means that the
haemoglobin molecules contain more
alpha globin than beta globin.
Pathology of β-thalassaemia
Iron levels are normal
The concentration of HbA2 is increased
HbF is increased both are trying to
compensate for the decrease in HbA1
Low MCV, hypochromic, microcytosis and
basophillic stippling
Pathology of α-thalassaemia
 HbA2 and HbF are normal in most cases
 Decreased or absent alpha-chains production
results in excess gamma chains during foetal life
and excess beta chains later. This causes the
tetramers, Hb Barts and Hb H which precipitate in
red cells and decrease red cell survival.
 Tests for Hb H inclusions are used to detect it
 DNA analysis may be required for definitive
diagnosis of alpha thalassaemia
Case E FBC Results
Ferritin
55µg/L
30-330
Hb electrophoresis Normal
Hb A2
4.8%
1.8-3.5
Hb F
1.5%
0.5-0.8
Hb H inclusions not seen in red cells