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Thalassaemia
- Together with haemoglobinopathies, these are hypochromic,
microcytic anaemias
- Thalassaemia is a genetic disorder which causes a decreased
rate of synthesis of either 1 or 2 globin chains (esp a
and ß)
- Caused by mutations in intergene controlling sites that
impairs or prevents gene expression, or by structural gene
deletions
- No structurally abnormal haemoglobin (Hb) is found
- Normally synthesized in the same ratios. Changes in the
ratio produces an excess of a or
ß chains
- a-thal distribution is worldwide,
however especially found around the Mediterranean
- ß-thal is especially distributed around South East
Asia and New Guinea
- Also find a, a:ß
forms
(1) a-Thalassaemia
a-chains affected
Four genes involved (2 a from
each parent)
Abnormality associated with a
genes because of deletions
(2) ß-thalassaemia
ß-chains
Two genes involved
Abnormality associated with ß genes because of mutations
affecting and decreasing the production of mRNA
ß-THALASSAEMIA
- An abnormality associated with one ß gene is called
ß-thal minor (ßTm)
- An abnormality associated with two ß genes is called
ß-thal major (ßTM)
- ß chain production may be decreased or absent resulting
in excess free a chains. If production
is decreased we refer to the phenotype as ß+,
if absent ßo
ßTM
- ßoßo - Most severe - no
ß chain production
- ßoß+ - Moderately severe
- some ß chain production
- ß+ß+ - Increased HbF with
normal or elevated HbA2 - the remainder HbA1
- Clinical severity can vary
- Decreased ß chain production causes a decrease in
total RBC Hb
- Patient undergoes chronic haemolysis due to excess a
chains that are precipitated in the cell and usually destroyed
in the spleen (splenomegaly)
- Bone marrow can expand within and deform the bone (extramedullary
haematopoiesis as both the liver and spleen attempt to increase
peripheral cell concentrations)
- Cardiac failure can occur due to the constant high output
of blood required to maintain an adequate perfusion of tissues
- If not treated in childhood, classic thal develops within
years
- Hepatomegaly and splenomegaly
- Chronic haemolysis that may be accompanied by gallstones,
gout and icterus (jaundice)
- Not usually detected until 6 months of age
- Excess iron from blood transfusions may lead to cardiac
and hepatic problems
- These sufferers are dependent on transfusions for survival
- As with other haemolytic anaemias, more iron is absorbed
from the gut exacerbating iron overload
- Not all the original iron is removed due to its large
excess
- Largely overcome by the use of desferroxamine
Haematological Profile:
| Hb |
Dec |
| RCC |
N - Inc (Marrow compensating
for ineffective haemopoiesis) |
| MCV |
Dec |
| MCH |
Dec |
| 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) |
Haemoglobin Electrophoresis:
To Differentiate From An Iron Deficiency:
Serum Iron: N - Inc
Serum Ferritin: N - Inc
% Saturation: N
Total Iron Binding Capacity: N
Reticulocyte Count: Inc
Bone Marrow:
- All findings appear the same as an iron deficiency using
Romanowsky stains
- Erythroid hyperplasia
- Micronormoblasts with ragged, small amount of cytoplasm
(not much Hb)
- a-chain precipitation produces
a stippling effect (use methyl violet stain)
- Coarse basophilic staining due to a-chains
seen with lead poisoning, enzyme deficiencies (pyrimidine
5'-nucleotidase) and thalassaemias
Treatment:
- Splenectomy (after 5yrs of age to allow the development
of resistance to infection)
- Continuous desferroxamine infusions to counter transfusions
(that are required to counter hyperstimulation of the bone
marrow) and the effects of haemolytic anaemia
- Bone marrow tranfusion is logistically impractical due
to the large number of patients requiring it
ßTm
- Heterozygous state (ie. one normal gene)
- ßßo, ßß+ - 50%
of normal production - minor disease
- Often confused with iron deficiency anaemia
- Clinically well except when: Stressed, Infected or Pregnant
Haematological Profile:
| Hb |
N - Dec |
| RCC |
Inc (Marrow compensating
for ineffective haemopoiesis) |
| MCV |
Dec |
| MCH |
Dec |
| Hypochromasia |
+ |
| Anisocytosis |
++ (Microcytes) |
| Poikilocytosis |
Target Cells + |
| Immature Forms |
Polychromasia
Coarse basophilic stippling |
Hb Electrophoresis:
HbA1: Present
HbF: N - Slightly Inc (Only compensating for 1 chain)
HbA2: Inc (4-5%, reason unknow but this feature is
used diagnostically differentiating from ßTM or aTm)
Treatment:
- Usually not requiring transfusion
- Counsel about children and hereditary disease
HbS / ßThalassaemia
- Occasionally an individual is heterozygous for a structural
Hb variant and thalassaemia
- Severity depends on ßo (moderately severe)
to ß+ (symptomless)
Haematological Profile:
- Haematological findingsrange fromblood picture similar
to sickle cell anaemia (no normal ß chains - ßoßs)
to one similar to heterozygous thalassaemia (50% N ß,
50% ß6(A3)glu-val)
- Microcytic (++), hypochromic (++) anaemia is typical
- A peripheral blood smear shows anisocytosis, poikilocytosis
and target cells
- Reticulocytosis
Haemoglobin Electrophoresis:
- Allows differentiation of HbS / ß-thal from sickle
cell anaemia or trait
- In HbS / ß-thal, HbS composes 50-95% of Hbtotal
while HbA ranges from 0-50%, HbF from 2-30%. The concentration
of HbS will always be greater than HbA because there
are less normal ß chains
- In AS (sickle cell trait), HbS is less than HbA, in SS
(sickle cell anaemia), there is no HbA. In contrast the HbS
concentration in HbS / ß-thal is equal to or greater
than the concentration of HbA
a-THALASSAEMIA
- Decreased synthesis of a chains
- Usually an a-gene deletion,
sometimes an abnormally functioning a
gene
- excess ß-chains
- Sometimes a functionally abnormal a-gene
- If 1 gene deleted - silent or carrier
type: aa/a-
- If 2 genes deleted - aTm: aa/--
or a-/a-
- If 3 genes deleted - aTM (HbH
disease formed by a tetrad of excess ß-chains): -a/--
- If 4 genes are deleted - hydrops foetalis (death in
utero; Hb Bart disease)
aTm
- relatively minor disorder
Blood Film:
- Slight hypochromia and microcytosis
- Usually with Basophilic Stippling
Iron Studies:
- Normal
Hb Electrophoresis:
-
Most frequent in South-East
Asia
-
Clinical symptoms include:
jaundice, pallor, splenomegaly (not as serious as ß-TM)
Blood Film:
- Occasionally transfusions are required
- If a lot of haemolysis requiring transfusions, splenectomy
may be required
- Ineffective haematopoiesis is not as severe as with the
ß-thalassaemias
- Clinical problems are less severe than with ß-thalassaemia
- RBC's are poorly haemoglobinized due to Dec. a-chain
synthesis and Dec. HbA production
- In addition to high oxygen affinity, HbH is unstable, precipitating
chronic haemolytic anaemia
Hb Lepore
-
Worldwide distribution but
especially found in Middle and Eastern Europe
-
Fusion of db
chains thought to arise during meiosis from erroneous recombination
of misaligned d and b
genes on separate chromosomes
-
Stable with normal functional
properties except for a slightly Inc. oxygen affinity
-
Pathophysiology is similar
to ß-thal with an excess of a-chains
due to abnormal hybrid globin chains
-
Excess a-chains
precipitate membrane damage and inflexibility leading to premature
RBC destruction and Inc. bone marrow production of abnormal
cells (ineffective erythropoiesis that contributes to the
anaemia because the abnormal cells are destroyed in the marrow)
-
Homozygotes and heterozygotes
have clinical similarities to ß-thal.
Blood Film (Homozygous form):
- Microcytic, hypochromic anaemia (similar to ß-thal.
)
- Anisocytosis and poikilocytosis (with target cells)
- Basophilic stippling
- Post-splenectomy: nucleated RBCs and RBCs with a-chain
precipitates
Blood Film (Heterozygous form):
-
HbA1 - Dec.
-
10% Hb Lepore
-
HbA2 - Dec.
-
HbF - Inc.
Hereditary Persistance of Foetal Hb (HPFH)
-
A group of heterozygous
disorders in which the absence (through deletion or inactivity)
of d- and b-chain
synthesis is compensated for by a persistent Inc. g-chain
production into adult life
-
This results in the absence
of HbA1 and HbA2 with only HbF synthesized
-
HbF production continues
at high levels throughout life preventing the symptoms of
thalassaemia as no accumulation or precipitation of excess
a-chains (which mostly combine
with g-chains to form HbF) occurs
-
No significant haematological
abnormalities
-
Because of this high concentration
of HbF, a cell-wide HbF distribution is seen rather than
the occasional occurrence seen with other diseases or in
specific foetal cells
-
Erythrocytosis as a result
of the high oxygen affinity of HbF
-
Microcytic and slightly
hypochromic
-
Mild anisocytosis and poikilocytosis
-
Reticulocytes - Normal
-
HbF - 20-30%
-
HbA2 - Normal
to Dec.
-
HbS
-
a-thalassaemia
only affects the a-chain so could
get homozygous (bs
/ bs) or heterozygous
(bs / b)state,
thus all four a-thalassaemia
gene combinations are possible
-
Clinical state of sickle
cell anaemia with thalassaemia in moderate to asymptomatic
amounts
-
Dec. synthesis of a-chains
means lower levels of HbS are synthesized than in sickle
cell trait or anaemia without a-thalassaemia.
-
This Dec. HbS concentration
Dec. HbS polymerization (and hence haemolysis)
-
Variable HbS depending on
the number of a-genes affected
-
(1 genes) - HbS = 35% of
Hb
-
(2 genes) - HbS = 28% of
Hb
-
(3 genes) - HbS = 20% of
Hb
-
HbA2 is intermediate
between normal and that in a-thal
-
In neonates with HbS/a-thal,
Hb Bart is also detectable
-
Note: a-thal
may also occur with any of the other b-chain
structural mutants and affect the clinical picture of these
haemoglobinopathies
Hb Constant Spring (HbCS)
-
Hb formed from combination
of two structurally abnormal a-chains
(each elongated by 31 amino acids at the carboxy-terminus)
with two normal b-chains
-
Common in Thailand
-
Abnormal a-chains
are ineffectively synthesized because of the reduced stability
of CS globin mRNA
-
Overall deficiency in a-chain
synthesis - a-thal.-like phenotype
-
Heterozygotes show no clinical
abnormalities
-
A mild anaemia with mild
jaundice and splenomegaly is normal
Hb Electrophoresis (Homozygous):
-
Hb Bart, a-thal
and HbCS usually require no treatment due to their mild
symptoms
-
HbH phenotypically resembles
b-thal and long-term transfusion
and splenectomy is most common
-
Haemosiderosis is overcome
by administration of iron chelators
-
Early treatment is required
to prevent clinical manifestations
New
look for June 2003
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