Haematology: The Hereditary Anaemias

OVERVIEW

• Sickle cell anaemia occurs commonly in individuals from African,
Middle Eastern and Indian populations
• Neonatal screening of appropriate populations can result in a
signifi cant decrease in mortality from sickle cell disease in early
life. The beta thalassaemias also occur at a very high frequency
in many tropical populations but are now encountered in every
country
• Carrier detection, counselling and prenatal diagnosis has reduced
the number of births of children with beta thalassaemia in many
countries
• Carefully monitored treatment of serious forms of beta thalassaemia
with transfusion and adequate chelation have greatly
improved the prognosis
• The severe forms of alpha thalassaemia are restricted to the Far
East and certain Mediterranean populations
• The homozygous state for the severe forms of alpha thalassaemia
results in stillbirth and a high frequency of obstetric complications

Hereditary anaemias include disorders of the structure or synthesis
of haemoglobin (Hb), deficiencies of enzymes that provide the red
cell with energy or protect it from chemical damage and abnormalities
of the proteins of the red cell’s membrane. Inherited diseases of
haemoglobin (haemoglobinopathies) are by far the most important.
The structure of human Hb changes during development . By the 12th week of gestation, embryonic haemoglobin is replaced by fetal haemoglobin (Hb F), which is slowly replaced after
birth by the adult haemoglobins, Hb A and Hb A2. Each type of haemoglobin
consists of two different pairs of peptide chains; Hb A has
the structure α2β2 (namely, two α chains plus two β chains), Hb A2
has the structure α 2δ 2 and Hb F, α 2γ2.
The haemoglobinopathies consist of structural haemoglobin variants
(the most important of which are the sickling disorders) and
thalassaemias (hereditary defects of the synthesis of either the α or
β globin chains).

The sickling disorders
Classifi cation and inheritance
The common sickling disorders consist of the homozygous state for
the sickle cell gene, that is, sickle cell anaemia (Hb SS), and the compound heterozygous state for the sickle cell gene and for either
Hb C (another β chain variant) or β thalassaemia (termed Hb SC
disease or sickle cell β thalassaemia). The sickle cell mutation
results in a single amino acid substitution in the β globin chain;
heterozygotes have one normal (βA) and one affected (βS) β chain
gene and produce about 60% Hb A and 40% Hb S; homozygotes
produce mainly Hb S with small amounts of Hb F. Compound heterozygotes
for Hb S and Hb C produce almost equal amounts of
each variant, whereas those who inherit the sickle cell gene from
one parent and β thalassaemia from the other make predominantly
sickle haemoglobin.

Pathophysiology
The amino acid substitution in the β globin chain causes red cell
sickling during deoxygenation, leading to increased rigidity and aggregation
in the microcirculation. These changes are reflected by a
haemolytic anaemia and episodes of tissue infarction.

Sickle cell trait (Hb A and Hb S)
• Less than half the Hb in each red cell is Hb S
• Occasional renal papillary necrosis
• Inability to concentrate the urine (older individuals)
• Red cells do not sickle unless oxygen saturation is < 40% (rarely
reached in venous blood)
• Painful crises and splenic infarction have been reported in severe
hypoxia, such as in unpressurized aircraft, or under anaesthesia
• Sickling is more severe where Hb S is present with another β
globin chain abnormality, such as Hb S and Hb C (Hb SC) or Hb S
and Hb D (Hb SD).

Clinical features

Sickle cell carriers are not anaemic and have no clinical abnormalities.
Patients with sickle cell anaemia have a haemolytic
anaemia, with a low haemoglobin concentration and a high reticulocyte
count; the blood film shows polychromasia and sickled erythrocytes.
Patients adapt well to their anaemia and it is the vascular occlusive
or sequestration episodes (‘crises’) that pose the main threat.
Crises take several forms. The commonest, called the painful crisis,
is associated with widespread bone pain and is usually self-limiting.
More serious and life-threatening crises include the sequestration of
red cells into the lung or spleen, strokes, or red cell aplasia associated
with parvovirus infections.

Diagnosis
Sickle cell anaemia should be suspected in any patient of an appro-priate racial group with a haemolytic anaemia. It can be confirmed
by a sickle cell test, although this does not distinguish between heterozygotes
and homozygotes. A definitive diagnosis requires haemoglobin
electrophoresis and the demonstration of the sickle cell
trait in both parents.

Sickle cell anaemia (homozygous Hb S)
• Anaemia (Hb 6.0–10.0 g/dL): symptoms milder than expected
as Hb S has reduced oxygen affinity (that is, gives up oxygen to
tissues more easily)
• Sickled cells may be present in blood fi lm: sickling occurs at
oxygen tensions found in venous blood; cyclical sickling episodes
• Reticulocytes: raised to 10–20%
• Red cells contain ≥ 80% Hb S (rest is fetal Hb)
• Variable haemolysis
• Hand and foot syndrome (dactylitis)
• Intermittent episodes, or crises, characterized by bone pain,
worsening anaemia, or pulmonary or neurological disease
• Chronic leg ulcers
• Gallstones

Complications of sickle cell disease
• Hand and foot syndrome: seen in infancy; painful swelling of digits
• Painful crises: later in life; generalized bone pain; precipitated by
cold, dehydration but often no cause found; self-limiting over a
few days
• Aplastic crisis: marrow temporarily hypoplastic; may follow parvovirus
infection; profound anaemia; reduced reticulocyte count
• Splenic sequestration crisis: common in infancy; progressive
anaemia; enlargement of spleen
• Hepatic sequestration crisis: similar to splenic crisis but with
sequestration of red cells in liver
• Lung or brain syndromes: sickling of red cells in pulmonary or
cerebral circulation and endothelial damage to cerebral vessels in
cerebral circulation
• Infections: particularly Streptococcus pneumoniae and Haemophilus
influenzae
• Gallstones
• Progressive renal failure
• Chronic leg ulcers
• Recurrent priapism
• Aseptic necrosis of humoral/femoral head
• Chronic osteomyelitis: sometimes due to Salmonella typhi.

Prevention and treatment
Pregnant women in at-risk racial groups should be screened in early
pregnancy and, if the woman and her partner are carriers, should be
offered either prenatal or neonatal diagnosis. As soon as the diagnosis
is established, babies should receive penicillin daily and be immunized
against Streptococcus pneumoniae, Haemophilus influenzae
type b and Neisseria meningitidis. Parents should be warned to seek
medical advice on any suspicion of infection. Painful crises should
be managed with adequate analgesics, hydration and oxygen. The
patient should be observed carefully for a source of infection and a
drop in haemoglobin concentration. Pulmonary sequestration crises
require urgent exchange transfusion together with oxygen therapy.
Strokes should be treated with an exchange transfusion; there is now
good evidence that they can be prevented by regular surveillance
of cerebral blood fl ow by Doppler examination and prophylactic
transfusion. There is also good evidence that the frequency of painful
crises can be reduced by maintaining patients on hydroxyurea,
although, because of the uncertainty about the long-term effects of
this form of therapy, it should be restricted to adults or, if it is used
in children, should be used only for a short period. Aplastic crises require
urgent blood transfusion. Splenic sequestration crises require
transfusion and, because they may recur, splenectomy is advised.

Treatment of major complications of sickle cell
disease
• Hand and foot syndrome: hydration; paracetamol
• Painful crises: hydration; analgesia (including graded intravenous
analgesics); oxygen (check arterial blood gases); blood cultures;
antibiotics
• Pulmonary infiltrates: especially with deterioration in arterial gases,
falling platelet count and/or haemoglobin concentration suggesting
lung syndrome requires urgent exchange blood transfusion to
reduce Hb S level together with oxygenation
• Splenic sequestration crisis: transfusion; splenectomy to prevent
recurrence
• Neurological symptoms: immediate exchange transfusion followed
by long-term transfusion
• Prevention of crises: ongoing trials of cytotoxic agent hydroxyurea
show that it raises Hb F level and ameliorates frequency and severity
of crises; long-term effects unknown.

Sickling variants
Hb SC disease is characterized by a mild anaemia and fewer crises.
Important microvascular complications, however, include retinal
damage and blindness, aseptic necrosis of the femoral heads and
recurrent haematuria. The disease is occasionally complicated by
pulmonary embolic disease, particularly during and after pregnancy;
these episodes should be treated by immediate exchange transfusion.
Patients with Hb SC should have annual ophthalmological
surveillance; the retinal vessel proliferation can be controlled with laser treatment. The management of the symptomatic forms of sickle
cell β thalassaemia is similar to that of sickle cell anaemia.

The thalassaemias
Classifi cation
The thalassaemias are classifi ed as α or β thalassaemias, depending
on which pair of globin chains is synthesized inefficiently. Rarer forms
affect both β and δ chain production: δβ thalassaemias.

Distribution
The disease is broadly distributed throughout parts of Africa, the
Mediterranean region, the Middle East, the Indian subcontinent and
South East Asia, and it occurs sporadically in all racial groups.
Like sickle cell anaemia, it is thought to be common because the
mutation protects carriers against malaria.

Inheritance.
The β thalassaemias result from over 150 different mutations of the
β globin genes, which reduce the output of β globin chains, either completely (β° thalassaemia) or partially (β+ thalassaemia). They are
inherited in the same way as sickle cell anaemia; carrier parents have
a one in four chance of having a homozygous child. The genetics
of the α thalassaemias is more complicated because normal people
have two α globin genes on each of their chromosomes 16. If both
are lost (αº thalassaemia) no α globin chains are made, whereas if
only one of the pair is lost (α+ thalassaemia) the output of α globin
chains is reduced. Impaired α globin production leads to
excess γ or β chains that form unstable and physiologically useless
tetramers: γ4 (Hb Bart’s) and β4 (Hb H). The homozygous
state for α° thalassaemia results in the Hb Bart’s hydrops syndrome,
whereas the inheritance of α° and α+ thalassaemia produces Hb H
disease.

The β thalassaemias
Heterozygotes for β thalassaemia are asymptomatic, have hypochromic
microcytic red cells with a low mean cell haemoglobin and mean
cell volume, and have a mean Hb A2 level of about twice
that of normal. Homozygotes, or those who have inherited
a different β thalassaemia gene from both parents, usually develop
severe anaemia in the fi rst year of life. This results from a
deficiency of β globin chains; excess α chains precipitate in the red
cell precursors leading to their damage, either in the bone marrow or
the peripheral blood. Hypertrophy of the ineffective bone marrow
leads to skeletal changes, and there is variable hepatosplenomegaly.
The Hb F level is always raised. If these children are transfused, the
marrow is ‘switched off ’, and growth and development may be normal.
However, they accumulate iron and may die later from damage
to the myocardium, pancreas, or liver. They are also prone
to infection and folic acid deficiency.
Milder forms of β thalassaemia (thalassaemia intermedia), al though
not transfusion dependent, are often associated with similar bone
changes, anaemia, leg ulcers and delayed development. The most
important form of β thalassaemia intermedia is Hb E β thalassaemia,
which results from the inheritance of Hb E and a β thalassaemia gene. This condition is the commonest form of severe thalassaemia
in many parts of Asia and is associated with a remarkably diverse
clinical course; some patients are transfusion dependent while others
may remain asymptomatic.

β Thalassaemia trait (heterozygous carrier)
• Mild hypochromic microcytic anaemia
• Haemoglobin 9.0–11.0 g/dL
• Mean cell volume 5.0–7.0 g/dL
• Mean corpuscular haemoglobin 20–22 pg
• No clinical features, patients asymptomatic
• Occasional symptomatic anaemia in pregnancy
• Often diagnosed on routine blood count
• Raised Hb A2 level

β Thalassaemia major (homozygous β thalassaemia)
• Severe anaemia
• Blood film
• Pronounced variation in red cell size and shape
• Pale (hypochromic) red cells
• Target cells
• Basophilic stippling
• Nucleated red cells
• Moderately raised reticulocyte count
• Infants are well at birth but develop anaemia in fi rst few months
of life when switch occurs from γ to β globin chains
• Progressive splenomegaly; iron loading; susceptibility to infection

The α thalassaemias
The Hb Bart’s hydropsfetalis syndrome is characterized by the stillbirth
of a severely oedematous (hydropic) fetus in the second half
of pregnancy. Hb H disease is associated with a moderately severe
haemolytic anaemia. The carrier states for αº thalassaemia and the
homozygous state for α+ thalassaemia result in a mild hypochromic
anaemia with normal Hb A2 levels. They can only
be distinguished with certainty by DNA analysis in a specialized
laboratory. In addition to the distribution mentioned above, α thalassaemia
is also seen in European populations in association with
mental retardation; the molecular pathology is quite different to
the common inherited forms of the condition. There are two major
forms of α thalassaemia associated with mental retardation (ATR);
one is encoded on chromosome 16 (ATR-16) and the other on the
X chromosome (ATR-X). ATR-16 is usually associated with mild
mental retardation and is due to loss of the β globin genes together
with other genetic material from the end of the short arm of chromosome

1. ATR-X is associated with more severe mental retardation
   and a variety of skeletal deformities, and is encoded by a gene
   on the X chromosome, which is expressed widely in different tissues
   during different stages of development. These conditions should be
   suspected in any infant or child with retarded development who has
   the haematological picture of a mild α thalassaemia trait.

Prevention and treatment
As β thalassaemia is easily identified in heterozygotes, pregnant women
of appropriate racial groups should be screened; if a woman is found
to be a carrier, her partner should be tested and the couple counselled.
Prenatal diagnosis by chorionic villus sampling can be carried out between
the ninth and 13th weeks of pregnancy.
Babies with β thalassaemia major should be observed very carefully
regarding growth, activity and steady-state haemoglobin level.
When it is certain that they require regular transfusion, they should
be given washed red cell transfusions at monthly intervals; it is vital
that the blood is screened for human immunodeficiency virus/acquired
immunodeficiency syndrome, hepatitis B and C viruses and,
in some countries, malaria.
To prevent iron overload, overnight infusions of desferrioxamine
together with vitamin C should be started, and the patient’s serum
ferritin, or better, hepatic iron concentrations, should be monitored;
complications of desferrioxamine include infections with Yersinia
spp., retinal and acoustic nerve damage and reduction in growth
associated with calcification of the vertebral discs.
The place of the oral chelating agent deferiprone is still under
evaluation. Although it appears not to maintain iron balance in up
to 50% of patients, and it causes neutropenia and variably severe
arthritis, recent work suggests that it may be more effective in removing iron from the heart than desferrioxamine; this observation
requires confirmation in prospective studies. Another recently developed
oral chelating agent, Exjade ® (ICL670), is still under investigation;
preliminary studies suggest that it may have comparable
activity to desferrioxamine in maintaining iron balance and that it
is relatively non-toxic, although further studies are required to confirm
that it does not have a deleterious effect on renal function. Bone
marrow transplantation, if appropriate HLA-DR-matched siblings
are available, may carry a good prognosis if carried out early in life.
Treatment with agents designed to raise the production of Hb F is
still at the experimental stage.
In β thalassaemia and Hb H disease, progressive splenomegaly or
increasing blood requirements, or both, indicate that splenectomy
may be beneficial. Patients who undergo splenectomy should be vaccinated
against S. pneumoniae, H. infl uenzae and N. meningitidis preoperatively,
and should receive a maintenance dose of oral penicillin
indefinitely.

Red cell enzyme defects
Red cells have two main metabolic pathways, one burning glucose
anaerobically to produce energy, the other generating reduced glutathione
to protect against injurious oxidants. Many inherited enzyme
defects have been described. Some of those of the energy pathway,
for example, pyruvate kinase deficiency, cause haemolytic anaemia;
any child with this type of anaemia from birth should be referred to
a centre capable of analysing the major red cell enzymes.
Glucose-6-phosphate dehydrogenase deficiency (G6PD) involves
the protective pathway. It affects millions of people worldwide, mainly
the same racial groups as are affected by the thalassaemias. G6PD
deficiency is sex linked and affects predominantly males.
It causes neonatal jaundice, sensitivity to broad (fava) beans and
haemolytic responses to oxidant drugs.

Red cell membrane defects
The red cell membrane is a complex sandwich of proteins that are required
to maintain the integrity of the cell. There are many inherited
defects of the membrane proteins, some of which cause haemolytic
anaemia. Hereditary spherocytosis is due to a structural change that
makes the cells more leaky. It is particularly important to identify
this disease because it can be ‘cured’ by splenectomy. There are many
rare inherited varieties of elliptical or oval red cells, some associated
with chronic haemolysis and response to splenectomy. A child with
chronic haemolytic anaemia with abnormally shaped red cells should
always be referred for expert advice.

Other hereditary anaemias
Other anaemias with an important inherited component include
Fanconi’s anaemia (hypoplastic anaemia with skeletal deformities),
Blackfan–Diamond anaemia (red cell aplasia) and several forms of
congenital dyserythropoietic anaemia.

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