22: Haematological disorders

Haemopoiesis is the process which maintains lifelong production of haemopoietic (blood) cells.
The main site of haemopoiesis in fetal life is the liver, whereas throughout postnatal life, it is the

bone marrow.
All haemopoietic cells are derived from pluripotent haemopoietic stem cells, which are crucial for
normal blood production; deficiency causes bone marrow failure because stem cells are

required for the ongoing replacement of dying cells.

Haemopoietic stem cells can also be used for treatment, e.g. cells from healthy donors can be
transplanted into children with bone marrow failure (stem cell transplantation).

Haemoglobin production in the fetus and newborn

Embryonic haemoglobins (Hb Gower 1, Hb Gower 2 and Hb Portland) are produced between 4
and 8 weeks gestation, after which haemoglobin production switches to fetal haemoglobin

(HbF).
HbF is made up of 2 chains and 2 chains (22) and is the main Hb during fetal life. HbF
has a higher affinity for oxygen than adult Hb (HbA), and is therefore better able to hold on to

oxygen, an advantage in the relatively hypoxic environment of the fetus (Fig. 22.1).
At birth, the types of Hb are: HbF, HbA and HbA2. HbF is gradually replaced by HbA and HbA2

during the first year of life.

By 1 year of age, the percentage of HbF is very low in healthy children and increased
proportions of HbF are a sensitive indicator of some inherited disorders of haemoglobin
production (haemoglobinopathies).

Haematological values at birth and the first few weeks of life

Features are:

At birth, the Hb in term infants is high, 1421.5 g/dl, to compensate for the low oxygen
concentration in the fetus. The Hb falls over the first few weeks, mainly due to reduced red cell

production, reaching a nadir of around 10 g/dl at 2 months of age (Fig. 22.2).

Preterm babies have a steeper fall in Hb to a mean of 6.59 g/dl at 48 weeks chronological

age.
Normal blood volume at birth varies with gestational age. In healthy term infants the average

blood volume is 80 ml/kg; in preterm infants the average blood volume is 100 ml/kg.
Stores of iron, folic acid and vitamin B12 in term and preterm babies are adequate at birth.
However, in preterm infants, stores of iron and folic acid are lower and are depleted more
quickly, leading to deficiency after 24 months if the recommended daily intakes are not

maintained by supplements.
White blood cell counts in neonates are higher than in older children (1025 10 9/L).

Platelet counts at birth are within the normal adult range (150400 109/L).

ANAEMIA
Def:

Anaemia is defined as an Hb level below the normal range.

The normal range varies with age, so anaemia can be defined as:
Neonate: Hb < 14g/dl
112 months: Hb < 10g/dl
112 years: Hb < 11g/dl.

Causes:
Figure 22.3

Reduced red cell productionineffective erythropoiesis or due to red cell aplasia

Increased red cell destruction (haemolysis)
Blood lossrelatively uncommon cause in children.
There may be a combination of these three mechanisms, e.g. anaemia of
prematurity.

Anaemia due

Ineffective erythropoiesis: red cell production occurs at a normal or increased

rate but differentiation or survival of the red cells is defective (e.g. iron deficiency).
Complete absence of red cell production (red cell aplasia)

to reduced red
cell production
1. ineffective
erythropoiesis

Diagnostic clues to ineffective erythropoiesis are:

Normal reticulocyte count

Abnormal mean cell volume (MCV) of the red cells: low in iron deficiency and
raised in folic acid deficiency.

Causes:

A: Iron

Iron deficiency
Folic acid deficiency
Chronic inflammation (JIA)
Chronic renal failure less EPO
Rarities: myelodysplasia, lead poisoning
Inadequate intake

deficiency

-Inadequate intake of iron is common in infants because additional iron is required for

-causes

the increase in blood volume accompanying growth and to build up the childs iron stores

Inadequate

(Fig. 22.5). A 1-year-old infant requires an intake of iron of about 8 mg/day, which is

intake

about the same as his father (9 mg/day) but only half that of his mother (15 mg/day).


Malabsorption
Blood loss

- Iron may come from:

Breast milk (low iron content but 50% of the iron is absorbed)
Infant formula (supplemented with adequate amounts of iron)
Cows milk (higher iron content than breast milk but only 10% is absorbed)

Solids introduced at weaning, e.g.cereals (cereals are supplemented with iron but only
1% is absorbed).
-Iron deficiency may develop because of a delay in the introduction of mixed feeding
beyond 6 months of age or to a diet with insufficient iron-rich foods, especially if it
contains a large amount of cows milk (Box 22.1).
-Iron absorption is markedly increased when eaten with food rich in vitamin C (fresh fruit
History, PE:

Clinical
features
Asymptomatic

and vegetables) and is inhibited by tannin in tea.

The history should include asking about blood loss and symptoms or signs

suggesting malabsorption
Pallor of the conjunctivae, tongue or palmar creases.
Some children have pica, a term which describes the inappropriate eating of non-

food materials such as soil, chalk, gravel or foam rubber (see Case History 22.1).
Get tired easily
young infants feed more slowly than usual.
They may appear pale but pallor is an unreliable sign unless confirmed by pallor
of the conjunctivae, tongue or palmar creases.

until Hb 67
g/dl.
Diagnosis

The diagnostic clues are:

Figure 22.4

Microcytic, hypochromic anaemia (low MCV and MCH)

Low serum ferritin.
Other main causes of microcytic anaemia
-thalassaemia trait (usually children of Asian, Arabic or Mediterranean origin)
Anaemia of chronic disease (e.g.due to renal failure).
Alpha-thalassaemia trait (usually children of African or Far Eastern origin)

Management

Dietary advice and supplementation with oral iron.

Sytron (sodium iron edetate) or Niferex (polysaccharide iron complex) do not

stain the teeth.

continued until the Hb is normal and then for a minimum of a further 3 months to
replenish the iron stores. With good compliance, the Hb will rise by about 1 g/dl
per week.

Failure to respond to oral iron usually means the child is not getting the treatment.
However, investigation for other causes, in particular malabsorption (e.g. due to
coeliac disease) or chronic blood loss (e.g. due to Meckel diverticulum) is
advisable if the history or examination suggests a non- dietary cause or if there is

failure to respond to therapy in compliant patients.

XX Blood transfusion should never be necessary for dietary iron deficiency. Even
children with an Hb as low as 23 g/dl due to iron deficiency have arrived at this
low level over a prolonged period and can tolerate it.

Treatment

of Treatment also carries a risk of accidental poisoning with oral iron, which is very toxic. A

iron

simple strategy is to provide dietary advice to increase oral iron and its absorption in all

deficiency

children with subclinical deficiency and to offer parents the option of additional treatment

with

normal with oral iron supplements.

Hb
2.

Red

cell

aplasia
causes:

Diagnosis

Congenital red cell aplasia (DiamondBlackfan anaemia)

Transient erythroblastopenia of childhood (TEC)
Parvovirus B19 infection (this infection only causes red cell aplasia in children

with inherited haemolytic anaemias and not in healthy children).

Rarities: Fanconi anaemia, aplastic anaemia, leukaemia

The diagnostic clues to red cell aplasia are:

Low reticulocyte count despite low Hb
Normal bilirubin
Negative direct antiglobulin test (Coombs test)
Absent red cell precursors on bone marrow examination.

A: Diamond
Blackfan
anaemia
(DBA)

is a rare disease (57 cases/million live births).

There is a family history in 20% of cases; the remaining 80% are sporadic.
Specific gene mutations in ribosomal protein (RPS) genes are implicated in some

cases.
Most cases present at 23 months of age, but 25% present at birth.
Affected infants have symptoms of anaemia; some have other congenital

anomalies, such as short stature or abnormal thumbs.

Treatment is by oral steroids; monthly red blood cell transfusions are given to
children who are steroid unresponsive and some may also be offered stem cell

B: Transient
erythroblastop

transplantation
is usually triggered by viral infections and has the same haematological features
as DiamondBlackfan anaemia.

enia of

The main differences between them is that, unlike DiamondBlackfan anaemia,

childhood

transient erythroblastopenia of childhood always recovers, usually within several

(TEC)

weeks, there is no family history or RPS gene mutations and there are no
congenital anomalies.

Increased red Haemolytic anaemia is characterised by reduced red cell lifespan due to increased red
cell destruction cell destruction in the circulation (intravascular haemolysis) or liver or spleen
(haemolytic

(extravascular haemolysis). The lifespan of a normal red cell is 120 days and the bone

anaemia)

marrow produces 173 000 million red cells per day. In haemolysis, red cell survival may
be reduced to a few days but bone marrow production can increase about eight-fold, so
haemolysis only leads to anaemia when the bone marrow is no longer able to
compensate for the premature destruc- tion of red cells.
In children, unlike neonates, immune haemolytic anaemias are uncommon. The main
cause of haemolysis in children is intrinsic abnormalities of the red blood cells:

Red cell membrane disorders (e.g. hereditary spherocytosis)

Red cell enzyme disorders (e.g. glucose-6- phosphate dehydrogenase deficiency-

G6PD def)
Haemoglobinopathies (abnormal haemoglobins, e.g. -thalassaemia major, sickle
cell disease).

Haemolysis from increased red cell breakdown leads to:

Anaemia
Hepatomegaly and splenomegaly
Increased blood levels of unconjugated bilirubin
Diagnosis

1. Red cell
membrane
disorders:

Excess urinary urobilinogen.

Raised reticulocyte count (on the blood film this is called polychromasia as the

reticulocytes have a characteristic lilac colour)

Unconjugated bilirubinaemia and increased urinary urobilinogen
Abnormal appearance of the red cells on a blood film (e.g. spherocytes, sickle

shaped or very hypochromic) (Fig. 22.6)

Positive direct antiglobulin test (only if an immune cause, as this test identifies

antibody-coated red blood cells)

Increased red blood cell precursors in the bone marrow.

HS occurs in 1 in 5000 births in Caucasians.

It usually has an autosomal dominant inheritance, but in 25% there is no family
history and it is caused by new mutations.

Hereditary

The disease is caused by mutations in genes for proteins of the red cell

spherocytosi

membrane (mainly spectrin, ankyrin or band 3). This results in the red cell losing

s (HS)

part of its membrane when it passes through the spleen. This reduction in its
surface-to-volume ratio causes the cells to become spheroidal, making them less
deformable than normal red blood cells and leads to their destruction in the
microvasculature of the spleen.

Clinical
features

The disorder is often suspected because of the family history.

Jaundice usually develops during childhood but may be intermittent; may cause
severe haemolytic jaundice in the first few days of life
Anaemia presents in childhood with mild anaemia (haemoglobin 911 g/dl), but the
haemoglobin level may transiently fall during infections
Mild to moderate splenomegaly depends on therate of haemolysis
Aplastic crisis uncommon, transient (24 weeks), caused by parvovirus B19 infection

Diagnosis

Gallstones due to increased bilirubin excretion

The blood film is usually diagnostic but more specific tests are available (e.g.

osmotic fragility, dye binding tests), although seldom required.

Autoimmune haemolytic anaemia is also associated with spherocytes and this
should be excluded with a direct antibody test in the absence of a family history of
hereditary spherocytosis.

Management

Most children have mild chronic haemolytic anaemia and the only treatment they
require is oral folic acid as they have a raised folic acid requirement secondary to

their increased red blood cell production.

Splenectomy is beneficial but is only indicated for poor growth or troublesome
symptoms of anaemia (e.g. severe tiredness, loss of vigour) and is usually
deferred until after 7 years of age because of the risks of post- splenectomy

sepsis.
Prior to splenectomy all patients should be checked that they have been
vaccinated against Haemophilus influenzae (Hib), meningitis C and Streptococcus

pneumoniae and lifelong daily oral penicillin prophylaxis is advised.

Aplastic crisis from parvovirus B19 infection usually requires one or two blood
transfusions over 34 weeks when no red blood cells are produced.

If gallstones are symptomatic, cholecystectomy may be necessary

2.

Red

cell

G6PD deficiency is the commonest red cell enzymopathy affecting over 100 million

enzyme

people worldwide. It has a high prevalence (1020%) in individuals originating from

disorders:

central Africa, the Mediterranean, the Middle East and the Far East.

Glucose-6phosphate

G6PD is the rate-limiting enzyme in the pentose phosphate pathway and is essential for

dehydrogena

preventing oxidative damage to red cells. Red cells lacking G6PD are susceptible to

se

oxidant-induced haemolysis.

(G6PD)

deficiency
G6PD deficiency is X-linked and therefore predominantly affects males. Females who
are heterozygotes are usually clinically normal as they have about half the normal G6PD
activity. Females may be affected either if they are homozygous or, more commonly,
when by chance more of the normal than the abnormal X chromosomes have been
inactivated (extreme Lyonisation the Lyon hypothesis is that, in every XX cell, one of
the X chromosomes is inactivated and that this is random).
In Mediterranean, Middle Eastern and Oriental populations, affected males have very low
or absent enzyme activity in their red cells. Affected Afro-Caribbeans have 1015%
normal enzyme activity.
Clinical

Neonatal jaundiceonset is usually in the first 3 days of life. Worldwide it is the most

manifestation

common cause of severe neonatal jaundice requiring exchange transfusion

Acute haemolysis precipitated by:

infection, the most common precipitating factor
certain drugs (see Box 22.2)
fava beans (broad beans)
naphthalene in mothballs.
Haemolysis due to G6PD deficiency is predominantly intravascular.
Pallor
This is associated with fever, malaise and the passage of dark urine, as it contains
haemoglobin as well as urobilinogen. The haemoglobin level falls rapidly and may drop
below 5 g/dl over 2448 h.

Diagnosis

Between episodes, almost all patients have a completely normal blood picture and no
jaundice or anaemia.
The diagnosis is made by measuring G6PD activity in red blood cells. During a
haemolytic crisis, G6PD levels may be misleadingly elevated due to the higher enzyme
concentration in reticulocytes, which are produced in increased numbers in response to
the destruction of mature red cells.

 A repeat assay is then required in the steady state to confirm the diagnosis.
Management The parents should be given advice about the signs of acute haemolysis (jaundice, pallor
and dark urine) and provided with a list of drugs, chemicals and food to avoid (Box
22.2).
Transfusions are rarely required, even for acute episodes
3.

These are red blood cell disorders which cause haemolytic anaemia because of

Haemoglobin

reduced or absent production of HbA (- and -thalassaemias) or because of the

opathies:

production of an abnormal Hb (e.g. sickle cell disease).

-Thalassaemias are caused by deletions (occasionally mutations) in the -

globin gene.
-Thalassaemia and sickle cell disease are caused by mutations in the -globin

gene.
Clinical manifestations of the haemoglobinopathies affecting the -chain are

Thalassaemia
s, SCD

delayed until after 6 months of age when most of the HbF present at birth has
been replaced by adult HbA (Fig. 22.7, Table 22.2).
A: Sickle cell
disease (SCD)

This is now the commonest genetic disorder in children in many European

countries, including the UK (prevalence 1 in 2000 live births).

Sickle cell disease is the collective name given to haemoglobinopathies in which

HbS is inherited.
HbS forms as a result of a point mutation in codon 6 of the -globin gene, which

causes a change in the amino acid encoded from glutamine to valine.

Sickle cell disease is most common in patients whose parents are black and
originate from tropical Africa or the Caribbean but it is also found in the Middle
East and in low prevalence in most other parts of the world except for northern
Europeans.

There
three

are
main Sickle cell anaemia (HbSS) patients are homozygous for HbS, i.e. virtually all their

forms of sickle Hb is HbS; they have small amounts of HbF and no HbA because they have the sickle
cell

disease mutation in both -globin genes.

and the sickle HbSC disease (HbSC) affected children inherit HbS from one parent and HbC from
trait:

the other parent (HbC is formed as a result of a different point mutation in -globin), so
they also have no HbA because they have no normal -globin genes.
Sickle -thalassaemia affected children inherit HbS from one parent and -
thalassaemia trait from the other. They have no normal -globin genes and most patients

can make no HbA and therefore have similar symptoms to those with sickle cell
anaemia.
Sickle trait inheritance of HbS from one parent and a normal -globin gene from the
other parent, so approximately 40% of the haemoglobin is HbS. They do not have sickle
cell disease but are carriers of HbS, so can transmit HbS to their offspring. They are
asymptomatic and are only identifiedas a result of blood tests.
Pathogenesis

In all forms of sickle cell disease, HbS polymerises within red blood cells forming rigid

tubular spiral bodies which deform the red cells into a sickle shape.
Irreversibly sickled red cells have a reduced lifespan and may be trapped in the
microcirculation, resulting in blood vessel occlusion (vaso-occlusion) and therefore
ischaemia in an organ or bone. This is exacerbated by low oxygen tension, dehydration

and cold.
The clinical manifestations of sickle cell disease vary widely between different
individuals. Disease severity also varies with different forms of sickle cell disease; in
general, HbSS is the most severe form of the disease. Some patients produce more HbF
(e.g. 1015% of their Hb may be HbF, while most patients with sickle cell disease have
HbF levels of 1%) and this results in a marked reduction in disease severity.

Clinical
features

These are listed in Figure 22.8.

Management

Prophylaxis Because of increased susceptibility to infection, especially encapsulated

organisms, e.g. Streptococcus pneumoniae and Haemophilus influenzae type B (HiB)
because of functional asplenia, children should be fully immunised, including against

pneumococcal, Haemophilus influenzae type B (HiB) and meningococcus infection.

To ensure full coverage of all pneumococcal subgroups, daily oral penicillin throughout

childhood should be given.

Patients should receive once-daily oral folic acid because of the increased demand for

folic acid caused by the chronic haemolytic anaemia.

Vaso-occlusive crises should be minimised by avoiding exposure to cold, dehydration,
excessive exercise, undue stress or hypoxia. This requires practical measures such as
dressing children warmly, giving drinks especially before exercise and taking extra care
to keep children warm after swimming or when playing outside in the winter.

Treatment of acute crises Painful crises should be treated with oral or intravenous
analgesia according to need (may require opiates) and good hydration (oral or

intravenous as required); infection should be treated with antibiotics; oxygen should be

given if the oxygen saturation is reduced. Exchange transfusion is indicated for acute
chest syndrome, stroke and priapism.

Treatment of chronic problems Children who have recurrent hospital admissions for
painful vaso-occlusive crises or acute chest syndrome (see Case History 22.2) may
benefit from hydroxyurea, a drug which increases their HbF production and helps protect
against further crises. It requires monitoring for side-effects, especially white blood cell
suppression.

The most severely affected children (15%) who have had a stroke or who do not
respond to hydroxyurea may be offered a bone marrow transplant. This is the only cure
for sickle cell disease but can only be safely carried out if the child has an HLA-identical
sibling who can donate their bone marrow the cure rate is 90% but there is a 5% risk of
fatal transplant-related complications.

Prognosis

Sickle cell disease is a cause of premature death due to one or more of these severe
complications;
around 50% of patients with the most severe form of sickle cell disease die before the
age of 40 years. However, the mortality rate during childhood is around 3%, usually from
bacterial infection.

Prenatal

Many countries with a high prevalence of haemoglobinopathies, including the UK,

diagnosis and

perform neonatal screening on dried blood spots (Guthrie test) collected in the

screening

first week of life.

Early diagnosis of sickle cell disease allows penicillin prophylaxis to be started in

early infancy instead of awaiting clinical presentation, possibly due to a severe

infection.
Prenatal diagnosis can be carried out by chorionic villus sampling at the end of
the first trimester if parents wish to choose this option to prevent the birth of an
affected child.

B: SC disease Children with SC disease usually have a nearly normal haemoglobin level and fewer
painful crises than those with HbSS, but they may develop proliferative retinopathy in
adolescence. Their eyes should be checked periodically.
They are also prone to develop osteonecrosis of the hips and shoulders.
C: Sickle cell This is asymptomatic and rarely causes problems except under conditions of low oxygen
trait (AS)

tension. General anaesthesia does not constitute a risk in this popula- tion as long as

they have been identified and hypoxia avoided.

D:

Thalassaemia

The -thalassaemias occur most often in people from the Indian subcontinent,

Mediterranean and Middle East (Fig. 22.12). In the UK, most affected children are born
to parents from the Indian subcontinent; in the past, many were born to Greek Cypriots,
but this has become uncommon through active genetic counsel- ling within their
community. There are two main types of thalassaemia both of which are
characterised by a severe reduction in the production of -globin (and thereby reduction
in HbA production). All affected individuals have a severe reduction in -globin and
disease severity depends on the amount of residual HbA and HbF production.

-Thalassaemia major This is the most severe form of the disease. HbA (22)

cannot be produced because of the abnormal -globin gene.

-Thalassaemia intermedia This form of the disease is milder and of variable
severity. The -globin mutations allow a small amount of HbA and/or a large
amount of HbF to be produced.

Clinical features (Fig. 22.13)

Severe anaemia, which is transfusion dependent, from 36 months of age and jaundice
Failure to thrive/growth failure
Extramedullary haemopoiesis, prevented by regular blood transfusions. In the absence of
regular blood transfusion, develop hepatosplenomegaly and bone marrow expansion; the latter
leads to the classical facies with maxillary overgrowth and skull bossing (very rare in the UK and
developed countries).

Management

The condition is uniformly fatal without regular blood transfusions, so all patients are given lifelong
monthly transfusions of red blood cells. The aim is to maintain the haemoglobin concentration above
10 g/dl in order to reduce growth failure and prevent bone deforma- tion. Repeated blood transfusion
causes chronic iron overload, which causes cardiac failure, liver cirrhosis, diabetes, infertility and
growth failure. For this reason, all patients are treated with iron chelation with sub- cutaneous
desferrioxamine, or with an oral iron chela- tor drug, such as deferasirox, starting from 2 to 3 years of
age. Patients who comply well with transfusion and chelation have a 90% chance of living into their
forties and beyond. However, compliance is difficult. Those who cannot comply have a high mortality in
early adulthood from iron overload. The complications of multiple transfusions are shown in Box 22.3.
An alter- native treatment for -thalassaemia major is bone marrow transplantation, which is currently
the only cure. It is generally reserved for children with an HLA- identical sibling as there is then a 90
95% chance of success (i.e. transfusion independence and long-term cure) but a 5% chance of
transplant-related mortality.
Prenatal diagnosis
For parents who are both heterozygous for - thalassaemia, there is a 1 in 4 risk of having an affected
child. Prenatal diagnosis of -thalassaemia (DNA analy- sis of a chorionic villus sample) should be
offered together with genetic counselling to help parents to make informed decisions about whether or
not to con- tinue the pregnancy.
E: -Thalassaemia trait
Heterozygotes are usually asymptomatic. The red cells are hypochromic and microcytic. Anaemia is
mild or absent, with a disproportionate reduction in MCH (1822 fl) and MCV (6070 fl). The red blood
cell count is therefore usually increased (>5.5 1012/L). The most important diagnostic feature is a
raised HbA2, usually about 5% , and in about half there is a mild elevation of HbF level of 13%. -
Thalassaemia

trait

can

cause

confusion

with

mild

iron

deficiency

because

of

the

hypochromic/microcytic red cells but can be distin- guished by measuring serum ferritin, which is low in
iron deficiency but not -thalassaemia trait. To avoid unnecessary iron therapy, serum ferritin levels
should be measured in patients with mild anaemia and microcytosis prior to starting iron supplements.
F: -Thalassaemias
Healthy individuals have four -globin genes. The manifestation of -thalassaemia syndromes
depends on the number of functional -globin genes.
The most severe -thalassaemia, -thalassaemia major (also known as Hb Barts hydrops fetalis) is
caused by deletion of all four -globin genes, so no HbA (22) can be produced. It occurs mainly in
families of South- east Asian origin and presents in mid-trimester with fetal hydrops (oedema and
ascites) from fetal anaemia, which is always fatal in utero or within hours of deliv- ery. The only long-
term survivors of -thalassaemia major are those who have received monthly intrauter- ine

transfusions until delivery followed by lifelong monthly transfusions after birth. The diagnosis is made
by Hb electrophoresis or Hb HPLC (high-performance liquid chromatography), which shows only Hb
Barts. When only three of the -globin genes are deleted (HbH disease), affected children have mild
moderate anaemia but occasional patients are transfusion- dependent.
Deletion of one or two -globin genes (known as -thalassaemia trait) is usually asymptomatic and
anaemia is mild or absent. The red cells may be hypochromic and microcytic, which may cause confu-
sion with iron deficiency.
4. Immune: Haemolytic disease of the neworn (Anaemia in the newborn), autoimmune
haemolytic anaemia
Reduced red blood cell production
There are two main but rare causes in the newborn and both cause red cell aplasia:
CongenitalinfectionwithparvovirusB19
Congenitalredcellaplasia(DiamondBlackfan anaemia). In this situation, the Hb is low and the red
blood cells look normal. The diagnostic clue is that the reticulocyte count is low and the bilirubin is
normal. Increased red cell destruction (haemolytic anaemia) This occurs either because of an antibody
destroying the red blood cells (i.e. an extrinsic cause) or because there is an intrinsic abnormality of
the surface or intra- cellular contents of the red blood cell. The main causes of haemolytic anaemia in
neonates are:
Immune (e.g. haemolytic disease of the newborn)
Red cell membrane disorders (e.g. hereditary spherocytosis)
Red cell enzyme disorders (e.g. glucose-6- phosphate dehydrogenase deficiency)
Abnormal haemoglobins (e.g. -thalassaemia major).
The diagnostic clues to a haemolytic anaemia are an increased reticulocyte count (due to increased
red cell production to compensate for the anaemia) and increased unconjugated bilirubin (due to
increased red cell destruction with release of this bile pigment into the plasma).
Haemolytic disease of the newborn (immune haemolytic anaemia of the newborn) is due to antibod-
ies against blood group antigens. The most important are: anti-D (a rhesus antigen), anti-A or anti-B
(ABO blood group antigens) and anti-Kell. The mother is always negative for the relevant antigen (e.g.
rhesus D-negative) and the baby is always positive; the mother then makes antibodies against the
babys blood group and these antibodies cross the placenta into the babys circulation causing fetal or
neonatal haemolytic anaemia. The diagnostic clue to this type of haemolytic anaemia is a positive
direct anti-globulin test (Coombs test). This test is only positive in antibody-mediated anaemias and so
is negative in all the other types of haemolytic anaemia. (These conditions are considered further in
Chapter 10.)
The most common causes of non-immune haemo- lytic anaemia in neonates are: G6PD (glucose-6-

phosphate dehydrogenase) deficiency and hereditary spherocytosis. Haemoglobinopathies, apart from

-thalassaemia, rarely present with clinical features in the neonatal period but are detected on
neonatal haemoglobinopathy screening (Guthrie test).
Blood loss
The main causes are:
Feto-maternal haemorrhage (occult bleeding into the mother)
Twin-to-twintransfusion(bleedingfromonetwin into the other one)
Bloodlossaroundthetimeofdelivery(e.g. placental abruption). The main diagnostic clue is severe
anaemia with a raised reticulocyte count and normal bilirubin. Anaemia of prematurity The main
causes

are:

Inadequateerythropoietinproduction

Reducedredcelllifespan

Frequentbloodsamplingwhilstinhospital Ironandfolicaciddeficiency(after23months). Bone marrow

failure syndromes Bone marrow failure (also known as aplastic anaemia) is a rare condition
characterised by a reduction or absence of all three main lineages in the bone marrow leading to
peripheral blood pancytopenia. It may be inherited or acquired. The acquired cases may be due to
viruses (especially hepatitis viruses), drugs (such as sulphona- mides, chemotherapy) or toxins (such
as benzene, glue); however, many cases are labelled as idiopathic because a specific cause cannot
be identified. The condition may be partial or complete. It may start as failure of a single lineage but
progress to involve all three cell lines. The clinical presentation is with:
Anaemiaduetoreducedredcellnumbers
Infectionduetoreducedwhitecellnumbers (especially neutrophils)
Bruising and bleeding due to thrombocytopenia. Inherited aplastic anaemia These disorders are all
rare. Fanconi anaemia This is the most common inherited form of aplastic anaemia. It is an autosomal
recessive condition. The majority of children have congenital anomalies, includ- ing short stature,
abnormal radii and thumbs, renal malformations, microphthalmia and pigmented skin lesions. Children
may present with one or more of these anomalies or with signs of bone marrow failure which do not
usually become apparent until the age of 5 or 6 years. Neonates with Fanconi anaemia nearly always
have a normal blood count but it can be diag- nosed by demonstrating increased chromosomal
breakage of peripheral blood lymphocytes. This test can be used to identify affected family members or
for prenatal diagnosis. Affected children are at high risk of death from bone marrow failure or
transformation to acute leukaemia. The recommended treatment is bone marrow transplantation using
normal donor marrow from an unaffected sibling or matched unrelated marrow donor.
ShwachmanDiamond syndrome
This rare autosomal recessive disorder is characterised by bone marrow failure, together with signs of
pancre- atic exocrine failure and skeletal abnormalities. Most are caused by mutations in the SBDS
gene, which can be used for identifying unusual cases or prenatal diag- nosis. The most common
haematological problem is an isolated neutropenia or mild pancytopenia. Like Fanconi anaemia, there
is an increased risk of trans- forming to acute leukaemia.
Bleeding disorders

Normal haemostasis
Haemostasis describes the normal process of blood clotting. It takes place via a series of tightly
regulated interactions involving cellular and plasma factors.
There are five main components:
Coagulation factors are produced (mainly by the liver) in an inactive form and are activated when
coagulation is initiated (usually by tissue factor (TF), which is released by vessel injury; see Fig. 22.14)
Coagulation inhibitors these either circulate in plasma or are bound to endothelium and are neces-
sary to prevent widespread coagulation throughout the body once coagulation has been initiated
Fibrinolysis this process limits fibrin deposition at the site of injury due to activity of the key enzyme
plasmin
Platelets are vital for haemostasis as they aggre- gate at sites of vessel injury to form the primary
haemostatic plug which is then stabilised by fibrin
Blood vessels both initiate and limit coagulation. Intact vascular endothelium secretes prostaglandin
I2 and nitric oxide (which promote vasodilatation and inhibit platelet aggregation). Damaged
endothelium releases TF and procoagulants (e.g. collagen and von Willebrand factor) and there are
inhibitors of coagulation on the endothelial surface (thrombomodulin, antithrombin and protein S) to
modulate coagulation.
The endpoint of the coagulation cascade is generation of thrombin. A simplified model is shown in
Figure 22.14. The two main pathways for thrombin genera- tion were identified many years ago as the
intrinsic and extrinsic pathways. Important components of these pathways are still being discovered. In
recent years, the crucial role of tissue factor (TF) in haemos- tasis has been recognised and it is now
thought that the extrinsic pathway is the one primarily responsible for initiating both normal
haemostasis and thrombotic disease.
Diagnostic approach
Defects in the coagulation factors, in platelet number or function or in the fibrinolytic pathway are
associated with an increased risk of bleeding. In contrast, defects in the naturally occurring inhibitors of
coagulation (e.g. antithrombin) or in the vessel wall (e.g. damage from vascular catheters) are associ-
ated with thrombosis. In some cases, both pro- and anticoagulant abnormalities can occur at the same
time, as seen in disseminated intravascular coagulation (DIC).
The diagnostic evaluation of an infant or child for a possible bleeding disorder includes:
Identifying features in the clinical presentation that suggest the underlying diagnosis, as indicated in
Box 22.4
Initial laboratory screening tests to determine the most likely diagnosis (Table 22.3)
Specialist investigation to characterise a deficiency or exclude important conditions that can present
with normal initial investigations, e.g. mild von Willebrand disease, factor XIII deficiency and platelet
function disorders.
The most useful initial screening tests are:
Full blood count and blood film

Prothrombin time (PT) measures the activity of factors II, V, VII and X
Activated partial thromboplastin time (APTT) measures the activity of factors II, V, VIII, IX, X, XI and
XII
If PT or APTT is prolonged, a 50 : 50 mix with normal plasma will distinguish between possible factor
deficiency or presence of inhibitor
Thrombintimetestsfordeficiencyordysfunction of fibrinogen
Quantitative fibrinogen assay
D-dimers to test for fibrin degradation products
Biochemical screen, including renal and liver function tests.
The bleeding time is no longer used to investigate platelet disorders, as it is unreliable. It has been
replaced by in vitro tests of platelet function on a platelet func- tion analyser, which can be performed
on a peripheral blood sample.
In the neonate, the levels of all clotting factors except factor VIII (FVIII) and fibrinogen are lower; pre-
term infants have even lower levels. Therefore the results have to be compared with normal values in
infants of a similar gestational and postnatal age. In view of this, and since it is often difficult to obtain
good-quality neonatal samples, it is sometimes neces- sary to exclude an inherited coagulation factor
defi- ciency by testing the coagulation of both parents.
Haemophilia
The commonest severe inherited coagulation disorders are haemophilia A and haemophilia B. Both
have X-linked recessive inheritance. In haemophilia A, there is FVIII deficiency (Fig. 22.15); it has a
frequency of 1 in 5000 male births. Haemophilia B (FIX deficiency)
has a frequency of 1 in 30 000 male births. Two-thirds of newly diagnosed infants have a family history
of haemophilia, whereas one-third are sporadic. Identify- ing female carriers requires a detailed family
history, analysis of coagulation factors and DNA analysis. Pre- natal diagnosis is available using DNA
analysis.
Clinical features
The disorder is graded as severe, moderate or mild, depending on the FVIII:C (or IX:C in haemophilia
B) level (Table 22.4). The hallmark of severe disease is recurrent spontaneous bleeding into joints and
muscles, which can lead to crippling arthritis if not properly treated (Fig. 22.16). Most children present
towards the end of the first year of life, when they start to crawl or walk (and fall over). Bleeding
episodes are most frequent in joints and muscles. Where there is no family history, non-accidental
injury may initially be suspected. Almost 40% of cases present in the neonatal period, particularly with
intracranial haemorrhage, bleeding post-circumcision or prolonged oozing from heel stick and
venepuncture sites. The severity usually remains constant within a family.
Management
Recombinant FVIII concentrate for haemophilia A or recombinant FIX concentrate for haemophilia B is
given by prompt intravenous infusion whenever there is any bleeding. If recombinant products are

unavaila- ble, highly purified, virally inactivated plasma-derived products should be used. The quantity
required
depends on the site and nature of the bleed. In general, raising the circulating level to 30% of normal is
suffi- cient to treat minor bleeds and simple joint bleeds. Major surgery or life-threatening bleeds
require the level to be raised to 100% and then maintained at 3050% for up to 2 weeks to prevent
secondary haem- orrhage. This can only be achieved by regular infusion of factor concentrate (usually
812-hourly for FVIII, 1224-hourly for FIX, or by continuous infusion) and by closely monitoring
plasma levels. Intramuscular injec- tions, aspirin and non-steroidal anti-inflammatory drugs should be
avoided in all patients with haemophilia.
Complications are listed in Box 22.5.
Home treatment is encouraged to avoid delay in treatment, which increases the risk of permanent
damage, e.g. progressive arthropathy. Parents are usually taught to give replacement therapy at home
when the child is 23 years of age and many children are able to administer their own treatment from
78 years of age.
Prophylactic FVIII is given to all children with severe haemophilia A to further reduce the risk of chronic
joint damage by raising the baseline level above 2%. Primary prophylaxis usually begins at age 23
years, and is given two to three times per week. If peripheral venous access is poor, a central venous
access device (e.g. Portacath) may be required. Prophylaxis has been shown to result in better joint
function in adult life. Similarly, patients with severe haemophilia B are usually given prophylactic FIX.
Desmopressin (DDAVP) may allow mild haemophilia A to be managed without the use of blood
products. It is given by infusion and stimulates endogenous release of FVIII:C and von Willebrand
factor (vWF). Adequate levels can be achieved to enable minor surgery and dental extraction to be
undertaken. DDAVP is ineffec- tive in haemophilia B.
Haemophilia centres should supervise the manage- ment of children with bleeding disorders. They
provide a multidisciplinary approach with expert medical,
nursing and laboratory input. Specialised physiother- apy is needed to preserve muscle strength and
avoid damage from immobilisation. Psychosocial support is an integral part of maintaining compliance.
Self-help groups such as the Haemophilia Society may provide families with helpful information and
support.
von Willebrand disease (vWD)
Von Willebrand factor (vWF) has two major roles:
Itfacilitatesplateletadhesiontodamaged endothelium
ItactsasthecarrierproteinforFVIII:C,protectingit from inactivation and clearance.
Von Willebrand disease (vWD) results from either a quantitative or qualitative deficiency of von
Willebrand factor (vWF). This causes defective platelet plug forma- tion and, since vWF is a carrier
protein for FVIII:C, patients with vWD also are deficient in FVIII:C (see Fig. 22.15).

There are many different mutations in the vWF gene and many different types of vWD. The inheritance
is usually autosomal dominant. The commonest subtype, type 1 (6080%), is usually fairly mild and is
often not diagnosed until puberty or adulthood.
Clinical features
These are:
Bruising Excessive, prolonged bleeding after surgery Mucosal bleeding such as epistaxis and
menorrhagia.
In contrast to haemophilia, spontaneous soft tissue bleeding such as large haematomas and haem-
arthroses are uncommon.
Management
Treatment depends on the type and severity of the disorder. Type 1 vWD can usually be treated with
DDAVP, which causes secretion of both FVIII and vWF into plasma. DDAVP should be used with
caution in children <1 year of age as it can cause hyponatraemia due to water retention and may cause
seizures, parti- cularly after repeated doses, and if fluid intake is not strictly regulated. More severe
types of vWD have to be treated with plasma-derived FVIII concentrate, as DDAVP is ineffective and
recombinant FVIII concen- trate contains no vWF. Cryoprecipitate is no longer used to treat vWD as it
has not undergone viral inactivation. Intramuscular injections, aspirin and non- steroidal anti-
inflammatory drugs should be avoided in all patients with vWD.
Acquired disorders of coagulation
The main acquired disorders of coagulation affecting children are those secondary to:
Haemorrhagicdiseaseofthenewborndueto
vitamin K deficiency (see Ch. 10) Liver disease
ITP (immune thrombocytopenia)
DIC (disseminated intravascular coagulation). Vitamin K is essential for the production of active forms
of factors II, VII, IX, X and for the production of naturally occurring anticoagulants such as proteins C
and S. Vitamin K deficiency therefore causes reduced levels of all of these factors. The main clinical
consequence of this is a prolonged prothrombin time and an increased risk of bleeding. Children may
become deficient in vitamin K due to: Inadequateintake(e.g.neonates,long-term chronic illness with
poor intake)
Malabsorption (e.g. coeliac disease, cystic fibrosis, obstructive jaundice)
Vitamin K antagonists (e.g. warfarin). Thrombocytopenia
Thrombocytopenia is a platelet count <150 109/L. The risk of bleeding depends on the level of the
platelet count:
Severe thrombocytopenia (platelets <20 109/L) risk of spontaneous bleeding
Moderate thrombocytopenia (platelets 2050 109/L) at risk of excess bleeding during operations
or trauma but low risk of spontaneous bleeding
Mild thrombocytopenia (platelets 50150 109/L) low risk of bleeding unless there is a major
operation or severe trauma.

Thrombocytopenia may result in bruising, petechiae, purpura and mucosal bleeding (e.g. epistaxis,
bleeding from gums when brushing teeth). Major haemorrhage in the form of severe gastrointestinal
haemorrhage, haematuria and intracranial bleeding is much less common. The causes of easy
bruising and purpura are listed in Table 22.5. While purpura may signify throm- bocytopenia, it also
occurs with a normal platelet count from platelet dysfunction and vascular disorders.
Immune thrombocytopenia (ITP)
Immune thrombocytopenia is the commonest cause of thrombocytopenia in childhood. It has an
incidence of around 4 per 100000 children per year. It is usually caused by destruction of circulating
platelets by anti- platelet IgG autoantibodies. The reduced platelet count may be accompanied by a
compensatory increase of megakaryocytes in the bone marrow.
Clinical features
Most children present between the ages of 2 and 10 years, with onset often 12 weeks after a viral
infection. In the majority of children, there is a short history of days or weeks. Affected children develop
petechiae, purpura and/or superficial bruising (see Case History 22.3). It can cause epistaxis and other
mucosal bleeding but profuse bleeding is uncommon, despite the fact that the platelet count often falls
to <10 109/L. Intra- cranial bleeding is a serious but rare complication, occurring in 0.10.5%, mainly
in those with a long period of severe thrombocytopenia.
Diagnosis
ITP is a diagnosis of exclusion, so careful attention must be paid to the history, clinical features and
blood film to ensure that another more sinister diagnosis is not missed. In the younger child, a
congenital cause (such as WiskottAldrich or BernardSoulier syndromes) should be considered. Any
atypical clinical features, such as the presence of anaemia, neutropenia, hepato- splenomegaly or
marked lymphadenopathy, should prompt a bone marrow examination to exclude acute leukaemia or
aplastic anaemia. A bone marrow exami- nation should also be performed if the child is going to be
treated with steroids, since this treatment may temporarily mask the diagnosis of acute lympho- blastic
leukaemia (ALL). Inadvertent steroid therapy in undiagnosed ALL mimicking ITP will compromise the
long-term outcome of such patients. Systemic lupus erythematosus (SLE) should also be considered.
However, if the clinical features are characteristic, with no abnormality in the blood other than a low
platelet count and no intention to treat, there is no need to examine the bone marrow.
Management
In about 80% of children, the disease is acute, benign and self-limiting, usually remitting spontaneously
within 68 weeks. Most children can be managed at home and do not require hospital admission.
Treat- ment is controversial. Most children do not need any therapy even if their platelet count is <10
109/L but treatment should be given if there is evidence of major
bleeding (e.g. intracranial or gastrointestinal haemor- rhage) or persistent minor bleeding that affects
daily lives such as excessive epistaxis or menstrual bleeding. The treatment options include oral
prednisolone, intra- venous anti-D or intravenous immunoglobulin and all have significant side-effects.

Platelet transfusions are reserved for life-threatening haemorrhage as they raise the platelet count only
for a few hours. The parents need immediate 24-hour access to hospital treatment, and the child
should avoid trauma, as far as possible, and contact sports while the platelet count is very low.
Chronic ITP
In 20% of children, the platelet count remains low 6 months after diagnosis; this is known as chronic
ITP. In the majority of children, treatment is mainly
supportive; drug treatment is only offered to children with chronic persistent bleeding that affects daily
activities or impairs quality of life. Children with signifi- cant bleeding are rare and require specialist
care. A variety of treatment modalities are available, including rituximab, a monoclonal antibody
directed against B lymphocytes. Newer agents such as thrombopoietic growth factors have shown
clinical response in adults and may be used in children with severe non- responsive disease.
Splenectomy can be effective for this group but is mainly reserved for children who fail drug therapy as
it significantly increases the risk of infections and patients require lifelong antibiotic prophylaxis. If ITP
in a child becomes chronic, regular screening for SLE should be performed, as the throm- bocytopenia
may predate the development of autoantibodies
Disseminated intravascular coagulation
Disseminated intravascular coagulation (DIC) describes a disorder characterised by coagulation
pathway acti- vation leading to diffuse fibrin deposition in the micro- vasculature and consumption of
coagulation factors and platelets.
The commonest causes of activation of coagulation are severe sepsis or shock due to circulatory
collapse, e.g. in meningococcal septicaemia, or extensive tissue damage from trauma or burns. DIC
may be acute or chronic and is likely to be initiated through the tissue factor pathway. The predominant
clinical feature is bruising, purpura and haemorrhage. However, the pathophysiological process is
characterised by microvascular thrombosis and purpura fulminans may occur.
No single test reliably diagnoses DIC. However, DIC should be suspected when the following
abnormalities coexist thrombocytopenia, prolonged prothrombin time (PT), prolonged APTT, low
fibrinogen, raised fibrinogen degradation products and D-dimers and microangiopathic haemolytic
anaemia. There is also usually a marked reduction in the naturally occurring anticoagulants, proteins C
and S and antithrombin.
The most important aspect of management is to treat the underlying cause of the DIC (usually sepsis)
while providing intensive care. Supportive care may be provided with fresh frozen plasma (to replace
clotting factors), cryoprecipitate and platelets. Anti- thrombin and protein C concentrates have been
used, particularly in severe meningococcal septicaemia with purpura fulminans. The use of heparin
remains controversial.
Thrombosis in children
Thrombosis is uncommon in children and about 95% of venous thromboembolic events are secondary
to underlying disorders associated with hypercoagulable states (see below). Thrombosis of cerebral
vessels usually presents with signs of a stroke. (The condition is considered further in Chapters 10 and

27.) Rarely, children may inherit abnormalities in the coagulation and fibrinolytic pathway that increase
their risk of developing clots even in the absence of underlying predisposing factors. These conditions
are termed con- genital prothrombotic disorders (thrombophilias). They are:

ProteinCdeficiency

ProteinSdeficiency

Antithrombindeficiency

FactorVLeiden

ProthrombingeneG20210Amutation.
Proteins C and S and antithrombin are natural antico- agulants and their deficiencies are inherited in
an auto- somal dominant manner. Heterozygotes are also predisposed to thrombosis, usually venous,
during the second or third decade of life and only rarely in child- hood. Homozygous deficiency of
protein C and protein S are very uncommon and present with life-threatening thrombosis with
widespread haemorrhage and
purpura into the skin (known as purpura fulminans) in the neonatal period. Homozygous antithrombin
deficiency is not seen, probably because it is lethal in the fetus.
Factor V Leiden is an inherited abnormality in the structure of the coagulation protein factor V, which
makes it resistant to degradation by activated protein C as part of the bodys normal anticoagulant
mecha- nism. The prothrombin gene mutation is associated with high levels of plasma prothrombin.
Acquired disorders are:
Catheter-relatedthrombosis
DIC(disseminatedintravascularcoagulation)
Hypernatraemia
Polycythaemia(e.g.duetocongenitalheart disease)
Malignancy
SLE(systemiclupuserythematosus)andpersistent antiphospholipid antibody syndrome. Diagnosis
Although inherited thrombophilia is very uncommon, these disorders predispose to life-threatening
throm- bosis and so it is important not to miss the diagnosis in any child presenting with an
unexplained thrombotic event. Therefore, screening tests for the presence of an inherited thrombophilia
should be carried out in the following situations: Any child with unanticipated or extensive venous
thrombosis, ischaemic skin lesions or neonatal purpura fulminans Any child with a positive family
history of neonatal purpura fulminans. The screening tests are assays for proteins C and S,
antithrombin assay, polymerase chain reaction (PCR) for factor V Leiden and for the prothrombin gene
mutation. Mutations in factor V (factor V Leiden) and the pro- thrombin gene, respectively, are present
in 5% and 2% of the northern European population. Children with protein C deficiency or factor V
Leiden have 46 times higher risk of developing recurrent thromboses. The risk increases significantly
if these conditions are inher- ited together. Therefore it is reasonable to screen chil- dren who develop
thrombosis for all of these factors in order to plan the best management to prevent thrombosis. In the
UK, current practice is not to screen asymptomatic children for genetic defects, which are not going to
affect their medical management, e.g. on the basis of family history alone, until they are old enough to
receive appropriate counselling and make decisions for themselves.