Paediatric Haematology Flashcards
Haemoglobin
Haemoglobin is formed of four protein subunits. These four subunits are made of two pairs of subunits. Fetal haemoglobin (HbF) has two alpha and two gamma subunits. Adult haemoglobin (HbA) has two alpha and two beta subunits.
Differences with Adult Haemoglobin
The structure gives fetal haemoglobin a greater affinity to oxygen than adult haemoglobin. Oxygen binds to fetal haemoglobin more easily and is more reluctant to let go. This is important, as fetal haemoglobin needs to “steal” oxygen away from the mother’s haemoglobin when nearby in the placenta. If the fetal and maternal haemoglobin had the same affinity for oxygen, there would be no incentive for the oxygen to switch from the maternal blood to fetal blood.
The affinity of fetal and adult haemoglobin with oxygen can be illustrated with the oxygen dissociation curve. This is an exam favourite. Along the x-axis is the partial pressure of oxygen, which is how much oxygen is crammed into a space. The higher the partial pressure, the more oxygen is in the area. On the y-axis is the percentage of the haemoglobin molecule that is bound to oxygen. This is how “full” the haemoglobin molecule is.
As the partial pressure of oxygen goes up, more oxygen will be bound to haemoglobin. Adult haemoglobin requires a higher partial pressure of oxygen for the molecule to fill with oxygen compared with fetal haemoglobin.
At birth
From 32 to 36 weeks gestation, production of HbF decreases. At the same time HbA is produced in greater quantities. Over time there is a gradual transition from HbF to HbA. At birth, around half the haemoglobin produced is HbF and half is HbA. By 6 months of age, very little fetal haemoglobin is produced. Eventually, red blood cells contain entirely HbA.
Fetal Haemoglobin in Sickle Cell Disease
In sickle cell disease, a genetic abnormality coding for the beta subunit is responsible for causing the sickle shape of the red blood cells. Fetal haemoglobin does not lead to sickling of red blood cells because there is no beta subunit in the structure.
Hydroxycarbamide can be used to increase the production of fetal haemoglobin (HbF) in patients with sickle cell anaemia. This has a protective effect against sickle cell crises and acute chest syndrome.
Causes of Anaemia In Infancy
Physiologic anaemia of infancy causes most cases of anaemia in infancy.
The other causes of anaemia in infants are:
Anaemia of prematurity
Blood loss
Haemolysis
Twin-twin transfusion, where blood is unequally distributed between twins that share a placenta
Haemolysis is a common cause of anaemia in infancy. There are a number of causes of haemolysis in a neonate:
Haemolytic disease of the newborn (ABO or rhesus incompatibility)
Hereditary spherocytosis
G6PD deficiency
Physiologic Anaemia of Infancy
There is a normal dip in haemoglobin around six to nine weeks of age in healthy term babies. High oxygen delivery to the tissues caused by the high haemoglobin levels at birth cause negative feedback. Production of erythropoietin by the kidneys is suppressed and subsequently there is reduced production of haemoglobin by the bone marrow. The high oxygen results in lower haemoglobin production.
Anaemia of Prematurity
Premature neonates are much more likely to become significantly anaemic during the first few weeks of life compared with term infants. The more premature the infant, the more likely they are to require one or more transfusions for anaemia. This becomes more likely if they are unwell at birth, particularly with neonatal sepsis.
Premature neonates become anaemic for a number of reasons:
Less time in utero receiving iron from the mother
Red blood cell creation cannot keep up with the rapid growth in the first few weeks
Reduced erythropoietin levels
Blood tests remove a significant portion of their circulating volume
Haemolytic Disease of the Newborn
Haemolytic disease of the newborn is a cause haemolysis (red blood cells breaking down) and jaundice in the neonate. It is caused by incompatibility between the rhesus antigens on the surface of the red blood cells of the mother and fetus. The rhesus antigens on the red blood cells vary between individual. This is different to the ABO blood group system.
Within the rhesus group, there are many different types of antigens that can be present or absent depending on the person’s blood type. The most important antigen within the rhesus blood group system is the rhesus D antigen.
When a woman that is rhesus D negative (does not have the rhesus D antigen) becomes pregnant, we have to consider the possibility that the fetus will be rhesus D positive (has the rhesus D antigen). It is likely at some point in the pregnancy the blood from the fetus will find a way into her bloodstream. When this happens, the fetal red blood cells display the rhesus D antigen. The mother’s immune system will recognise the rhesus D antigen as foreign and produce antibodies to the rhesus D antigen. The mother has then become sensitised to rhesus D antigens.
Usually, this sensitisation process does not cause problems during the first pregnancy (unless the sensitisation happens early on, such as during antepartum haemorrhage). During subsequent pregnancies, the mothers anti-D antibodies can cross the placenta into the fetus. If that fetus is rhesus positive, these antibodies attach themselves to the red blood cells of the fetus and causes the immune system of the fetus to attack its own red blood cells. This leads to haemolysis, causing anaemia and high bilirubin levels. This leads to a condition called haemolytic disease of the newborn.
A direct Coombs test (DCT) can be used to check for immune haemolytic anaemia. This will be positive in haemolytic disease of the newborn.
Causes of Anaemia in Older Children
The key causes of anaemia in older children are:
Iron deficiency anaemia secondary to dietary insufficiency. This is the most common cause overall.
Blood loss, most frequently from menstruation in older girls
Rarer causes of anaemia in children include:
Sickle cell anaemia
Thalassaemia
Leukaemia
Hereditary spherocytosis
Hereditary eliptocytosis
Sideroblastic anaemia
Worldwide, a common cause of blood loss causing chronic anaemia and iron deficiency is helminth infection, with roundworms, hookworms or whipworms. This can be very common in developing countries and those living in poverty. It is more unusual in the UK. Treatment is with a single dose of albendazole or mebendazole.
Categorising Anaemia
Anaemia is initially subdivided into three main categories based on the size of the red blood cell (the MCV). These have different underlying causes:
Microcytic anaemia (low MCV indicating small RBCs)
Normocytic anaemia (normal MCV indicating normal sized RBCs)
Macrocytic anaemia (large MCV indicating large RBCs)
Causes of Microcytic Anaemia
A helpful mnemonic for understanding the causes of microcytic anaemia is TAILS.
T – Thalassaemia
A – Anaemia of chronic disease
I – Iron deficiency anaemia
L – Lead poisoning
S – Sideroblastic anaemia
Causes of Normocytic Anaemia
There are 3 As and 2 Hs for normocytic anaemia:
A – Acute blood loss
A – Anaemia of Chronic Disease
A – Aplastic Anaemia
H – Haemolytic Anaemia
H – Hypothyroidism
Causes of Macrocytic Anaemia
Macrocytic anaemia can be megaloblastic or normoblastic. Megaloblastic anaemia is the result of impaired DNA synthesis preventing the cell from dividing normally. Rather than dividing it keeps growing into a large, abnormal cell. This is caused by a vitamin deficiency.
Megaloblastic anaemia is caused by:
B12 deficiency
Folate deficiency
Normoblastic macrocytic anaemia is caused by:
Alcohol
Reticulocytosis (usually from haemolytic anaemia or blood loss)
Hypothyroidism
Liver disease
Drugs such as azathioprine
Symptoms of anaemia
There are many generic symptoms of anaemia:
Tiredness
Shortness of breath
Headaches
Dizziness
Palpitations
Worsening of other conditions
There are symptoms specific to iron deficiency anaemia:
Pica describes dietary cravings for abnormal things such as dirt and can signify iron deficiency
Hair loss can indicate iron deficiency anaemia
Signs of anaemia
Generic signs of anaemia:
Pale skin
Conjunctival pallor
Tachycardia
Raised respiratory rate
Signs of specific causes of anaemia:
Koilonychia refers to spoon shaped nails, which can indicate iron deficiency
Angular chelitis can indicate iron deficiency
Atrophic glossitis is a smooth tongue due to atrophy of the papillae and can indicate iron deficiency
Brittle hair and nails can indicate iron deficiency
Jaundice occurs in haemolytic anaemia
Bone deformities occur in thalassaemia
Investigating anaemia
Initial Investigations:
Full blood count for haemoglobin and MCV
Blood film
Reticulocyte count
Ferritin (low iron deficiency)
B12 and folate
Bilirubin (raised in haemolysis)
Direct Coombs test (autoimmune haemolytic anaemia)
Haemoglobin electrophoresis (haemoglobinopathies)
Reticulocytes are immature red blood cells. A high level of reticulocytes in the blood indicates active production of red blood cells to replace lost cells. This usually indicates the anaemia is due to haemolysis or blood loss.
Further investigation will depend on the suspected underlying cause.
Managing anaemia
Management depends on establishing the underlying cause and directing treatment accordingly. Iron deficiency can be treated with iron supplementation. Severe anaemia may require blood transfusions.
Iron deficiency anaemia
The bone marrow requires iron to produce haemoglobin. There are several scenarios where iron stores can be used up and the patient becomes iron deficient:
Dietary insufficiency. This is the most common cause in children.
Loss of iron, for example in heavy menstruation
Inadequate iron absorption, for example in Crohn’s disease
Iron is mainly absorbed in the duodenum and jejunum. It requires the acid from the stomach to keep the iron in the soluble ferrous (Fe2+) form. When there is less acid in the stomach, it changes to the insoluble ferric (Fe3+) form. Therefore, medications that reduce the stomach acid, such as proton pump inhibitors (lansoprazole and omeprazole) can interfere with iron absorption. Conditions that result in inflammation of the duodenum or jejunum such as coeliac disease or Crohn’s disease can also cause inadequate iron absorption.
Tests for iron deficiency
Iron travels around the blood as ferric ions (Fe3+) bound to a carrier protein called transferrin. Total iron binding capacity (TIBC) basically means the total space on the transferrin molecules for the iron to bind. Therefore, total iron binding capacity is directly related to the amount of transferrin in the blood. If you measure iron in the blood and then measure the total iron binding capacity of that blood, you can calculate the proportion of the transferrin molecules that are bound to iron. This is called the transferrin saturation. It is expressed as a percentage. The formula is:
Transferrin Saturation = Serum Iron / Total Iron Binding Capacity
Ferritin is the form that iron takes when it is deposited and stored in cells. Extra ferritin is released from cells when there is inflammation, such as with infection or cancer. If ferritin in the blood is low, this is highly suggestive of iron deficiency. High ferritin is difficult to interpret and is likely to be related to inflammation rather than iron overload. A patient with a normal ferritin can still have iron deficiency anaemia, particularly if they have reasons to have a raised ferritin, such as infection.
Serum iron varies significantly throughout the day, with higher levels in the morning and after eating iron containing meals. On its own serum iron is not a very useful measure.
Total iron binding capacity can be used as a marker for how much transferrin is in the blood. It is an easier test to perform than measuring transferrin. Both TIBC and transferrin levels increase in iron deficiency and decrease in iron overload.
Transferrin saturation gives a good indication of the total iron in the body. In normal adults it is around 30%, however if there is less iron in the body, transferrin will be less saturated. When iron levels go up, transferrin will be more saturated. It can increase shortly after eating a meal rich in iron or taking iron supplements, so a fasting sample is better.
Blood Test
Normal Range
Serum Ferritin
12 – 200 ug/L
Serum Iron
14 – 31 μmol/L
Total Iron Binding Capacity
54 – 75 μmol/L
Two things can increase the values of all of these results (except TIBC, which will be low), giving the impression of iron overload:
Supplementation with iron
Acute liver damage (lots of iron is stored in the liver)
Managing iron deficiency
Management involves treating the underlying cause and correcting the anaemia. In children the underlying cause is usually dietary deficiency, so input from a dietician can be helpful.
Iron can be supplemented with ferrous sulphate or ferrous fumarate. This slowly corrects the iron deficiency. Oral iron causes constipation and black coloured stools. It is unsuitable where malabsorption is the cause of the anaemia.
Blood transfusions are very rarely necessary. Children are generally able to tolerate a low haemoglobin well and can be given time to correct their anaemia.
Leukaemia
Leukaemia is the name for cancer of a particular line of the stem cells in the bone marrow. This causes unregulated production of certain types of blood cells. Types of leukaemia can be classified depending on how rapidly they progress (chronic is slow and acute is fast) and the cell line that is affected (myeloid or lymphoid).
Types of Leukaemia
The types of leukaemia that affect children from most to least common are:
Acute lymphoblastic leukaemia (ALL) is the most common in children
Acute myeloid leukaemia (AML) is the next most common
Chronic myeloid leukaemia (CML) is rare
Rarer and very specialist leukemias exist, but you are very unlikely to encounter them.
Ages of leukaemias
ALL peaks aged 2 – 3 years
AML peaks aged under 2 years
Pathophysiology of leukaemia
Leukaemia is a form of cancer of the cells in the bone marrow. A genetic mutation in one of the precursor cells in the bone marrow leads to excessive production of a single type of abnormal white blood cell.
The excessive production of a single type of cell can lead to suppression of the other cell lines, causing underproduction of other cell types. This results in a pancytopenia, which is a combination of low:
Red blood cells (anaemia),
White blood cells (leukopenia)
Platelets (thrombocytopenia)
