3. *Anaemia

Question 1

What is anaemia and what are the 2 general causes?

Answer 1

• Anaemia is a reduction in the amount of haemoglobin in a given volume of blood below what would be expected in comparison with a healthy subject of the same age and gender
  
  • The RBC and Hct are usually also reduced
  • NOTE: you could have a low haemoglobin concentration if you have an increase in plasma volume. You would be able to identify this as the patient would have oedema as a result of fluid retention along with an increased plasma volume
  • But anaemia is usually due to a reduction of the absolute amount of haemoglobin in the blood stream
  • In a healthy person, anaemia due to an increase in plasma volume cannot persist because the excess fluid in the circulation is excreted

Question 2

What are the different mechanisms that anaemia can be caused by?

Answer 2

• Reduced production of red blood cells/haemoglobin in the bone marrow
  
  • Loss of blood from the body (haemorrhage, malena, haematouria/ haemoglobin uria)
  • Reduced survival of red blood cells in the circulation (haemolysis – the rate of breakdown of haemoglobin has increased which would also show up as jaundice)
  • Pooling of red blood cells in a very large spleen (haemolytic anaemias have splenomegaly as a symptom as the red cells are taken up by the spleen when they are broken down)

Question 3

What is the difference between a mechanism and a cause of anaemia

Answer 3

• Cause - could be a condition causing reduced synthesis of haem or one causing reduced synthesis of globin. You also need to explore what caused these (e.g. a reduction in iron or a gametic disorder)
  
  • There could be several causes to a single mechanism

Question 4

What happens in thalassaemias?

Answer 4

Reduced synthesis of globins happens in hereditary defects called thalassemias. This could be a reduced synthesis of the alpha chain or the beta chain (e.g. if you are making reduced alpha chains then the excess beta chains can’t form a normal Hb molecule). A reduction in other chains would not cause anaemia as they are only a minor component of the Hb molecule

Question 5

How are anaemias classified?

Answer 5

Classified by the size of the RBC
• Microcytic - usually HYPOchromic (as the same defect in Hb synthesis causes both)
• Normocytic - usually NORMOchromic (reduced number of cells but they are a normal size)
• Macrocytic - usually NORMOchromic (macrocytic anaemia doesn’t occur due to a lack of sythesis of Hb but due to some other defect)

Question 6

What are the causes of microcytic anaemia?

Answer 6

• Defect in HAEM synthesis
○ Iron deficiency – due to a dietary deficiency or a blood loss
○ Anaemia of chronic disease – this is anaemia in people with chronic inflammation as there will be a reduced synthesis of Hb. Initially this would result in normocytic and normochromic anaemia but if the condition is severe and chronic it can lead to microcytic and hypochromic anaemia
• Defect in GLOBIN synthesis (THALASSAEMIA)
○ Defect in ALPHA chain synthesis (alpha thalassaemia)
○ Defect in BETA chain synthesis (BETA thalassemia)

Question 7

What happens in macrocytic anaemias?

Answer 7

• Macrocytic anaemia usually results from abnormal haemopoiesis so that the red cell precursors continue to synthesise haemoglobin and other cellular proteins but they fail to divide normally
  
  • As a result, the red cells end up being much LARGER than normal and fewer of them are produced

Question 8

What is megaloblastic anaemia?

Answer 8

• One cause of macrocytic anaemia is megaloblastic erythropoiesis
• This refers specifically to a delay in the maturation of the nucleus while the cytoplasm continues to mature and the cell continues to grow. There is a defect in DNA synthesis but there is nothing wrong with the ribosomes so protein synthesis continues to occur and the cells get bigger
• A megaloblast is an abnormal bone marrow erythroblast
• Megaloblasts are larger than normal and shows nucleo-cytoplasmic dissociation (a mature cytoplasm but a primitive nucleus)
It is possible to suspect megaloblastic anaemia from the peripheral blood features but to be sure requires bone marrow examination

Question 9

What else would be a mechanism for macrocytic anaemia apart from megaloblastic erythropoiesis?

Answer 9

• An alternative mechanism of macrocytosis is premature release of cells from the bone marrow (also known as increased reticulocyte count)
  
  • Young red cells (reticulocytes) are about 20% LARGER than mature red cells so if there is an increase in the proportion of young red cells (reticulocytosis) in the circulation, the MCV will be increased. This is easily distinguishable form megaloblastic anaemia as they will have a low reticulocyte count due to the defect in DNA synthesis

Question 10

What are the causes of macrocytic anaemia?

Answer 10

• Megaloblastic anaemia as a result of a lack of vitamin B12 or folic acid. in the elderly vitamin B12 deficiency becomes more common as it Is not absorbed properly
  
  • Use of drugs interfering with DNA synthesis e.g. chemotherapy or azathioprine. These will interfere with the DNA of haematopoietic cells as a side effect
  • Liver disease and ethanol toxicity
  • REMEMBER: in megaloblasts there is an asynchrony between the nucleus and cytoplasm
  • Recent major blood loss with adequate iron stores – if you’ve lost blood initially this will be seen as normocytic anaemia as the body compensates by increasing plasma volume but in a few days the bone marrow will start spitting out reticulocytes to try and compensate. The increase in reticulocytes means an increased MCV
  • Haemolytic anaemia (reticulocytes also increased because of loss of red cells)

Question 11

What are the mechanisms for normocytic normochromic anaemia?

Answer 11

• MCV and MCH are normal
  
  • Recent blood loss
  • Failure of production of red blood cells (due to a defect in stem cells or a reduced number of haematopoietic stem cells)
  • Pooling of red blood cells in the spleen

Question 12

What are the causes of normocytic normochromic anaemia?

Answer 12

• Causes of recent blood loss -
○ Bleeding peptic ulcer
○ Oesophageal varices
○ Trauma from a road traffic accident (bleeding into tissues)
• Failure of production of red blood cells can be caused by:
○ Early stages of iron deficiency or anaemia of chronic disease
○ Renal failure – erythropoietin drops causing anaemia
○ Bone marrow failure or suppression – a drop in number of stem cells. Cancer drugs can supress bone marrow function
○ Bone marrow infiltration – cancer spreading to the bone marrow causing fibrosis of stem cells
• Hypersplenism e.g. portal cirrhosis

Question 13

What is haemolytic anaemia?

Answer 13

Anaemia resulting from shortened survival of red blood cells in the circulation

Question 14

When would haemolysis occur without anaemia?

Answer 14

If the bone marrow can produce enough red blood cells to make up for the shortened life span

Question 15

What are the two different types of haemolysis?

Answer 15

Haemolysis can result from an instrinsic abnormality of the red cells
Haemolysis can result from an extrinsic factor acting on normal red cells and damaging them

Question 16

What are the different ways that a haemolytic anaemia can be classified?

Answer 16

○ Inherited haemolytic anaemia - can result from abnormalities of the cell membrane, the haemoglobin or the enzymes in the red blood cell
○ Acquired haemolytic anaemia - usually results from extrinsic factors such as micro-organisms, chemicals or drugs that damage the red cell
Haemolytic anaemia can also be classified as intravascular or extravascular
○ Intravascular haemolysis occurs if there is very acute damage to the red cell and they are lysing within the circulation. You will get passage of Hb in the urine if this occurs. This is because when a cell is lysed in the circulation, Hb usually binds to heptaglobin and the complex is cleared by the liver. The body can then conserve the iron. But if haemolysis is occurring at a high rate then this mechanism is overwhelmed and free Hb passes in the urine
○ Extravascular haemolysis occurs when defective red cells are removed by the SPLEEN

Often haemolysis is partly intravascular and partly extravascular

Question 17

What would cause the red cells to burst?

Answer 17

An abnormal cell membrane
abnormal haemoglobin
A defect in the glycolytic pathway e.g. pyruvate kinase deficiency or a defect in the pentose phosphate shuttle

Question 18

What is the function of glucose 6 phosphate dehydrogenase and why is it important for the survival of red blood cells?

Answer 18

○ G6PD is an enzyme involved in the pentose phosphate pathway. The pathway provides reduction potential and protects red cells from oxygen damage
○ Pentose phosphate pathway is a metabolic pathway parallel to glycolysis that generates NADPH and pentoses
○ The G6PD pathway is the only source of reduced glutathione in red blood cells
○ The oxygen carrying role of red blood cells puts them at substantial risk of damage from oxidising free radicals except for the protective effects of G6PD

Question 19

Describe 3 causes of acquired haemolytic anaemias

Answer 19

○ Damage to membrane – an autoimmune haemolytic anaemia would involve producing antibodies that damage your own blood cells and the cells would be cleared by the spleen. Snake bites may damage red cells and cause haemolysis
○ Damage to whole red cell – (macroengiopathic haemolytic anaemia). Endothelial damage in small blood vessels or fibrin deposition which trap red cells and cause them to fragment. This might be due to the haemolytic urine syndrome which is associated with microvascular damage in the kidneys
○ Oxidant exposure: Components of the red cell membrane and Hb can be oxidised.
▪ Drugs which cause damage include depasone which is used to treat leprosy or skin diseases and primaquine which is used to treat malaria. You are more likely to have an episode of acute haemolysis if you have a deficiency of G6PD and you are given one of these drugs
▪ Another oxidant that people are exposed to are broad beans which shouldn’t be ate if you have a G6PD deficiency

Question 20

When would you suspect that a haemolytic anaemia is present in a patient?

Answer 20

• Otherwise unexplained anaemia that is normochromic and usually either normocytic or macrocytic as there is nothing wrong with Hb synthesis
  
  • Evidence of morphologically abnormal red cells
  • Evidence of increased red cell breakdown (shown by an increase in non-conjugated bilirubin and lactate dehydrogenase will also be high)
  • Evidence of increased bone marrow activity

Question 21

What would polychromatic macrocytes indicate?

Answer 21

An increased reticulocyte count

Question 22

What happens in autoimmune haemolytic anaemia and what can be seen on a blood film?

Answer 22

Autoantibodies are produced directed at own antigens and red cells are binding to splenic macrophages and they are removed early from the circulation. However, the macrophage may also just remove part of the red cell membrane where the antibody and complement are particularly concentrated which causes spherocytosis

Question 23

Why are the different areas that inherited haemolytic anaemias can damage and give examples of each type

Answer 23

Membrane- hereditary spherocytes
Hb - sickle cell anaemia
Glycolysis pathway - pyruvate kinase deficiency
Pentose shunt - glucose-6-phosphate dehydrogenase deficiency

Question 24

What are the different areas that acquired haemolytic anaemias can act on and give examples

Answer 24

Membrane - immune - autoimmune haemolytic anaemia
Whole red cell - mechanical - Microangiopathic haemolytic anaemia
Whole red cell - oxidant - drugs and chemicals
Whole red cell - microbiological - malaria

Question 25

What is hereditary spherocytes is?

Answer 25

• This is a type of haemolytic anaemia or chronic compensated haemolysis resulting from an inherited intrinsic defect of the red cell membrane
  
  • After entering the circulation the cells lose membrane in the spleen and thus become spherocytic