Anaemia and Polycythaemia

Question 1

What is anaemia?

Answer 1

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

• By definition, the Hb concentration is reduced
• The RBC count and the Hct/PCV are usually also reduced

Question 2

What is anaemia due to?

Answer 2

Anaemia = reduced Hb concentration

This could be due to:

• Reduction of the absolute amount of haemoglobin in the blood stream - USUALLY
• increase in the volume of plasma (rather than a decrease in the amount of haemoglobin) - occasionally

BUT

• In a healthy person, anaemia resulting from an increase in plasma volume cannot persist because the excess fluid in the circulation is excreted
  
  • Therefore it only happens occasionally if there is something wrong with this mechanism - therefore in non-healthy people
  • e.g. Maybe a kidney problem severe enough to cause major fluid build-up in the body
• For practical purposes, anaemia can therefore be regarded as a resulting from a decrease of the absolute amount of haemoglobin in the circulation
  
  • Especially in otherwise healthy people

Question 3

Broadly speaking, state four mechanisms of anaemia.

Answer 3

• Reduced production of red cells/haemoglobin in the bone marrow
• Loss of blood from the body
• Reduced survival of red cells in the circulation
• Pooling of red cells in a very large spleen

Question 4

How does blood loss lead to anaemia? (extra for understanding)

Answer 4

Rapid blood loss:

• When blood is lost, the body tries to maintain BP by maintaining blood volume
• However, as a result, the blood is diluted → reduced Hct (ratio of RBCs in a given blood volume)
• This results in reduced Hb conc. → anaemia
• Eventually, increased production of red blood cells by the bone marrow may correct the anemia.
• However, over time, bleeding reduces the amount of iron in the body
• Therefore the bone marrow is not able to increase production of new red blood cells (and Hb) to replace those lost

Question 5

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

Answer 5

Mechanism - i.e. the process that went wrong to result in Hb reduction

• Might be reduced synthesis of haemoglobin in the bone marrow

Cause - i.e. the condition which led to the mechanism

• Could be either a condition causing reduced synthesis of haem or one causing reduced synthesis of globin

Question 6

State the different classes of anaemia.

Answer 6

Classified on the basis of cell size

• Microcytic (usually also hypochromic)
• Normocytic (usually also normochromic)
• Macrocytic (usually also normochromic)

Question 7

State the common causes of microcytic anaemia.

Answer 7

Defect in haem synthesis

• Iron deficiency
• Anaemia of chronic disease

Defect in globin synthesis (thalassaemia)

• Defect in α chain synthesis (α thalassaemia)
• Defect in β chain synthesis (β thalassaemia)

Question 8

What mechanism usually causes macrocytic anaemia?

Answer 8

Macrocytic anaemia = average cell size is increased

• Haemopoiesis is abnormal
  
  • Haemopoiesis = formation of blood cellular components
• Therefore the red cell precursors continue to synthesize haemoglobin and other cellular proteins but fail to divide normally
• As a result, the red cells end up larger than normal

NOTE: This is describing megaloblastic erythropoiesis

Question 9

What is megaloblastic erythropoiesis?

Answer 9

Megaloblastic erythropoiesis is one of the causes of macrocytic anaemia.

• This refers specifically to a delay in maturation of the nucleus while the cytoplasm continues to mature and the cell continues to grow
• Essentially you get continued cell growth without division → macrocytosis

Question 10

Describe the characteristics of a megaloblast.

Answer 10

Megaloblast = an abnormal bone marrow erythroblast (immature erythrocyte - containing a nucleus)

• Larger than normal
• Shows nucleo-cytoplasmic dissociation
  
  • i.e. Nucleus and cytoplasm not maturing at the same rate

It is possible to suspect megaloblastic anaemia from the peripheral blood features but to be sure requires bone marrow examination

NOTE:

• Basophilic cytoplasm - cytoplasm which takes up basic dye
• Reticulated chromatin - interlacing; like a web

Question 11

What is an alternative mechanism of macrocytosis?

Answer 11

Premature release of cells from the bone marrow

• Reticulocytes (young red cells) are about 20% larger than mature red cells
• So if there is an increased proportion reticulocytes in the circulation, the average red cell size (MCV) will be increased

Question 12

State the two most common causes of megaloblastic anaemia.

Answer 12

• B12 deficiency
• Folate deficiency

NOTE:

• B12 and folate are required for DNA synthesis so their deficiency results in impaired DNA synthesis
• Impaired DNA synthesis affects cell division which results in continued cell growth without division

Question 13

State some other common causes of macrocytic anaemia.

Answer 13

Megaloblastic anaemia:

• Use of drugs interfering with DNA synthesis (e.g. chemotherapy)

Non-megaloblastic anaemia:

• Liver disease and ethanol toxicity
• Recent major blood loss with adequate iron stores
  
  • Increased reticulocytes
    
    • If you’ve lost blood, the bone marrow will start releasing reticulocytes too early (i.e. premature) to compensate
• Haemolytic anaemia
  
  • Increased reticulocytes
    
    • Loss of red cells results in premature reticulocytes being released from bone marrow - again compensation

Question 14

State three mechanisms of normocytic normochromic anaemia.

Answer 14

• Recent blood loss
• Failure to produce red blood cells
• Pooling of red blood cells in the spleen

Question 15

State five causes of normocytic normochromic anaemia.

Answer 15

Recent blood loss:

• Peptic ulcer, oesophageal varices, trauma

Failure of production of red cells:

• Early stages of iron deficiency or anaemia of chronic disease
• Renal failure
• Bone marrow failure or suppression
• Bone marrow infiltration

Pooling of red cells in the spleen:

• Hypersplenism, e.g. portal cirrhosis
  
  • Hypersplenism = spleen is overactive so reduces too many red cells from circulation (not just the old ones)
  • Liver cirrhosis can cause portal hypertension
  • This can lead to congestion of intrasplenic blood flow → blood and hence RBCs pool in spleen

Question 16

Define haemolytic anaemia.

Answer 16

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

Question 17

What can haemolysis result from?

Answer 17

An intrinsic abnormality of the red cells

Extrinsic factors acting on normal red cells

Question 18

State two different classes of haemolytic anaemia.

Answer 18

Inherited haemolytic anaemia can result from abnormalities in the:

• Cell membrane
• Haemoglobin
• Enzymes in the red cell
• i.e. The problem is intrinsic

Acquired haemolytic anaemia usually results from extrinsic factors that damage the red cell, such as:

• Micro-organisms
• Chemicals
• Drugs

BUT extrinsic factors can interact with red cells that have an intrinsic abnormality

• In that case the haemolytic anaemia would fit into both classifications

Question 19

What is another way of classifying haemolytic anaemia?

Answer 19

Intravascular:

• Intravascular haemolysis occurs if there is very acute damage to the red cell

Extravascular:

• Extravascular haemolysis occurs when defective red cells are removed by the spleen
  
  • The spleen filters circulating blood
  • As blood is being drained from the red pulp back into the blood (splenic sinusoids → veins), RBCs have enter from the red pulp back into the cirulation
  • Red cells with structural defects or ones that are old/worn-out cannot squeeze through the narrow gaps between the endothelial cells of the sinusoids
  • They are subsequently phagocytosed by macrophages in the red pulp → extravascular haemolysis

Often haemolysis is partly intravascular and partly extravascular

In general though: more defective cells → more haemolysis → reduction in ciruclating red cells → haemolytic anaemia

Question 20

When would you suspect haemolytic anaemia?

Answer 20

• Otherwise unexplained anaemia which is normochromic and normocytic/macrocytic
• Evidence of morphologically abnormal RBCs
• Evidence of increased bone marrow activity
• Evidence of increase red cell breakdown

Question 21

State some important signs of haemolytic anaemia.

Answer 21

Jaundice because of the increased break down of red blood cells there is an increase in bilirubin

The increase in bilirubin can also increase the risk of getting gallstones

• Bilirubin (BR) actively secreted into bile which is stored in the gallbladder
• In situations of high heme turnover, such as chronic hemolysis, unconjugated BR may be present in bile at higher than normal concentrations
• Unconjugated BR tends to form precipitates with Ca which contributes to the formation of gallstones

Question 22

Give the causes of inherited haemolytic anaemia.

Answer 22

• Defect in cell membrane
  
  • e.g. hereditary spherocytosis
• Defect in Hb
  
  • e.g. sickle cell anaemia
• Defect in glycolytic pathway
  
  • e.g. pyruvate kinase deficiency
    
    • Mature RBCs don’t have mitochondria so rely on glycolysis for ATP production
    • Insufficient ATP leads to haemolysis
• Defect in enzyme in pentose shunt
  
  • e.g. G6PD deficiency

Question 23

Give the causes of acquired haemolytic anaemia

Answer 23

Damage to red cell membrane

• Autoimmune haemolytic anaemia (AIHA)
• Snake bite

Damage to whole red cell

• Mechanical - micro-angiopathic haemolytic anemia (MAHA)
• Oxidant exposure - drugs and chemicals
  
  • e.g. dapsone, primaquine
  • These drugs can precipitate episodic haemolysis in individuals with enzyme deficiency (e.g. G6PD)
• Microbiological - malaria

Question 24

What is hereditary spherocytosis?

Answer 24

This is 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 cell and become spherocytic

Question 25

What happens in hereditary spherocytosis?

Answer 25

• Red cells become less flexible due to their spherical shape
  
  • Therefore they and are removed prematurely (i.e. before they are aged/old) by the spleen → extravascular haemolysis
• The bone marrow responds to haemolysis by an increased output of red cells leading to polychromasia and reticulocytosis
  
  • Reticulocytosis = increase in reticulocyte count in the blood
• Haemolysis leads to increased bilirubin production, jaundice and gallstones

Question 26

How can you test for spherocytosis?

Answer 26

Osmotic fragility test:

• Spherocytes are more prone to haemolyse when osmotic pressure is reduced
  
  • Essentially even at reduced osmotic pressure (i.e. less water flowing into cell), the cell would be more prone to haemolyse

However, this test is often not needed

Question 27

How can hereditary spherocytosis be treated?

Answer 27

• The only effective treatment is splenectomy, but this has its own risks so is only done in severe cases
  
  • To prevent extravascular haemolysis
  • A good diet is important so that a secondary folic acid deficiency does not occur
• Alternatively, one folic acid tablet can be taken daily
  
  • Folic acid helps promote new RBC formation to compensate for those lost by extravascular haemolysis

Question 28

Explain how G6PD deficiency can cause haemolytic anaemia.

Answer 28

• G6PD is an important enzyme in the pentose phosphate shunt
• It is essential for the protection of the red cell from oxidant damage
• Oxidants may be generated in the blood stream, e.g:
  
  • During infection
  • May be exogenous

Question 29

Which group of people are most likely to be affected by hereditary spherocytosis?

Answer 29

The gene for G6PD is on the X chromosome so affected individuals are usually hemizygous males (but occasionally homozygous females)

• Hemizygous - i.e. males only inherit one copy of the X chromosome

Pattern of inheritance = X-linked recessive

Question 30

Give some examples of extrinsic oxidants.

Answer 30

• Foodstuffs (e.g. broad beans)
• Chemicals (e.g. naphthalene)
• Drugs (e.g. dapsone, primaquine)

Question 31

Describe the kind of haemolysis caused by G6PD deficiency.

Answer 31

Intermittent, severe intravascular haemolysis as a result of infection or exposure to an exogenous oxidant

• These episodes of intravascular haemolysis are associated with the appearance of considerable numbers of irregularly contracted cells
• Haemoglobin is denatured and forms round inclusions known as Heinz bodies, which can be detected by a specific test
  
  • Heinz bodies are removed by the spleen, leaving a defect in the cell

Question 32

How can G6PD deficiency be treated?

Answer 32

• Acute haemolysis sometimes requires blood transfusion
• Thereafter, prevention is important - i.e. prevention of oxidant exposure

Question 33

What is autoimmune haemolytic anaemia?

Answer 33

• Autoimmune haemolytic anaemia results from production of autoantibodies directed at red cell antigens
• The immunoglobulin bound to the red cell membrane is recognized by splenic macrophages, which remove parts of the red cell membrane, leading to spherocytosis
• Complement components can also be bound to the immunoglobulin molecule
• They are also recognised by receptors on splenic macrophages

Question 34

How exactly does the condition autoimmune haemolytic anaemia lead to haemolysis?

Answer 34

The spherocytes are less flexible than normal red cells

The combination of cell rigidity and recognition of antibody AND complement on the red cell surface by splenic macrophages leads to removal of cells from the circulation by the spleen

Question 35

Describe the diagnosis of acute haemolytic anaemia.

Answer 35

• Finding spherocytes and an increased reticulocyte count
  
  • Spherocytosis → increased extravascular haemolysis → premature reticulocyte release from bone marrow as compensation
• Detecting immunoglobulin ± complement on the red cell surface
• Detecting antibodies to red cell antigens or other autoantibodies in the plasma

Question 36

How can autoimmune haemolytic anaemia be treated?

Answer 36

• Use of corticosteroids and other immunosuppressive agents
  
  • Supraphysiological amount of cortisol has immunosuppressive effects
• Splenectomy for severe cases

Question 37

What is microangiopathic haemolytic anaemia?

Answer 37

Mechanical disruption of the red blood cell membrane in circulation (small blood vessels)

• You get formation of a fibrin mesh due to increased activation of the coagulation system
• The red blood cells are physically cut by these protein networks
• The resulting fragments are the schistocytes on a blood film

Question 38

How can microangiopathic heamolytic anaemia be treated?

Answer 38

• Removing the cause, e.g:
  
  • Teating severe hypertension
    
    • Hypertension → atherosclerosis → thrombosis
  • Stopping a causative drug
    
    • e.g. a pro-thrombotic drug
• Plasma exchange when it is caused by an antibody in the plasma that is leading indirectly to fibrin deposition

Question 39

What is polycythaemia?

Answer 39

A high concentration of red blood cells in your blood

Question 40

Which red blood cell parameters are increased in polycythaemia compared with normal subjects of the same age and gender?

Answer 40

• RBC
• Hb
• Hct

Question 41

What is the difference betwee true and pseudo- polycythaemia

Answer 41

True = increase in total volume of red cells in the circulation

Pseudo- = reduced plasma volume

Both of these would lead to an increased RBC concentration

Question 42

State some causes of true polycythaemia

Answer 42

Too much blood:

• Blood doping
  
  • Blood transfusion one’s red cell count to improve athletic performance
• Over-transfusion by medical negligence

Appropriately increased erythopoeitin:

• High altitude → hypoxia

Inappropriately increased erythropoeitin:

• Erythropoietin is inappropriately administered to haematologically normal subject
  
  • Same end result and intention as blood doping
• Renal or other tumour inappropriately secretes erythropoietin
  
  • Mainly renal tumour - since kidneys are the normal site of erythropoeitin production
  • Other tumour site - e.g. liver

Abnormal bone marrow function:

• Inappropriately increased erythropoiesis that is independent, or largely independent, of erythropoietin
• This condition is an intrinsic bone marrow disorder called polycythaemia vera
• It is classified as a myeloproliferative neoplasm
  
  • This is overproduction of blood cells in the bone marrow
  • Arise from myeloid stem cell lineages - i.e. abnormal stem cell proliferation

Question 43

What are the consequences of polycythaemia?

Answer 43

Hyperviscosity of the blood - i.e. thick blood

• This can lead to vascular obstruction

Question 44

How can polycythaemia be treated?

Answer 44

• If there is no physiological need for a high haemoglobin, or if hyperviscosity is extreme, blood can be removed to thin the blood
• If there is intrinsic bone marrow disease, drugs can be used to reduce bone marrow production of red cells

Question 45

How might the following contexts help you interpret a FBC showing polycythaemia?

Answer 45

• A young healthy athlete - be very suspicious
• A breathless cyanosed patient ‒ probably due to hypoxia
• An abdominal mass ‒ it could be carcinoma of the kidney
• Splenomegaly ‒ a pointer to polycythaemia vera
  
  • Excessive red blood cell production by bone marrow
  • This results in an increased number of red blood cells that need to be filtered by the spleen → splenomegaly