Haemolyti Anaemias An Haemoglobinpathies

Question 1

Overarching definition of thalassaemia

Answer 1

Reduced rate of synthesis of normal alpha or beta globin chains. More frequently present in south Asian, middle or Far Eastern. Alpha globin chain on chromosomes 16 and beat globin chain on chromosome 11

Question 2

How does thalassaemia cause anaemia

Answer 2

Normally have a 1;1 ratio of alpha and beta globin chains but in thalassaemia have different amounts. This leads to the chain in excess forming aggregates and an imbalance in the b/a tetramer meaning less haemaglobin present for oxygen transport.

Question 3

How many of each globin chain in haemoglobin and on which chromosomes are they found

Answer 3

2 beta (found on chromosome 11) and 2 alpha (found on chromosome 16) BUT have 4 globin genes coding for the 2 alpha chains (2 from each parent). 2 from each parent

Question 4

What is beat thalasaemia minor

Answer 4

Where one of the beta globin chains has a mutation. Causes microcytosis but total level of blood is normal as bone marrow responds by producing more RBC. Only time get anaemia is during pregnancy or a persistent infection

Question 5

What is beta thalassaemia major

Answer 5

Synthesis of globin chains is totally absent due to both having a mutation. Need blood transfusion for 1st couple moths of life because cant produce HbA to replace HbF due to lack of beta globin chains

Question 6

What happens when all 4 genes are deleted of lost during alpha thalassaemia

Answer 6

Death in Utero. Cant survive

Question 7

What happens if only 1 of alpha genes is deleted in alpha thalassaemia

Answer 7

It’s silent. Patients are asymptomatic without anaemia

Question 8

What is haemoglobin H disease.

Answer 8

Where 3 alpha globin genes aren’t functional. Leads to severe microcytosis, anaemia, haemolytic and splenomegaly

Question 9

What happens when 2 globin genes are deleted. Normal alpha thalasaemia

Answer 9

Minimal anaemia but shows microcytosis and hypochromia

Question 10

Differences between thalassaemia major, intermedia and minor

Answer 10

Major- transfusion dependant
Intermedia - require transfusion intermittently
Minor- require no transfusion

Question 11

Consequences of thalassaemia

Answer 11

Extramedullary haemopoesis- making RBC outside of bone marrow. Results in splenomegaly, hepatomegaly (because making RBC here) and haemopoesis in the bone cortex which can impair growth
Also less o2 = EPO = more defective red cells = iron overload.
Overall reduced life expectancy

Question 12

Treatment of thalasaemia

Answer 12

Transfusions
Iron chelation (bind to iron so excess of it doesn’t cause harm)
Folic acid
Immunisation (becomes immunocompromised due to overactive spleen)
Stem cell trasnsplantation (v rare)
Pre conception counselling holistic care

Question 13

What is sickle cell disease

Answer 13

Common Hb variant is HbS found often in west Africans. Gives resistance to malaria. Also can have sick-b-thalasaemia, HbS/C or HbS/E. HbS has uncharged valine instead of charged glutamic acid.

Question 14

What happens to RBC with HbS at low oxygen

Answer 14

Polymerise deforming it to a sickle shape. After repeated episodes of this cell loses elasticity and fails to return to normal shape when normal oxygen levels return

Question 15

4 consequences of sickle cell formation

Answer 15

Vaso-occlusive episodes- sickle cells get trapped and blocks capillaries causing pain
Anaemia- sickle cells undergo early haemolytic due to suckling
Jaundice- (and gallstones) due to increased bilirubin
Splenic atrophy - due to splenic infarction due to vasooclussion. This can lead to increased risk towards encapsulated bacteria

Question 16

Sickle cell treatment

Answer 16

Haemopoetic stem cell transplantation
Folic acid
Hydroycarbomide - increase Hb
Red cell exchange

Question 17

Inherited causes of haemolytic anaemia

Answer 17

Glycolysis defect - pyruvate kinase deficiency limits ATP production
Penthouse p pathway - G6PDH deficiency leads to oxidative damage
Membrane protei e.g herdiatary spherocytosis
Haemoglobin defect e.g sickle cell

Question 18

Acquired causes of haemolytic anaemia

Answer 18

Mechanical damage - microangiopathic anaemia
Antibody damage - autoimmune haemolytic anaemia
Oxidant damage - exposure to chemicals
Heat damage - severe burns
Enzymatic damage - snake venom

Question 19

How can mechanical damage cause miroangiopathic haemolytic anaemia

Answer 19

Red cells are damaged by physical trauma. May be due to cells being damaged by shear stress as the pass through defective heart valve e.g in aortic valve stenosis
Disseminated intracapsular coagulation - bleeding and clotting occur at same time which means RBC damaged by vessel laden with fibrin strands (due to increased activation of coagulation cascade.

Question 20

What are the shape of red blood cells present after mechanical damage

Answer 20

Schistocytes - red blood cell fragments almost

Question 21

What causes immune haemolytic anaemia

Answer 21

Infection, lymphoproliferative disorders e.g leukaemia or reactions to drugs e.g cephalosporins

Question 22

What do warm autoimmune haemolytic anemia’s cause

Answer 22

React best in warm temps. Antibodies (IgG) recognise epitomes on RBC membrane. Macrophages in spleen recognise them once antibody has bound and remove cell or nibble bit off = spherocytosis. Causes splenomegaly because spleen does extra

Question 23

What happens during cold autoimmune haemolytic anaemia

Answer 23

IgM autoantibodies recognise red cell epitopes. Bind best at cooler temps e.g in fingertips. Bind causing agglutinate which blood capillaries causing ischeamic conditions causing numb finger (or other distal parts of body). When get back into warmer space IgM falls off BUT may have created hole in membrane or macrophage might recognise it in spleen and destroy the cell

Question 24

What causes anaemia in a pyruvate kinase defiancey

Answer 24

Pyruvate kinase needed to catalyse final step in glycolysis. Since RBC lack mitochondria glycolysis is only ATP supply. Without it K+/Na+ atp dependant pump doesn’t work and red cells lose K+ to plasma. Water follows down conc gradient and cell shrinks and dies

Question 25

What causes anaemia in a G6PDH deficiency

Answer 25

It’s rate limiting enzyme of lentos phosphate pathway which produced NADPH. Need NADPH to protect against oxidative stress and maintaining levels of glutathione. This is RBC only source and therefore in infection or exposure to medication RBC are under threat from oxidative stress and phagocytosis in the spleen. = jaundice.

Question 26

Mutations which cause hereditary spherocytosis

Answer 26

Spectrin - links plasma membrane to actin cytoskeleton
Ankyrin - links integral membrane protein to spectrin-actin cytoskeleton
Band 3 - involved in linkage of cytoskeleton to plasma membrane
Protein 4.2 - regulated association of protein 3 with ankyrin

Question 27

Why are the 4 previously mentioned protein important in membrane structure

Answer 27

Facilitate vertical interaction between cytoskeleton and plasma membrane. Disruption of this would reduce membrane surface area Because membranes is unsupported resulting in a spherocyte.

Question 28

How do spherocytes cause anaemia

Answer 28

Spherocytes are un-flexible and become trapped and damaged as they pass through spleen reducing their life span by haemolysis.

Question 29

Symptoms of some one with hereditary spherocytosis

Answer 29

Jaundice, splenomegaly and Howell-jolly bodies seen. Mild patients don’t require treatment but those with more severe may need splenectomy as spherocytes no longer lasted by spleen