Red Blood Cell Production

Question 1

Describe the process of erythropoiesis.

Answer 1

Start of with the stem cell, which becomes the Proerthroblast. Then when we have the early (basophilic) erythroblast we have “Phase 1” occurring in the cell which is ribosome synthesis.
Then this differentiates into the late (polychromatophil) erythroblast. Haemoglobin starts to accumulate in the cell as it is synthesized.
In the normoblast stage the nucleus gets extruded and we get the reticulocyte which has no nucleus (Hb is still being formed from left over mRNA). Eventually we get the erythrocyte.

Question 2

What is the main hormone which controls erythropoiesis and how does it stimulate production?

Answer 2

Erythropoietin (EPO). Erythropoietin is a glycosylated polypeptide hormone, 90% is produced by the kidneys (and is only produced when needed, it is not stored). It stimulates the bone marrow to produce red blood cells.

Question 3

What is the main stimulus of EPO production and how is it detected?

Answer 3

Reduced O2 blood tensions detected while the blood passes through the kidney tissues. Anything that causes low levels of O2 in the blood e.g. high altitude, renal issues, [Hb] issues will stimulate EPO secretion.

Question 4

Where is EPO produced?

Answer 4

Peritubular interstitial cells of outer cortex.

Question 5

What are the components that are required for RBC production?

Answer 5

• Haemocytoblast
• Iron and globin
• Vitamin B12 and folic acid
• Along with EPO to stimulate

Question 6

At which points in erythropoiesis is Hb synthesised and where in the cell does synthesis occur?

Answer 6

65% of Hb is synthesized in the erythoblast and 35% at the reticulocyte stage.
The haem synthesis mainly occurs in the mitochondria and globin synthesis occurs on polyribosomes.

Question 7

How does Iron (Fe), which is required for harm synthesis, enter the cell?

Answer 7

Circulating Fe is bound to transferrin (two Fe to one transferrin) and when it comes to the cell it binds to a transferrin receptor on the cell and undergoes endocytosis. The Fe is released into the cytoplasm and is stored (and transported around) in the cell as ferritin.

Question 8

What does Fe combine with (in the mitochondria) to produce haem?

Answer 8

Protophorphyrin

Question 9

How is Protophorphyrin formed in the mitochondria?

Answer 9

Glycine, vitamin B6 and succinyl CoA will react (catalyzed to produce δ - ALA) which then undergoes various reactions within the cytoplasm and re-enters the mitochondria now as protoporphyrin.

Question 10

How is the final Haemoglobin molecule formed?

Answer 10

Haem leaves mitochondria into the cytoplasm where it combines with the 4 globin chains (2 alpha, 2 beta).

Question 11

Where does Iron come from in our diet?

Answer 11

Meat, eggs, vegetables and dairy foods, a normal western diet provides around 15mg daily.

Question 12

What are the potential causes of iron deficiency?

Answer 12

• Decreased uptake due to inadequate intake in diet or malabsorption in GI tract
• Increased demand by our body e.g. in pregnancy or if we’re having a growth spurt
• Increased loss of iron due to GI bleed or during menstruation

Question 13

What are the symptoms of iron deficiency?

Answer 13

Leads to microcytic anaemia (most common). The red cells are much smaller and have low levels of Hb.

Question 14

Why are vitamin B12 and folic acid (folate) important for maturation of RBC’s?

Answer 14

Folic acid is essential for DNA synthesis, being involved in formation of thymidine triphosphate.
B12 is a coenzyme for methionine synthase in methylation of homocysteine to methionine.

Question 15

What are the causes of vitamin B12 deficiency?

Answer 15

• Inadequate uptake e.g. vegans
• An absorption defect like blind loop syndrome, tropical sprue or coeliac deficiency
• IF deficiency (B12 usually binds to intrinsic factor (IF) so if you have a deficiency you cannot transport B12 to the bone marrow) may be caused by pernicious anemia, gastrectomy (as IF found in small intestine) and crohns.

Question 16

What are the causes of folate deficiency?

Answer 16

• Inadequate intake, a folate free diet causes deficiency within a few weeks
• Malabsorption e.g. coeliac disease
• Excess utilisation of folate e.g. pregnancy, haemolysis, cancer
• Drugs e.g. anticonvulsants may induce malabsorption of folate

Question 17

What are the symptoms of a Vitamin B12/Folate deficiency?

Answer 17

Macrocytic (large RBC) anaemia. We may also have reduced WBC and platelet count, megaloblastic (larger nuclei) change in bone marrow, megaloblastic anaemia, sore tongue, abnormal gut mucosa.
In B12 deficiency you also may get demyelination of CNS.

Question 18

What is the typical lifespan of a RBC and what contributes to an RBC’s longevity?

Answer 18

Lifespan of about 120 days, during which a great amount of stress is placed on it. The ability of the RBC’s to deform will influence their longevity.

Question 19

Give examples of hereditary and acquired haemolytic anaemia.

Answer 19

Hereditary:
- Haemoglobinopathies - sickle cell diseases, thalassaemias.
- Red cell enzymopathies - G6PD deficiency, PK deficiency.
- Red cell membrane disorders - hereditary spherocytosis, hereditary elliptocytosis.
Acquired:
- Immune - autoimmune, alloimmune, drug induced.
- Non-immune - red cell fragmentation, infection - secondary.

Question 20

On what chromosomes are the global genes present?

Answer 20

Occurs on chromosomes 11 & 16 in clusters.

Expression of α and β globin closely balanced.

Question 21

What does a mutation (deletion) in global gene lead to?

Answer 21

Abnormal synthesis of globin chain as in sickle diseases.

Reduced rate of synthesis of normal α or β globin chains as in Thalassaemias.

Question 22

What is the difference between α-Thalassaemia and β-Thalassaemia?

Answer 22

In Alpha: There can be loss of 1, 2, 3, or 4 alpha chains.
In Beta:
Loss of 1 β-chain causes mild microcytic anaemia (thalassaemia trait).
Loss of both (β0) causes thalassaemia major.
Excess α-chains precipitate in erythroblasts causing haemolysis and ineffective erythropoiesis.

Question 23

Name the 2 main RBC enzymes and the 2 metabolic pathways they support.

Answer 23

• Glucose-6-phosphate dehydrogenase (G-6-PD) - Pentose phosphate pathway.
• Pyruvate kinase (PK) - Glycolytic pathway.

Question 24

What happens when a patient has G6PD deficiency?

Answer 24

NADPH and GSH generation impaired.
Acute haemolysis on exposure to oxidant stress - oxidative drugs, fava beans (broad beans), or infections.
Hb precipitation - Heinz bodies.
G6PD deficiency = enzymopathy.
Affects 400 million people worldwide.
**It has has an evolutionary benefit - people with this are not seriously affected by malaria.

Question 25

What is the glycolytic pathway?

Answer 25

Generates ATP to maintain red cell shape and reformability.

Regulates intracellular cation concentration via cation pumps.

Question 26

What happens when a patient has PK deficiency?

Answer 26

ATP depleted cells lose large amounts of potassium and water, ∴ becomes dehydrated and rigid.
Cation pumps fail to function.
Causes chronic, non-spherocytic haemolytic anaemia.
Excessive haemolysis leads to jaundice, gallstones.

Question 27

What is Jaundice (in RBC)?

Answer 27

Jaundice is an accumulation of bilirubin which is what RBC’s break down into. This also leads to gallstones.