25A06: Exam Report

With respect to red blood cell production, outline the following:
1. the site (10% of marks).
2. the stimuli (5% of marks).
3. the process (15% of marks).
With respect to red cell breakdown, outline the following;
1. the usual lifespan in neonates and adults (10% of marks).
2. the process of red cell aging, degradation and clearance (40% of marks).
3. the process of haemoglobin breakdown (20% of marks).

72% of candidates passed this question.

The explicit structure and mark allocation provides a guide to answering this question and was applied appropriately in most instances.

There were no marks awarded for the structure-function relationship of red cells and this information may reflect awareness of past questions on the topic with a different emphasis.

More detailed answers included information such as different site of production in the fetus, duration of time for erythropoesis (7 days), changes in aging red blood cells, and different clearance pathways [haemolysis (10%) and spleen and liver phagocytosis (90%)].

Haemoglobin breakdown in general was well answered and needed to include heme breakdown into iron and biliverdin and a description of the fate of each of these components.

Q1i / 25A06: With respect to red blood cell production, outline the following

A

i

Derived
- yolk sac at 3-4 weeks of foetal life.
- Liver and spleen from 6 weeks to 7 months of foetal life
At 7 months gestation, bone marrow = main source
From birth, blood cells solely from marrow.
Fatty replacement of long bones as one ages → haemopoiesis from 18 years of age confined to central skeleton, proximal ends of femur, humerus.

ii

Production dependent on haemopoietic growth factors:
- EPO (in kidney, key for RBC differentiation, maturation and proliferation).
  - Half-life 6-9 hours
  - Produced by interstitial peritubular cells of kidney (90%) and liver (10%)
- Stem cell factor (acting on Pluripotent Hematopoietic Stem Cells (PHSC) to begin differentiation)

iii

Duration 7 days
PHSC → Myeloid stem cell → CFU (erythroblast) → Proerythroblast → Basophilic erythroblast → polychromatic erythroblast → pyknotic erythroblast via mitosis and then → Reticulocyte via maturation.
- Erythroblasts contain progressively more Hb and nuclear chromatic condenses.
- Eventually the pyknotic nucleus is expelled in the late erythroblast to form the reticulocyte which enters circulation.
- Figure 51.2 Red Blood Cell Development
Reticulocytes have some RNA capable of Hb synthesis but then mature over 1-2 days and lose this RNA.
The final maturation of RBCs requires Vitamin B12 and folic acid key for synthesis of thymidine triphosphate, essential for DNA formation.

B

i, ii

Mature RBCs survive for 120 days in circulation and are removed by phagocytosis in the reticuloendothelial system (RES) in the spleen and liver.
Neonatal RBC = 60-90 day lifespan (fetal Hemoglobin, immature RES, oxidative stress)
As RBCs age, decreased ATP generation due to inefficiency of:
- Embden-Meyerhof pathway (anaerobic glycolysis)
- Hexose monophosphate shunt
  - 5% of glucose undergoes oxidation by this shunt
  - NADPH is formed from NADP
  - This is linked to glutathione generation
- Methaemoglobin reductase pathway
- Rapoport-Leubering shunt
- Figure 51.6 →
Glutathione (from above) helps maintain the integrity of the RBC membrane
Deficiency of NADPH (ageing) leads to haemolysis due to accumulation of hydrogen peroxide which weakens the membrane.
Thus, ageing → decreased ATP production + membrane instability → diminished cellular integrity → RBC destruction by RES in liver and spleen.

iii

RBC Damage and Bilirubin Metabolism Pathway

graph TD A[67d / damaged RBC
rupture + release of Hb, phagocytes by act. M] --> B[HEME] A --> C[GLOBIN
α-acids
recycled] B --> D[opened by
HEME OXYGENASE] D --> E[BILIVERDIN] D --> F[FREE IRON Fe++] E --> G[BILIVERDIN
REDUCTASE] G --> H[UNCONJUGATED
BILIRUBIN] H --> I[- lipid soluble
- toxic
- easily crosses
placenta / BBB] I --> J[bound to ALBUMIN] J --> K[carried to liver] F --> L[transported to blood
by TRANSFERRIN &
recycled] K --> M[PRE-HEPATIC] M --> N[taken up by hepatocytes via
FACILITATED DIFFUSION] N --> O[UGT family enzymes conjugate
with bilirubin & Glucuronic Acid] O --> P[CONJUGATED
BILIRUBIN
- h2o soluble] P --> Q[excreted into Bile by
ACTIVE TRANSPORT] Q --> R[BILE] R --> S[excreted
into SI] R --> T[stored in GB] S --> U[In ileum/colon
converted to] U --> V[UROBILINOGEN
by bacteria by
removing Glucuronic Acid] V --> W[UROBILINOGEN
- lipid solv
- 10% reabsorbed & transp by Albumin
- 90% further oxidized to] W --> X[STERCOBILIN] X --> Y[excreted in feces] W -.->|enterohepatic circ| Z[URINE] Z --> AA[EXTRA
HEPATIC] style A fill:#ffcccc style B fill:#ffcccc style E fill:#ffcccc style F fill:#ffcccc style H fill:#ffcccc style C fill:#ffcccc style P fill:#ffcccc style R fill:#ffcccc style V fill:#ffcccc style W fill:#ffcccc style X fill:#ffcccc

Sources: Kam and Power, 4^th Edition

Author: Alex Fagarasan

25A06: Exam Report

With respect to red blood cell production, outline the following:

the site (10% of marks).

the stimuli (5% of marks).

the process (15% of marks).

With respect to red cell breakdown, outline the following;

the usual lifespan in neonates and adults (10% of marks).

the process of red cell aging, degradation and clearance (40% of marks).

the process of haemoglobin breakdown (20% of marks).

Q1i / 25A06: With respect to red blood cell production, outline the following

A

i

ii

iii

B

i, ii

iii