1. Red Blood Cells and Haemoglobin

Question 1

How are red blood cells (RBCs) produced?

Answer 1

The process of RBC production - called erythropoiesis.

Production of RBCs is controlled by erythropoietin,

a hormone produced in the kidneys.

RBCs start as immature cells in the 
red bone marrow and 
after about seven
days of maturation they 
are released into the bloodstream. 

The stages of
RBC formation are:
Proerythroblast → 
Prorubricyte → 
Rubricyte → 
Normoblast →
Reticulocyte 
(nucleus ejected by this phase, allowing the centre of the cell to indent giving the cell its biconcave shape – these now squeeze out of the bone marrow and
into the circulation) → 
Erythroblast

Hypoxia (e.g. altitude or anaemia) stimulates the kidney to release erythropoietin,

which acts on the red bone marrow
where it increases the
speed of reticulocyte formation.

Question 2

How are worn out RBCs removed
from the circulation?

Survival

What happens to membrane

Destroyed by?

Answer 2

RBCs survive for about 120 days.

Their cell membranes are exposed to a
lot of wear and tear as
they squeeze through blood capillaries.

Without a nucleus and other organelles,
RBCs cannot synthesise new components.

Worn out RBCs are removed from the 
circulation and destroyed by fixed
phagocytic macrophages 
in the spleen and the liver 
and the breakdown products are recycled.

Question 3

What happens to the breakdown

products of RBCs?

Answer 3

Haemoglobin gets split into
its haem and globin components –

the globin
is broken down into amino acids

and the haem gets broken
down into iron and biliverdin.

The iron combines with the
plasma protein transferrin,
which transports the iron in the bloodstream.

In the muscle, liver and spleen,
iron detaches from transferrin
and combines with iron-storing proteins –
ferritin and haemosiderin.

When iron is released from its storage site
or absorbed from the gut,
it combines with transferrin a
nd gets transported to the
bone marrow where it is used for RBC production.

Biliverdin gets converted into bilirubin,
which enters the circulation
.and is transported to the liver where
it is secreted into the bile.

Question 4

Why is haemoglobin essential?

Answer 4

Oxygen is relatively insoluble in water
and therefore only approximately 1.5%
of total oxygen is carried dissolved in the plasma.

The remaining 98.5% is bound to haemoglobin.

Haemoglobin increases the oxygen-carrying capacity
of blood approximately 70-fold.

Question 5

Describe the molecular structure

of haemoglobin.

Answer 5

The haemoglobin molecule is a

tetramer composed of four subunits.

Each subunit consists of a polypeptide chain (globin)
in association with a haem group.

A haem group consists of a
central charged iron atom
held in a ring structure called a porphyrin.

Different forms of haemoglobin exist
depending on the structure of these
polypeptide chains.

In normal adults 98% of all haemoglobin
is in the form of HbA1 (2 α chains and 2 β chains).

The remaining 2% is in the form of HbA2
(2 α chains and 2 δ chains).

Fetal haemoglobin (HbF) is composed of
2 α chains and 2 γ chains. 

HbF changes to HbA at around six months of life.

Question 6

What happens to haemoglobin in sickle cell anaemia?

Answer 6

Sickle cell anaemia is an inherited

autosomal recessive blood disorder

in which there is an abnormal β polypeptide chain

due to a genetic mutation in the amino acid sequence

where the amino acid valine
is replaced by glutamic acid.

In the heterozygous state this confers
an advantage against malaria
as the shortened lifespan of the erythrocyte
prevents th blood-borne phase of the mosquito
from completing its life cycle.

In the homozygous state the
abnormal haemoglobin is susceptible
to forming solid, non-pliable sickle-like structures when exposed to low PaO2,

causing the erythrocytes to obstruct the microcirculation,
leading to painful crises and infarcts.

Question 7

What happens to haemoglobin in thalassaemia?

Answer 7

Thalassaemia is an inherited
autosomal recessive blood disorder in which
the genetic defect results in a

reduced rate of synthesis of one of the
globin chains that make up haemoglobin.

This can result in the formation of
abnormal haemoglobin molecules,
causing anaemia.

Thalassaemia can be α or β depending on which globin chain is being underproduced.

Thalassaemia is a quantitative problem where
too few globin chains are synthesised,

whereas sickle cell anaemia is a
qualitative problem with the
synthesis of an incorrectly
functioning globin chain.

Question 8

How does oxygen bind to haemoglobin?

Answer 8

Oxygen binds to the ferrous iron (Fe2+) 
in haemoglobin by forming a reversible bond. 
.
There is no oxidative reaction 
and so the iron atom always
remains in the ferrous form.

In the condition methaemoglobinaemia,

the ferrous iron is oxidised into the ferric (Fe3+) form.

Each molecule of haemoglobin can bind

four molecules of oxygen
(i.e. one at each ferrous ion within each haem group).

There are several factors that
influence binding including
local oxygen tension,
local tissue environment
(temperature, CO2, hydrogen ions and 2,3 DPG)
and the allosteric change
and cooperative binding behaviour of oxygen to haemoglobin

Question 9

Can the dissolved fraction of

oxygen be dismissed?

Answer 9

Even though dissolved oxygen represents
a small fraction of total oxygen carrying
capacity of the blood,

it still constitutes an important fraction.

Severe anaemia illustrates the point,

e.g. for a Jehovah’s Witness who has
experienced a massive intra-operative haemorrhage and refuses blood transfusion.

One therapeutic option would be the use of
hyperbaric oxygen therapy; at three atmospheres and using 100% oxygen the dissolved fraction
of oxygen would meet total body oxygen requirements.

The dissolved fraction of oxygen is also responsible for triggering the hypoxic respiratory drive.

This is of clinical significance in patients with COPD who are chronic CO2 retainers,
because giving them high-flow oxygen to increase
their PaO2 may lead to loss of their hypoxic drive.

In 2008, the British Thoracic Society published guidelines on the use of emergency oxygen in adults.

The guidelines recommend that oxygen be
administered to patients whose oxygen saturations fall below the target
range (94–98% for most acutely ill patients and 88–92% for those at risk of
type 2 respiratory failure with raised CO2 levels in the blood).