Blood Physiology

Erythropoiesis
 objectives:

1- RBCs origin.
2- regulation of erythropoiesis
3- Erythrocytes metabolism
4- Types of anemia
5- Causes of Polycythemia
 Red blood cells (erythrocytes):

• The primary functions of red blood cells are to transport

oxygen from the lungs to the various tissues of the body, and
to transport carbon dioxide from the tissues to the lungs.

• Red blood cells (RBCs) are non-nucleated,biconcave discs.

• Because they lack of mitochondria and ribosomes, RBCs are

incapable of aerobic respiration,This prevents them from
consuming the oxygen they are meant to transport to other
tissues.
• The red cell membrane is flexible and exhibits a
remarkable deformability; the RBC being able to
change its shape as it passes through narrow capillaries
and then return, undistorted, to its original biconcave
shape.

• The biconcave shape of the RBC, which provides a high

surface to volume ratio, allows for maximum surface
area (which facilitates gas transport) and greatest
deformability.

• Cytoskeletal proteins (spectrin and actin) give

membrane durability and flexibility to withstand the
stretch and bend as squeezed through small capillaries
Circulating erythrocytes live for about 120 days.
• As an RBC ages and its membrane proteins
(especially spectrin)deteriorate, the
membrane grows increasingly fragile. Without
a nucleus or ribosomes, an RBCcannot
synthesize new spectrin.

• Many RBCs die in the spleen, which has been

called the "erythrocyte graveyard.“

• The spleen has channels as narrow as 3 μm

that severely test the ability of old, fragile
RBCs to squeeze through the organ.
• An enlarged and tender spleen may indicate diseases in
which RBCs are rapidly breaking down.

• The average normal RBC count in adult male is

5,200,000 ± 300,000 per microliter of blood, and in
adult female is 4,700,000 ± 300,000 per microliter of
blood.

• At birth, the average RBC count is about 5,700,000 per

microliter of blood.

• The number of RBCs varies with age, sex, and altitude.

Each RBC has a mean diameter of about 7.5
micrometers and a thickness of 2.5 micrometers at the
thickest point and 1 micrometer or less in the center.
 Erythropoiesis:
•
Erythropoiesis: It is the process of erythrocyte
formation or production.

• Erythropoiesis occurs at different anatomical

sites during the course of development from
embryonic to adult life.
 Stages of Erythropoiesis (Stages of
differentiation of RBCs):
• Maturation proceeds with hemoglobin formation in the cytoplasm.

• After the cytoplasm of late normoblast is filled with hemoglobin

and the nucleus is extruded from the cell and the endoplasmic
reticulum is reabsorbed, at this stage the cell is called reticulocyte.

• During the reticulocyte stage, the cell passes to the blood and after
1-2 days in blood, it becomes mature erythrocyte.

• The concentration of reticulocytes among all the red cells of the

blood is normally0.5% -1.5% in adults.

• Reticulocyte count is used as a clinical measurement of

erythropoietic activity.The basic substances needed for normal RBC
and hemoglobin production are amino acids (proteins),iron, vitamin
B12, folic acid, and vitamin B6.
• Regulation of erythropoiesis: The main factor
stimulating RBC production is hypoxia(O2 deficiency
inside the cells).

• Any condition that causes the quantity of O2

transported to the tissues(O2 carrying capacity of the
blood) to decrease (decreased tissue oxygenation),
increases the rate of RBC production.

Examples on factors that decrease tissue

oxygenation are:
1. At very high altitudes, O2 quantity in air is
greatly decreased, and insufficient O2 is transported to
the tissues.
2. Diseases of the heart and lungs.
3. Anemia.
• On the other hand, when the rate of O2
transport to the tissues rises above normal,
the rate of RBC production is depressed.

• Hypoxia increases the rate of RBC production

by stimulating the secretion of the important
regulating hormone "erythropoietin". So
hypoxia does not act directly on bone marrow,
but it causes marked increase in
erythropoietin production and the
erythropoietin stimulates RBC production until
tissue hypoxia is relieved .
• In the normal person, about 90% of all erythropoietin is formed in
the kidneys, and the remainder is formed in other tissues, mainly
the liver.

…. It has a half-life of hours and is broken down in the liver.

• When both kidneys are removed from a person or when the

kidneys are destroyed by renal disease, the person invariably
becomes very anemic, because only 10% of the normal
erythropoietin formed in other tissues (mainly in the liver) which
are insufficient to form RBC needed by the body.

• Other factors stimulating erythropoietin production include

androgens, cobalt salts, epinephrine and norepinephrine, and
several of the prostaglandins.

• Androgens (male sex hormones) can also stimulate erythropoietin

production, and it is for this reason that RBC count in male is more
than in female.
Effect of erythropoietin on erythropoiesis:
• Erythropoietin is a glycoprotein.
• It stimulates formation of proerythroblasts from committed stem
cells (CFU-E) in bone marrow, and once these proerythroblasts are
formed, the erythropoietin causes these cells to pass more rapidly
through the different erythroblastic stages than normally, further
speeding up the production of new cells.

• The rapid production of cells continues as long as the person

remains in the low oxygen state or until enough red blood cells are
produced to carry adequate amount of O2 to the tissues despite
the low oxygen. At this time, the rate of erythropoietin production
decreases to a level that will maintain the required number of red
cells but not an excess.

• IL-1, IL-3, IL-6, and GM-CSF also play part in erythropoiesis by their
role in the development of the CFU-E stem cells.
• Human erythropoietin can be produced by
recombinant deoxyribonucleic acid (DNA)
technology.

• It is used for management of anemia in cases

of chronic renal failure, for treatment of
chemotherapy induced anemia in persons
with malignancies, and treatment of anemia
in persons with human immune deficiency
virus (HIV) infection who are being treated
with zidovudine.
 Erythrocyte metabolism:
• The RBC anaerobic glycolysis is importance for the
following reasons:
1. Provide energy, in terms of ATP molecules, to various
biological activities of RBCs .
2. Provide Nicotinamide adenine dinucleotidephosphate
(NADPH) against oxidative stress.NADPH is the reduced
form of NADP+.

The only source of NADPH in RBCs is via the Hexose

monophosphate shunt.
Erythrocytes require NADPH to maintain normal levels
of reduced glutathione (GSH) that is required to counteract
against oxidative stress.
• This is because oxygen is toxic and without reduced
glutathione, peroxides spontaneously formed from
molecular oxygen would oxidize the lipid components of
the red blood cell membranes.

• Oxidized membranes are significantly less flexible than

normal membranes, and result in damage to the red blood
cells when the cells attempt to transit capillaries.

• In addition, peroxides tend to damage hemoglobin,

resulting in precipitation of the protein. Insoluble
aggregates of hemoglobin have severely impaired oxygen
carrying capacity, and insoluble protein aggregates tend to
be inflexible enough to prevent the normal deformations of
the red blood cell.
 3. Provides nicotinamide adenine dinucleotide
(NAD+) in red blood cells is required to keep the Hb
inferrous state. Oxygen tends to oxidize the
hemoglobin iron from +2 to the more stable +3
oxidationstate (resulting in methemoglobin). This is a
problem: the +3 state of heme iron binds oxygen very
poorly.

NAD+ is used to supply reducing equivalents to

methemoglobin reductase, the enzyme that returns
the hemoglobin to the +2 oxidation state.

4. To produce 2,3 diphosphoglycerate through

Rapaport-Luebering pathway for regulation of Hb
affinity to O2.
 Anemia:
• Anemia: It is defined as a reduction in blood Hb level
and/or in RBC count below the normal range for the
patient's age and sex.

• Classification of anemia: Anemia can be classified,

according to the cause, into anemia due to:
1. Inadequate production of normal RBCs by the bone
marrow.
2. Excessive destruction of RBCs (hemolysis).
3. Blood loss (hemorrhage).
• Inadequate production of normal RBCs by the
bone marrow:
• Examples:
1. Due to deficiency of essential factors (iron, vitamin B12
and folic acid).

2. Aplastic anemia (bone marrow aplasia).

• Vitamin B12 and Folic acid are required for DNA synthesis,
so they are important for maturation of RBCs.

• If B12 or folic acid is deficient, DNA synthesis and nuclear

maturation is slowed, where as cytoplasmic maturation
(largely dependent on RNA function) is relatively
unimpeded.
• Consequently,erythropoiesis is delayed with production of the
erythroblastic cells in the bone marrow, which grow but cannot
divide rapidly and become larger than normal (called
megaloblasts).
• The production of larger than normal erythrocytes (called
macrocytes) which are abnormal in shape and break easily leading
to decreased number of RBCs in blood and anemia develops which
is called megaloblasticanemia or maturation failure anemia.

• B12 deficiency can occur due to lack of B12 in diet or more

commonly due to lack of a factor (intrinsic factor) which is secreted
by gastric mucosa and is bound to B12 so that to protect it from
digestive enzymes and also assists in absorption of vitamin B12 in
the ileum.

• In a condition called "pernicious anemia" there is failure of

secretion of intrinsic factor by stomach due to atrophy of gastric
mucosa,so megaloblastic anemia develops.
• In aplastic anemia, bone marrow may be
destroyed and become unable to produce
blood cells, such as following excessive x-ray
exposure or the use of certain drugs that
cause bone marrow aplasia (lack of
functioning bone marrow).
 •• Excessive destruction of RBCs
(hemolysis):
• Hemolytic anemia results from abnormalities of
red cell membrane or Hb, or other causes.

• In which there is excessive destruction of RBCs.

Examples are hereditary spherocytosis (a
common membrane defect, in which the RBCs
are small and spherical in shape, and fragile),

• sickle cell anemia, deficiency of G6PD

(misleadingly also called favism), and
erythroblastosis fetalis
 ••• Blood loss (hemorrhage):
• Acute hemorrhage is loss of large volume of blood
over a short period.
• After rapid hemorrhage, the body replaces plasma
within 1-3 days, but this leaves a low concentration of
RBCs, which will return to normal within 3-4 weeks if
no more hemorrhage occurs.

• Chronic hemorrhage is loss of small volume of blood

over long period.
• Therefore, this person needs continuous formation of
new RBCs, so he needs more iron than normal, with
time if this person doesn't receive extra iron, store of
iron is going to be depleted, and then the person will
suffer from iron deficiency anemia.
 Anemia has potential consequences:
• 1. The tissues suffer hypoxia (oxygen deprivation). Severe anemic
hypoxia can cause life –threatening necrosis of brain, heart, and
kidney tissues.

• 2. Blood osmolarity is reduced. More fluid is thus transferred from

the blood stream to the intercellular spaces, resulting in edema.

It is suggested that the low concentration of Hb in patients with

anemia causes a reduced inhibition of basal endothelium-derived
relaxing factor (NO) activity and leads to generalized vasodilatation
and consequently low blood pressure.

The consequent of low blood pressure may be the stimulus for

neurohormonal activation and salt and water retention.
• 3. Blood viscosity is reduced.

• 4. The heart and lungs also must work harder

to compensate for the blood's low capacity to
carry oxygen.

• Because the heart has to work harder to

get blood and oxygen to the tissues, anemia,
particularly severe anemia, can result in
cardiac failure and arrest.
 Polycythemia:
• Polycythemia: It is an increased concentration of erythrocytes in the
circulating blood that is above normal for sex and age.

• Polycythemia could be:

• 1. Relative polycythemia is due to reduction in plasma volume. This may
occur because of dehydration that occurs in conditions such as diarrhea.

• 2. Absolute or true polycythemia, which could be;

a. Secondary polycythemia that is related to increased erythropoietin
production. It is seen forexample in those living at high altitudes.

b. Primary polycythemia (polycythemia vera) is caused by a gene

aberration that occurs in the cellline that produces the blood cells.

The blast cells continue producing red cells even when too many cells
are already present. This causes excess production of red cells without
erythropoietin stimulus, and usually there is excess production of white
blood cells and platelets as well.
• The principal dangers of polycythemia are
increased blood volume, blood pressure, and
viscosity.
 Factors affecting blood viscosity:

• ■ The plasma proteins and formed elements (red cells, white cells, and
platelets) increase the viscosity of blood.

Of these formed elements, red cells have the greatest effect on

viscosity.Therefore, viscosity is strongly dependent on Hct, as Hct
increases, there is a disproportionate increase in viscosity.

• ■ Temperature: As temperature decreases, viscosity increases (increases ~

2% for each °C decrease in temperature).

• ■ Flow rate of blood: Low flow rates marked increased in viscosity

Increased

• ■ Vessel diameter: Small vessel diameters (e.g., in arterioles less than 300
microns), there is a paradoxical decrease in blood. This occurs because the
hemotocrit decreases in small vessels relative to the hemotocrit of large
feed arteries.