Chap - Blood

15
Sitc of Production

Again there are two

diferent views about the site
production, these are qred cells
(a) Extravascular site, and bone ya an
(b) Intravascular site Smal Cob osies mo e eonwalad

Extravascular site- This

theory suggests that the red blood cells are tormed
extravascularly in the bone marrow, and
thereafter poured int0 the bl0od
Stream, and the rate of
production is regulated through the rate of
of the cell destruct!on

Intravascular site This theory advocates that the red blood cells are formed
intravascularly in closed small
capillaries under bone marrow, and are thrown
into circulation, following their maturation as well as
opening of these closed
capillaries.
The site of red cells
production in the prenatal and post natal
life als0 varies.

Prenatal life

During the embryonic life of the animals,

embryonic yolk sac
(mesoderm) is the first site of red cell
production. During the entire life span
of an animal this is the
only stage of red cells
production when erythropoiesis
Occurs within the blood vessels
(intravascular erythropoiesis), Whereas in
all other stages of the life, the site of red cells
production (erythropoiesis) is
Cxtravascular.

Theprocess of red cell production

during the other stages in the
prenatal life of the individual takes place in the liver, spleen, lymph nodes,
Chap-1. Blood 16

and thymus gland_The formation of red blood cells in

liver, spleen and other
places, during early stages in prenatal life is called
"hepatic stage of red
cell formation"

After the development of bone marrow in the

prenatal life of an

individual, the hepatic stage of red cells formation

begins to
rede stop, and the
bone marrow begins to produce erythrocytes. This stage of red cell
production
in the bone, is called "myeloid stage of red cells formation".

Postnatal life

The red
bonemarrow is the only chief site of red blood cells
production at birth, and throughout the life span of an individual.
Bone marrow
1S Of twO
types : (1) red bone marrow and (i1) yellow bone marrow. The red
bone marrow
produces erythrocytes, leucocytes, and platelets, whereas, yellow
bone marrow cannot
produce any of these formed elements. At birth, all bone
marrows are of red
variety but as the age advances the red marrow iS gradually
replaced by the yellow variety. But in some extreme demands, the liver and

spleen may again begin to generate RBC even in adult life. Further more, in
extreme demand to produce the RBC (in hypoxia), the yellow bone marrow

may be converted into the red bone marrow.

Stages of differentiation

The precursors of the red blood cells are called "stem cells"

(mother cells). This cell gives rise to myeloid as well as lymphatic cells.

These stem cells are not fixed cells. They further migrate to different places
In haematopoietic tissues, that 15, the stem cells migrate to liver (after its

and spleen. After the development of

development during prenatal life), to

bone marrow, these stem cells migrate into bone marrow, and produces blood
Chap - 1. Blood
17

Colony forming
unil-blast Erythrocylcs
Pluripotential
hematopietic stem
cell
Neutropils
Colony
forming
unit (spleen) -Eosinophils

FBasophils

Monocy tes

Colony
formingunit
(mmegakaryocytes) Megakaryocytes
Lymphoid T-Lymphocytes
stem cell

Pluripotential B-Lymphocytes
hematopictic stem
Macrophases
cell
Platelcts

Fig. 1-3. Structure showing different types of committed stem cel ls

cells. As such, these mother stem cells are migrating cells, according to the

development of the haematopoietic tissues

These stem cells in the bone marrow are called "pluripotentiâl

haematopoietic stem cell" (PHSC), which produces all types of blood cells.

These stem cells (PHSC) are also reproduced and maintain itself in the bone

marrow, though their number reduces with age

The pluripotential haematopoietic stem cells which form

erythrocytes, monocytes, lymphocytes, eosinophils, basophils and platelets,

are committed t0 a particular line of cell, and are called "Com mitted stem

cells". The committed stem cells that produce erythrocytes, are called "Colony

forming unit - Erythrocyte" (CFU-E)

Chap -I.
Blood
18
The
following committed stem cells
production of
are formed, based on tRe
a
particular line of cells.
Type of cell production
Committed stem cell
Granulocytes &Monocytes
Colony forming unit granulocytes and
monocytes (CFU GM) -

Erythrocytes Colony forming unit erythrocytes

(CFU - E).
Lymphocytes Colony forming lymphoid stem cell
(LSC)
4
Mega karyocytes
Colony forming unit mega karyocytes
(CFU - M).

For the RBC

forming unit
production, the first identified cell is called "colony
- erythrocyte". This
is
production The proerythroblast is therecognized as first cell for
first precursor of RBC
erythrocyte
Proerythroblasts are also called "Pronormoblasts"
production.
divide several
Proerythroblasts further
times and forms
many mature
cells The first
generation cells following
proerythroblasts, are called "basophilic Procrythroblast
erythroblast", which stain with basic
dyes
with scanty of
hemoglobin. The basophilic
erythroblast gIves rise to
Erythroblast
(Basophil)
polychromatophilic erythroblast which in
turn gives rise to Erythroblast
orthrochromatophilic (Polychromatophil)
erythroblast, filled with hemoglobin (34 %).
The nucleus becomes smaller and
smaller Erythroblast
as the cells mature, and is
absent in the (Orthrochromatic)
reticulocyte and erythrocyte. The removal
Reticulocyte
or extrusion of nucleus and
endoplasmic
reticulum from the stage of orthochromatic Erythrocyte
erythrocyte, is called "reticulocyte". The
reticulocyte contains a small remnant of
golgi apparatus, mitochondria, and a few Fig. 1-4. Stages of RBC formation

other cytoplasmic organelles. The reticulocytes will then pass

into blood
capillaries by the process of diapedesisi.e., Squeezing through the pores of
capillary membrane The remaning basophilic materials present in the
reticulocytes (golgi/mitochodria/cytoplasmic organelles), disappear within the
Chap - 1.
Blood 19

next to 2 days and then these cells are the mature red cells called
"erythrocytes".
Regulation of Production
RBCS production is a continuous process, and for this reason
many factors/inducers/stimulators, are essentially
required for regular
production of RBCs, as well as increased production in emergency situations.
The factors influencing RBC production are,
(a) NutrientsS,
(b) Erythropoietin and
(c) Vitamins.

Nutrients
Of the nutrients, aminoacids, and minerals of
biological value
are considered very important for synthesis of globin part of hemoglobin, and
for the formation of nucleoprotein in RBC. Calcium helps in conserving more
iron and its subsequent assimilation.

Erythropoietin
Erythropoietin (EP) is a humoral substance circulating in blood,
and has been detected in the urine of normal
individuals, and the concentration
rises in hypoxia. Its production also increases in response to anemia, which
results in accelerated erythropoiesis. The kidney is an
important source in
production of EP, but its synthesis continues in nephrectomized animals
showing that other tissues also contributes to EP production. Erythropoietin
has been found in almost all species and is not
species specific
Erythropoietin stimulates the synthesis of RNA, hemoglobin and
several enzymes in erythoid cells. Nuclear RNA
synthesis is increased, soos
after exposing cells to the hormone, indicating its
marrow
transcription role
to induce synthesis of specific erythoid cells. EP facilitates the iron entry in
bone marrow for Hb synthesis, and increases release of erythoid cells in
circulation.

Stimulus for Erythropoietin Secretion

Any condition, that
causes decreased quantity of
oxygen supply
in the tissues, (anaemia due to haemorrhage) or due to
damage major portions
to
of bone nmarrow (X-ray therapy), or high altitude, where quantity of oxygen in
air is greatly reduced (insufficient oxygen supply to tissues), the red cell
4

Chap-. Blood
20
(
production is considerably increased. Various
diseases of circulation that
low blood flow cause
through peripheral vessels, particularly those that
of oxygen cause failure
absorption by blood as it passes through
the rate of blood cell lungs, can also increase
and many
production. It is
apparent in
prolonged cardiac failure,
lung diseases.
Therefore, under the above said
severe and is detected conditions, where hypoxia is
by the kidney, then the JGA
(Juxta glomerular apparatus)
produces erythropoietin, which
ultimately
leads to the
erythrocytes
Erythropoietin following its release, chiefly from production.
%) and liver (10 %), it acts upon
kidney (90
a
plasma protein (plasma globulin) called
"erythropoietinogen" and splits it into
glycoprotein
The
glycoprotein erythropoietin molecule then acts erythropoietin molecule.
on the stem cells in the
bone marrow which
ultimately leads to erythrocytes formation.
production red cells continue, as long as the animal
of Rapid
remains in low oxygen
State, or until enough red cells are
of
produced to transport the adequate amount
oxygen the tissues. At the time
to
of adequate amount of
erythropoietin production will decrease to a level that willsupply
the tissues, oxygen to

the required number maintain

of red cells, but not in
an excess.

Hypoxia due to
(a) high altitude hypoxic blood Secretion of
(b) Severe haemorrhage throguh kidney Erythropoietin
(c) Advanced emphysema (Cause production of) (Kidney)
(d) Low Hb
acts on

Plasma globulin i.e.

(Erythropoietinogen)
-Splits into

Glycoprotein
Erythropoietin
molecule

acts on
Maintains More Produce Bone marrow
Tissue erythrocytes
Oxygenation haemopoietic
stem cells

Stimulus for erythrocytes production