Erythropoiesis

ERYTHROPOIESIS
Dr. Raghuveer Choudhary
Associate Prof of Physiology
Dr S.N.M.C, Jodhpur

HEMOPOIESIS: INTRO
 Hemo: Referring to blood cells
 Poiesis: “The development or production
of”
 The word Hemopoiesis refers to the
production & development of all the
blood cells:
 Erythrocytes: Erythropoiesis
 Leucocytes: Leucopoiesis
 Thrombocytes: Thrombopoiesis.
 Begins in the 20th week of life in the
fetal liver & spleen, continues in the
bone marrow till young adulthood &
beyond!

 It is the process of development, differentiation
and maturation of RBCs from primitive stem
cells

 Monophyletic and polyphyletic theory

 Things to learn:-
Site, Stages, Duration, Regulating
factors, Clinical abnormalities

Sites of erythropoiesis

• Mesoblastic stage-
in the yolk sac
Starts at 2 weeks of intrauterine life
intravascular
• Hepatic stage-
2-7 months
Both liver and spleen
• Myeloid stage

Myeloid stage
• Occurs in bone marrow

• Starts at 5 months of fetal life and takes over
completely at birth

• Red bone marrow of all bones

• Late adult life, red marrow of flat bones

SITES OF HEMOPOIESIS

 Active Hemopoietic  Appendicular
marrow is found, in skeleton:
 Bones of the Upper &
children throughout Lower limbs
the:
 In Adults active
 Axial skeleton:
hemopoietic marrow
 Cranium
 Ribs.
is found only in:
 Sternum  The axial skeleton
 Vertebrae  The proximal ends
 Pelvis of the appendicular
skeleton.

In the adult, red blood cells, many white
blood cells, and platelets are formed in
the bone marrow. In the fetus, blood cells
are also formed in the liver and
spleen, and in adults such
extramedullary hematopoiesis may
occur in diseases in which the bone
marrow becomes destroyed or fibrosed

In children, blood cells are actively
produced in the marrow cavities of all the
bones.

By age 20, the marrow in the cavities of
the long bones, except for the upper
humerus and femur, has become inactive .

Active cellular marrow is called red
marrow; inactive marrow that is infiltrated
with fat is called yellow marrow.

The bone marrow is actually one of the largest organs
in the body, approaching the size and weight of the
liver. It is also one of the most active.
Normally, 75% of the cells in the marrow belong to the
white blood cell-producing myeloid series and only
25% are maturing red cells, even though there are over
500 times as many red cells in the circulation as there
are white cells.
This difference in the marrow reflects the fact that the
average life span of white cells is short, whereas that of
red cells is long.

STEM CELLS

 These cells have extensive proliferative
capacity and also the:
 Ability to give rise to new stem cells (Self
Renewal)
 Ability to differentiate into any blood cells
lines (Pluripotency)
 They grow and develop in the bone
marrow.
 The bone marrow & spleen form a
supporting system, called the
 “hemopoietic microenvironment”

CLONAL HEMOPOIESIS
PLURIPOTENT STEM CELL

MULTIPLICATION COMMITTMENT

COMMITTED
STEM CELL STEM CELL
MULTIPLICATION
COMMITTED
STEM CELL
PROGENITOR
CELL

CFU: COLONY
FORMING UNIT

Hematopoietic stem cells (HSCs) are bone marrow cells
that are capable of producing all types of blood cells.

They differentiate into one or another type of
committed stem cells (progenitor cells). These in turn
form the various differentiated types of blood cells.

There are separate pools of progenitor cells for
megakaryocytes, lymphocytes, erythrocytes, eosinoph
ils, and basophils; neutrophils and monocytes arise
from a common precursor.

Stem cells

• Totipotential stem cells- convert into any
tissue type

• Pluripotent stem cell- Pluripotent
hematopoeitic stem cell

• Committed stem cells- CFU E, CFU G, CFU
M, etc

PROGENITOR CELLS

 Committed stem cells lose their capacity
for self-renewal.
 They become irreversibly committed.
 These cells are termed as “Progenitor
cells”
 They are regulated by certain hormones
or substances so that they can:
 Proliferate
 Undergo Maturation.

ERYTHROID PROGENITOR CELLS

 BFU-E: Burst Forming Unit – Erythrocyte:
 Give rise each to thousands of nucleated
erythroid precursor cells, in vitro.
 Undergo some changes to become the Colony
Forming Units-Erythrocyte (CFU-E)
 Regulator: Burst Promoting Activity (BPA)

Stages of erythropoiesis
Pronormoblast

Early normoblast

Intermediate normoblast

Late normoblast

Reticulocyte

Erythrocyte

Stages of RBC Maturation

Figure 19.6

ERYTHROPOIESIS

15-20µm- basophilic cytoplasm, nucleus
with nucleoli.

14-17µm-mitosis, basophilic cytoplasm,
nucleoli disappears.

10-15µm-’POLYCHROMASIA’
Hb appears, nucleus condenses.

7-10µm- PYKNOTIC Nucleus.
Extrusion, Hb is maximum.

7.3µm- Reticulum of basophilic material
in the cytoplasm.

7.2µm- Mature red cell with Hb.

Pronormoblast
•15-20 microns
•Mitosis present
•Nucleus with multiple
nucleoli
•Basophilic cytoplasm
with polyribosomes
•No hemoglobin

Basophilic normoblast
 Large nucleus
 Basophilic cytoplasm
 Active mitosis
 Slight reduction in size

Polychromatophilic
normoblast
 Chromatin lumps
 Hb starts appearing
 Reduced mitoses

Orthochromatic normoblast
 Small and pyknotic
nucleus
 Eosinophilic cytoplasm
 Mitoses absent

Reticulocyte
 Reticular nuclear
fragments
 Nucleus extruded
 Slightly larger than RBCs

Basophilic Dividing
Proerythroblast Polychromatophilic
erythroblast Polychromatophilic
or (or intermediate)
or Erythroblast or
pronormoblast Erythroblast or
Early Normoblast
Normoblast
Normoblast

Orthochromatic
Orthochromatic (Acidophilic)
Reticulocyte erythroblast erythroblast
(brilliant cresyl Reticulocyte Extruding Or
blue dye) 1 Nucleus Late
Erythroblast

32

1.Reticulocytes
Young erythrocytes
Contain a short network of clumped
ribosomes and RER.
Enter the blood stream
Fully mature with in 2 days as their contents
are degraded by intracellular enzymes.
Count = 1-2% of red cells
Provide an index of rate of RBC
formation

Erythrocytes Production (Erythropoiesis)
PHSC
Hemocytoblasts:
•Cell size large 20-25 mircon
Myeloid •Nucelus large
Stem cells •Less cytoplasm
•Mitosis present

Proerythroblast:
•Cell size decrease 15-17 mircon

Basophilic 1 Erythroblast:
•Cell size 12-15 mircon
•Nucelus Condensed
•Mitosis present
•Nucleoli Rudimentary
•Produces huge number of Ribosomes
•Hb synthesis starts

Polychromatophil 2 Erythroblast:
•Nucelus Condensed
•Mitosis Absent

Orhochromatic 3 Erythroblast:
•Nucelus More Condensed

Reticulocyte:
•Young Erythrocytes

34

Erythrocytes Production (Erythropoiesis)
1. PHSC

2. Myeloid stem cells

3. Proerythroblast

4. Basophilic Erythoroblasts (Early erythroblasts) (early Normoblast)

5. Polychromatophil Erythroblasts (Intermediate erythroblast or
Normoblast)

6. Orhochromatic Erythroblasts (Late Erythroblast or Normoblasts)

7. Reticulocytes
 Young erythrocytes

8. Erythrocytes

35

Duration

Differentiation phase: from pronormoblast to
reticulocyte phase- 5 days

Maturation phase: from reticulocyte to RBC-
2 days

Factor needed of
Erythropoiesis
1. Erythropoietin ( Released in response to
Hypoxia)
2. Vitamin B 6 (Pyridoxine)
3. Vitamin B 9 (Folic Acid)
4. Vitamin B 12 (Cobolamin)
Essential for DNA synthesis and RBC
maturation
5. Vitamin C  Helps in iron absorption (Fe+++ 
Fe++)
6. Proteins  Amino Acids for globin synthesis
7. Iron & copper  Heme synthesis
8. Intrinsic factor  Absorption of Vit B 12
9. Hormones
37

Hematopoiesis
Factors affecting erythropoiesis:-
C) Hormonal factors:
i-Androgens: increase erythropoiesis by stimulating the
production of erythropoietin from kidney.
ii-Thyroid hormones:
 Stimulate the metabolism of all body cells including the
bone marrow cells, thus, increasing erythropoiesis.
 Hypothyroidism is associated with anemia while
hyperthyroidism is associated with polycythaemia.

Hematopoiesis
iii-Glucocorticoids:
 Stimulate the general metabolism and also stimulate the bone
marrow to produce more RBCs.
 In Addison’s disease (hypofunction of adrenal cortex) anemia
present, while in Cushing’s disease (hyperfunction of adrenal
cortex) polycythaemia present.

Hematopoiesis

iv-Pituitary gland: Affects erythropoiesis both
directly and indirectly through the action of
several hormones.
v- Haematopoietic growth factors: Are secreted by
lymphocytes, monocytes & macrophages to
regulate the proliferation and differentiation of
proginator stem cells to produce blood cells.

Hematopoiesis
D)-State of liver & bone marrow:
i-Liver: Healthy liver is essential for normal
erythropoiesis because the liver is the main site
for storage of vitamin B12 , folic acid, iron &
copper. In chronic liver disease anemia occurs.
ii-Bone marrow: When bone marrow is destroyed
by ionizing irradiation or drugs, aplastic anemia
occurs.

 Erythropoietin (Formation & role)1
Glycoprotein, Mol wt= 34,000.
Erythropoietin, a hormone, produced
mainly by the kidneys(90%) and also
by liver(10%), stimulates
erythropoiesis by acting on
committed stem cells to induce
proliferation and differentiation of
erythrocytes in bone marrow.
Site of Action: BONE Marrow

Regulation of erythropoiesis

1. Tissue Oxygenation

Erythropoietin

 Glycoprotein with 165 amino acids, 4
oligosaccharide chains and molecular weight
of 34,000
 Production- 85% by peritubular capillary bed
interstitial cells(Kidney) and 15% by
perivenous hepatocytes( Liver)
 Also seen in brain, salivary
glands, uterus, oviducts

Factors increasing erythropoietin secretion:
(i) Hypoxia
(ii) Androgens
(iii) Growth Hormone
(iv) Catecholamines
(v) Prostaglandins
Factors inhibiting erythropoietin secretion:
(i) Estrogen
(ii) Theophylline

Action of Erythropoietin:
1. Formation of Pronormoblast from stem cell
2. Speeds up the differentiation through various
stages of erythropoiesis

Mechanism of Action:
• Formation of ALA synthetase
• Activation of Adenylyl Cyclase
• Synthesis of transferrin receptors

Maturation factors

Vitamin B12 and Folic acid:
 Essential for DNA synthesis (Thymidine
triphosphate)
 Abnormal and diminished DNA
 Failure of division and maturation
 Macrocytic / Megaloblastic anemia

Pernicious Anemia

Intrinsic factor of Castle- secreted by parital
cells of gastric mucosa
Essential for absorption of Vitamin B12 by
enteric route

Other Factors

 Cobalt
 Copper
 Proteins
 Vitamin C

Clinical Aspects

Anemias: Reduced RBC count / reduced Hb
concentration

Polycythemia: Increased RBC count
 Polycythemia vera
 Secondary polycythemia- due to hypoxia

Erythropoiesis

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