Chapter

Erythropoiesis
10
„ DEFINITION
„ SITE OF ERYTHROPOIESIS
„ IN FETAL LIFE
„ IN NEWBORN BABIES, CHILDREN AND ADULTS
„ PROCESS OF ERYTHROPOIESIS
„ STEM CELLS
„ CHANGES DURING ERYTHROPOIESIS
„ STAGES OF ERYTHROPOIESIS
„ FACTORS NECESSARY FOR ERYTHROPOIESIS
„ GENERAL FACTORS
„ MATURATION FACTORS
„ FACTORS NECESSARY FOR HEMOGLOBIN FORMATION

„ DEFINITION „ IN NEWBORN BABIES, CHILDREN AND ADULTS

Erythropoiesis is the process of the origin, development In newborn babies, growing children and adults, RBCs
and maturation of erythrocytes. Hemopoiesis or hema­ are produced only from the red bone marrow.
topoiesis is the process of origin, development and 1. Up to the age of 20 years: RBCs are produced from
maturation of all the blood cells. red bone marrow of all bones (long bones and all
the flat bones).
„ SITE OF ERYTHROPOIESIS 2. After the age of 20 years: RBCs are produced
from membranous bones like vertebra, sternum,
„ IN FETAL LIFE ribs, scapula, iliac bones and skull bones and from
the ends of long bones. After 20 years of age,
In fetal life, the erythropoiesis occurs in three stages:
the shaft of the long bones becomes yellow bone
marrow because of fat deposition and looses the
1. Mesoblastic Stage
erythropoietic function.
During the first two months of intrauterine life, the RBCs In adults, liver and spleen may produce the blood cells
are produced from mesenchyme of yolk sac. if the bone marrow is destroyed or fibrosed. Collectively
bone marrow is almost equal to liver in size and weight.
2. Hepatic Stage It is also as active as liver. Though bone marrow is the
site of production of all blood cells, comparatively 75%
From third month of intrauterine life, liver is the main
of the bone marrow is involved in the production of
organ that produces RBCs. Spleen and lymphoid
leukocytes and only 25% is involved in the production
organs are also involved in erythropoiesis.
of erythrocytes.
But still, the leukocytes are less in number than the
3. Myeloid Stage
erythrocytes, the ratio being 1:500. This is mainly because
During the last three months of intrauterine life, the RBCs of the lifespan of these cells. Lifespan of erythrocytes
are produced from red bone marrow and liver. is 120 days whereas the lifespan of leukocytes is very
 72 Section 2 t Blood and Body Fluids

short ranging from one to ten days. So the leukocytes Committed PHSCs are of two types:
need larger production than erythrocytes to maintain the 1. Lymphoid stem cells (LSC) which give rise to
required number. lymphocytes and natural killer (NK) cells
2. Colony forming blastocytes, which give rise to
„ PROCESS OF ERYTHROPOIESIS myeloid cells. Myeloid cells are the blood cells other
than lymphocytes. When grown in cultures, these
„ STEM CELLS cells form colonies hence the name colony forming
Stem cells are the primary cells capable of self-renewal blastocytes.
and differentiating into specialized cells (Chapter 1). Different units of colony forming cells are:
Hemopoietic stem cells are the primitive cells in the i. Colony forming unit-erythrocytes (CFU-E) –
bone marrow, which give rise to the blood cells. Cells of this unit develop into erythrocytes
Hemopoietic stem cells in the bone marrow are called ii. Colony forming unit-granulocytes/monocytes
uncommitted pluripotent hemopoietic stem cells (PHSC). (CFU-GM) – These cells give rise to granulocytes
PHSC is defined as a cell that can give rise to all types of (neutrophils, basophils and eosinophils) and
blood cells. In early stages, the PHSC are not designed monocytes
to form a particular type of blood cell. And it is also not iii. Colony forming unit-megakaryocytes (CFU-M)
possible to determine the blood cell to be developed – Platelets are developed from these cells.
from these cells: hence, the name uncommitted PHSC
(Fig. 10.1). In adults, only a few number of these cells „ CHANGES DURING ERYTHROPOIESIS
are present. But the best source of these cells is the
umbilical cord blood. Cells of CFU-E pass through different stages and finally
When the cells are designed to form a particular become the matured RBCs. During these stages four
type of blood cell, the uncommitted PHSCs are called important changes are noticed.
committed PHSCs. Committed PHSC is defined as a 1. Reduction in size of the cell (from the diameter of 25
cell, which is restricted to give rise to one group of blood to 7.2 µ)
cells. 2. Disappearance of nucleoli and nucleus

FIGURE 10.1: Stem cells. L = Lymphocyte, R = Red blood cell, N = Neutrophil, B = Basophil,
E = Eosinophil, M = Monocyte, P = Platelet.
 Chapter 10 t Erythropoiesis 73

3. Appearance of hemoglobin 4. Late normoblast

4. Change in the staining properties of the cytoplasm. 5. Reticulocyte
6. Matured erythrocyte.
„ STAGES OF ERYTHROPOIESIS
1. Proerythroblast (Megaloblast)
Various stages between CFU-E cells and matured RBCs
are (Fig. 10.2): Proerythroblast or megaloblast is the first cell derived
1. Proerythroblast from CFU-E. It is very large in size with a diameter of
2. Early normoblast about 20 µ. Its nucleus is large and occupies the cell
3. Intermediate normoblast. almost completely. The nucleus has two or more nucleoli

FIGURE 10.2: Stages of erythropoiesis. CFU-E = Colony forming unit-erythrocyte,

CFU-M = Colony forming unit-megakaryocyte, CFU-GM = Colony forming unit-granulocyte/monocyte.
 74 Section 2 t Blood and Body Fluids

and a reticular network. Proerythroblast does not contain during the first week after birth. Later, the reticulocyte
hemoglobin. The cytoplasm is basophilic in nature. count remains constant at or below 1% of RBCs. The
Proerythroblast multiplies several times and finally forms number increases whenever production and release of
the cell of next stage called early normoblast. Synthesis RBCs increase.
of hemoglobin starts in this stage. However, appearance Reticulocyte is basophilic due to the presence of
of hemoglobin occurs only in intermediate normoblast. remnants of disintegrated Golgi apparatus, mitochondria
and other organelles of cytoplasm. During this stage, the
2. Early Normoblast cells enter the blood capillaries through capillary mem­
The early normoblast is little smaller than proerythroblast brane from site of production by diapedesis. Important
with a diameter of about 15 µ. In the nucleus, the events during erythropoiesis is given in Table 10.1
nucleoli disappear. Condensation of chromatin network
occurs. The condensed network becomes dense. The 6. Matured Erythrocyte
cytoplasm is basophilic in nature. So, this cell is also
Reticular network disappears and the cell becomes the
called basophilic erythroblast. This cell develops into
matured RBC and attains the biconcave shape. The cell
next stage called intermediate normoblast.
decreases in size to 7.2 µ diameter. The matured RBC
is with hemoglobin but without nucleus.
3. Intermediate Normoblast
It requires 7 days for the development and maturation
Cell is smaller than the early normoblast with a diameter of RBC from proerythroblast. It requires 5 days up to the
of 10 to 12 µ. The nucleus is still present. But, the stage of reticulocyte. Reticulocyte takes 2 more days to
chromatin network shows further condensation. The become the matured RBC.
hemoglobin starts appearing.
Cytoplasm is already basophilic. Now, because of the TABLE 10.1: Important events during erythropoiesis
presence of hemoglobin, it stains with both acidic as well Stage of erythropoiesis Important event
as basic stains. So this cell is called polychromophilic or
Proerythroblast Synthesis of hemoglobin starts
polychromatic erythroblast. This cell develops into next
stage called late normoblast. Early normoblast Nucleoli disappear
Intermediate normoblast Hemoglobin starts appearing
4. Late Normoblast Late normoblast Nucleus disappears
Diameter of the cell decreases further to about 8 to 10 µ. Reticulum is formed.
Nucleus becomes very small with very much condensed Reticulocyte Cell enters capillary from site of
chromatin network and it is known as ink-spot nucleus. production
Quantity of hemoglobin increases. And the cyto­ Reticulum disappears
Matured RBC
plasm becomes almost acidophilic. So, the cell is now Cell attains biconcavity
called orthochromic erythroblast. In the final stage of
late normoblast just before it passes to next stage, the
„ FACTORS NECESSARY FOR
nucleus disintegrates and disappears. The process by
which nucleus disappears is called pyknosis. The final ERYTHROPOIESIS
remnant is extruded from the cell. Late normoblast Development and maturation of erythrocytes require varie-
develops into the next stage called reticulocyte.
ty of factors, which are classified into three categories:
1. General factors
5. Reticulocyte
2. Maturation factors
Reticulocyte is otherwise known as immature RBC. 3. Factors necessary for hemoglobin formation.
It is slightly larger than matured RBC. The cytoplasm
contains the reticular network or reticulum, which is „ GENERAL FACTORS
formed by remnants of disintegrated organelles. Due to
the reticular network, the cell is called reticulocyte. The General factors necessary for erythropoiesis are:
reticulum of reticulocyte stains with supravital stain. i. Erythropoietin
In newborn babies, the reticulocyte count is 2% to ii. Thyroxine
6% of RBCs, i.e. 2 to 6 reticulocytes are present for iii. Hemopoietic growth factors
every 100 RBCs. The number of reticulocytes decreases iv. Vitamins.
 Chapter 10 t Erythropoiesis 75

i. Erythropoietin iv. Vitamins

Most important general factor for erythropoiesis is Some vitamins are also necessary for the process of
the hormone called erythropoietin. It is also called erythropoiesis. Deficiency of these vitamins cause
hemopoietin or erythrocyte stimulating factor. anemia associated with other disorders.
Vitamins necessary for erythropoiesis:
Chemistry
a. Vitamin B: Its deficiency causes anemia and
Erythropoietin is a glycoprotein with 165 amino acids. pellagra (disease characterized by skin lesions,
diarrhea, weakness, nervousness and dementia).
Source of secretion
b. Vitamin C: Its deficiency causes anemia
Major quantity of erythropoietin is secreted by peritubular and scurvy (ancient disease characterized
capillaries of kidney. A small quantity is also secreted by impaired collagen synthesis resulting in
from liver and brain. rough skin, bleeding gum, loosening of teeth,
poor wound healing, bone pain, lethargy and
Stimulant for secretion
emotional changes).
Hypoxia is the stimulant for the secretion of c. Vitamin D: Its deficiency causes anemia and
erythropoietin. rickets (bone disease – Chapter 68).
d. Vitamin E: Its deficiency leads to anemia and
Actions of erythropoietin
malnutrition.
Erythropoietin causes formation and release of new
RBCs into circulation. After secretion, it takes 4 to 5 days „ MATURATION FACTORS
to show the action.
Erythropoietin promotes the following processes: Vitamin B12, intrinsic factor and folic acid are necessary
a. Production of proerythroblasts from CFU-E of for the maturation of RBCs.
the bone marrow
b. Development of proerythroblasts into matured 1. Vitamin B12 (Cyanocobalamin)
RBCs through the several stages – early normo- Vitamin B12 is the maturation factor necessary for
blast, intermediate normoblast, late normoblast erythropoiesis.
and reticulocyte
c. Release of matured erythrocytes into blood. Even Source
some reticulocytes (immature erythrocytes) are Vitamin B12 is called extrinsic factor since it is obtained
released along with matured RBCs. mostly from diet. Its absorption from intestine requires
Blood level of erythropoietin increases in anemia. the presence of intrinsic factor of Castle. Vitamin B12
is stored mostly in liver and in small quantity in muscle.
ii. Thyroxine When necessary, it is transported to the bone marrow to
Being a general metabolic hormone, thyroxine promote maturation of RBCs. It is also produced in the
accelerates the process of erythropoiesis at many levels. large intestine by the intestinal flora.
So, hyperthyroidism and polycythemia are common. Action
iii. Hemopoietic Growth Factors Vitamin B12 is essential for synthesis of DNA in RBCs.
Its deficiency leads to failure in maturation of the cell
Hemopoietic growth factors or growth inducers are the
and reduction in the cell division. Also, the cells are
interleukins and stem cell factor (steel factor). Generally
larger with fragile and weak cell membrane resulting in
these factors induce the proliferation of PHSCs.
macrocytic anemia.
Interleukins (IL) are glycoproteins, which belong to the
Deficiency of vitamin B12 causes pernicious anemia.
cytokines family.
So, vitamin B12 is called antipernicious factor.
Interleukins involved in erythropoiesis:
a. Interleukin-3 (IL-3) secreted by T-cells
2. Intrinsic Factor of Castle
b. Interleukin-6 (IL-6) secreted by T-cells, endothelial
cells and macrophages Intrinsic factor of castle is produced in gastric mucosa
c. Interleukin-11 (IL-11) secreted by osteoblast. by the parietal cells of the gastric glands. It is essential
 76 Section 2 t Blood and Body Fluids

for the absorption of vitamin B12 from intestine. In the „ FACTORS NECESSARY FOR
absence of intrinsic factor, vitamin B12 is not absorbed HEMOGLOBIN FORMATION
from intestine. This leads to pernicious anemia.
Deficiency of intrinsic factor occurs in: Various materials are essential for the formation of hemo­
i. Severe gastritis globin in the RBCs. Deficiency of these substances decre-
ii. Ulcer ases the production of hemoglobin leading to anemia.
iii. Gastrectomy. Such factors are:
Hematinic principle 1. First class proteins and amino acids: Proteins of
high biological value are essential for the formation
Hematinic principle is the principle thought to be of hemoglobin. Amino acids derived from these
produced by the action of intrinsic factor on extrinsic proteins are required for the synthesis of protein
factor. It is also called or antianemia principle. It is a
part of hemoglobin, i.e. the globin.
maturation factor.
2. Iron: Necessary for the formation of heme part of
3. Folic Acid the hemoglobin.
3. Copper: Necessary for the absorption of iron from
Folic acid is also essential for maturation. It is required the gastrointestinal tract.
for the synthesis of DNA. In the absence of folic acid,
4. Cobalt and nickel: These metals are essential for
the synthesis of DNA decreases causing failure of
maturation. This leads to anemia in which the cells are the utilization of iron during hemoglobin formation.
larger and appear in megaloblastic (proerythroblastic) 5. Vitamins: Vitamin C, riboflavin, nicotinic acid and
stage. And, anemia due to folic acid deficiency is called pyridoxine are also essential for the formation of
megaloblastic anemia. hemoglobin.