HEMA 1A Lec 1st Shift Reviewer • The anatomical sites of blood cell

Hematopoiesis development are as follows:

o Following gastrulation and
Prepared by: C3
mesoderm formation, the first
hematopoietic cells are
HEMATOPOIESIS DEFINED generated in the yolk sac. The
• Hematopoiesis is the process of blood first blood cells are primitive red
cell production, differentiation, and blood cells (erythroblasts)
development formed during the first 2 to 8
• The hematopoietic system includes: weeks of life
o Bone marrow o The onset of circulation between
o Liver the yolk sac and embryo proper
o Spleen confounds the precise
o Lymph nodes determination of hematopoietic
o Thymus sources. Mesenchymal
stem/progenitor cells and HSCs
ORIGIN OF BLOOD CELLS circulate together in the
peripheral blood during the first
Types of Human Stem Cells trimester to the secondary
1. Totipotential Stem Cells ontogenic sites of
• Present in the first few hours hematopoiesis, the liver and the
bone marrow. Gradually, the
after an ovum is fertilized
liver becomes the site of blood
• The most versatile type of stem
cell development. By the second
cell
month of gestation, the liver
• Can develop into any human
becomes the major site of
cell type (e.g. embryo to fetus)
hematopoiesis, and granular
2. Pluripotential Stem Cells
types of leukocytes have made
• Present several days after
their initial appearance. The
fertilization
liver predominates from about
• Develop into any cell type, the second to fifth months of
except they cannot develop into fetal life.
a fetus o In the fourth month of gestation,
3. Multipotential Stem Cells the bone marrow begins to
• Derived from pluripotent stem function in the production of
cells blood cells. After the fifth fetal
• Found in adults but are limited month, the bone marrow begins
to specific types of cells to form to assume its ultimate role as
tissues the primary site of
hematopoiesis (medullary
Early Development of Blood Cells hematopoiesis).
• Embryonic blood cells, excluding the
lymphocyte type of WBC, originate from
the mesenchymal tissue that arises from
the embryonic germ layer, the
mesoderm
• The Aorta-Gonad-Mesonephros
Region (or paraaortic splanchnopleure),
produces potent HSCs and multipotent
progenitor cells before appearing in the
yolk sac, respectively

TRIPLE C NOTES 1
 sternum, skull bones, pelvis,
and to some extent the proximal
epiphyses of the femur and
humerus
• Extramedullary Hematopoiesis
o Spleen, liver, and lymph nodes
revert back to producing
immature blood cells
o Enlargement of spleen and liver
occurs
o Undifferentiated primitive blood
cells are present in these areas
Figure 1. Hematopoiesis in various organs before and and are able to proliferate if an
after birth. appropriate stimulus is present
o Occurs when the bone marrow:
BONE MARROW SITES AND  Becomes dysfunctional
FUNCTION in cases such as
• Found within the cavities of all bones aplastic anemia,
• May be present in 2 forms: infiltration by malignant
o Yellow Marrow cells, or
 Normally inactive overproliferation of a
 Composed mostly of cell line (e.g. leukemia)
adipose tissue  Is unable to meet the
o Red Marrow demands placed on it,
 Normally active in the as in the hemolytic
production of most anemias
types of RBCs, WBCs,
and Platelets (see
Figure 2)
• One of the body’s largest organs
o Represents 3.5-6% of total body
weight and averages around
1,500 g in adults
o Hematopoietic marrow is
organized in the bone
vasculature (see Figure 3)
• Consists of the hematopoietic cells
(erythroid, myeloid, lymphoid, and Figure 2. Normal Bone Marrow Biopsy.
megakaryocyte), adipose tissue,
osteoblasts and osteoclasts, and stroma
• During the first few years of life, the
marrow of all bones is red and cellular
o Initially found in both
appendicular and axial
skeletons in young persons but
progressively becomes confined
to the axial skeleton and
proximal ends of long bones in
adults
o By age 18, red marrow is found
only in the vertebrae, ribs, Figure 3. The development of blood cells: humerus
bone, cortical bone, red, and yellow bone marrow.

TRIPLE C NOTES 2
CELLULAR ELEMENTS OF BONE
MARROW
Progenitor Blood Cells
• The pluripotent stem cell is the first in a
sequence of steps of hematopoietic cell
generation and maturation
• The progenitor of all blood cells is called
the multipotential hematopoietic stem
cell
• Stem cells have the capacity for self-
renewal as well as proliferation and
differentiation into progenitor cells
• “Stem Cell Plasticity” is a concept where
stem cells are amazingly adaptable and
are able to generate an assortment of
seemingly unrelated types of cells
• “Multipotent Adult Progenitor Cells”
(MAPCs) are master cells which express Figure 4. General Model of Hematopoiesis where
an enzyme called telomerase that keeps blood cell development progresses from an HSC.
cells from aging
• Hematopoietic cells can be divided into Erythropoiesis
3 phases according to cell maturity • Occurs in distinct anatomical sites called
o Primitive, Multipotential Cells Erythropoietic Islands, specialized
 The most immature niches in which erythroid precursors
group capable of self- proliferate, differentiate, and enucleate
renewal and o Each island consists of a
differentiation into all macrophage surrounded by a
blood cell lines cluster of erythroblasts
o Intermediate Cells • Erythroid cells account for 5-38% of
 This group consists of nucleated cells in the normal bone
committed progenitor
cells destined to
Granulopoiesis
develop into distinct cell
• Myeloid cells account for 23-85% of the
lines
nucleated cells in normal bone marrow
o Mature Cells
• Recognized as a maturational unit
 The most developed
group with specific • Maturing cells spend 3-6 days in the
functions proliferating pool and can exit into the
circulation rapidly with a 6-10 hour
• Hematopoietic Progenitor Cells
lifespan
(HPCs) can be mobilized from the bone
marrow to the blood by a wide variety of
stimuli, including hematopoietic growth Lymphopoiesis
factors and chemokines • Unlike other cell lines, lymphocytes and
plasma cells are produced in lymphoid
follicles
• Lymphoid cells account for 1-5% of the
nucleated cells in the normal bone
marrow

TRIPLE C NOTES 3
Megakaryopoiesis • Cytokines that act independently or in
• Takes place adjacent to the sinus conjunction with other interleukins to
endothelium encourage hematopoietic growth
• Megakaryocytes protrude through the • Cell signaling molecules and a part of
vascular wall as small cytoplasmic the cytokine super family of signaling
processes to deliver platelets into the molecules
sinusoidal blood • First described as signals for
o Develop into platelets in communication between (inter-between)
approximately 5 days white blood cells (leuk-from leukocytes)
• Method of immune cross-talk and
Other Cells Found in Bone Marrow communication
Marrow Stromal Cells • Primary messengers and directors of the
• Composed of reticulum cells, immune system
histiocytes, adipose cells, and • There are 35 known interleukins
endothelial cells however there are many more to be
• Structure where hematopoietic found and characterized
cells are suspended in a • They can cause:
delicate semifluid state o Cellular proliferation
Mast Cells o Cell activation
• Connective tissue cells of o Inflammation
mesenchymal origin o Physiological changes (e.g.
• Normally observed in the bone fever, pain)
marrow o Allergies as with histamine
• Increased numbers can be seen release and growth
in a variety of abnormal
conditions (e.g. chronic HEMATOPOIETIC GROWTH
infections) FACTORS
Macrophages • Each hematopoietic growth factor is
• Also called reticulum cells or encoded by a single gene
histiocytes • The gene for erythropoietin is located on
• Appear as large cells in the chromosome 7
bone marrow • The major role of hematopoietic growth
• The appearance of the factors appear to be regulating the
cytoplasms will vary, depending proliferation and differentiation of HPCs
on what the cell has ingested as well as regulating the survival and
Bone Cells function of mature blood cells
• Also called osteoblasts o Biological effects are mediated
• Bone matrix-synthesizing cells through specific binding
that resemble plasma cells and receptors on the surface of
are usually observed in groups target cells
• Osteoclasts resemble • Used and tested in clinical trials for the
megakaryocytes treatment of a variety of hematological
o Bone-remodeling cells disorders
• Capable of mobilizing HPCs
INTERLEUKINS • A striking feature of growth factors is the
• Protein molecules that work in diversity of the target population.
conjunction with hematopoietic growth Examples of various factors and the
factors to stimulate proliferation and target cells are:
differentiation of specific cell lines

TRIPLE C NOTES 4
 o G-CSF and GM-CSF
predominantly affect myeloid Nuclear Characteristics
cells Chromatin Patterns
o IL-7 stimulates T and B • Demonstrates characteristic
lymphocytes patterns in terms of maturity and
o IL-12 targets natural killer cells cell type recognition
• The mobilization of HPCs from the bone • In general, the overall pattern
marrow to the peripheral blood progresses from a loose-looking
circulation is a complicated process arrangement to a more clumped
regulated by multiple adhesive pattern as a cell matures
interactions between the HPCs and the • Terms used:
bone marrow extracellular matrix o Smooth or
homogeneous
o Fine
o Delicate
o Lacy or thready
o Smudged
o Clumped
Figure 5. Characteristics of Human Hematopoietic o Pyknotic (dense or
Growth Factors compact)
• Examples:
EXAMINATION OF MATURING o Lymphocytes exhibit a
smooth or
BLOOD CELLS
homogeneous pattern
• A comprehensive examination of bone
of chromatin throughout
marrow involves examination of both
development until the
bone marrow smears and histological mature stage, when
tissue sections clumped
• The examination of a stained peripheral heterochromatin is more
blood smear is an important component obvious
of the complete blood count (CBC) o Granulocytes progress
from having a fine to a
General Cellular Characteristics highly clumped pattern
Overall Cell Size o Monocytes have a lacy
• Except for the megakaryocytic pattern, which becomes
maturational series, finer as the cell matures
erythrocytes and leukocytes o Erythrocytes continue to
decrease in overall size as develop a more
maturation progresses clumped pattern as
Nuclear-Cytoplasmic Ratio (N:C) maturation progresses,
• The amount of space occupied until the extremely
by the nucleus in relationship to dense (pyknotic)
space occupied by the nucleus is lost
cytoplasm (extruded) from the
• The size of the nucleus mature cell
generally decreases as a cell Nuclear Shape
matures • Usually in young cells, it is
o Consequently, the N:C round or oval
Ratio decreases in o Monocytes have a
many cell types with slightly folded nuclear
maturation shape

TRIPLE C NOTES 5
 • Nuclear shape becomes • In general, cytoplasmic color
distinctive for those that retain progresses from darker blue
their nucleus (indicating active protein
o Lymphocytes usually synthesis) in younger cells to
continue to have a lighter blue or pink in mature
round or oval nucleus. cells
Some cells may have a • Immature erythrocytes have a
small cleft in the very distinctive dark-blue
nucleus cytoplasm that becomes paler
o Monocytes have a and gray looking as the cell
kidney bean-shaped synthesizes hemoglobin
nucleus, but folded or • As mature cells, lymphocytes
horseshoe shapes are are usually noted for their pale
common sky-blue cytoplasmic color
o Mature neutrophils, Granulation
eosinophils, and • Granulation progresses from no
basophils have granules to non-specific
segmented nuclei granulation to specific
attaches to one another granulation
by fine filaments • Erythrocytes never exhibit
Presence of Nucleoli granulation throughout their life
• Generally not visible in mature cycle
cells • Granules vary in several ways:
• Present in earliest cell stages of o In size, ranging from
erythrocytes, leukocytes, and very fine to coarse
megakaryocytes o In color, including red
• Related to the rate of synthesis (azurophilic), blue
of ribosomal RNA (basophilic), and orange
• Examples: (eosinophilic)
o Lymphoblasts have 1-2 o In the amount of
nucleoli granulation per cell
o Myeloblasts have 1-5 Cytoplasmic Shape
nucleoli • The most distinctive variation in
o Monoblasts usually cytoplasmic shape occurs in
have 1-2 but some blast forms, monocytes,
occasionally may have and megakaryocytes
3-4 nucleoli • Pseudopods may be observed
o Erythroblasts may have in mature monocytes and in
0-2 nucleoli that may some leukocyte blast forms
stain darker than in Quantity of Cytoplasm
other types of blast cells • Actual quantity of cytoplasm
o Megakaryoblasts increases with age
typically have 1-5 • Abnormalities of lymphocytes
nucleoli frequently demonstrate
increased amounts of cytoplasm
Cytoplasmic Characteristics Vacuolization
• Increases with age
Staining Color and Intensity • Except for monocytes,
• Varies with cell maturity and vacuolization of the cytoplasm is
type commonly seen in older cells
and in abnormal conditions

TRIPLE C NOTES 6
 • Anticoagulants can also
produce vacuoles as artifacts if
the blood is stored for a longer-
than-acceptable period
Inclusion Bodies
• Important to know because they
aid in the identification of cell
types
• Various erythrocytic and
leukocytic inclusions are
indicative of specific diseases
• Some may be seen on a Wright-
stained blood smear but others
require special staining
techniques

MATURE BLOOD CELLS IN

PERIPHERAL BLOOD
• Identification of blood cells by
microscopic examination of a peripheral
smear can be performed more
systematically if the morphologist
assesses the various maturational
features as outlined in the preceding
section

Figure 6. Normal adult values and selected

characteristics of mature leukocytes in peripheral
blood

TRIPLE C NOTES 7