Hematopoiesis
solely in hematopoiesis
Hematopoiesis
• Hematopoiesis is a continuous regulated
process of blood cell production that includes
cell renewal, proliferation, differentiation and
maturation
• These processes result in the formation,
development and specialization of all the
functional blood cells that are released from the
bone marrow to the circulation
• In healthy adults, hematopoiesis is restricted
primarily to the bone marrow
• During fetal development, the restricted
sequential distribution of cells initiates in the
yolk sac and then progresses in the aorta-gonad
mesonephros (AGM) region (mesoblastic
phase), then to the fetal liver (hepatic phase)
and finally resides in the bone marrow
(medullary phase)
- Mesoblastic (yolk sac) phase
 Early in embryonic development, cells
from the mesoderm migrate to the yolk
sac, where small nests of blood cell
production can be visualized and
begins between 10th and 14th days of
gestation. These cells are referred to as
“blood islands”
 Some of these cells from primitive
erythroblasts in the central cavity of
the yolk sac, while the others
(angioblasts) surround the cavity of the
yolk sac.
 These primitive yet transient yolk sac
erythroblast are important in early
embryogenesis to produce hemoglobin
(Gower-1, Gower-2 and Portland)
needed for delivery of oxygen to
rapidly developing embryonic tissues
 Yolk sac hematopoiesis differs
from hematopoiesis that occurs later in
the fetus and the adult. In that, it occurs
intravascularly, or within developing
blood vessels
- Hepatic (liver) phase
 The hepatic phase begins at 5-7 gestational
weeks and is characterized by recognizable
clusters of developing erythroblasts,
granulocytes and monocytes
 The developing erythroblast in this phase
signal the beginning of definitive
erythropoiesis with a decline in the
primitive hematopoiesis in the yolk sac
 Lymphoid cells begin to appear in this
phase, hemopoiesis occurs extravascularly
with the liver remaining the major site of
hematopoiesis during the second trimester
of
fetal life
 Production of megakaryocytes also begins
during this phase. The spleen gradually decreases
granulocytic production and involves itself
 Fetal hemoglobin (HgF) is the predominant
hemoglobin, but detectable levels of adult
hemoglobin (HgA) may be present
- Myeloid/medullary phase
 Prior to the 5th month of fetal development,
hematopoiesis begins in the bone marrow
cavity
 This transition is called medullary
hematopoiesis because it occurs in the
medulla or inner part of the bone
 Hematopoietic activity, especially myeloid
activity, is apparent during this phase and
the M:E ratio gradually approaches 3:1
(adult levels)
 Measurable levels of erythropoietin (EPO),
granulocyte colony-stimulating factor (G-
CSF), granulocyte-macrophage colony-
stimulating factor (GM-CSF), and
hemoglobins F and A can be detected
• Blood cell production, maturation and death
occur in the organs of the RES
(Reticuloendothelial system)
- RES includes bone marrow, spleen, liver,
thymus, lymph nodes
- RES functions in hematopoiesis, phagocytosis
and immune defense
• At birth, the bone marrow is very cellular with
mainly red marrow, indicating very active blood
cell production
- Red marrow is gradually replaced by inactive
yellow marrow composed of fat
- Under physical stress, yellow marrow may
revert to active red marrow
Pediatric and Adult Hematopoiesis
• Bone marrow
- Newborn – 80-90% of bone marrow is active
red marrow
- Young adult (age 20) – 60% of bone marrow is
active. Hematopoiesis is confined to the
proximal ends of large flat bones, pelvis, and
sternum
- Older adult (age 55): 40% of bone marrow is
active; 60% is fat
- Cellularity – ratio of marrow cells to fat (red
marrow/yellow marrow) and is described in
adults as
 Normocellular – marrow has 30-70%
hematopoietic cells
 Hypercellular/hyperplastic – marrow has
>70% hematopoietic cells
 Hypocellular/hypoplastic – marrow has
<30% hematopoietic cells
 Aplastic – marrow has few or no
hematopoietic cells
- M:E (myeloid:erythroid) ratio – ratio of
granulocytes and their precursors to nucleated
erythroid precursors. Normal ratio is between
3:1 and 4:1
dane.
  Granulocytes are more numerous because
of their short survival (1-2 days) as
compared to erythrocytes with a 120 day
life span
 Lymphocytes and monocytes are excluded
from the M:E ratio
- Stem cell theory – hematopoiesis involves the
production of pluripotent stem cells that
develop into committed progenitor cells
(lymphoid or myeloid) and finally mature blood
cells
 Progenitor cells
o Lymphoid – different into either B or T
lymphocytes in response to cytokines,
interleukins, growth factors, lymphokines,
CSFs
o Myeloid – give rise to the multipotential
progenitor CFU-GEMM (colony-forming-
unit-granulocyte-erythrocyte-macrophage-
megakaryocyte), which will differentiate
into committed progenitor cells and finally
mature blood cells in response to
cytokines, interleukins, colony
stimulating factors, growth factors
• Lymphoid tissue
- Primary lymphoid tissue
 Bone marrow – site of
pre-B cell differentiation
 Thymus – site of pre-T cell differentiation
 Ag-independent lymphopoiesis
- Secondary lymphoid tissue
 B and T lymphocytes enter the blood and
populate secondary lymphoid tissue, where
antigen contact occurs
 Includes lymph nodes, spleen, gut-
associated tissue (Peyer’s patches)
 Ag-dependent lymphopoiesis depends on
antigenic stimulation of T and B
lymphocytes
Bone marrow
• Bone marrow is one of the largest organs located
within the cavities of the cortical bones
• Two major components
- Red marrow – active marrow consisting of
developing blood cells and their progenitor
- Yellow marrow – inactive marrow, composed
primarily of adipocytes (fat cells) with
undifferentiated mesenchymal cells and
macrophages
• During infancy and early childhood, all the bones in
the body contain primarily of red (active) marrow
- Between 5 and 7 years of age, adipocytes
become more abundant and begin to occupy the
spaces in the long bones previously dominated
by active marrow
• The process of replacing the active marrow by
adipocytes (yellow marrow) during development is
called regression
- Eventually results in restriction of the active
marrow in the adult to the sternum, vertebrae,
scapulae, pelvis, ribs, skull and proximal portion
of the long bones
• Hematopoietically inactive yellow marrow is
scattered throughout the red marrow so that in
adults, there is approximately equal amounts of red
and yellow marrow in these areas
• Yellow marrow is capable of reverting back to active
marrow in cases of increased demand on the bone
marrow, such as excessive blood loss or hemolysis
• Adipocytes are large cells with a single fat vacuole;
role in regulating the volume of the marrow; also
secrete cytokines or growth factors that may
stimulate HSC numbers and homeostasis
• Others that are important in hematopoiesis
include: endothelial cells and reticular adventitial
cells, macrophages and lymphocytes, stromal cells
• Hematopoietic microenvironment or niche, plays
an important role in nurturing and protecting HSCs
and regulating a balance among their quiescence,
selfrenewal and differentiation
• Stromal cells form an extracellular matrix in the
niche to promote cell adhesion and regulate HSCs
through complex signaling networks involving
cytokines, adhesion molecules and maintenance
proteins
Liver
• The liver serves as the major site of blood cell
production during the second trimester of fetal
development
• The hepatocytes in the liver have many functions:
- Protein synthesis and degredation
- Coagulation factor synthesis
- Carbohydrate and lipid metabolism
- Drug and toxin clearance
- Iron recycling and storage
- Hgb degredation in which bilirubin is conjugated
and transported to the small intestine for
eventual excretion
• Kupffer cells are macrophages that remove
senescent cells & foreign debris from the blood that
circulates through the liver; also secrete mediators
that regulate protein synthesis in the hepatocytes
• Liver pathophysiology
- In porphyrias, hereditary or acquired defects in
the enzyme involved in heme biosynthesis result
in the accumulation of the various intermediary
poryphrins that damage hepatocytes,
erythrocyte precursors and other tissues
- In severe hemolytic anemias, the liver
increases the conjugation of bilirubin and the
storage of iron
- The liver sequesters membrane-damaged RBCs
and removes them from the circulation
- It can maintain hematopoietic stem and
progenitor cells to produce various blood cells
(called extramedullary hematopoiesis) as a
response to infectious agents or in pathologic
myelofibrosis
- It is directly affected by storage diseases
of the monocyte/macrophage (Kupffer) cells as a
dane.
 result of enzyme deficiencies that cause
hepatomegaly with ultimate dysfunction of the
liver (Gaucher disease, Nieman-pick disease,
Tay-Sach’s disease)
Spleen
• Largest lymphoid organ and has three types of
splenic tissue
- White pulp – scattered follicles with germinal
centers containing lymphocytes, macrophages
and dendritic cells
- Marginal zone – surrounds the white pulp and
forms a reticular meshwork containing blood
vessels, macrophages, memory B cells and CD4-
T - It may also be indicated in severe refractory
cells
- Red pulp – composed primarily of vascular
sinuses separated by cords of reticular cell
meshwork (cords of Billroth) containing loosely
connected specialized macrophages
• As RBCs pass through the cords of Billroth, there is a
decrease in the flow of blood, which leads to
stagnation and depletion of RBCs glucose supply.
These cells are subject to increased damage and
stress that may lead to their removal from the spleen
• The spleen also serves as a storage site for platelets.
In a healthy individual, approximately 30% of the
total platelet count is sequestered in the spleen
• Two methods of removing senescent or
abnormal red blood cells from the circulation
- Culling – cells are phagocytized with
subsequent degradation of cell organelles
- Pitting – splenic macrophages remove
inclusions or damaged surface membrane from
the
circulating RBCs
• Spleen Pathophysiology
- As blood enters the spleen, it may follow one or
two routes
 Slow-transit pathway – through the red
pulp, in which the RBCs have a more difficult
time passing through the tiny openings
created by the interendothelial junctions of
adjacent endothelial cells o The
combination of the slow passage and the
continued RBC maturation creates an
environment that is acidic, hypoglycemic
and hypoxic
o Increased environmental stress on the
RBCs circulating through the spleen
leads to possible hemolysis
 Rapid-transit pathway – blood cells enter
the splenic artery and pass directly to the
sinuses in the red pulp and continue to the
venous system to exit the spleen
• Aggregates of T-lymphocytes surround arteries
that pass through these germinal centers, forming a
region called periarterial lymphatic sheath or PALS
• Interspersed along the periphery of the PALS are
lymphoid nodules containing primarily B response to foreign antigens
lymphocytes. Activated B lymphocytes are found in
the germinal centers
• When splenomegaly occurs, the spleen becomes
enlarged and is palpable
- This occurs as a result of many conditions such
as chronic leukemias, inherited membrane or
enzyme defects in RBCs, hemoglobinopathy,
thalassemia, malaria and the myeloproliferative
disorders
• Splenectomy may be beneficial in cases of excessive
destruction of RBCs such as autoimmune hemolytic
anemia when treatment with corticosteroids does
not effectively suppress hemolysis or in severe
hereditary spherocytosis
immune thrombocytopenic purpura or in
storage disease/disorders with portal
hypertension and splenomegaly resulting in
peripheral cytopenias
- After splenectomy, platelet and leukocyte count
increase transiently
• In sickle cell anemia, repeated splenic infarcts
caused by sickled RBCs trapped in the small-vessel
circulation of the spleen cause tissue damage and
necrosis, which often results in autosplenectomy
• Hypersplenism is an enlargement of the spleen
resulting in some degree of pancytopenia despite the
presence of a hyperactive bone marrow
- The most common cause is congestive
splenomegaly secondary to cirrhosis of the
liver and portal hypertension
- Often causes thrombosis, vascular stenosis,
other vascular deformities such as aneurysm of
the
splenic artery and cysts
Lymph nodes
• Lymph nodes can be divided into an outer region
called the cortex and an inner medulla. An outer
capsule forms trabeculae that radiate through the
cortex and provide support for the macrophages and
lymphocytes located in the node
• The lymph is the fluid portion of blood that escapes
into the connective tissue and is characterized by a
low protein concentration and the absence of RBCs
• After antigenic stimulation, the cortical region of
some follicles develops foci of activated B cell
proliferation called germinal centers. Follicles with
germinal centers are called secondary follicles, while
those without are called primary follicles
• Located between the cortex and medulla is a region
called paracortex which contains predominantly T
cells and numerous macrophages
• The medullary cords lie toward the interior of the
LN (consisting of plasma cells and B cells); three
functions
- Site of lymphocyte proliferation from the
germinal centers
- Involved in the initiation of the specific immune
dane.
 - Filter particulate matter, debris and bacteria • The thymus retains the ability to produce new T
entering the lymph node via the lymph cells, however, has been shown after irradiation
• Lymph node pathophysiology treatment that may accompany bone marrow
- Lymph nodes by their nature, are vulnerable to transplantation
the same organisms that circulate through the • Thymus pathophysiology
tissue - Nondevelopment of thymus during gestation
- Sometimes, increased numbers of results in the lack of formation of T lymphocytes.
microorganisms enter the nodes, overwhelming Related manifestations seen in patients with this
the macrophages and causing adenitis (infection condition are failure to thrive, uncontrollable
of lymph nodes) infections, and death in infancy
- More serious is the frequent entry into the - Adults with thymic disturbance are not
lymph nodes of malignant cells that have been affected because they have developed and
broken loose from malignant tumors maintained a pool of T lymphocytes for life
- These malignant cells may grow and metastasize • Medullary hematopoiesis – blood cell production
to other lymph nodes in the same group within the bone marrow. Begins in the 5 th month of
gestation and continues throughout life
Thymus • Extramedullary hematopoiesis – blood cell
• The thymus tissue originates from endodermal and production outside the bone marrow. Occurs when
mesenchymal tissue and populated initially by the bone marrow can’t meet body requirements and
primitive lymphoid cells from the yolk sac and the mainly in the liver and spleen, with hepatomegaly
liver and splenomegaly
• In adults, T cell progenitors migrate to the thymus
from the bone marrow for further maturation Theories on Blood Cell Formation
• The thymus resembles other lymphoid tissue in that • Monophyletic theory – all blood cells come from
the lobules are subdivided into two areas: the one origin stem cell, the hemocytoblast rec
cortex (a peripheral zone) and the medulla (central • Polyphyletic theory – also known as the dualistic
zone) theory which suggest different groups of blood cells
- Both areas are populated with the same cellular originate from different stem cells
components—lymphoid cells, mesenchymal - RBC, WBC, platelets – hemohistioblast
cells, reticular cells, epithelial cells, dendritic - Monocytes, lumphocytes and plasma cells –
cells and many macrophages—although in tissue hemohistioblast
different proportions • Growth factors
• The function of the cortex seems to be that of a Committed Growth factor Mature cell
“waiting zone” densely populated with progenitor T progenitor
cells CFU- Thrombopoietin, Thrombocytes
- When these progenitor T cells migrate from the MEG GM-CSF
bone marrow and first enter the thymus, they have CFU- CFUM GM-CSF, M-CSF, Monocytes
no identifiable CD4 and CD8 surface markers GM IL-3
(double negative), and they locate to the
CFU- CFU- GM-CSF, G-CSF, Neutrophils
corticomedullary junction
GM G IL-3
- Under the influence of chemokines, cytokines
and receptors, these cells move to the cortex and CFU- CFU- Erythropoietin, Erythroid
express both CD4 and CD8 (double positive) GM E GM CSF, IL-3
- Subsequently they give rise to mature T cells CFU-Eo GM-CSF, IL-3, Eosinophils
that expresss either CD4 or CD8 surface antigen IL5
as they move toward the medulla CFU-Ba IL-3, IL-4 Basophils
- Eventually, the mature T cells leave the thymus
to populate specific regions of other lymphoid
tissue, such as the T cell-depended areas of the
spleen, lymph nodes, and other lymphoid tissues
• The lymphoid cells that do not express the
appropriate antigens and receptors, or are self-
reactive, dies in the cortex or medulla as a result of
apoptosis and are phagocytized macrophages
• The medulla contains only 15% mature T cells and
seems to be holding zone for mature T cells until
they are needed by the peripheral lymphoid tissues
• The thymus also contains other cell types including B
cells, eosinophils, neutrophils, and other myeloid
cells
• Hardly recognizable in old age due to atrophy

dane.