HEMATOPOIESIS: THE ORIGIN OF CELL DEVELOPMENT
HEMATOPOIESIS: THE ORIGIN OF CELL DEVELOPMENT
Hematopoiesis is defined as the production, development, differentiation, and maturation of all blood cells.Within these four functions is cellular machinery that outstrips most high-scale manufacturers in terms of production quotas, customs specifications, and quality of final product. When one considers that the bone marrow is able to produce 3 billion red cells, 1.5 billion white cells, and 2.5 billion platelets per day per body weight,1 the enormity of this task in terms of output is almost incomprehensible. Within the basic bone marrow structure lies the mechanism to
1. constantly supply the peripheral circulation with mature cells.
2. mobilize the bone marrow to increase production if hematological conditions warrant.
3. compensate for decreased hematopoiesis by providing for hematopoietic sites outside of
the bone marrow (non-bone marrow sites, the liver and spleen).
The bone marrow is extremely versatile and serves the body well by supplying life-giving cells with a multiplicity of functions. Various organs serve a role in hematopoiesis, and these organs differ from fetal to adult development.
The yolk sac, liver, and spleen are the focal organs in fetal development. From 2 weeks until 2
months in fetal life, most erythropoiesis takes place in the fetal yolk sac. This period of development, the mesoblastic period, produces primitive erythroblasts and embryonic hemoglobins (Hgbs) such as Hgb Gower I and Gower II and Hgb Portland. These Hgbs are constructed as tetramers with two alpha chains combined with either epsilon or zeta chains. As embryonic Hgbs, they do not survive into adult life and do not participate in oxygen delivery. During the hepatic period, which continues from 2 through 7 months of fetal life, the liver
and spleen take over the hematopoietic role White cells and megakaryocytes begin to appear in small numbers. The liver serves as an erythroid-producing organ primarily but also gives rise to fetal Hgb, which consists of alpha and gamma chains. The spleen, thymus, and lymph nodes also become hematopoietically active during this stage, producing red cells and lymphocytes;
from 7 months until birth, the bone marrow assumes the primary role in hematopoiesis, a role that continues into adult life. Additionally, Hgb A, the majority adult Hgb (alpha 2, beta 2), begins to form.
The full complement of Hgb A is not realized until 3 to 6 months postpartum, as gamma chains from hemoglobin F are diminished and beta chains are increased
Hematopoiesis within the bone marrow is termed intramedullary hematopoiesis. The term extramedullary hematopoiesis describes hematopoiesis outside the bone marrow environment, primarily the liver and spleen.
Because these organs play major roles in early fetal hematopoiesis, they retain their hematopoietic memory and capability. The liver and spleen can function as organs of hematopoiesis if needed in adult life. Several circumstances within the bone marrow
(infiltration of leukemic cells, tumor, etc.) may diminish the marrow’s normal hematopoietic capability and force these organs to once again perform as primary or fetal organs of
hematopoiesis. If extramedullary hematopoiesis develops, the liver and spleen become enlarged, a condition known as hepatosplenomegaly. Physical evidence of hepatosplenomegaly will be an individual who looks puffy and protrusive in the left upper abdominal area.
Hepatosplenomegaly is always an indicator that hematological health is compromised.
Because these organs play major roles in early fetal hematopoiesis, they retain their hematopoietic memory and capability. The liver and spleen can function as organs of hematopoiesis if needed in adult life. Several circumstances within the bone marrow
(infiltration of leukemic cells, tumor, etc.) may diminish the marrow’s normal hematopoietic capability and force these organs to once again perform as primary or fetal organs of
hematopoiesis. If extramedullary hematopoiesis develops, the liver and spleen become enlarged, a condition known as hepatosplenomegaly. Physical evidence of hepatosplenomegaly will be an individual who looks puffy and protrusive in the left upper abdominal area.
Hepatosplenomegaly is always an indicator that hematological health is compromised.
THE SPLEEN AS AN INDICATOR ORGAN OF HEMATOPOIETIC HEALTH
Few organs can match the versatility of the spleen. This small but forgotten organ is a powerhouse of prominent red cell activity such as filtration, production, and cellular
immunity. Under normal circumstances, the organ cannot be felt or palpated on physical examination. This fist-shaped organ, located on the left side of the body under the rib cage, weighs about 8 ounces, is soft in texture, and receives 5% of the cardiac output per minute.
The spleen, a blood-filled organ, consists of red pulp, white pulp, and the marginal zone. The function of the red pulp is primarily red cell filtration, whereas the white pulp deals with lymphocyte processing and the marginal zone with storage of white cells and platelets.
The Functions of the Spleen
There are four main tasks of the spleen that relate to red cell viability and the spleen’s immunologic capability.The first function is the reservoir, or storage, function of the spleen. The spleen harbors one third of the circulating mass of platelets and one third of the granulocyte
mass and may be able to mobilize platelets into the peripheral circulation as necessary. In the event of splenic rupture or trauma, large numbers of platelets may be spilled into the peripheral circulation. This event may predispose to unwanted clotting events, because platelets serve as catalysts for hemostasis.
The second function of the spleen is the filtration function
The spleen has a unique inspection mechanism and
examines each red cell and platelet for abnormalities
and inclusions. Older red cells may lose their elasticity
and deformability in the last days of their 120-day life
span and are culled from the circulation by splenic
phagocytes. Bilirubin, iron, and globin byproducts
released through the culling process are recycled
through the plasma and circulation.
Red cells that are filled with inclusions (Howell
Jolly bodies, Heinz bodies, Pappenheimer bodies, etc.)
are selectively reviewed and cleared. Inclusions are “pitted”
and pulled from the red cell without destroying the
cellular integrity, and red cells are left to continue their
journey through the circulation.2 Antibody-coated red
cells have their antibodies removed and usually reappear
in the peripheral circulation as spherocytes, a
smaller, more compact red cell structure with a shortened
life span. One of the least appreciated roles of the
spleen is the immunologic role. As the largest secondary
lymphoid organ, the spleen plays a valuable role in the
promotion of phagocytic activity for encapsulated
organisms such as Haemophilus influenzae, Streptococcus
pneumoniae, or Neisseria meningitidis. The spleen
provides opsonizing antibodies, substances that strip
the capsule from the bacterial surface. Once this is
accomplished, the unencapsulated bacteria is more vulnerable
to the phagocytic reticuloendothelial system
(RES)3 and less able to mount an infection to the host
system. Without a functioning spleen, this important
function is negated and can lead to serious consequences,
including fatality, for the infected individual.
The final function of the spleen is its hematopoietic
function, discussed earlier in this chapter.
can cause difficulty for patients and these conditions
are discussed in later chapters. Traditionally, the
spleen was seen as an inconsequential organ, easily discarded
and one that was not necessary to life function.
While it is true that the splenectomy procedure may
provide hematological benefit to patients who have
problems with their spleen, it is equally true that individuals
who do not have spleens have additional risks,
as mentioned earlier. There have been reports in the literature
of overwhelming postsplenectomy infections
(OPSIs) that may occur years after the spleen has been
removed. In most cases, these infections occur within 3
years, but they have been reported as long as 25 years
after the splenectomy. Many individuals die from OPSIs
or at the very least have multiorgan involvement. As an
organ of the hematopoietic system, the spleen has
immense capability and provides a high value and versatilityexamines each red cell and platelet for abnormalities
and inclusions. Older red cells may lose their elasticity
and deformability in the last days of their 120-day life
span and are culled from the circulation by splenic
phagocytes. Bilirubin, iron, and globin byproducts
released through the culling process are recycled
through the plasma and circulation.
Red cells that are filled with inclusions (Howell
Jolly bodies, Heinz bodies, Pappenheimer bodies, etc.)
are selectively reviewed and cleared. Inclusions are “pitted”
and pulled from the red cell without destroying the
cellular integrity, and red cells are left to continue their
journey through the circulation.2 Antibody-coated red
cells have their antibodies removed and usually reappear
in the peripheral circulation as spherocytes, a
smaller, more compact red cell structure with a shortened
life span. One of the least appreciated roles of the
spleen is the immunologic role. As the largest secondary
lymphoid organ, the spleen plays a valuable role in the
promotion of phagocytic activity for encapsulated
organisms such as Haemophilus influenzae, Streptococcus
pneumoniae, or Neisseria meningitidis. The spleen
provides opsonizing antibodies, substances that strip
the capsule from the bacterial surface. Once this is
accomplished, the unencapsulated bacteria is more vulnerable
to the phagocytic reticuloendothelial system
(RES)3 and less able to mount an infection to the host
system. Without a functioning spleen, this important
function is negated and can lead to serious consequences,
including fatality, for the infected individual.
The final function of the spleen is its hematopoietic
function, discussed earlier in this chapter.
Potential Risks of Splenectomy
Spleens that are enlarged, infarcted , or minimally functioningcan cause difficulty for patients and these conditions
are discussed in later chapters. Traditionally, the
spleen was seen as an inconsequential organ, easily discarded
and one that was not necessary to life function.
While it is true that the splenectomy procedure may
provide hematological benefit to patients who have
problems with their spleen, it is equally true that individuals
who do not have spleens have additional risks,
as mentioned earlier. There have been reports in the literature
of overwhelming postsplenectomy infections
(OPSIs) that may occur years after the spleen has been
removed. In most cases, these infections occur within 3
years, but they have been reported as long as 25 years
after the splenectomy. Many individuals die from OPSIs
or at the very least have multiorgan involvement. As an
organ of the hematopoietic system, the spleen has
(Table 2.1). If splenic removal is decided upon,
the surgeon should leave some splenic tissue in place
and carefully manage the asplenic patient; asplenic
individuals represent a more vulnerable population.
THE BONE MARROW AND THE MYELOID:ERYTHROID RATIO
The bone marrow is one of the largest organs of the body, encompassing 3% to 6% of body weight and weighing 1500 g in the adult.4 It is hard to conceptualize the bone marrow as an organ, because it is not a solid organ that one can easily touch, measure, or weigh.Because bone marrow tissue is spread throughout the body, one can visualize it only in that context. It is composed of yellow marrow, red marrow, and an intricate supply of nutrients and blood vessels. Within this structure are erythroid cells (red cells), myeloid cells (white
cells), and megakaryocytes (platelets) in various stages of maturation, along with osteoclasts, stoma, and fatty tissue.5 Mature cells enter the peripheral circulation via the bone marrow sinuses, a central structure lined with endothelial cells that provide passage for mature cells
from extravascular sites to the circulation .
The cause and effect of hematological disease usually find root in the bone marrow, the central factory for production of all adult hematopoietic cells. In the first 18 years
of life, bone marrow is spread throughout all of the major bones of the skeleton, especially the long bones.
Gradually, as the body develops, the marrow is replaced by fat until the prime locations for bone marrow in the adult are the iliac crest, located in the pelvic area, and the sternum, located in the chest area. In terms of cellularity
there is a unique ratio in the bone marrow termed the myeloid:erythroid (M:E) ratio. This numerical designation provides an approximation of the myeloid elements in the marrow and their precursor cells and the erythroid elements in the marrow and their precursorcells. The normal ratio of 3 to 4:1 reflects the relationship between production and life span of the various cell types. White cells have a much shorter life span than red cells, 6 to 10 hours for neutrophils as opposed to 120 days for erythrocytes,5 and thus need to be produced
at a much higher rate for normal hematopoiesis.
ALTERATIONS IN THE MYELOID:ERYTHROID RATIO
The M:E ratio is sensitive to hematological factors that may impair red cell life span, inhibit overall production, or cause dramatic increases in a particular cell line. Each of these conditions reflects bone marrow dynamics through alterations of the M:E ratio. Many observationsin the peripheral smear can be traced back to the pathophysiological events at the level of bone marrow. A perfect example of this is the bone marrow’s response to anemia. As anemia develops and becomes more severe, the patient becomes symptomatic and the kidney
senses hypoxia due to a decreased Hgb level. Tissue hypoxia stimulates an increased release of erythropoietin (EPO), a red cell-stimulating hormone, from the kidney. EPO travels through the circulation and binds with a receptor on the youngest of bone marrow precursor
cells, the pronormoblast. The bone marrow has the capacity to expand production six to eight times in response to an anemic event.6 Consequently, the bone marrow delivers reticulocytes and nucleated red blood cells to the peripheral circulation prematurely if the kidney
senses hypoxic stress. What will be observed in the peripheral blood smear is polychromasia (stress reticulocytes, large polychromatophilic red cells) and nucleated red cells. Both of these cell types indicate that the bone marrow is regenerating in response to an event.
This dynamic represents the harmony between bone marrow and peripheral circulation.
THE ROLE OF STEM CELLS AND CYTOKINES
A unique feature to the bone marrow microenvironment is the presence of stem cells. These multipotential cells resemble lymphocytes and are available in the bone marrow in the ratio of one stem cell for every 1000 non-stem cell elements.1 Stem cells were demonstratedin the classic experiment of Till and McCullugh in 1961.
These investigators irradiated the spleens and bone marrows of mice, rendering them acellular, and then injected them with bone marrow cells. Within days, colonies appeared on the spleens of the mice and were referred to as colony-forming units-spleen (CFU-S), with cells capable of regenerating into mature hematopoietic cells. In present-day terminology, CFU-S
are the pluripotential stem cells .
Multipotential stem cells are capable of differentiation into nonlymphoid or lymphoid precursor committed cells.7 Nonlymphoid committed cells will develop into the entire white cell, red cell, or megakaryocytic family (CFU-GEMM). The lymphocytic committed cell (LSC) will develop into T cells or B cells, which are of different origins. T cells are responsible for cellular immunity
ERYTHROPOIETIN
Erythropoietin (EPO), a cytokine, is a hormone produced by the kidneys that functions as a targeted erythroid growth factor. This hormone has the ability to stimulate red cell production through a receptor on the pronormoblast, the youngest red cell precursor in the
bone marrow. EPO is secreted on a daily basis in small amounts and functions to balance red cell production.10 If the body becomes anemic and Hgb levels decline, the
kidney senses tissue hypoxia and secretes more EPO; consequently, red cell production is accelerated and younger red cells are released prematurely.
Normal red cell maturation from the precursor cell the pronormoblast takes 5 days; with accelerated erythropoiesis, the maturation is decreased to 3 to 4 days. Human
recombinant erythropoietin (r-HuEPO) is available as a pharmaceutical product and can be used for individuals experiencing renal disease, for individuals who have become anemic as a result of chemotherapy, or for individuals who refuse whole blood products on religious
grounds.
These investigators irradiated the spleens and bone marrows of mice, rendering them acellular, and then injected them with bone marrow cells. Within days, colonies appeared on the spleens of the mice and were referred to as colony-forming units-spleen (CFU-S), with cells capable of regenerating into mature hematopoietic cells. In present-day terminology, CFU-S
are the pluripotential stem cells .
Multipotential stem cells are capable of differentiation into nonlymphoid or lymphoid precursor committed cells.7 Nonlymphoid committed cells will develop into the entire white cell, red cell, or megakaryocytic family (CFU-GEMM). The lymphocytic committed cell (LSC) will develop into T cells or B cells, which are of different origins. T cells are responsible for cellular immunity
(cell-to-cell communication), whereas B cells are responsible for humoral immunity, the production of circulating antibodies directed by plasma cells. Each of these committed cells evolves into their adult form through proliferation, differentiation, and maturation.
Chemical signals such as cytokines and interleukins are uniquely responsible for promoting a specific lineage of cell.
Most of these substances are glycoproteins that will target specific cell stages. They control replication , clonal or lineage selection and are responsible for maturation
rate and growth inhibition of stem cells.8 Many cytokines are available as pharmaceutical products.
Recombinant technology has made it possible to purify and produce cytokines such as EPO, granulocytecolony stimulating factor (G-CSF), and granulocytemacrophage
colony-stimulating factor (GM-CSF).
These products are used to stimulate a specific cell production to yield therapeutic benefit for the patient. Specific conditions in which recombinant cytokines have been useful are as follows9:
1. Recovery from neutropenia resulting from myelotoxic therapy
2. Graft versus host disease after bone marrow transplant therapy
3. To increase white counts in patients with AIDS on antiretroviral therapy
Chemical signals such as cytokines and interleukins are uniquely responsible for promoting a specific lineage of cell.
Most of these substances are glycoproteins that will target specific cell stages. They control replication , clonal or lineage selection and are responsible for maturation
rate and growth inhibition of stem cells.8 Many cytokines are available as pharmaceutical products.
Recombinant technology has made it possible to purify and produce cytokines such as EPO, granulocytecolony stimulating factor (G-CSF), and granulocytemacrophage
colony-stimulating factor (GM-CSF).
These products are used to stimulate a specific cell production to yield therapeutic benefit for the patient. Specific conditions in which recombinant cytokines have been useful are as follows9:
1. Recovery from neutropenia resulting from myelotoxic therapy
2. Graft versus host disease after bone marrow transplant therapy
3. To increase white counts in patients with AIDS on antiretroviral therapy
ERYTHROPOIETIN
bone marrow. EPO is secreted on a daily basis in small amounts and functions to balance red cell production.10 If the body becomes anemic and Hgb levels decline, the
kidney senses tissue hypoxia and secretes more EPO; consequently, red cell production is accelerated and younger red cells are released prematurely.
Normal red cell maturation from the precursor cell the pronormoblast takes 5 days; with accelerated erythropoiesis, the maturation is decreased to 3 to 4 days. Human
recombinant erythropoietin (r-HuEPO) is available as a pharmaceutical product and can be used for individuals experiencing renal disease, for individuals who have become anemic as a result of chemotherapy, or for individuals who refuse whole blood products on religious
grounds.
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