Hematopoiesis Flashcards
Continuous, regulated process of renewal, proliferation, differentiation, and maturation of all blood cell lines
Hematopoiesis
These processes result in the formation, development, and specialization of all functional blood cells that are released from the bone marrow into the circulation
Renewal, proliferation, differentiation, and maturation
System that serves as a functional model to study stem cell biology, proliferation, and maturation and their contribution to disease and tissue repair
Hematopoietic system
Hematopoiesis in healthy adults is restricted primarily to the
Bone marrow
During fetal development, the restricted, sequential distribution of cells is initiated in the
Yolk sac
Hematopoiesis is considered to begin around the eighteenth day of embryonic development after fertilization. True or False?
False; nineteenth
Formation of primitive erythroblasts is seen in what stage of hematopoiesis?
Mesoblastic or Yolk Sac Phase
It is known as the stage for primitive hematopoiesis
Mesoblastic or Yolk Sac Phase
How does yolk sac hematopoiesis differ from hematopoiesis that occurs later in the fetus and adult?
Yolk sac hematopoiesis occurs intravascularly (or within developing blood vessels)
The major site of adult blood formation in the embryo
Yolk sac
Embryonic hemoglobins formed by immature erythrocytes in the yolk sac
Gower-1
Gower-2
Portland
Globin chain combination of Gower I
2 epsilon 2 zeta
Globin chain combination of Gower II
2 alpha 2 epsilon
Globin chain combination of Portland
2 zeta 2 gamma
The hepatic phase of hematopoiesis begins at 5 to 7 gestational weeks. True or False?
True
Event that signals the beginning of definitive hematopoiesis with a decline in primitive hematopoiesis of the yolk sac
Development of erythroblast; in addition to the appearance of lymphoid cells
Major site of hematopoiesis during the second trimester of fetal life
Liver
Hematopoiesis in the fetal liver reaches its peak by the _____ month of fetal development, then gradually declines after the _____ month, retaining minimal activity until _____ weeks after birth
Third
Sixth
1 to 2
The first fully developed organ in the fetus
Thymus
Major site of T cell production in fetus
Thymus
Organ that produce B cells in fetus
Kidney and spleen
Production of megakaryocytes begins during what stage of hematopoiesis?
Hepatic Phase
Hepatic stage of hematopoiesis occurs intravascularly or extravascularly?
Extravascularly
Hemoglobins produced during the hepatic phase of hematopoiesis
Fetal hemoglobin (Hb F)
Adult hemoglobin (Hb A)
Predominant hemoglobin in hepatic stage of hematopoiesis
Fetal hemoglobin (Hb F)
Percentage of adult hemoglobin (Hb A) in hepatic stage of hematopoiesis
<1%
Globin chain combination fetal hemoglobin (Hb F)
2 alpha 2 gamma
Hematopoiesis in the bone marrow
Medullary (Myeloid) Phase
Site of medullary hematopoiesis
Medulla or inner part of the bone cavity
Medullary hematopoiesis begins between the fifth and sixth month of fetal development. True or False?
False; fourth and fifth
Myeloid-to-erythroid ratio during medullary hematopoiesis
Gradually approaches 3:1 to 4:1 (normal adult levels)
Primary site of hematopoiesis by the end of 24 weeks’ gestation
Bone marrow
Measurable levels of erythropoietin (EPO), granulocyte col- ony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and hemoglobins F and A can be detected in medullary hematopoiesis. True or False?
True
Main type of hematopoiesis during the second and third trimester of pregnancy
Medullary (Myeloid) Phase
Hemoglobins produced during medullary hematopoiesis
Hb A
Hb A2
Globin chain combination adult hemoglobin (Hb A)
2 alpha 2 beta
Globin chain combination adult hemoglobin (Hb A2)
2 alpha 2 delta
In adult hematopoiesis, the red marrow is found only in the
Ribs
Sternum
Scapula
Skull
Vertebrae
Pelvic bone
Proximal end of long bones
Site of adult hematopoietic tissue
Bone marrow (major site)
Lymph nodes
Spleen
Liver
Thymus
Primary site of adult hematopoiesis
Bone marrow
Secondary site of adult hematopoiesis
Liver and spleen
Reference range for normal adult Hgb
Hb A: 95-97%
Hb A2: 2-3%
≤1%: Hb F
Type of hematopoiesis seen during compensatory state such in case of bone marrow failure, certain diseases, malignancies, and infection
Extramedullary hematopoiesis
Type of hematopoiesis that results to hepatomegaly and splenomegy
Extramedullary hematopoiesis
Formation and activation of blood cells outside the bone marrow
Extramedullary hematopoiesis (EMH)
Extramedullary hematopoiesis (EMH) occurs mainly in
Liver and spleen
Two major components of normal bone marrow
Red marrow
Yellow marrow
Composition of red marrow
Developing blood cells and their progenitors
Composition of yellow marrow
Adipocytes (fat cells), with undifferentiated mesenchymal cells and macrophages
Hematopoietically active marrow
Red marrow
Hematopoietically inactive marrow
Yellow marrow
One of the largest organs in the body, is located within the cavities of the cortical bones
Bone Marrow
During infancy and early childhood, all the bones in the body contain primarily yellow (inactive) marrow. True or False?
False; red (active) marrow
The process of replacing the ac- tive marrow by adipocytes (yellow marrow) during development
Retrogression
Retrogression occurs between 8 and 9 years of age. True or False?
False; 5 and 7
The ratio of the red marrow to the yellow marrow
Marrow cellularity
Marrow cellularity in adults
Approximately equal amounts of red and yellow marrow in hematopoietic active sites
Marrow cellularity, typically increases with age. True or False?
False; decreases
Yellow marrow is capable of reverting back to active marrow. True or False?
True
Cells originated from mesenchymal cells that migrate into the central cavity of the bone
Stromal cells
Stromal cells include:
Perivascular
Adipocytes (fat cells)
Lymphocytes
Endothelial cells
Glial cells
Reticular adventitial cells (fibroblasts)
Osteoblasts
Osteoclasts
Macrophages
Broad, flat cells that form a single continuous layer along the inner surface of the arteries, veins, and vascular sinuses
Endothelial cells
Large cells with a single fat vacuole
Adipocytes
Cells involved in cytokine production
Macrophages
Adipocytes
Lymphocytes
Endothelial cells
Bone-forming cells
Osteoblasts
Bone-resorbing cells
Osteoclasts
Responsible for the incomplete layer of cells on the abluminal surface of the vascular sinuses
Reticular adventitial cells
Stromal cells play a critical role in the regulation of hematopoietic stem and progenitor cell survival and differentiation. True or False?
True
The nutrient and oxygen requirements of the marrow are fulfilled by the
Nutrient and periosteal arteries, which enter via the bone foramina
The nutrient artery supplies blood only to the marrow. True or False?
True
Periosteal arteries provide nutrients for the osseous bone and the marrow. True or False?
True
Hematopoietic cells located in the end-osteal bed receive their nutrients from the
Nutrient artery
Key stromal cells thought to support HSCs in bone marrow niches
Osteoblasts
Endothelial cells
Mesenchymal stem cells
CXCL12-abundant reticular cells
Perivascular stromal cells
Glial cells
Macrophages
Ratio between granulocyte lineage and erythrocyte lineage
Myeloid:Erythroid Ratio
Normal Myeloid:Erythroid Ratio
3:1
Excluded from the M:E ratio are
Lymphocyte and its precursors, plasma cells, monocytes and its precursors, histiocytes,
nonnucleated erythrocytes, and nonhematopoietic stromal cell
M:E ratio during infection. Interpret the results
6:1; Increase
M:E ratio during leukemia. Interpret the results
25:1; Increase
M:E ratio during myeloid hyperplasia. Interpret the results
20:1; Increase
M:E ratio during myeloid hypoplasia. Interpret the results
3:20; Decrease
M:E ratio during erythroid hyperplasia. Interpret the results
1:20; Decrease
M:E ratio during erythroid hypoplasia. Interpret the results
5:1;Increase
Used to evaluate hematopoietic cell production
M:E Ratio
Normocellular marrow cellularity value
Marrow has 30 to 70% HSCs
Hypercellular/Hyperplastic marrow cellularity value
Marrow has >70% HSCs
Hypocellular/Hypoplastic marrow cellularity value
Marrow has <30% HSCs
Aplastic marrow cellularity value
Marrow has few or no HSCs
Types of Bone marrow Specimen
Direct aspirate smears
Anticoagulated aspirate smears
Crush smears
Histologic/ Cell block
Imprints/ Touch preparation
Concentrate/ Buffy coat smear
Most commonly used site for BM collection
Posterior iliac crest
Most commonly used site for BM collection for newborn and infants
Upper end of tibial bone
Instrument/s used for Trephine (Core) biopsy
Trephine biopsy needle / Jamshidi needle / Westerman-Jensen needle
Instrument/s used for Bone marrow Aspirate
Aspiration needle / University of Illinois sternal needle
Bone marrow smears should be retained for
10 years
Bone Marrow Differential requires counting at least 500, and preferably 1000 cells be counted. True or False?
True
Two most common erythrocytic stages with fried egg appearance
Polychromatophilic and orthochromic normoblast
The largest cell in the Bone Marrow
Megakaryocyte
The most predominant cell in the Bone Marrow
Metamyelocyte
the largest cell in the Venous Blood
Monocytes
The bone marrow is estimated to be capable of producing approximately 2.5 billion erythrocytes, 2.5 billion platelets, and 1-billion granulocytes per kilogram of body weight daily. True or False?
True
Appearance of osteoblasts
Water-bug or comet appearance
Osteoblasts are commonly mistaken as
Plasma cells
Osteoclasts are commonly mistaken as
Megakaryocyte
The identification and origin of HSCs can be determined by immunophenotypic analysis using
Flow cytometry
Cytokines that exert a negative influence on hematopoiesis
TGF-Beta
TNF-Alpha
Interferons
Cytokines or Hematopoietic growth factors that exert a positive influence on HSCs and progenitor cells
KIT ligand
FLT3 ligand
GM-CSF
IL-1
IL-3
IL-6
IL-11
Organ that synthesize coagulation factors
Liver
Macrophages that remove senescent cells and foreign debris from the blood that circulates through the liver
Kupffer cells
The largest lymphoid organ in the body
Spleen
Amount of blood contained in the spleen of a healthy individual
350 mL
Three types of splenic tissue
White pulp
Red pulp
Marginal zone
Cells in white pulp
Lymphocytes
Macrophages
Dendritic cells
Cells in marginal zone
Macrophages
Memory B cells
CD4 T cells
Cells in red pulp
Specialized macrophages
The spleen uses two methods for removing senescent or abnormal RBCs from the circulation:
Culling
Pitting
Process in which the cells are phagocytized with subsequent degradation of cell organelles
Culling
Process in which splenic macrophages remove inclusions or damaged surface membrane from the circulating RBCs
Pitting
The spleen serves as a storage site for platelets. True or False?
True
Approximate amount of platelet sequestered in the spleen
30% of the total platelet count
The combination of the slow pas- sage and the continued RBC metabolism creates an environment that is acidic, hypoglycemic, and hypoxic. True or False?
True
Splenectomy will lead to
Pancytosis
Hypersplenism will lead to
Pancytopenia
How does sickled RBCs lead to autosplenectomy
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
Spontaneous splenic infarction leading to hyposplenism
Autosplenectomy
Graveyard of the RBCs
Spleen
Storage site of blood cells
Spleen
Area in white pulp where B cells reside
Primary follicles
Area in white pulp where activated B cells reside
Germinal center or Secondary follicle
Area in white pulp where T cells reside
PALS (periarteriolar lymphoid sheaths)
Cord of billroth is seen in
Red pulp
The red pulp makes up more than one half of the total volume of spleen. True or False?
True
Poikilocytes produced by pitting
Bite cells
Inclusion bodies of RBC in person with G6PD Deficiency
Heinz bodies
RBC lifespan
120 days
Old senescent RBCs are deformable. True or False?
False; rigid
The absence of splenic function)
Asplenia
Fluid portion of blood that escapes into the connective tissue and is characterized by a low protein concentration and the absence of RBCs
Lymph
Three main functions if lymph nodes
They are a site of lymphocyte proliferation
They are involved in the initiation of the specific immune response to foreign antigens
They filter particulate matter, debris, and bacteria entering the lymph node via the lymph
Infection or inflammation of the lymph node due to increased numbers of microorganisms entering the nodes
Adenitis
Site of T cell production
Bone marrow
Site of T cell maturation
Thymus
Site of B cell production
Bone marrow
Site of B cell maturation
Bone marrow
Two major types of hematopoietic progenitor cells
Noncommitted or undifferentiated HSCs
Committed progenitor cells
Two theories describing the origin of hematopoietic progenitor cells
Monophyletic theory
Polyphyletic theory
Theory suggesting that all blood cells are derived from a single progenitor stem cell called a pluripotent hematopoietic stem cell
Monophyletic theory
Theory suggesting that each of the blood cell lineages is derived from its own unique stem cell
Polyphyletic theory
Most widely accepted theory among experimental hematologists
Monophyletic theory
Cells capable of self-renewal, are pluripotent and give rise to differentiated progeny, and are able to reconstitute the hematopoietic system of a lethally irradiated host
Hematopoietic Stem Cells
The undifferentiated HSCs can differentiate into progenitor cells committed to either lymphoid or myeloid lineages. True or False?
True
Lineage-specific progenitor cells which proliferates and differentiates into T, B, and natural killer lymphocyte and dendritic lineages
Common lymphoid progenitor
Lineage-specific progenitor cells which proliferates and differentiates into individual granulocytic, erythrocytic, monocytic, and megakaryocytic lineages
Common myeloid progenitor
Number of cells produced by the bone marrow
2.5 billion erythrocytes, 2.5 billion platelets, and 1 billion granulocytes per kilogram of body weight daily
Most of the cells in normal bone marrow are precursor cells at various stages of maturation. True or False?
True
Three possible fates of HSCs
Self-renewal
Differentiation
Apoptosis
Explain the symmetric division
Both daughter cells may follow the path of differentiation, leaving the stem cell pool
Explain the asymmetric division
One daughter cell may return to the stem cell pool and the other daughter cell may follow the path of differentiation or undergo apoptosis
Model suggesting that the HSC randomly commits to self-renewal or differentiation
Stochastic model of hematopoiesis
Model suggesting that the microenvironment in the bone marrow deter- mines whether the HSC will self-renew or differentiate
Instructive model of hematopoiesis
Model suggesting that HSCs receive low-level signals from the hematopoietic inductive microenvironment to amplify or repress genes associated with commit- ment to multiple lineages
Multilineage priming model
A bipotential progenitor cell of mesodermal origin that gives rise to hematopoietic and endothelial lineages
Hemangioblast
Changes in the nucleus during cell maturation
Loss of nucleoli
Decrease in the diameter of the nucleus
Condensation of nuclear chromatin
Possible change in the shape of the nucleus
Possible loss of the nucleus
Changes in the cytoplasm during cell maturation
Decrease in basophilia
Increase in the proportion of cytoplasm
Possible appearance of granules
HSCs exist in the marrow in the ratio of
1 per 1000 nucleated blood cells
Can be calculated to establish the percentage of cells in mitosis in relation to the total number of cells
Mitotic index
Factors affecting the mitotic index
Duration of mitosis and the length of the resting state
Normal mitotic index
1% to 2%
Increased mitotic index implies
Increased proliferation
Rate of mitosis in case of megaloblastic anemia
Prolonged
G0
Resting stage
G1
Cell growth and synthesis of components necessary for cell division
S
DNA replication
G2
Premitotic phase
M
Mitosis
A group of specific glycoproteins that regulate the proliferation, differentiation, and maturation of hematopoietic precursor cells
Hematopoietic growth factors or cytokines
Diverse group of soluble proteins that have direct and indirect effects on hematopoietic cells
Cytokines
Cytokines include:
Interleukins (ILs)
Lymphokines
Monokines
Interferons
Chemokines
Colony-stimulating factors (CSFs)
Responsible for stimulation or inhibition of production, differentiation, and trafficking of mature blood cells and their precursors
Cytokines
Normal physiologic process that eliminates unwanted, abnormal, or harmful cells
Apoptosis/programmed cell death
KIT ligand is also known as
Stem cell factor (SCF)
Characteristics shared by interleukins
- They are proteins that exhibit multiple biologic activities, such as the regulation of autoimmune and inflammatory reactions and hematopoiesis.
- They have synergistic interactions with other cytokines.
- They are part of interacting systems with amplification
potential. - They are effective at very low concentrations.
A complex, regulated process for maintaining adequate numbers of eryth- rocytes in the peripheral blood
Erythropoiesis
Erythropoiesis occurs in the
Bone marrow
Earliest identifiable colony of RBCs
Burst- forming unit-erythroid (BFU-E)
Serves as a differentiation factor that causes the CFU-E to differentiate into pronormoblasts
EPO
The earliest visually recognized erythrocyte precursors in the bone marrow
Pronormoblasts
Lineage-specific glycoprotein produced in the renal peritubular interstitial cells
EPO
Small amount of EPO is produced by the liver. True or False?
True
Stimulus that activates production and secretion of EPO
Oxygen availability in the kidney
Two major categories of leukopoiesis
Myelopoiesis
Lymphopoiesis
Main site of production of TPO
Liver
Cytokines are used as priming agents to increase the yield of HSCs during apheresis for transplantation protocols. True or False?
True
Foundation of the adult hematopoietic system
Hematopoietic stem cells (HSCs)
Three types of human stem cell
Totipotential
Pluripotential
Multipotential
The most versatile type of stem cell
Totipotential stem cells
It is an ideal environment of HSC is the allowance for: Self renewal, Proliferation and Differentiation, Apoptosis
Hematopoietic microenvironment
Specialized cells within the BM that provide protective and nourishing environment to the HSCs
Stromal cells
Function of stromal cells
Secrete substances that make up the extracellular matrix which are essential for cell growth and support of the HSCs
Origin of dendritic cells
CLP
Precursor of dendritic cells
Monocytes
RBC precursors
Rubriblast to Reticulocyte
Granulocyte precursors
Myeloblast to Band cells
Platelet precursors
Megakaryoblast
Promegakaryocyte
Megakaryocyte
Not a true leukocyte
Mast cell
Mature cell/s developed from G-M (Granulocyte-Monocyte) Progenitor
Basophil
Neutrophil
Eosinophil
Monocyte
Macrophage
Mature cell/s developed from E-B (Eosinophil-Basophil) Progenitor
Basophil
Eosinophil
Mature cell/s developed from M-E (Megakaryocyte-Erythrocyte) Progenitor
Platelets
RBCs
Mature cell/s developed from CMP (Common Myeloid Progenitor)
Granulocytes
Erythrocytes
Monocytes/Macrophages
Megakaryocytes
Mature cell/s developed from CLP (Common Lymphoid Progenitor)
Lymphocytes (B cell, T cell, and NK cell)
Plasma cells
Dendritic cells
Functional characterization of HSCs can be accomplished through in vitro techniques using
Culture assays
Lymphoid pan T cell marker/s
CD2
CD3
Helper / Inducer T cell marker/s
CD4
Suppressor / Cytotoxic T cell marker/s
CD8
Pan Myeloid cell marker/s
CD13
CD33
Monocyte marker/s
CD11
CD14
Lymphoid, pan B cell marker/s
CD19
CD20
Hematopoietic stem cell marker/s
CD34
NK Cell marker/s
CD16
CD56
Pre-CALLA (Common acute
lymphoblastic leukemia) marker/s
CD10
CFU-GEMM cell line
Granulocyte
Erythrocyte
Megakaryocyte
Monocyte
CFU-E cell line
Erythrocyte
CFU-Meg cell line
Megakaryocyte
CFU-M cell line
Monocyte
CFU-GM cell line
Granulocyte, monocyte
CFU-BASO cell line
Myeloid to basophil
CFU-EO cell line
Myeloid to eosinophil
CFU-G cell line
Myeloid to neutrophil
CFU-pre-T cell line
T lymphocyte
CFU-pre-B cell line
B lymphocyte