hematology 1 week 2

ch.5,6,7,8,9

Erythroid means what

erythrocytes

what are Myeloids

granulocytes, monocytes, megakaryocytes(platelets)

innate immunity

what is a Lymphoid

lymphocytes= B,T, NK cells

adaptive immunity

what is the old theory of blood cell development name

polyphyletic therory

what is the polyphyletic therory

Each blood cell lineage originates from its own unique stem cell

what is the now accepted blood cell development theory

Monophyletic Theory

what is the Monophyletic Theory

All blood cells originate from a single pluripotent HSC

order of monophyletic theory

blood stem cell

myeloid stem cell lymphoid stem cell

rbc, platelets, myeloblast lymphoblast

granulocytes b cell, t cell, NK cell

plasma cell

what does pluripotency mean

can give rise to multiple cell types

what are hematopoietic stem cells HSC’s capable of

Self-renewal
Pluripotency
Differentiation into committed progenitor cells

what are the common progenitors

lymphoid and myeloid

which cells are lymphoid progenitor cells?

T cells

B cells

Natural Killer cells

Dentritic cells

which cells are myeloid progenitor cells

granulocytes

erthrocytes

monocytes

megakaryocytes

How are early human HSc’s identified

by maker CD34+ via flow cytometry

what are the 4 stem cell cycle kinetics

Need determines production
Self-renewal

Proliferation
Apoptosis

what does proliferation in stem cell cycle kinetics entail?

Commitment
Differentiation
Maturation

what are the general maturation features of morphologic changes during hematopoiesis

Cell volume decreases
 Nucleus-to-cytoplasm ratio decreases
 Nucleus changes
 Cytoplasmic changes

what are the growth factors/cytokines/hormones considered?

a group of specific glycoproteins

what do growth factors do?

regulate the proliferation, differentiation, and maturation of hematopoietic precursor cells

whats EPO, what does it do, where is it from?

erythropoietin

Simulates proliferation of erythroid progenitors ( I response to hypoxia

kidney

whats TPO, what does it do, where is it from?

thrombopoietin

regulates platelet production

liver

whats CSF, what does it do

colony stimulating factor

stimulates granulocyte colonies

prenatal hematopoiesis occuris in what phases

3 phases

Mesoblastic (Yolk Sac)
Hepatic (Liver)
Medullary/Myeloid (Bone Marrow)

where does the MESOBLASTIC/EMBRYONIC PHASE begin and what does it do

Begins in the yolk sac 2-3 weeks after fertilization
 The mesoderm gives rise to the first blood cell

Unique early hemoglobins for oxygen transport
 Gower-1
 Gower-2
 Portland
 Phase lasts to ~5 to 7 weeks

HEPATIC PHASE

After ~5 to 7 weeks gestation, yolk sac disappears as liver becomes primary site of hematopoiesis

hematopoiesis occurs extravascularly in this phase
 Platelets appear by week 9 of gestation
 Hgb F replaces embryonic Hgbs

MEDULLARY (MYELOID) PHASE

By 4 - 5 months and throughout life, the bone marrow is the primary
site of hematopoiesis
 All stages of maturation of all cell lines detectable
myeloid-to-erythroid ratio gradually approaches 3:1
 Both fetal and adult hemoglobins detectable= Hb F and Hb A

what are the changes in hbg production as fetus develops

Embryonic hemoglobins: Gower 1, Gower 2, Portland
 Fetal hemoglobin: Hgb F
 Adult hemoglobins:Hgb A, Hgb A2, Small levels of Hgb F

what are the adult hematopoietic tissues

primary lymphoid tissue(T& B cell development):matures & waits to be used
 Bone marrow
 Thymus
secondary lymphoid tissue (immune response to antigens):stays after exposure
 Spleen
 Lymph nodes
 Mucosa-associated lymphoid tissue (MALT)

bone marrow

principal site of blood cell formation in healthy
adults
 Intramedullary hematopoiesis

bone marrow production per day, per kg body weight values for RBC,WBC,platelets

3 billion RBC
 1.5 billion WBC
 2.5 billion PLT

what does hyperplastic mean

excessive cell proliferation busy marrow

what does hypoplastic means

decreased cell production slow marrow not effective

what does aplastic mean

no cell production

where do blood cells pass through to get into circulation

Blood cells pass through gaps in intravascular compartments
(sinuses) in bone marrow to get into the circulation

what is bone marrow stroma

Supportive tissue inside bone marrow

what is bone marrow stroma make up of

macrophages

reticular cells(fibroblast)

adipocytes

endothelial cells

osteoblasts

osteoclast

what doe macrophages do in bone marrow stroma

ingest debris or waste, and produce cytokines to induce hematopoiesis

what does Reticular cells (fibroblasts) in bone marrow stroma

provide support for the marrow (like a mesh)

what are adipocytes do in bone marrow stroma and what do they do?

fat cells, increase over time which leads to less marrow and decreased hematopoiesis with old age
 Regulate marrow volume & secrete growth factor

what do Endothelial cells do?

Regulate blood flow in/out of bone marrow

what are osteoblast and osteoclasts

bone forming cells

bone breakdown cells

red vs yellow marrow

Red marrow (active hematopoiesis): Developing blood cells

Yellow marrow (inactive): Mostly adipocytes, but can revert to
red marrow if needed

whats Extramedullary hematopoiesis

hematopoiesis that
occurs at sites other than the middle marrow

what are the sites for EXTRAMEDULLARY HEMATOPOIESIS

Lymph nodes, spleen, liver, and thymus

what does megaly mean

enlarged

what is splenomegaly

enlarged spleen

what is hepatomegaly

enlarged liver

what does the spleen contain

largest volume of macrophages and lymphocytes in the body

what are the functions of the spleen

Filtration (“pitting and culling”) of RBC by macrophages – littoral cells
Immunologic (antigen recognition, phagocytosis, and antibody
formation)
Platelet Storage

describe splenic structure

White pulp: lymphocytes and macrophages
Red pulp: vascular sinuses separated by cords of
reticular cell meshwork (cords of Billroth), RBCs
and littoral macrophages

how is the circulation through the cords of spleen

is slow
 Depletes glucose and oxygen of RBCs
 Acidic environment
 Only the strong survive the spleen!

what are the effects of SPLENECTOMY

Transient increase in platelets and leukocytes
Increased defective RBCs
Increased RBC inclusions

Increased risk for infections with encapsulated bacteria

liver

Enlarged when stressed
 Main functions in the body are not hematopoietic

Filtration – “Kupffer cells”
 macrophages in the liver

lymph node structure

Outer cortex: B cells surrounded by T cells macrophages
 Inner medulla: B cells, plasma cells and macrophage

lymph node functions

Filter debris, bacteria, & particulate matter through fluid from all over
the body
 Immunologic – antibody production
 Lymphocyte proliferation
 Initiation of immune response to foreign antigen

thymus function

Lymphopoietic function= supplies all
lymphoid organs with immunocompetent T
cells

thymus structure

Cortex: “waiting zone” for immature T cells:Recognition of foreign antigen
 Medulla: “holding zone” for mature T cells before
they migrate to other lymphoid organs

Primary lymphoid organs:

Bone marrow and thymus
 B and T cells develop from non-functional precursors into
immunocompetent cells

Secondary lymphoid organs:

Spleen and lymph nodes
 Immunocompetent B and T cells further divide and
differentiate in response to antigens

what is a BFU-E

burst forming unit erythroid

what is a CFU-E

colony forming unit erythroid

RBC development order

PSC

CFU-GEMM

BFU-E

CFU-E

what does bfu-e need?

large amounts of erythropoietin

long culture times

what are burst made up of

thousands of RBC precursors

what do cfu-e need?

lower levels of erythropoeitin

short culture times

cfu-e give rise to what

pronormoblast

what is EPO

glycoprotein hormone made by kidneys to stimulate kidneys

what does EPO do

Stimulates lineage commitment and maturation of RBC precursor
cells in the marrow
Stimulates RNA synthesis of erythroid cells

factors that influence erythropoietin production

hypoxia

3 major effects of epo

Early release of reticulocytes

Inhibition of erythroid apoptosis

Reduced bone marrow transit time

what are the overall changes in the maturation of erythrocytes

Nucleus: decreases and condenses and is then ejected
•Cytoplasm: very blue getting lighter towards pink/red
•N:C ratio: decreases
•Cell size: decreases
•Chromatin: condenses
•RNA/ribosomes: increase with maturation, but then
production stops when nucleus is ejected
•Hemoglobin: increases

order of maturation of erythrcytes

Pronormoblast (rubriblast)
• Basophilic normoblast
(prorubricyte)
• Polychromatophilic normoblast
(rubricyte)
• Orthochromic normoblast
(metarubricyte)
• Reticulocyte (polychromatophilic
erythrocyte)
• Erythrocyte

Pronormoblast

nucleus: 1-2

cytoplasm: dark blue(concentration of ribosomes and RNA)

nucleus with immature chromatin

Basophilic Normoblast

nucleus:1

cytoplasm:deeper darker blue

high N:C ratio

Polychromatophilic
Normoblast

no nucleus

cytoplasm:pink and blue mixed making it grayish blue

last stage capable of mitosis

most hgb produced in this stage

Orthochromic Normoblast

nucleus:1 pyknotic

cytoplasm:salmon pink increase

nucleus removed by extrusion

howell-jolly bodies often seen

Reticulocyte

no nucleus

cytoplasm: bluish tinge

Erythrocyte

No nucleus
Cytoplasm: Biconcave disc, pink color

rbc general changes

Decreased generation of ATP
• Decreased surface-to-volume ratio
• Shape becomes more spheroidal
• All metabolic activities gradually shut down

Extravascular hemolysis

Accounts for 90% of RBC degradation
• Occurs mainly in the spleen and liver
• Membrane failure leads to loss of flexibility, trapping RBCs in the spleen
• Phagocytized by macrophages in the spleen (Littoral cells )
• Iron is recycled (Stored in macrophages as ferritin)

Intravascular hemolysis

10% of RBC destruction occurs within blood vessels

Occurs inside blood vessels due to turbulence, mechanical stress, or vessel damage
RBC rupture releases hemoglobin into the bloodstream

The Spleen’s Role in RBC Clearance

The spleen creates a stressful environment for RBCs

Low pH, low glucose, oxidative stress

Eryptosis

apoptosis, but in nonnucleated cells
• Characterized by membrane blebbing,
shrinkage, and phospholipid component of the
cell membrane exposure

rbc lack what and rely on what

RBCs lack mitochondria and rely on anaerobic glycolysis (Embden-
Meyerhof pathway) for ATP production

metabolic pathways in rbcs

Glycolytic (Embden Meyerhof) Pathway
Hexose Monophosphate Pathway
Luebering Rapoport Pathway or Shunt
Methemoglobin Reductase Pathway

GLYCOLYTIC PATHWAY is also called?

Embden Meyerhof pathway

what is Embden Meyerhof pathway

anaerobic gylcolysis primary source of atp

Anaerobic glycolysis

Process that generates ATP from glucose in the absence of oxygen

how many phases in GLYCOLYTIC PATHWAY/ embden-meyerhof

3 phases

embden-meyerhof pathway function, key product, and clinical issue

ATP production

ATP

pyruvate kinase deficiency=hemolysis

Hexose Monophosphate Pathway (HMP) function, key product, and clinical issue

oxidative protection

NADPH

G6PD deficiency= Heinz bodies

Methemoglobin Reductase Pathway function, key product, and clinical issue

iron reduction

Fe2+ from Fe3+

methemoglobinemia/ cyanosis

Rapoport-Luebering Pathway function, key product, and clinical issue

O2 delivery

2,3-BPG

right shift(better O2 release )

HMP pathways makes what instead of ATP

NADPH

2 ATP per what

per 1 glucose molecule

Defects in metabolism can include the following:

Failure to provide sufficient reduced glutathione, which protects other elements in the cell from
oxidation

Three major changes occur as a reticulocyte matures into an
erythrocyte

Increase in shear resistance

Loss of surface area because of membrane lipid loss
Acquisition of a biconcave shape

RBC Membrane Deformability

Aging RBCs lose surface area, increasing MCHC and causing splenic entrapment and destruction

rbc membrane composition?

8% carbohydrates, 40% lipids, 52% proteins

key proteins for RBC membrane instructions and function

Band 3, Protein 4.1, Protein 4.2,
Spectrin

what is spectrin

key cytoskeletal protein