Hematopoiesis & Erythropoiesis Flashcards
(199 cards)
1
Q
blood volume in females
A
4-5L
2
Q
blood volume in males
A
5-6L
3
Q
blood pH
A
7.35-7.45
4
Q
Blood composition (55%)
A
Plasma/Serum (fluid)
Water, proteins, other solutes
5
Q
Blood composition (45%)
A
Formed elements (cells)
RBCs, WBCs, Platelets
6
Q
Blood Specific Gravity
A
1.049-1.065
7
Q
Centrifuge Blood Sample (Top, middle, bottom)
A
Top layer - Plasma/Serum
Middle - “Buffy Coat” - WBCs + platelets
Bottom Layer - RBCs
8
Q
Hematocrit
A
% of packed red cells
9
Q
Anticoagulant used
A
Plasma
Clotting factors present
10
Q
Example of clotting factor
A
Fibrinogen
11
Q
No anticoagulant used
A
Serum
Some clotting factors consumed
12
Q
Gold/Red Top in a blood separation sample
A
No anticoagulant
13
Q
Green/Purple/Blue - Blood Separation
A
Anticoagulant present
14
Q
Blood Collection - Capillary
A
Adult - fingerstick
Baby - Heel stick
15
Q
Blood Collection - Venipuncture
A
Median Cubital
Median Cephalic
16
Q
Blood Collection - Arterial
A
Radial Artery
Brachial Artery
Femoral Artery
17
Q
WBC Count (Conventional Units)
A
4.8-10.8 x 10^3/ microL
18
Q
RBC Count - Male
A
4.7-6.1 x 10^6 / microL
19
Q
RBC Count - Female
A
4.2-5.4 x 10^6 / microL
20
Q
Hematocrit (HTC) Male
A
42-52%
21
Q
Hematocrit (HTC) - Female
A
37-47%
22
Q
Major Blood Functions
A
Transport oxygen to cells
Transport CO2 and wastes away
Provides defense
Regulates body pH, body temperature, fluid balance
23
Q
Major blood functions are required to maintain
A
Homeostasis
24
Q
Homeostasis
A
maintaining a constant environment or equilibrium
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Hematopoiesis
Formation of blood cells
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Hematopoiesis Characteristics
Takes place in hematopoietic tissue
Maintains a cell population of erythrocytes, leukocytes, platelets.
Responsible for the maturation and division of hematopoietic stem cells
27
Platelets
G
28
Erythrocytes
A
29
Neutrophils
I,E,C
30
Eosinophil
D
31
Basophil
J
32
Lymphocytes
B,H
33
Monocytes
F
34
**Platelets (Thrombocyte)**
Size?
Nucleus?
Average Life Span?
Function?
Size: 1-4 micro m
Cytoplasmic fragment, no nucleus
Average lifespan: 10 days
Function: homeostasis
35
Platelets Homeostasis
Process in which blood clots and bleeding is arrested
36
Neutrophil Function
Inflammation & Phagocytosis
1st line of defense against infections
Most abundant
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Platelets (Thrombocyte)
38
Neutrophils
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Neutrophil Nucleus
2-5 lobes connected by a thin filament
Segmentation allows passing through openings between lining cells
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Neutrophil cytoplasm
light pink with **secondary granules** (pink/neutral)
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Average life span neutrophils
6-10 hrs
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Eosinophil
43
Eosinophil function
defense in parasitic and fungal infections
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Eosinophil nucleus
bi-lobed with condensed chromatin
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Eosinophil cytoplasm
secondary granules (reddish/orange)
46
Basophil
47
Basophil function
mediates allergic reactions
48
Basophil Nucleus
often obscured by large secondary granules
least abundant WBC in circulation
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Basophil cytoplasm
dark secondary granules
* histamine → vasoconstriction
* Heparin → blood thinner
granules are water soluble
50
What do granules in basophils contain?
Histamine and Heparin (play a role in homeostasis)
51
histamine
vasoconstriction
52
heparin
blood thinner (anticoagulant)
53
Lymphocyte function
immune response and **viral** infection
54
lymphocytes
55
Lymphocyte nucleus
clumped chromatin
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lymphocyte cytoplasm
stains blue, periphery more intense
57
Lymphocyte granules
* usually none
* can have a few (countable) **azurophilic** granules - reddish pink
58
Monocyte
59
Monocyte function
phagocytosis
60
Monocyte nucleus
* Horseshoe-shaped/lima bean/convoluted
* Lacy, fine chromatin
Shape/outline of monocyte is irregular
61
Monocyte cytoplasm
* Dull gray-blue
* Cloudy
* Many small, red-purple staining granules
* Vacuoles often present
62
A - Lymphocyte
B - Monocyte
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A - Lymphocyte
B - Monocyte
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Surrounding cells Lymph vs. Mono
Lymph - indented by RBCs
Mono - project pseudopods between or compressing nearby RBCs
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Mature RBC - Erythrocyte
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Major function of mature RBC
Oxygen transport from lungs to tissues
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Shape of RBC
6-8 micro m **Biconcave Disc** (shallow middle)
Allows for max surface area for gaseous exchange
Hemoglobin is 95% dry weight
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Mature RBC lifespan
120 day lifespan
Can travel 200-300 miles during this time
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Organs within hematopoietic system
Bone Marrow
Liver
Spleen
Lymph Nodes
Thymus
70
Embryo Developmental Stage
Mesoblastic phase
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Fetal Developmental Stage
Hepatic Phase
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Birth Developmental Stage
Medullary Phase
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Embryo - Mesoblastic phase
* 2 weeks - 2 months gestation
* Yolk sac - mesoderm layer
* Forms primitive erythroid cells
* Hemoglobin formed
* Hgb Gower-1
* Hgb Gower-2
* Hgb Portland
All referred to as embryonic hemoglobin
74
Fetus - Hepatic Phase
* 2 months - 7 months gestation
* Liver and Spleen
* Additionally forms WBCs and **Megakaryocytes (**platelets precursor)
* Hgb formed
* Fetal hemoglobin
* Hemoglobin A1 (small amounts)
75
Birth - Medullary Phase
| (bone marrow)
* 7 months - rest of life!
* Bone marrow = intramedullary hematopoiesis
* Red marrow
* Diapedesis
* Hgb formed post birth
* Hemoglobin A1
* Hemoglobin A2 ( small amounts)
76
Infancy and Early Childhood
Volume of red marrow in infant and adult are approximately equal.
As one is aging, the distal long bones and axial skeleton is expanding
At 4 years, yellow marrow (fat) starts replacing red marrow → limits hemopoietic sites
77
Adolescence and Adulthood
Only active hemopoietic/red marrow in axial skeleton
* Sternum
* Ribs
* Pelvis
* Vertebrae
* Skull
Other bones contain primarily yellow marrow
78
At the age of 40+
Only find hematopoietic/red marrow in:
* Sternum
* Ribs
* Pelvis
* Vertebrae
* 50% red, 50% yellow marrow
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Preferred bone marrow aspiration sites
Pelvis and Sternum
Last to be replaced by yellow marrow
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Monophyletic Blood Cell Development Theory
All blood cells arise from one precursor cell that is multipotential or pluripoential and called stem cells
**Considered Proven Theory**
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Polyphyeltic Blood Cell Developmental Theory
Each blood cell comes from its own seperate precursor
## Footnote
**Old Theory - Disproven**
82
Stem cells (Pluripotential vs multipotential)
Pluripotential → can develop into _any cell line_ in the body
Multipotential → can develop into _any blood cell line_ in the body
Cell stays in bone marrow until stimulus for development is given
Once stimulation, converts to a **progenitor** cell → committed to that cell line
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Cytokines
Soluble messages to tell early cells to differentiate
84
Types of cytokines
Interleukins (IL) and Colony Stimulating Factors (CSF)
* Mediate proliferation, differentiation, maturation of hematopoietic progenitor cells
* One CSF or IL may affect more than one cell line or multiple stages within a cell line
* May require combination to get needed effect
85
Thrombopoietin
Stimulates **CFU - Meg** and causes release of platelets
86
Erythropoietin
Stimulates **CFU-E** and regulates erythroid progenitor cells to mature
* Glycoprotein produced by the peritubular interstitial cell in the juxtaglomerular apparatus (kidney tubules). Detects amount of oxygen
87
Lymphoid stem cell (LSC) can differentiate into
T and B Cells
88
T cells
* Immune functions of cellular nature
* cytotoxic
* suppressing activities
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B cells
Immune Function → Antibody production
* can further develop into plasma cells → secrete antibodies
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Myeloid Stem Cell
Develops into CFU-GEMM
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CFU-GEMM gives rise to
**CFU-GM** → CFU G and CFU M
## Footnote
**CFU-Eo**
**CFU-Bas**
**CFU-Meg**
**CFU-E/BFU-E**
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CFU G
Neutrophil
93
CFU M
Monocyte/Macrophage
94
CFU-Eo
Eosinophil
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CFU-Bas
Basophil / Mast Cell
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CFU-Meg
Thrombocytes
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BFU-E → CFU-E
Erythrocytes
98
BFU?
Burst Forming Unit
99
Normal Myeloid : Erythroid ratio
2:1 - 5:1
* Myeloid → non-erythroid cells originating from myeloid stem cell (mainly granulocytes)
* Erythroid → any erythroid stage
WBCs have a shorter life span than RBCs
100
Erythrocyte maturation
101
Erythroid nucleus & contents
* **Nucleus** → site of DNA/RNA synthesis
* Large → small/pyknotic as it matures
* * **Chromatin**
* DNA, histones, proteins
* Euchromatin → active/finely dispersed/nucleoli present
* Heterochromatin → inactive/condensed nucleoli absent - more heterochromatin as it matures.
Eventually nucleus is extruded
102
Immature Erythroid Cytoplasm
* Small amount since nucleus is so big. High N:C ratio
* Early stages have many ribosomes (RNA) - **Basophilic cytoplasm**
* Within cytoplasm
* Golgi zone → light staining near nucleus
* Mitochondria → energy production and hemoglobin formation (Fe into heme ring)
103
Mature Erythroid
* As hemoglobin is formed, less and less RNA
* Dark blue cytoplasm shifts to pink
* N:C ratio decreases → eventually no nucleus
* No golgi zone
* no mitochondria
104
Synchronous development
nucleus and cytoplasm mature at same rate
105
Asynchronous development
Growth/maturation of nucleus and cytoplasm is not at the same rate
* Abnormal development
* Example: Megaloblastic anemia
106
Megaloblastic anemia
107
Erythrocyte Maturation - as RBC develops….
* Cell volume decreases
* N:C ratio decreases
* Chromatin condense
* Nucleoli disappears
* RNA in cytoplasm decreases
* Hemoglobin synthesis
* gradually increases until a stopping point
108
Erythrocytes capable of mitosis
* Pronormoblast
* Basophilic normoblast
* Polychromatophilic normoblast
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Normoblast is also called
Rubriblast
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Pronormoblast is also called
Rubriblast
111
Basophilic Normoblast is also called
Prorubricyte
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Polychromatophilic Normoblast is also called
Rubricyte
113
Orhtochromatic normoblast is also called
Metarubricyte
114
Polychromatophilic Erythrocyte (Macrocyte) is also called
DIffusely Basophilic Erythrocyte
115
Erythrocyte is also called
erythrocyte
116
**Pronormoblast/Rubriblast**
Size?
Nucleus?
Cytoplasm?
NC ratio?
BM%?
Size → 12-24 microm
nucleus → round, central. 2-3 nucleoli, fine diffuse chromatin (euchromatin)
Cytoplasm → stains deep blue (RNA). Often a visible golgi zone
117
Pronormoblast/Rubriblast
118
Pronormoblast/Rubricyte
119
Pronormoblast/Rubricyte
120
Pronormoblast/Rubriblast
121
**Basophilic Normoblast/Prorubricyte**
Size?
Nucleus?
Cytoplasm?
NC ratio?
BM%?
* size → 12-17 microm
* Nucleus → Round, central, no nucleoli, some chromatin **granularity**
* Cytoplasm → Slightly less Basophilic “cornflower blue”
* NC ratio → 6:1 - 4:1
* BM% → 1-5%
122
Basophilic Normoblast/Prorubcricyte
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Pronormoblast vs. Basophilic Normoblast
Maturation differences
* Less nucleoli
* Beginning chromatin granularity
* Cytoplasm less basophilic
* golgi zone disappears
* slightly smaller in size with decreasing NC ratio
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Pronormoblast
125
Basophilic normoblast
126
**Polychromatophilic Normoblast / Rubricyte**
Size?
Nucleus?
Cytoplasm?
NC?
BM%
Size → 10-15 micro m
Nucleus → round central, or slightly eccentric. Nucleoli - none. Chromatin is moderately compacted condensed **“soccer ball”**
Cytoplasm → hemoglobin synthesis beginning → stains lavender instead of blue
NC ratio → 4:1 - 2:1
BM → 5-30%
127
Last stage capable of mitosis in Erythrocytes?
Polychromatic Normoblast / Rubricyte
Gives rise to 2 orthochromatic normoblasts
128
Polychromatic normoblast / Rubricyte
129
Basophilic normoblast vs Polychromatophilic Normoblast
Maturation differences
* Nucleus can move off center
* chromatin more mature and begins to become pyknotic
* Cytoplasm shifts from blue to purple (hemoglobin)
* Slight smaller in size and NC ratio
130
Polychromatophilic Normoblast
131
**Orthochromatic Normoblast / Metarubricyte (aka nBRC)**
size?
Cytoplasm?
NC ratio?
BM%
size → 8 -12 micro m
nucleus → Last nucleated stage. Round, central or eccentric. **Completely pyknotic dark chromatin.** “Most perfect circle”
Cytoplasm → **Pink or slightly purple cytoplasm.** Hemoglobin increasing main constituent. RNA decreasing
NC Ratio → 1:1 - 1:2
BM% → 5-10% can be found in circulation of newborns in normal conditions
Cannot divide further
132
Orthochromatic Normoblast
133
Orthochromatic Normoblast
134
Orthochromatic normoblast
135
**Polychromatophilic Erythrocyte (Macrocyte) / Diffusely Basophilic Cell**
Size?
Nucleus?
Cytoplasm?
Size → 8-10 micro m
Nucleus → NONE
Cytoplasm → blue/gray (due to **Polychromatophilia**), due to residual RNA. Contains mitochondria, loses organelles within 48 hrs in maturation to mature RBC
Last stage to synthesize hemoglobin
136
Last stage to synthesize hemoglobin?
Polychromatophilic Erythrocyte
137
Polychromatophilic Erythrocyte
138
Polychromatophilic Erythrocyte
139
Orhochroamtic Normoblast → Polychromatophilic Erythrocyte
Maturation Differences
* **Nucleus leaves**
* cytoplasm is similar in color - pink/purple
* Cell is similar in size
140
Wrights stain
Polychromatophilic Erythrocyte
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New Methylene Blue (Vital Stain)
Reticulocyte
142
**Erythrocyte**
Size?
Nucleus?
Cytoplasm?
Size → 7-8 micro m
Nucleus → none
Cytoplasm → pink with central pallor
**Found in peripheral blood**
**No longer able to synthesize new hemoglobin (no mitochondria present)**
143
Mature Erythrocytes
144
Polychromatiophilic Erythrocyte → Erythrocyte
Maturation Differences
* Cytoplasm loses purple tinge
* Central pallor develops
* slightly smaller in size
145
RBC membrane - Permeability
* Selective barrier
* Water and anions (-) → passive diffusion
* Cations (+) and other substances → active transport
* **Potassium primarily found inside the RBC (25:1)**
* **Sodium is primarily found outside the RBC (1:12)**
* ATP depletion leads to loss of gradient and cell dehydration
* Crucial in
* Controlling RBC volume
* Preventing **Colloid Osmotic Hemolysis**
146
RBC membrane - Composition
* Highly Elastic → capable of membrane extension
* Chemical composition
* 50% proteins
* 40% phospholipids and glycolipids
* 10% cholesterol
147
Layers of RBC membrane
1. **Outer Hydrophilic Portion →** Contains glycolipid, glycoprotein and protein
2. **Central Hydrophobic Portion** → Contains protein, cholesterol, phospholipids
3. **Inner Hydrophilic Layer** → contains protein
148
Cholesterol in the membrane
* Equally distributed across the central hydrophobic layer → 25% of RBC membrane lipids
Provides continual exchange with plasma cholesterol → affected by body lipid transport
If abnormal, can affect RBC morphology
149
Acanthocytes
150
Choline phospholipids
* Phosphatidyl choline + sphongomyelin
* Located on outer half bilayer → closer to the plasma
151
Amino Phospholipids
Phosphatidylethanolamine and Phosphatidyl Serine
**Almost exclusively on inside layer of bilayer**
If outside, can initiate clotting mechanism
152
Integral Membrane Proteins
Traverse entire membrane from outer surface to the inner cytoplasmic side
## Footnote
**Ex: Glycophorin**
153
Glycophorin in membrane
* 20% of total membrane proteins
* composed of 60% carbohydrate
* Contributes most of the membrane **sialic acid**
* causes RBC to have a **negative charge** that makes them repel each other in the bloodstream
154
Peripheral Membrane proteins
Cytoplasmic surface of the membrane
Beneath bilayer and forms cytoskeleton
**Ex: Spectrin**
155
RBC Cytoskeleton - Inner Hydrophilic Layer
Provides rigid support and stability to bilayer
Responsible for deformability of membrane
156
Major component of RBC Cytoskeleton Inner Hydrophilic Layer
Spectrin
Ankyrin
Actin
Adducin
Other cytoskeletal proteins
157
Most important and abundant peripheral membrane protein
Spectrin
158
Spectrin - Inner Hydrophilic Layer
25-30% of total membrane protein
Makes up 75% of cytoskeleton
Binds other peripheral proteins to make skeletal network
159
RBC Deformability
Critical for RBC survival through microvasculature + Oxygen deliver function
160
Depleted ATP
**Spectrin** phosphorylation decreases → loss of deformability
Increased **calcium** accumulation and membrane deposition → increased rigidity
161
Primary Function of Hemoglobin
Delivery and release of oxygen to the tissues
Facilitation of carbon dioxide
162
Hemoglobin weight in RBC
33% of RBC by volume
95% of RBC dry weight
163
Male Hemoglobin Normal Range
14-18 g/dL
164
Female Normal Hemoglobin Range
12-16 g/dL
165
Infant Normal Hemoglobin Range
14-22g/dL
166
What does hemoglobin consist of?
4 heme rings + 4 iron molecules + 4 globin chains
167
Hemoglobin synthesis starts in nucleated RBC stage
Hemoglobin synthesis is dependent on:
1. Synthesis of protoporphyrins (precursor of heme)
2. Adequate iron delivery and supply
3. Adequate globin synthesis
65% occurs during nucleated (immature) RBC stages
35% occurs during polychromatophilic erythrocyte / reticulocyte stage
168
1 heme ring =
1 porphyrin = 4 pyrrole rings
169
Primary hemoglobin structure
number and sequence of amino acids in each globin chain
170
secondary hemoglobin structure
twisting of the amino acid chain (2D helical)
171
Tertiary hemoglobin structure
bending the twisted amino acid chains into 3D shape (pretzel shape)
172
Quartenary hemoglobin structure
Assembling each 3D chain with heme groups
Complete, functional hemoglobin molecule
173
Hemoglobin A1
2 alpha + 2 beta
Most abundant → 95-98%
174
Hemoglobin A2
2 alpha + 2 delta
2-5%
175
Hgb F
2 alpha + 2 gamma
Fetal hemoglobin
Less than 2%
176
Abnormal hemoglobin - unable to carry oxygen
1. MetHemoglobin
2. Carbocyhemoglobin
3. Sulfhemoglobin
177
MetHemoglobin
* Iron is. oxidized to **Ferric State** (Fe3+) → no longer binds oxygen
* Reversible through strong reducing substance administration
* Example Causes: ingestion of strong oxidant drug/enzyme deficiency
178
Carboxyhemoglobin
* Oxygen is replaced with carbon monoxide (CO) → binding is x200 stronger
* Reversible through inhalation → oversaturate blood with oxygen
* Example causes: car running in garage
179
Sulfhemoglobin
* Sulfur is incorporated into heme structure
* Irreversible
* Example Causes: Ingestion of sulfur containing drugs/ chronic constipation
180
90% of RBCs energy (ATP) comes from
**Non-oxidative pathways.**
Even through it carries oxygen to other cells to be used for energy
181
3 phases of Erythrocyte lIfe
1. Erythropoiesis of RBC production
2. Release from marrow to circulation
3. Destruction and death
182
Reticuloendothelial System (RES)
Cellular and immunologic defense system in the body → detects if something is wrong in RBC
Phagocytic cells (Histocytes, monocytes, **macrophages**) in → **spleen**, liver, lymph nodes, bone marrow
Helps to remove RBC's from circulation
183
Primary site of RBC phagocytosis
spleen
184
Spleen - Home to **littoral cells**
most sensitive detectors for RBC abnormalities
* Example of RBC abnormalities →
* Senescent (old), nearing 120 life span → membrane loses deformability and elasticity
* Abnormal RBC morphologies and inclusions
* RBC coated in antibodies
Additional function → sequestering (separately storing) ⅓ platelets and granulocytes
185
Removal of inclusions is called
pitting
186
removal of RBC from circulation is called
culling
187
RBC destruction and contents released
Hemolysis
188
RBC hemoglobin is broken down into
1. Fe molecule - put back into plasma iron pool (**reused**)
2. Globin - degraded for protein to amino acid (**reused**)
3. Polyphyrin (heme) ring - has to be metabolized by the body to an excretable form **(not reused)**
189
Extracellular Hemolysis
RBC broken w/i RES system
90% of RBC destruction under normal conditions
190
Intracellular hemolysis
RBC lyses in blood vessel
10% of RBC destruction under normal conditions
191
How does extracellular hemolysis work
192
Extra vascular hemolysis process (slide46/53)
_Within RES_
* Heme disassemble to Biliverdin
* Biliverdin converted to **Unconjugated Bilirubin** aka indirect Bilirubin
Released to blood and **carried by albumin to liver**
_Within hepatocyte of liver_
* Unconjugated Bilirubin is conjugated → **Conjugated Bilirubin** “Direct Bilirubin”
**Urobilinogen** then
* is eliminated in the stool
* Reabsorbed into blood and excreted by the kidneys in urine
193
Intravascular Hemolysis Process ( slide 57/53)
Hemoglobin Released in blood vessel
* Circulates → **Hemoglobinemia**
* Filtered at the kidney → **Haptoglobinuria**
* Carried by **Haptoglobin** to Liver
* Proceeds with extravascular hemolysis
* Gets oxidized to **methmoglobin**
* Globin seperates
* Metheme
* Stays together and binds abumin - **Methemalbumin** and carried to liver
* seperates
* **Hemopexin** carries heme to liver
* iron is recycled
194
Erythropoiesis is sustained in a steady state
Equal amounts of red cell production and destruction daily
Both equal about 1%
195
Erythropietin
When less oxygen is being delivered to the kidneys **(EPO)** is being released. It is a hormone that goes to bone marrow and produces more RBC
196
When do we need more RBC?
in increase in oxygen demand / decrease in oxygen tension
ex: blood loss / anemia / high altitudes
197
If the bone marrow cannot keep up with RBC needs
Hematopoiesis starts to occur elsewhere (ex: liver and spleen) → **Extra-medullary Hematopoiesis**
198
Hormonal influences that decrease Erythropoiesis
When these are low → low erythropoiesis
* Hypopituitarism
* Hypothyroidism
* Hypoadrenalism (Addison's Disease)
199
Hormonal influences that Increase Erythropoiesis
When these are high → high RBC production
* Hyperadrenalism (Cushings disease)
* Increased estrogen
* Increased androgens
