Week 1 Flashcards
(278 cards)
1
Q
ATP generation in RBCs is dependent on ______ metabolism.
A
anaerobic
2
Q
5 types of white blood cells in order of abundance
A
Neutrophils Lymphocytes Monocytes Eosinophils Basophils
3
Q
Function of neutrophils
A
Finds, ingests (phagocytose), and digests bacteria, cellular debris, and dead tissue
4
Q
PAMP
A
Pathogen-associated molecular patterns
- Foreign molecular structures on pathogens recognized by PRRs
5
Q
DAMP
A
- Stress/damage indicator molecules from body cells recognized by PRRs
6
Q
Receptors that recognize PAMPs and DAMPs
A
Pattern-recognition receptors
(PRR)
EX: TLRs
7
Q
TLR recognizes foreign pattern-> ______->_______->_______->_______
A
signaling cascade
NF-KB
expression of chemokines and cytokines
inflammation
8
Q
Bridge between innate and adaptive immunity
A
Dendritic cells
9
Q
Where do dendritic cells predominantly reside?
A
Interfaces between body and world:
- Skin
- GI tract
- Mucosal membranes
10
Q
B cells
A
protect extracellular space (tissue fluid, blood, secretions)
- Recognize antigens via surface receptors
- Secrete antibodies into fluid
- (they DO NOT require the simultaneous recognition of an associated MHC molecule—like T cells)
- Fully differentiated B cell = plasma cell (antibody production factory)
11
Q
T cell function
A
Surveys bodys cells
12
Q
T cell development
A
produced in bone marrow, mature in thymus
13
Q
Short ranged mediators produced by T cells
A
lymphokines
14
Q
Marker for Helper T cells
A
CD4
15
Q
Marker for killer T cells
A
CD8
16
Q
Units for Hgb
A
grams/dl
17
Q
Reticulocytes circulate __ days in bone marrow and ___ days in blood before maturation
A
3
1
18
Q
Reticulocyte count
A
% of reticulocytes when 1000 RBCs are counted
19
Q
Normal reference values for reticulocytes
A
0.4-1.7%
20
Q
Absolute reticulocytes
A
% of reticulocytes x RBC count
21
Q
Reticulocyte Index
A
measurement of production of RBCs, way to correct reticulocyte count and stress reticulocytes (marrow pushes out immature reticulocytes)
22
Q
RI
A
decreased production of reticulocytes → ↓ (RBCs)
23
Q
RI > 2 with anemia =
A
loss of RBCs → increase compensatory production of reticulocytes
24
Q
Hematocrit
A
a. Proportion of blood by volume made up of red blood cells, value determined by measuring the length of the RBC layer and dividing it by the total length of the column of blood (RBCs+buffy coat+plasma), always reported as percentage
25
Basic shape and composition of an erythrocyte (5)
1. Biconcave disc shape
2. Lacks nucleus
3. Lacks mitochondria
4. Contain lots of hemoglobin
5. Membrane is highly elastic
26
Hematopoiesis
Formation of blood cellular components
27
Erythropoiesis
process by which RBCs are produced in bone marrow
28
Hemolysis
RBC destruction
29
Hemostasis
stopping of bleeding (platelets + endothelium + coagulation proteins)
30
Thrombosis
Formation of blood clot inside blood vessel that obstructs the flow of blood
31
Platelets are derived from ____
large cells in the bone marrow called megakaryocytes
32
1 megakaryocyte = _____ platelets
5000
33
Leukemia vs lymphoma
a. Leukemia: cancer cells in blood and bone marrow
| b. Lymphoma: cancer cells predominantly outside of bone marrow/blood (lymph nodes, lymphoid tissue)
34
Acute leukemia vs. chronic leukemia
- Acute Leukemia: cells are immature in their degree of differentiation and that clinical course is usually rapid without intervention
- Chronic Leukemia: cells are more mature in their differentiation and the disease follows a more indolent clinical course.
35
Lymphoid leukemia vs myeloid leukemia
- Lymphoid Leukemia: arising from lymphocytic lineage
| - Myeloid Leukemia: arising from one of the other cell types in the marrow
36
Hemoglobin reference range
14.3- 18.1 g/dL
37
Hematocrit reference range
39.2-50.2%
38
RBC reference range
4.76-6.09 x 10*12/L
39
MCV reference range
80 - 100 fL
40
MCH reference range
27.5-35.1 pg
41
MCHC reference range
32.0-36.0 g/dL
42
Platelet Count reference range
150-400 x 10*9/L
43
Mean Platelet Volume reference range
9.6-12.8 fL
44
Red cell distribution width CV reference range
11.7-14.2 %
45
Red Cell Distribution Width SD reference range
37.1-48.8 fL
46
WBC reference range
4.0-11.1 x 10*9/L
47
Neutrophils absolute reference range
1.8-6.6 10*9/L
48
Lymphocyte absolute reference range
1.0-4.8 10*9/L
49
Monocytes absolute reference range
0.2-0.9 10*9/L
50
Eosinophils absolute reference range
0.0-0.4 10*9/L
51
Basophils absolute reference range
0.0-0.2 10*9/L
52
NRBC percent reference range
0%
53
NRBC absolute reference range
0 10*9/L
54
calculation of MCV using Hct and RBC
MCV = Hct/RBC
55
Calculation of MCH
Hgb/RBC
56
Calculation of MCHC
= (Hgb/Hct) x 100
57
Red blood cell counting and platelet counting
- Impedance Transducer and Histograms
- Blood passes through an aperature, creates change in resistance between electrodes create pulse signals proportional to cell size and platelet volume
- Platelets and RBCs can be counted simultaneously
58
Flow cytometry
- allows characterization of cells based on DNA/RNA content
i. Make cell membrane permeable, label DNA/RNA with dye, bounce lasers off them, and then look at scattergram
ii. Intensity of fluorescence signal directly proportional to the nucleic acid content of the cell
iii. Measure side fluorescence vs. forward scatter
59
When is a differential performed?
When requested or flagged by analyzer
60
Info provided by a differential
- Morphology of RBCs, WBCs, platelets
- abnormally formed elements in the peripheral blood
- relative or absolute quantification of the different WBC populations
61
Characteristics of RBCs
round, smooth, little variation in diameter, typically not touching/overlapping, central pallor
62
Characteristics of platelets
small, fine granules
63
Characteristics of neutrophils
cytoplasm with fine granules, nucleus has clumped chromatin
- Most abundant white cells in blood of adults
64
Too many neutrophils
Neutrophelia
65
Too few neutrophils
Neutropenia
66
Characteristics of lymphocytes
smaller, scant cytoplasm, round nucleus with dense chromatin
| i. Absolute lymphocyte count changes as children age (most abundant at age 2-8 years)
67
Too many lymphocytes
Lymphocytosis
68
Too few lymphocytes
lymphocytopenia
69
Monocyte characteristics
normally largest cells, nucleus is irregular and lobulated, amply cytoplasm (gray-blue), irregularly shaped
70
Too many monocytes
monocytosis
71
Too few monocytes
monocytopenia
72
Eosinophil characteristics
bi-lobed nucleus, slightly larger than neutrophils, spherical granules (larger, red-orange)
- count remains constant throughout life
73
Too many eosinophils
eosinophilia
74
Basophil characteristics
similar in size to neutrophils, nucleus obscured by purple-black granules, least abundant white cell in peripheral blood
- Count remains constant throughout life
75
Too many basophils
Basophilia
76
White blood cell count
total number of white blood cells (neutrophils, lymphocytes, monocytes, basophils and eosinophils) in a microliter or liter of blood.
77
White blood cell differential
percentage of white cells in an individual that are neutrophils, lymphocytes, monocytes, basophils or eosinophils
78
Absolute Count DIFF# =
= (DIFF% x WBC) / 100
79
Speed of innate immune response
Fast
80
Immature dendritic cells are activated by
cytokines and chemokines
81
Location of adaptive immune response
in lymphoid tissue NOT periphery
82
T lymphocytes recognize antigens at ____
antigenic determinant (epitome)
83
Antigen presenting molecule recognized by T helper cells
MHC Class II
84
Antigen presenting molecule recognized by Cytotoxic killer T cells
MHC Class I
85
B cells release ____ to neutralize toxins or prevent binding to target cell
antibodies
86
Most abundant antibody
IgG
87
Mechanism of IgG
i.2 adjacent IgG molecules bind an antigen -> cooperate to activate COMPLEMENT, a system of proteins that enhances inflammation and pathogen destruction
88
First antibody to appear in blood after exposure to new antigen
IgM
89
Antibody inserted into B cell membranes as their antigen receptor
IgD
90
Most important antibody in secretions
IgA
91
Antibody that attaches to mast cells in tissues
IgE
92
Mechanism of IgE
attaches to mast cells in tissues -> encounters antigen causes mast cell to make prostaglandins, leukotrienes and cytokines, and release its granules which contain mediators of inflammation (like histamine).
93
Measurements to determine anemia
i. Hemoglobin concentration (g/dL), hematocrit (%) and red blood cell count
ii. MCHC, MCV, Red cell distribution width (RDW), WBC (#cells/vol) + differential, and platelet count (#cells/vol).
iii. RBC morphology via blood smear
iv. Reticulocyte count (%), reticulocyte production index – can use this to look at production of RBC
94
Reticulocyte count when there is increased RBC production
3.5-5 fold increase from normal range
95
Stress factors for reticulocyte index: mild, moderate, and severe anemia
1. Stress factor = 1.5 (mild anemia), 2.0 (moderate anemia), 2.5 (severe anemia)
96
Physical exam of anemic patient
vital signs (tachycardia, tachypnea, dyspnea), color of skin (pallor), conjunctiva, lymph nodes, size of liver and spleen, cardiovascular and pulmonary findings.
97
Symptoms of anemic patient
SOB, fatigue, rapid HR, dizziness, pain with exercise (claudication), angina and pallor
98
Iron in aqueous solutions
form insoluble hydroxides unless bound (protein, heme, etc.)
99
Fe salts are more soluble at ____ pH
low
100
Iron distribution:
1. hemoglobin
2. myoglobin
3. ferritin
4. hemosiderin
5. enzymes
1. Hemoglobin = 65%
2. Myoglobin = 6%
3. Intracellular Fe storage (Ferritin = 13% + Hemosiderin = 12%) = 25%
4. Enzymes = 3.6%
101
Daily losses of iron
small
| - loss from exfoliation of skin and mucosal surfaces (GI, skin); in the urine or with menstruation.
102
Transferrin
main iron transport protein, 84kDa plasma protein, produced in liver, binds 2 ferric iron (Fe3+) mols for 1 mol protein, high affinity and specificity
103
Transferrin + iron -> _____->_________
Transferrin + iron -> travels to bone marrow/maturing normoblasts -> binds cell surface receptors, “transferring receptors”
104
Transferrin- Transferrin receptor complex->
enter bone marrow cell via invagination of clathrin coated pits to form endosome
105
Endosome becomes acidified (due to H+ entry) ->_____->_____->______
transferrin releases iron -> iron exits endosome via DMT1 transporter -> stored by Ferritin, or used to make Hgb and RBC in circulation
106
After 120 days, RBCs are _______
removed from circulation by splenic macrophages, releasing iron from heme and stored by ferritin until needed
107
Location of absorption for iron
duodenum
108
What maintains solubility and availability of iron until it reaches the duodenum?
gastric pH and gastroferrin
109
Absorption of non-heme bound iron (5 steps)
a. Enters duodenum as ferric iron and is converted to ferrous iron by surface reductase (mediated by duodenal cytochrome b-like protein - DCYTB).
i. Iron changes valence several times as it passes through cells
b. DMT1: apical ferric iron transporter, divalent (Fe2+) metal iron transporter
c. Ferritin: stores iron in cell, protein coat with iron in middle, can bind up to 4500 Fe molecules
d. Ferroportin: transports ferrous iron across basolateral membrane
e. Hephaestin (a ferroxidase): facilitates basolateral iron export, controls how much ferroportin you have, produced by liver.
110
What increases iron absorption?
i. Presence of protein (amino acids), vitamin C (maintains iron is appropriate valence state), increased amount of iron presented to the duodenum, increased erythropoietic activity (non-specific increases absorption).
111
What decreases iron absorption?
Phytates, oxalates and other food constituents (precipitate iron making it less available), decreased amount of iron presented to duodenum.
112
Hepcidin
25 aa peptide produced in liver, made in response to high iron intake, inflammation/infection.
Production of hepcidin is reduced by anemia and/or hypoxia
113
Low hepcidin
- increased iron absorption by intestinal epithelial cells
| - Plasma transferrin is saturated with iron and iron accumulated in liver stores
114
High hepcidin (during inflammation/infection)
= hepcidin binds ferroportin and degrades it
a. Plasma iron decreased -> limits erythropoiesis because less ferroportin
- Loss of export of iron out of cell and increased -> accumulation of iron in ferritin in cell -> Iron deficiency anemia
115
Hematologic changes assocuiated with iron deficiency
decrease in hemoglobin synthesis in marrow, decrease in cell proliferation
116
Systemic changes associated with iron deficiency
defective muscle performance, neuropsychological dysfunction, ridges on nails, koilonychia (flat or concave nails), papillary atrophy of tongue. Dysphasia, esophageal webs, gastritis, immune dysfunction.
117
Major causes of iron deficiency
excessive losses (bleeding), failure to accumulate iron to replace the small on-going losses, inability to gain iron required during excessive demand (growth/pregnancy).
118
Iron depletion (stage 1)
iron stores decreased (diminished ferritin levels),
i. Normal serum iron, transferrin saturation, hemoglobin concentration, and erythropoiesis.
ii. Iron absorption may increase slightly.
119
Iron deficient (stage 2)
iron stores depleted, decrease in serum iron, increase in iron binding capacity, decrease in percent saturation -> iron loading of normoblasts impaired
i. Erythrocytes normal (mild increase in free erythrocyte)
120
Iron deficiency anemia (stage 3, final)
transferrin increased, serum iron very low, saturation of transferrin so low it cannot meet erythropoiesis needs, cells produced are microcytic and hypochromic.
121
Treatment of iron deficient anemia
Iron salts orally, Iron by IM or IV route
122
Causes of iron over accumulation (3)
i. Increase in iron intake from diet
ii. Increase in absorption of iron: hemochromatosis
1. Mutation in HLA-H gene which encodes from protein that acts as co-factor for absorption results in an increase in absorption of iron
iii. Repeated transfusions of iron for chronic anemia: hemosiderosis
123
Accumulation of iron damages: (3)
heart, liver, and endocrine organs
124
Treatments of iron over accumulation
Depends on cause
1. Increased absorption: tx=therapeutic phlebotomy to reduce iron burden to body until ferritin levels are in normal range.
2. For repeat transfusions: iron chelators used to return iron to normal levels.
125
Hemoglobin structure
1) Tetramer (2 pairs of globin polypeptide chains - alpha and non-alpha)
2) Heme prosthetic group within each globin chain (protoporphyrin ring bound to iron)
BINDS OXYGEN
126
Fe2+ vs. Fe3+ iron in Hemoglobin
Fe2+ = ferrous form, must be in this form in RBC to bind O2
Fe3+ = ferric form, can't bind O2
127
what converts Fe3+ --> Fe2+
cytochrome B5 reductase
128
Allostery
```
when oxygen (substrate) binds to hemoglobin at one site, hemoglobin has a change in configuration, which alters its binding affinity of additional oxygen molecules at another site.
→ Hemoglobin picks up oxygen in lungs (high O2 levels) and unloads it in tissues (low O2 levels).
```
129
Positive coopertivity
binding of substrate (oxygen) leads to increased affinity for additional substrate (more oxygen!).
- 1 oxygen binds → configuration of Hgb changes so other 3 sites have a higher binding affinity.
- As number of occupied sites increases, affinity for remaining sites continues to increase.
130
Hemoglobin T state
Taut
-Deoxygenated, under conditions where oxygen concentration is low → none of the 4 binding sites are occupied, binding affinity to oxygen is relatively low
-Contains inter-and intra-salt bonds, H-bonding, and hydrophobic interactions within molecule
131
Hemoglobin R state
-Oxygenated, as oxygen becomes more available, 1 oxygen binds, the configuration changes and the other sites have higher binding affinity for oxygen.
→ Sequential breaking of salt bonds leads to the R-configuration.
132
Why is oxygen dissociation curve for Hemoglobin sigmoidal in shape?
positive coopertivity
133
p50
partial pressure of O2 when hemoglobin is 50% saturated
Myoglobin has a much higher p50 than hemoglobin
134
Things that shift the curve to the right (decrease O2 affinity)
1) low pH
2) increase CO2
3) increase temp
4) increase 2,3-BPG concentration
135
Bohr effect
low pH = decrease oxygen affinity
| high pH = increase oxygen affinity
136
CO2 and oxygen affinity
- CO2 is released into bloodstream, and carbonic anhydrase converts CO2+H20→ carbonic acid→ bicarbonate and H+ (drops the pH). → Bohr Effect.
- Tissues with higher metabolic rate will release more CO2 and lactic acid, leading to a drop in pH → shifts curve to right, allowing greater release of oxygen to the tissues.
137
Temperature and oxygen affinity
- Higher temps=more oxygen unloaded to tissues, less is bound by Hgb
- When you exercise your temperature rises because metabolic rates are higher, therefore increased need for oxygen). Curve shifts to the right.
138
How does 2,3-BPG effect HgB oxygen binding affinity?
- Alters O2 affinity by binding deoxyhemoglobin, stabilizing it in T conformation → decreases Hgb affinity for oxygen, shift curve right
- High 2,3-BPG = decreased O2 affinity, curve shifts right, increase O2 delivery to tissues
139
Myoglobin
Monomer, cannot undergo allosteric regulation/cooperativity
- Myoglobin curve is shaped like a hyperbola: very high O2 affinity at very low O2 concentrations.
- Myoglobin bad for O2 transport but good for storage
- Holds tightly to O2, doesn’t release until very low O2 levels
- High O2 affinity allows transfer of O2 from hemoglobin to myoglobin when O2 very low
140
Alpha-like genes
chr16
2 copies from each parent (total of 4 copies)
Zeta --> alpha2 --> alpha1
141
Beta-like genes
chr11
1 copy from each parent
(total 2 copies)
Epsilon → gamma → delta → beta
142
Embryos (at 4-14 weeks) contain what kinds of Hgb?
3 distinct hemoglobins with higher affinity for O2 than hemoglobin A
(allows for O2 transfer from mom to baby)
Hemoglobin Gower I
Hemoglobin Gower II
Hemoglobin Portland
Fetal hemoglobin (HbF) predominates
143
Hemoglobin at birth
65-95% HbF and 20% HbA
HbF = a2y2 → higher O2 affinity
144
Hemoglobin in adults
96-97% HbA (a2/B2)
2% HbA2 (a2/d2)
˂1% HbF
HbF remains high in premature babies and infants of diabetic mothers around age 5
145
HbA2 (a2/d2)
functions like HbA → Bohr effect, cooperatitivity, response of 2,3-BPG
BUT more heat stable and has slightly higher O2 affinity.
Can be used diagnostically for Beta-thalassesmias, sickle cell trait, hyperthyroidism and megaloblastic anemias.
146
HbF
(a2/y2)
- HbF binds 2,3-BPG poorly → stabilizes R Hgb state, shift curve left.
- Stronger Bohr effect (20% increase) in HbF → H+ ions transferred from placental circulation to maternal circulation → increase pH of fetal circulation → increase O2 affinity, shift curve left
--> transfer of oxygen from maternal circulation to fetal circulation
147
high affinity hemoglobins
| 3 + EX
1) causes elevated RBC (erythrocytosis) because O2 deliver to tissues is reduced, signaling body to increase erythropoiesis
2) affected people are generally well, plethoric (red-appearing)
3) dx by measuring p50
EX) Hemoglobin Chesapeake
148
Low affinity hemoglobins (4)
1) less common
2) causes reduced RBC production due to increased O2 delivery to tissues
3) presents as cyanosis with possible mild anemia
4) dx by measuring p50
149
Unstable hemoglobins
spontaneously denature, may or may not have altered O2 affinity
aka Heinz body anemia
treat with folic acid to boost RBC production
150
Examples of unstable hemoglobins (3)
EX) Hemoglobin Zurich: single point mutation, no effect on O2 binding, but increases CO binding.
EX) Hemoglobin Poole: mutation in gamma chain → infants have hemolytic anemia which resolves within a few months (gamma chain replaced by delta/beta)
EX) Hemoglobin Koln: most common, mutation in B-chain, increase O2 affinity
151
Methemoglobinemia
Hgb in ferric form (fe3+) and can't bind oxygen
--> shift curve left, p50 goes down
Normal methemoglobin is 1%
152
NAPH methemoglobin reductase
keeps iron in its ferrous form in the erythrocyte
153
Acquired Methemoglobinemia
- exposure to drugs/chemicals that cause oxidation of heme by reaction with free radicals of hydrogen peroxide or NO or OH can generate methemoglobin.
- treat with methylene blue, and remove drug/chemical causing problem from system
154
Methylene blue for treatment of methemoglobinemia
provide artificial electron acceptor from the reduction of methemoglobin via the NADPH-dependent pathway.
155
Genetic methemoglobinemia
homozygous deficiency of cytochrome b5 reductase or mutation in hemoglobin resulting in production of hemoglobin M.
156
Diagnosis of Methemoglobinemia
person looks cyanotic but arterial partial pressure of O2 is normal, blood looks dark-red/chocolate/brown-blue and doesn’t change with O2 exposure
157
Newborns and methemoglobinemia
Newborns are susceptible because HbF is more readily oxidized to ferric state, also decreased amount of cytochrome b5 reductase
May become cyanotic with well water, raw spinach, disinfectants, benzocaine.
158
Carbon Monoxide poisoning
CO binds heme with an affinity 240x that of oxygen
CO binds heme → allosteric change, other 3 hemes unload oxygen less well → increase Hgb O2 affinity → decreased O2 delivery to tissues
159
Symptoms, diagnosis and treatment of CO poisoning
Symptoms: headache, malaise, nausea, dizziness, NOT cyanotic (still look pink) = “cherry red” appearance, higher levels: seizures, coma, MI, 40% of people have late neurological defects.
Diagnosis: co-oximetry
Treatment: 100% O2 or hyperbaric O2 (competes with CO for binding sites on the heme)
160
How does a pules oximeter work?
-Probe is a photo detector and 2 light emitting diodes
One at 660nm-red = where deoxyhemoglobin absorbs maximally
One at 940nm-infrared = where oxyhemoglobin absorbs maximally
- The emitter and detector face each other through the tissue (placed on the finger)
- Only PULSATILE FLOW (arterial blood flow) is measured
161
Pulse Ox measures _________ NOT _______ or ________
oxygen saturation
NOT partial pressure of O2 or carrying capacity of O2
162
Innacurate pulse ox readings can be caused by...(3)
1) Probe placed wrong? Only 1 diode is working?
2) Shivering/seizing patient, nail polish, deeply pigmented skin, anemia, shock
3) Abnormal hemoglobins (ie: carboxyhemoglobin absorbs at 660nm so will give a falsely high reading, methemoglobin absorbs at 660nm and 940nm so it will also give inaccurate results).
163
Where does hematopoiesis occur during the embryonal stage?
Yolk sac
164
Where does hematopoiesis occur during the fetal stage?
liver and spleen (lesser extent)
165
Where does hematopoiesis occur in adult?
Bone marrow
166
Hematopoiesis outside of the bone marrow after birth is called
extramedullary hematopoiesis
167
In general, stem cell->____->____->______
Stem cells → progenitor cells → precursor cells → mature into the mature cells found in the peripheral blood, lymphoid organs and reticuloendothelial system.
168
Pluripotential
gives rise to all myeloid (non-lymphoid) blood elements (GEMM = granulocyte, erythroid, monocyte, megakaryocyte)
1.Some ability to self-renew or they commit to becoming a progenitor stem cell.
169
Multipotential
Can give rise to both lymphoid and myeloid elements
1.Ability to self-renew or they commit to becoming pluripotent stem cells
170
Progenitor cell
limited ability to self-renew, irreversibly committed to differentiate along one or, at most, 2 lineages of myeloid cells
171
Precursor
recognizable, maturing cells, capable of cell division up to a point, but CANNOT self-renew, give rise to mature, functional cells in peripheral blood, lymphoid organs and reticuloendothelial system
172
Erythropoietin
helps differentiate and mature erythropoietic cells
1. Hypoxia → Increase EPO = Promote erythropoiesis
a. Increase stem cell activation, mitosis and maturation, hemoglobin level, and release of retics → Increase oxygen blood levels → decrease EPO
173
Thrombopoietin
helps differentiate, mature, and finally release platelets into the periphery
174
Interleukin-5 (IL-5):
promotes production of eosinophils
1.Signals Promyelocyte → Eosinophilic myelocyte
175
Interleukin-3 (IL-3):
promotes production of basophils
1.Signals Promyelocyte → Basophilic myelocyte
176
Granulocyte colony-stimulating factor (G-CSF):
stimulates granulopoiesis
1. In early stages helps differentiate progenitor cells into myeloid lineage (as opposed to lymphoid or monocytic lineage)
2. At promyelocyte stage → helps differentiation into specific lineage (Neutrophil, basophils, eosinophils)
177
Stem Cell Factor (SCF):
signals differentiation to mast cell lineage
1. Mast cells NOT found in peripheral blood, only found in tissues
a. Appearance: one prominent nucleus
178
Granulocyte-monocyte colony-stimulating factor (GM-CSF)
Promotes granulopoiesis and monopoiesis
179
Monocyte colony-stimulating factor (M-CSF)
Stimulates differentiation into Monocyte lineage (monopoiesis)
180
Erythropoesis:
Progenitor cell →_____---->_____----->_____->______
Progenitor cell → proerythroblast (pro=first lineage commitment) + EPO growth factor → Basophilic Erythroblast → Polychromatophilic Erythroblast → orthochromatophilic erythroblast
All occurs in bone marrow
181
Orthochromatophilic erythroblast + EPO allows...
exit to periphery and → Reticulocyte (2-3 days in periphery) → Erythrocyte (120 days in periphery)
182
Thrombopoiesis is also known as
Megakaryopoiesis
183
Thrombopoiesis:
Progenitor cell->____->_____
Progenitor cell → Megkaryoblast + Throbopoietin→ promegakaryocyte + thrombopoietin
Occurs in Bone Marrow
184
Granulopoiesis:
Progenitor Cell + G-CSF →____->____->____
Progenitor Cell + G-CSF → Myeoblast → Promyelocyte + G-CSF → Basophilic OR Neutrophilic OR Eosoniphilic myelocyte (mitotic pool = blast and promyelocyte)
in Bone Marrow (takes 8-12 days)
185
Neutrophilic myelocyte →____->____->____
Neutrophilic myelocyte → Neutrophilic metamyelocyte → Band → Neutrophil
186
Neutrophils can hang out in... (3)
Neutrophils can hang out in marginated pool (vessel walls), circulating pool (peripheral blood), or tissue pool
187
Neutrophils kill via:
Phagocytosis (physiologically silent) of degranulation (can cause necrosis, inflammation, pain, burning, etc.)
188
IL-3 growth factor signal->____->_____->_____
IL-3 growth factor signals → Basophilic myelocyte → Basophilic metamyelocyte → Basophil
189
Basophil appearance
bi-lobed nucleus, very dark purple, dense, large granules (often can’t see nucleus due to granules)
190
IL-5 growth factor signal-> ____->_____->_____
IL-5 growth factor signals → Eosinophilic myelocyte → Eosinophilic metamyelocyte → Eosinophil
191
Eosinophil appearance
orange-ish color, bi-lobed nucleus
192
Monopoiesis:
Monoblast + M-CSF growth factor
Monoblast + M-CSF growth factor → Promonocyte + M-CSF → Monocyte
takes 2-3 days in bone marrow to generate
193
Monocytes spend up to ___ days in circulation and then become _______ once they enter the tissue.
20
| Macrophages
194
General time frame of granulopoiesis
- 3-5 days in Mitotic Pool (Blast + Promyelocyte)
- 2.5-7 days in Maturation Pool (Myelocyte + Metamyelocyte)→ Storage pool (Band + Neutrophil)
NO cell division once out of mitotic pool
TOTAL time in Bone Marrow = 8-12 days
195
General time frame of erythropoiesis
Takes 2-7 days to go from proerythroblast to orthochromatophilic erythroblast
Orthochromatophilic erythroblast spends 1 day in bone marrow before exiting (due to EPO) into periphery (and becoming a retic)
196
Time that erythrocytes circulate in blood
120 days
197
Time that reticulocytes exist in peripheral blood
2-3 days
198
Time that platelets exist in peripheral blood
few days
199
Time that eosinophils exist in peripheral blood
7 days
200
Time that neutrophils exist in peripheral blood
7 hour half life
201
Time that monocytes exist in peripheral blood
20 days then enter tissue and become macrophages (months)
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Process of bone marrow biopsy and aspirate
a. Go through iliac crest where vast majority of hematopoiesis is occurring
b. Pull out small amount of liquid portion of marrow (blood cells) = aspirate - evaluate morphology
c. Then do a core (biopsy) - evaluate cellularity
i. Core = core out a piece of bone marrow containing bone and marrow cells
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Core biopsy evaluation (4)
i. Marrow Cellularity
ii. Myeloid:Erythroid Ratio
iii. Megakaryocyte frequency
iv. Focal Findings
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Aspirate evaluation (3)
i. Cellular differential
ii. Cellular morphology
iii. Iron content
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Marrow cellularity
the portion of marrow that is hematopoietically active, non-hematopoietically active marrow is occupied by fat.
i. Changes with age → On average: 100-your age
ii. If ½ of marrow is occupied by hematopoietic cells and ½ by fat, the cellularity is 50%
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Hypercellular marrow and causes (2)
cells increased in quantity
1. Increased proliferation due to hypoxia, or increased signalling by HGFs
2. Hematopoietic neoplasms
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Hypocellular marrow and causes (5)
decreased cell quantity
1. Autoimmune attack on marrow cells
2. Viral attack on marrow cells
3. Hematopoietic neoplasms
4. Malnourished state (rare)
5. If cells are ABSENT = aplastic
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Leukocytes
nucleated cells of the blood, WBCs
| - form the buffy coat
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Mononuclear cells
leukocytes whose nucleus has a smooth outline, monocytes (immature→macrophages in tissue) and lymphocytes. Can be hard to distinguish macrophages and lymphocytes.
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Polymorphonuclear cells
cells whose nucleus is lobulated, also called granulocytes because they usually have prominent cytoplasmic granules.
1.They are eosinophils, basophils and neutrophils.
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Granulocytes
white blood cells that have cytoplasmic granules, also known as polymorphonuclear cells, they are eosinophils, basophils and neutrophils.
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Mast cells
granules full of histamine, role in allergy and anaphylaxis. Very similar to basophil granulocytes.
213
Plasma
yellow fluid portion of blood in which the particulate components (blood cells) are suspended. 55% of blood volume.
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Serum
the clear liquid that does not contain blood cells nor clotting factor, it is the blood plasma with fibrinogens removes, includes all proteins not used in blood clotting and electrolytes, antibodies, hormones, etc.
215
Color of granules for neutrophil, eosinophil, and basophil
Neutrophil has colorless granules, Eosinophil has red granules, and Basophil has blue granules.
216
Central lymphoid organs
ones in which lymphocytes develop = bone marrow and thymus
1. T cells mature in the thymus
2. B cells mature in the bone marrow
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Peripheral lymphoid organs (4)
where mature cells are organized to trap and respond to foreign invaders, includes lymph nodes, spleen, Peyer’s patch and mesenteric lymph nodes of gut, tonsils, adenoids.
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describe the process of recirculation of lymphocytes (long one, sorry)
Lymphocytes in the blood encounter cells lining certain postcapillary venules in peripheral lymphoid tissues (especially lymph nodes).
1. These endothelial cells in lymph node are unusual - not flat, but HIGH AND CUBOIDAL.
a. Also contain molecules on their surface that correspond with molecules on lymphocytes
b. These features allows lymphocytes to bind and pass between endothelial cells into the lymph node
2.Lymphocyte may stay in node, or pass into lymph which drains from that lymph node to the next node in the chain. → Large lymph channels (thoracic duct, near heart)→venous blood→circulatory loop starts over again.
3. 2 circulations: blood and lymphatic
1. Lymphocytes cross from blood to lymph at nodes and from lymph back to blood at heart.
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Antigen
substance that can be recognized by the immune system
220
Immunogen
an antigen in a form that can give rise to an immune response, that is, which can immunize
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Antigenic determinant and epitope
small part of a large antigenic molecule, fits (lock and key) into lymphocytes receptor and activates lymphocyte
1.An isolated antigenic determinant is not usually an immunogen; it can be recognized by antibody, but is too small to trigger an immune response.
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Tolerogen
antigen delivered in a form, or by a route, which does not give rise to an immune response
1. Furthermore prevents an immune response to subsequently administered immunogen which has the same epitopes
2. Ability to respond to one particular antigen is “turned off”
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Process of lymphocyte activation by antigen
a. Each lymphocyte has receptors, there are many copies on each cell, but all are identical (ie: each cell has single specificity)
b. The antigenic determinant (presented by the dendritic cell) fits into the lymphocyte receptor.
c. To activate T or B cell:
i. 1. The fit between receptor and antigen must be good enough
ii. 2. Several nearby receptors must be simultaneously bound by antigen
iii. 3. For T-cells only, other cell surface molecules must be involved too.
d. Activated cell proliferates and differentiates.
i. Lymphocytes can divide every 6 hours, 1 can give rise to 64,000 at the end of 4 days.
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Humoral immunity
antibody mediated response
225
Location of humoral immunity
extra-cellularly, where bacteria live
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Main cells involved in humoral immunity
B lymphocytes
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Once B lymphocytes are activated by antigen, they become ___, which transform into _____
B-lymphoblasts
| plasma cells
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Most plasma cells die, but the ones that survive become ____
long term memory cells
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Can humoral immunity be transferred by serum?
Yes sir
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Main players of cell mediated immunity
T lymphocytes
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Activated t lymphocytes activate...
Macrophages, NK cells, and cytotoxic T lymphocytes
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Can cell mediated immunity be transferred by serum?
No ma'am
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Normal total white blood cell count
4,500-10,500/µL of blood (4.5-10.5x10^9/L)
234
Neutrophil differential
40-60%
235
Eosionophil differential
1-4% (higher in developing countries)
236
Lymphocyte differential
20-40%
237
Monocyte differential
2-8%
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Basophil differential
0.5-1%
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Major causes of underproduction anemia (4)
1. Chronic inflammation or infection
2. Lead intoxication
3. Renal insufficiency
4. Endocrine disorders
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Clinical features of chronic inflammation or infection anemia
May include: fever, arthralgias, arthritis, fatigue
For infection, symptoms and signs relate to the focus (e.g. pain, cough, swelling)
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Lab findings of chronic inflammation or infection anemia
a. Mild-moderate anemia
b. Severity proportional to underlying disease
c. May be normochromic/normocytic or microcytic with some hypochromia
d. decrease in serum Fe, decrease in TIBC (Transferrin iron binding capacity)*, decrease in EPO for Hct, decrease in retic count, increased or normal ferritin*
*Differentiates this type of anemia from iron deficient anemia
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Pathophysiology of lead intoxication anemia
Maturing Erythroid Cell:
a. Protoporphyrin ring + iron in the middle → heme → Hemoglobin
b. Lead: inhibits protoporphyrin ring synthesis and inhibits enzyme that puts iron into ring
i. Too much lead → no hemoglobin in red cells
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Clinical features of lead intoxication anemia
Personality changes, irritability, headache, weakness, weight loss, abdominal pain and vomiting with insidious nature
244
Lab findings of lead intoxication anemia (6)
a. Mild-moderate anemia, decreased retic count
b. Microcytosis and mild hypochromia
c. Basophilic stippling
d. Increase in protoporphyrin without iron
e. May see concurrent iron deficiency confounding the diagnosis
f. Lead levels increased
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Pathophysiology of renal insufficiency anemia
no EPO made by kidneys → decreased RBC production
a. Iron + Erythropoietin → Erythroid proliferation → RBC production
246
Clinical features of renal insufficiency anemia (5)
Signs and symptoms may be interrelated with those of renal dysfunction:
I. Fatigue, pallor, decreased exercise tolerance, dyspnea, tachypnea
247
Lab findings of renal insufficiency anemia (4)
Usually don’t see anemia until kidney function
248
Clinical features of endocrine disorder associated anemia
a. Hyper or hypoactivity, weight gain/loss, skin, nail, hair changes (suggests hyper/hypothyroidism)
b. Nausea, vomiting, dehydration, weakness, circulatory collapse (suggests adrenal insufficiency)
249
Lab findings of endocrine disorder associated anemia
Hypothyroidism: mild anemia, most normochromic, normocytic (may be microcytic or macrocytic)
Hyperthyroidism: usually normocytic, may be microcytic
Adrenal: mild anemia, normocytic
*****All have reduced retic count and index
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Pathophysiology of the anemia of malignancy/sepsis:
| ____ and ____ are secreted, and do what?
Tumor necrosis factor (TNF) secreted → decreases iron production and decreases erythropoietin → inhibit erythroid proliferation → decreased RBC production
2.Interferin Beta (INF-B) secreted → inhibit erythroid proliferation → decreased RBC production
251
Pathophysiology of chronic infection/inflammation:
| ___ and ___ are secreted and do what?
IL-1 secretion → decrease iron and decrease erythropoietin → inhibit erythroid proliferation → decreased RBC production
Interferon gamma (INFy) secreted → Inhibit Erythroid proliferation → decreased RBC production
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Erythropoietin is used to treat anemias for which there is... (3)
1) Absolute deficiency
2) Decrease of EPO out of proportion to the hemocrit level/degree of anemia (AND response to administration has been documented)
3) Done for some anemias of chronic infection/Inflammation/Malignancy as well as renal insufficiency anemia
253
Transfusion of red cells is used to treat anemia when...
severity of anemia has resulted in severe cardiovascular decompensation
254
2 critical co-factors for normal hematopoiesis:
| synthesis of _____ from _______
B12 and folate
methionine from homosysteine
255
What happens to red cell precursors when there is a deficiency in folic acid or B12?
The cells increase in size, arrest in S phase of mitosis, undergo destruction in marrow, resulting in ineffective erythropoiesis and anemia.
256
Dietary sources of Folate
1. Widespread in food: cereals, breads (1/3), fruits and veggies (1/3), meats and fish (1/3).
2. Human milk has enough folate for infants.
3. Overcooking leads to loss of folates from food.
257
Where is folate absorbed?
Jejunum
258
Duration and storage of folate
hydrolyzed, reduced and methylated before distribution to tissues or liver for storage (as methyltetrahydrofolate).
Liver stores undergo turnover, secretion in bile and reabsorption (enterohepatic circulation).
259
Dietary sources of B12
Originally synthesized by bacteria and algae (works it way up the food chain), we eat it through eggs, meat and milk (NO PLANTS).
260
Process of absorption of B12:
| B12 comes in, released in acidic stomach→
Intrinsic Factor (secreted by gastric parietal cells) binds B12 and brings it through the gut until it reaches terminal ileum → Absorbed in terminal ILEUM
2.B12 then binds transcobalamin binding protein II in plasma and transported to liver for storage or to other tissues for use.
261
How long is B12 stored in the liver?
6 months
| Therefore, disease doesn't progress as rapidly
262
Common causes of folate deficiency
most frequently due to inadequate dietary intake → megaloblastic anemia
a.Also caused by malabsorption (tropical sprue or parasite), inborn errors of folate metabolism, increased demands (hemolysis, pregnancy, rapid growth, psoriasis), alcohol consumption (decreased dietary intake and disruption of cycling from liver to tissues).
263
Causes of B12 deficiency
usually associated with malabsorption
a. Autoimmune disease
b. Intrinsic factor deficiency (congenital, atrophic gastritis, gastrectomy—no paretial cells= no IF)
c. Malabsorption (pancreatic insufficiency, bacterial overgrowth, parasites, AIDS)
d. Defective transport/storage (transcobalamin II deficiency)
e. Metabolic defect
264
Time to develop clinical state folate deficiency
weeks to months (rapid)
265
Time to develop clinical state B12 deficiency
years (slow)
266
Neurologic and neuropsychiatric abnormalities- folate deficiency
not seen
267
Neurologic and neuropsychiatric abnormalities- B12 deficiency
sensory loss first (numbness, tingling), loss of proprioception, ataxia, spasticity, gait disturbances, + Babinski signs, cognitive/emotional changes
Neuro defects may be irreversible
268
Therapy for cobalmin (B12) deficiency
IM or SQ injections of B12 (daily for 2 wks, weekly until HCT is normal, then monthly for life).
If absorption is normal, oral replacement works.
269
Therapy for folate deficiency
1 mg/day orally or parenterally
270
Type 1 Helper T cells (Th1)
recognize antigen --> release lymphokine --> attract macrophages
271
Th17 Helper T cells
stimulate inflammation (more powerful than Th1)
272
Th2 Helper T cells
stimulate macrophages to become alternatively activated
-important in parasite immunity
273
Follicular helper T cell (Tfh)
stimulation by antigen --> migrate from T cell areas of lymph nodes into B cell follicles
Help B cells get activated to make IgM, IgG, IgE, and IgA antibody subclasses
274
Regulatory T cells (Treg)
make lymphokines to suppress activation of other helper T cells
-keep immune response in check
275
Type I immunopathology
immediate hypersensitivity
276
Type II immunopathology
autoimmunity
277
Type III immuopathology
antibody against antigen
278
Type IV immunopathology
T cell mediated
