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Hematology > Hematopoiesis and Iron Metabolism - Lectures 3 and 4 > Flashcards

Hematopoiesis and Iron Metabolism - Lectures 3 and 4 Flashcards

1
Q

Where is the major site of hematopoiesis from 6 weeks until 6-7 months of fetal life?

A

Spleen and Liver

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2
Q

Where is the major site of hematopoiesis after 6-7 months of fetal life?

A

Bone Marrow

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3
Q

Where is the major site of hematopoiesis until 6 weeks of fetal life?

A

Yolk Sac

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4
Q

What replaces hematopoietic bone marrow in long bones and in 50% of hematopoietic areas of other bones?

A

Fat

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5
Q

Can fatty marrow, spleen, and liver revert to hematopoiesis?

A

Yes

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6
Q

Which cell can become any blood cell and can repopulate a bone marrow from which all cells have been eliminated?

A

Hematopoietic Stem Cells (a pluripotent stem cell)

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7
Q

What is the general name of the two cells made directly from hematopoietic stem cells, and what is each cell called?

A

Hematopoietic Progenitor Cells

  • Common Myeloid Progenitor Cell (CFU-GEMM)
  • Common Lymphoid Progenitor Cell
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8
Q

How common is the Hematopoietic Stem Cell in the bone marrow?

A

~1 in every 20 million nucleated cells

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9
Q

What surface markers do hematopoietic stem cells have?

A

CD34+

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10
Q

How many mature cells can one hematopoietic stem cell make?

A

~1 million

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11
Q

What are the mature cells?

A
  • Red Cells
  • Megakaryocytes (platelets)
  • Monocytes
  • Granulocytes (neutrophils, eosinophils, basophils)
  • Lymphocytes (B and T cells)
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12
Q

What are the stromal cells, and what do they secrete?

A

Stromal cells include:
- adipocytes, fibroblasts, osteoblasts, endothelial cells, and macrophages

Stromal cells secrete:

  • collagen, glycoproteins, and glycosaminoglycans to form an extracellular matrix
  • growth factors for stem cell survival
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13
Q

What is a niche?

A

The area of the bone marrow that provides a suitable environment for stem cell growth and division formed by stromal cells

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14
Q

Mesenchymal stem cells are important in the formation of which cell type?

A

Stromal cells

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15
Q

What is present in a niche?

A

Growth factors [like stem cell factor (SCF)], adhesion molecules (like jagged proteins that bind to KIT and NOTCH receptors on stem cells), and cytokines necessary for stem cell growth and differentiation

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16
Q

What is mobilization, and what growth factor is important for it to occur?

A

The movement of stem cells across the blood vessel endothelium into the blood which requires granulocyte colony-stimulating factor (G-CSF)

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17
Q

What is homing, and what chemokine is important for it to occur?

A

The movement of stem cells across the blood vessel endothelium out of the blood which requires stromal-derived factor 1 (SDF-1)

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18
Q

What is the first step of hematopoiesis?

A

Self-renewal (replication of one pluripotent hematopoietic stem cell into another one pluripotent hematopoietic stem cell)

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19
Q

What is the major source of growth factors for hematopoiesis, what are the two growth factors not made by this source, and where are these two growth factors made?

A
  • Stromal cells (90% of growth factors)
  • Erythropoietin - Kidneys
  • Thrombopoietin - Liver
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20
Q

What type of receptors are the hematopoietic receptor superfamily?

A

JAK-STAT receptors

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21
Q

What are the 3 main signal transduction pathways following hematopoietic growth factors binding to their receptors?

A
  • JAK/STAT pathway (STAT dimers act as transcription factor in the nucleus)
  • Mitogen-activated protein (MAP) kinase pathway (JAK activates RAS/RAF to activate MAP kinase which results in gene expression that acts on cell cycle/proliferation)
  • Phosphatidylinositol 3 (PI3) pathway (JAK activates PI3 kinase to block apoptosis)
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22
Q

What do Janus-associated kinase (JAK) proteins associate with?

A

The intracellular domain of growth factor receptors

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23
Q

What are the two main phases of the cell cycle, and what occurs in each?

A
  • M phase - cell physically divides

- Interphase - chromosomes (DNA) are duplicated and cell growth occurs

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24
Q

What are the two parts of the M phase of the cell cycle, and what occurs in each part?

A
  • Mitosis - nuclear division occurs

- Cytokinesis - cell fission occurs

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25
Q

What are the three phases of interphase of the cell cycle, and what occurs in each part?

A
  • G1 phase - cell begins to commit to replication
  • S phase - DNA content doubles (chromosomes replicate)
  • G2 phase - cell organelles are copied and cytoplasmic volume increases
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26
Q

Where are the two checkpoints of the cell cycle?

A

at the end of the G1 and G2 phases

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27
Q

Which classes of molecules control the checkpoints of the cell cycle, and how do they act to control the cycle?

A
  • Cyclin-dependent protein kinases (Cdk) - phosphorylate downstream protein targets
  • Cyclins - bind to Cdks to regulate their activity
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28
Q

What is the morphology of apoptosis?

A
  • Cell shrinkage
  • Condensation of nuclear chromatin
  • Fragmentation of the nucleus
  • Cleavage of DNA
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29
Q

Which proteases are responsible for initiating apoptosis?

A

Caspases

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30
Q

Which molecule is released from the mitochondria during intracellular apoptotic activation and activates caspases?

A

Cytochrome C

- which binds to APAF-1 to activate the caspases

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31
Q

The level of what molecule is increased by p53, and what molecule tightly controls p53 levels?

A
  • p53 increases the level of BAX resulting in apoptosis

- MDM2 controls p53 levels

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32
Q

What are the major pro-apoptotic and anti-apoptotic molecules within a cell?

A

BAX - pro-apoptotic

BCL-2 - anti-apoptotic

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33
Q

How can BCL-2 result in malignant disease, and what disease is caused?

A

BCL-2 is translocated from chromosome 18 to the immunoglobulin heavy chain locus on gene 14 in the t(14:18) translocation of follicular lymphoma (result is over-expression of the BCL-2 gene)
Note: (BCL = B Cell Lymphoma)

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34
Q

What are the two domains of transcription factors?

A
  • DNA binding domain

- Activation domain

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35
Q

What are the three major families of adhesion molecules, and what do they involve?

A
  • Immunoglobulin superfamily - antigen receptors (TCR, immunoglobulins, antigen-independent surface adhesion molecules)
  • Selectins - Leukocyte and platelet adhesion to endothelium in infection or coagulation
  • Integrins - Cell adhesion to extracellular matrix
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36
Q

Where is hematopoietic tissue confined in adults?

A

Confined to the central skeleton (skull, vertebrae, sternum, ribs, sacrum, pelvis, and some in proximal femur)

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37
Q

What are a large family of glycoproteins that mediate attachment of marrow precursors, mature leukocytes, and platelets to endothelium, extracellular matrix, and to each other?

A

Adhesion molecules

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38
Q

What does CFU-GEMM stand for?

A

Colony Forming Unit - Granulocyte, Erythrocyte, Monocyte, and Megakaryocyte

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39
Q

What are the separate stages of RBC development from pluripotent hematopoietic stem cell to erythrocyte?

A
  • Hematopoietic stem cell
  • CFU-GEMM
  • BFU-E (Burst-Forming Unit Erythroid)
  • CFU-E (Colony-Forming Unit Erythroid)
  • Pronormoblast (dark blue cytoplasm)
  • Progressively smaller normoblasts with progressively more hemoglobin and a nucleus
  • Reticulocyte (no nucleus, but RNA to continue producing hemoglobin)
  • Erythrocyte (no nucleus or RNA)
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40
Q

How many RBCs can a single pronormoblast give rise to?

A

16

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41
Q

Are nucleated RBCs (pronormoblasts) ever seen in the blood?

A

Not except in some marrow disease or extramedullary erythropoiesis (erythropoiesis outside the marrow)

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42
Q

What regulates erythropoiesis?

A

Erythropoietin

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43
Q

Where is erythropoietin made?

A

Peritubular interstitial cells of the kidney

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44
Q

What stimulates erythropoietin production?

A

Hypoxia-inducable factors (HIF-2alpha and beta) caused by oxygen tension in the tissues of the kidneys

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45
Q

What are some caused of HIF production?

A

Anemia, hemoglobin can’t give up O2, low atmospheric O2, and cardiac, pulmonary, or renal function impairs O2 delivery to the kidneys

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46
Q

What are the 2 transcription factors activated by erythropoietin receptor stimulation?

A

GATA-1 and FOG-1

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47
Q

Which cells contain erythropoietin receptors?

A

BFU-E and CFU-E

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48
Q

What is the main indication of (reason for using) recombinant erythropoietin?

A

End-stage renal disease

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49
Q

What is often given with recombinant erythropoietin to maximize its effects?

A

Iron

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50
Q

What, besides erythropoietin is needed for erythropoiesis, and can cause anemia if absent or low?

A

Iron, cobalt, vitamins (especially B12, folate, C, E, B6, thiamine, and riboflavin) and hormones (androgens and thyroxine)

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51
Q

What is the structure of hemoglobin A (Hb A), the dominant hemoglobin 6 months after birth?

A

4 polypeptide chains (alpha2beta2) each with its own hemoglobin

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52
Q

What are the other types of hemoglobin present in small quantities in adults, and what are their 4 chains?

A
  • Hb F (alpha2gamma2)

- Hb A2 (alpha2delta2)

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53
Q

Where is hemoglobin made?

A

In the mitochondria where 4 heme groups come together to form hemoglobin

54
Q

What happens when O2 is unloaded from hemoglobin?

A

the beta chains are pulled apart and 2,3-diphosphoglycerate (2,3-DPG) enters, which lowers the affinity of hemoglobin for O2

55
Q

What is the P-50 of hemoglobin?

A

26.6 mmHg

56
Q

If Hb has a lower affinity for oxygen does the saturation curve shift to the right or to the left?

A

To the right

57
Q

If Hb has a higher affinity for oxygen does the saturation curve shift to the right or to the left?

A

To the left

58
Q

What are the normal O2 operating limits for Hb in vivo (both % and mmHg)?

A

Low (venous) - 40 mmHg at 70% saturation

High (arterial) - 95 mmHg at 95% saturation

59
Q

What are some molecules that lower the affinity of Hb for O2 (shift to the right)?

A

2,3-DPG, H+, CO2, HbS

60
Q

What are some molecules that increase the affinity of Hb for O2 (shift to the left)?

A

HbF, lower 2,3-DPG, lower H+

61
Q

What is the cause of Methemoglobinemia?

A

Circulating Hb has an iron in the Fe3+ state instead of the normal Fe2+ state (can be caused by methemoglobin reductase deficiency or inherited Hb M, which is a structurally abnormal Hb, or by toxins that oxidize Hb)
- all of these result in cyanosis

62
Q

How do RBCs generate energy?

A

Glucose enters the RBC via facilitated transfer and glycolysis produces 2 ATP per glucose as well as NADH which is used by methemoglobin reductase to reduce Fe3+

63
Q

What is ATP in RBCs used for?

A

The Na/K ATPase to maintain the osmotic equilibrium within the RBC despite high amounts of intracellular proteins (i.e., hemoglobin)

64
Q

What produces NADPH within RBCs, and what enzyme is crucial to this process?

A

The pentose phosphate shunt produces NADPH, and glucose-6-phosphate dehydrogenase (G6PD) is crucial to this process

65
Q

What is NADPH used for in RBCs?

A

Mainly to reduce disulfide (S-S) groups in glutathione to sulphydril (SH) groups to maintain structure and function of both hemoglobin and the RBC membrane

66
Q

What are the parts of the RBC membrane?

A
  • lipid bilayer
  • integral membrane proteins
  • membrane skeleton
67
Q

What forms the membrane skeleton?

A

Structural proteins (alpha and beta spectrin, ankyrin, protein 4.1, and actin)

68
Q

What proteins are important in maintaining the RBC biconcave shape?

A

alpha and beta spectrin, ankyrin, protein 4.1, and actin

69
Q

What is the most common cause of anemia?

A

Iron deficiency

70
Q

What causes microcytic hypochromic anemia, and what are the clinical presentations?

A
  • Caused by defect in hemoglobin synthesis

- decreased mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) (i.e., small, pale red blood cells)

71
Q

What 3 proteins mediate the transport and storage of iron?

A

transferrin, transferrin receptor 1 (TfR1), and ferritin

72
Q

How is most iron bound to transferrin?

A

RBCs broken down by macrophages release iron into blood where transferrin picks it up; small amount through dietary absorption

73
Q

Which cells contain transferrin receptors so transferrin can release iron into the RBCs?

A

Erythroblasts

74
Q

What in ferritin actually binds iron?

A

Apoferritin

75
Q

What is iron stored as in macrophages?

A

ferritin and hemosiderin

76
Q

What is the difference between ferritin and hemosiderin as far as solubility?

A

Ferritin is a water soluble protein-iron complex while hemosiderin is an insoluble protein-iron complex

77
Q

Is ferritin or hemosiderin visible under light microscopy?

A

Hemosiderin

78
Q

What is iron in muscle found as?

A

Myoglobin

79
Q

What happens to ferritin, TfR1, delta-aminolevulinic acid synthase (ALA-S), and divalent metal transporter 1 (DMT-1) levels in times of iron overload?

A
  • tissue ferritin increases
  • ALA-S increases
  • TfR1 decreases
  • DMT-1 decreases
80
Q

What happens to ferritin, delta-aminolevulinic acid synthase (ALA-S), DMT-1 and TfR1 levels in iron deficiency?

A
  • ferritin decreases
  • ALA-S decreases
  • TfR1 increases
  • DMT-1 increases
81
Q

How do iron levels control ferritin, TfR1, ALA-S, and DMT-1 levels?

A

Iron regulatory protein (IRP) binds to iron response elements (IREs) on ferritin, TfR1, ALA-s, and DMT-1 mRNA, and whether the binding is upstream (5’) of the coding region or downstream (3’) of the coding region determines whether or not the mRNA is translated to protein

82
Q

If IRP binds upstream of the coding gene, is protein translation of ferritin, TfR1, ALA-S, and DMT-1 increased or decreased?

A

Decreased

83
Q

If IRP binds downstream of the coding gene, is protein translation of ferritin, TfR1, ALA-S, and DMT-1 increased or decreased?

A

Increased

84
Q

Does IRP bind to IREs when iron levels are high or low?

A

Low

85
Q

What causes pathological changes of the liver, endocrine organs, pancreas, and heart when iron levels are high?

A

Iron is transferred to parenchymal (functional) cells of these organs

86
Q

What organ produces hepcidin?

A

Liver

87
Q

What is the major hormonal regulator of iron homeostasis?

A

Hepcidin

88
Q

How does hepcidin regulate iron homeostasis?

A

Hepcidin inhibits iron release from macrophages and intestinal epithelial cells by interacting with the transmembrane iron exporter ferroportin by accelerating degradation of ferroportin mRNA

89
Q

What is the role of ferroportin?

A

Iron export from cells, especially in macrophages and intestinal epithelial cells

90
Q

What happens when hepcidin levels are raised?

A

Iron absorption and release from macrophages is reduced

91
Q

How many molecules of iron can bind to transferrin?

A

2

92
Q

What stimulates hepcidin expression?

A

When membrane bound hemojuvelin (HJV) binds to bone morphogenetic protein (BMP)

93
Q

What stimulates HJV binding to BMP?

A

High diferric transferrin levels block TfR1 binding to HFE, which allows TfR2/HFE binding which stimulates HJV/BMP binding and therefore hepcidin synthesis

94
Q

What digests HJV thus decreasing hepcidin synthesis, and when does this occur?

A

Matriptase 2 digests membrane bound HJV in iron deficiency thus reducing hepcidin synthesis

95
Q

Which proteins are released from early erythroblasts to suppress hepcidin production?

A

GDF 15 and TWSG1

96
Q

What is the result of hypoxia and inflammatory cytokines (IL-6) on hepcidin secretion?

A
  • hypoxia suppresses hepcidin secretion

- IL-6 increases hepcidin secretion

97
Q

Is much iron obtained from diet?

A

No, most iron is recycled via RBC destruction by macrophages and release of the iron from macrophages via ferroportin to transferrin then to TfR1 on erythroblasts

98
Q

Is heme iron or inorganic iron more absorbable?

A

heme iron

99
Q

Is ferrous (FE2+) or ferric (Fe3+) iron more absorbable?

A

Ferrous (Fe2+)

100
Q

Is iron absorption increased or decreased in inflammation and pregnancy?

A
  • inflammation - decreased

- pregnancy - increased

101
Q

What part of the GI tract absorbs iron?

A

duodenum

102
Q

Why is iron absorption in acidic conditions (like with vitamin C or HCl) favorable over alkali conditions?

A

acidic conditions keep the iron in the reduced ferrous (Fe2+) form

103
Q

What happens to heme iron once it is absorbed into the duodenal enterocyte?

A

the heme is digested to release iron

104
Q

Which iron transporters are active in iron absorption from the duodenum, and on which surface of the enterocytes are they located?

A
  • DMT-1 - apical (lumen) surface to absorb iron from gut

- ferroportin - basolateral surface to release iron from enterocytes into plasma

105
Q

What reduces iron from the ferric (Fe3+) to the ferrous (Fe2+) form on the apical (lumen) surface of enterocytes, and what oxidizes iron from the ferrous (Fe2+) to the ferric (Fe3+) form on the basolateral surface so it can be transported by transferrin?

A
  • ferrireductase - apical surface (Fe3+ to Fe2+)

- ferrioxidase - basolateral surface (Fe2+ to Fe3+)

106
Q

How much iron is typically absorbed via diet?

A

Only enough to compensate for iron lost from the body, which isn’t much

107
Q

Who is at the most risk to develop iron deficiency?

A

pregnant women, adolescents, and menstruating females

108
Q

What are the two groups of white blood cells (leukocytes)?

A
  • Phagocytes

- Immunocytes

109
Q

What cells are phagocytes?

A

Granulocytes (neutrophils, eosinophils, and basophils) and monocytes

110
Q

What cells are immunocytes?

A

B cells, T cells, and NK cells

111
Q

What are the soluble proteins that are closely associated with the function of phagocytes and lymphocytes?

A

immunoglobulins and complement

112
Q

What is the lifespan of neutrophils in blood?

A

6-10 hours

113
Q

What are the stages of neutrophil development, and where is each located?

A
  • myeloblast, promyelocyte, myelocyte, metamyelocyte, band neutrophil, and neutrophil
  • all are found in bone marrow, but only bands and neutrophils are found in the blood
114
Q

When do granules appear in neutrophil development?

A
  • primary granules - promyelocyte

- secondary granules - myelocyte

115
Q

Which neutrophil precursor has a large nucleus, fine chromatin, and 2-5 nucleoli?

A

myeloblast

116
Q

When do nucleoli disappear in neutrophil precursors?

A

myelocytes

117
Q

Which neutrophil precursors are non-dividing cells?

A

metamyelocytes

118
Q

What are the cells in monocyte development and where are they found?

A
  • monoblasts (marrow)
  • promonocytes (marrow)
  • monocytes (blood)
  • macrophage (tissue)
119
Q

What are the two main roles of eosinophils?

A
  • allergic response and defense against parasites
120
Q

What cells become mast cells in tissues?

A

Basophils

121
Q

Which cells in granulocyte development can undergo mitosis and which cannot?

A
  • Dividing cells:
    • myeloid progenitor cells
    • myeloblasts
    • promyelocytes
    • myelocytes
  • Non-dividing cells:
    • metamyelocytes
    • bands
    • segmented granulocytes
122
Q

Which contains more granulocytes, blood or marrow?

A

marrow (10-15x more than blood)

123
Q

Does the marrow contain more erythroid cells or myeloid cells?

A

myeloid cells (within a 2:1 to 12:1 ratio)

124
Q

What are the two pools of granulocytes in blood?

A
  • circulating (included in blood count)

- marginating (not included in blood count)

125
Q

How long are granulocytes in blood and in peripheral tissue?

A
  • 6-10 hours in blood

- 4-5 days in tissues

126
Q

What are the growth factors for granulocytes?

A

IL-1, IL-3, IL-5, IL-6, IL-11, granulocyte-macrophage colony-stimulating factor (GM-CSF), M-CSF, and G-CSF

127
Q

What cytokines stimulate stromal cells and T lymphocytes to release cytokines that increase granulocyte production during infection?

A

endotoxin, IL-1, TNF

128
Q

What is the result of G-CSF administration?

A

increase in circulating neutrophils

129
Q

What are some clinical applications of G-CSF?

A
  • post-chemotherapy, radiotherapy, or stem cell transplantation
  • acute myeloid leukemia
  • myelodysplasia
  • lymphomas
  • severe neutropenia
  • severe infection
  • peripheral blood stem cell harvesting
130
Q

What does G-CSF administration reduce?

A

infections, hospital stays, and antibiotic usage

131
Q

What is another name for a macrophage?

A

histiocyte

Hematology (3 decks)

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