Hematopoiesis Flashcards

1
Q

T or F. Hematopoiesis is regulated at both levels of differentiation and cell division.

A

T

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2
Q

How is a pluripotent stem cell defined?

A

By its ability to salvage all the elements of hematopoiesis after it has been wiped out by irradiation or chemotherapy.

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3
Q

How can pluripotent stem cells be identified?

A

Characteristic cell surface markers (CD34+ CD38-). Cannot be identified by morphology.

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4
Q

T or F. Pluripotent stem cells are common.

A

F. <1 in 20 million.

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5
Q

T or F. Pluripotent stem cells express receptors for key growth factors.

A

T

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6
Q

T or F. Pluripotent stem cells are critical for bone marrow transplants and gene therapy methods.

A

T

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7
Q

What does BFU stand for?

A

Burst Forming Units

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8
Q

What does CFU stand for?

A

Colony Forming Units

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9
Q

BFU and CFU are currently defined by their responsiveness to what?

A

A handful of key known growth factors.

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10
Q

What are the 4 key growth factors in hematopoiesis?

A
  1. TPO
  2. EPO
  3. G-CSF
  4. GM-CSF
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11
Q

What are the 5 cells in the morphologic maturation of granulocyte precursors?

A
  1. Blast
  2. Promyelocyte
  3. Myelocyte
  4. Metamyelocyte
  5. Bands and Neutrophils
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12
Q

What is the key regulator of granulopoiesis?

A

G-CSF

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13
Q

What are the 3 ways in which disease states can affect granulopoiesis?

A
  1. Increase in overall numbers
  2. Shifted left or right
  3. Maturation arrest (blocked part way through)
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14
Q

What cell is responsible for platelet production?

A

Megakaryocytes

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15
Q

What is special about megakaryocytes?

A

They are polyploid. Their nuclei have divided multiple times, so instead of being diploid (2n) they contain an average of 16-32 haploid genomes.

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16
Q

How do megakaryocytes make platelets?

A

They extend snake-like tubes called proplatelets into fenestrated bone marrow blood vessels (sinuses). Mature platelets are shed off one at a time from the ends of proplatelets.

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17
Q

What is the major regulator of thrombopoiesis?

A

TPO (thrombopoietin)

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18
Q

T or F. TPO is synthesized at a constant rate in the liver.

A

T

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19
Q

What cells can TPO bind to?

A

Both platelets and megakaryocytes.

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20
Q

What happens when TPO binds to megakaryocytes?

A

Stimulates platelet production from immature precursors and mature megakaryocytes.

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21
Q

What allows more TPO to bind to megakaryocytes thus stimulating thrombopoiesis?

A

Low platelet count.

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22
Q

What are the 5 cells in erythryopoiesis?

A
  1. Blasts
  2. Pronormoblasts
  3. Basophilic erthyroblasts
  4. Polychromatophilic erythroblasts
  5. Normochromic erythroblasts
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23
Q

How many cell divisions are there in erythropoiesis?

A

5

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24
Q

Nascent red cells are known as what?

A

Reticulocytes (polychromasia)

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25
Q

As a patient ages, the cellularity of the bone marrow does what?

A

Declines

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26
Q

What are the 4 requirements for red cell production?

A
  1. Heme synthesis
  2. Globin synthesis
  3. DNA synthesis
  4. Regulation
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27
Q

What are the 4 requirements for heme synthesis?

A
  1. Iron
  2. B6
  3. Succinyl CoA
  4. Glycine (which requires B12 and folate)
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28
Q

What are the 2 requirements for globin synthesis?

A
  1. Normal globin genes (alpha and beta)

2. Amino acids

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29
Q

What 2 things can cause problems with globin production?

A
  1. Malnutrition

2. Gene mutations (more common in ‘Merica)

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30
Q

T or F. The nucleus must be replicated several times in red cell production.

A

T

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31
Q

What is required in DNA synthesis in red cell production?

A

Adequate nutrition and deoxynucleoside triphosphates (which requires ribonucleotide reductase and thymidine). Thymidine requires B12 and folate.

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32
Q

What hormone regulates red cell production?

A

EPO (erythropoietin)

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33
Q

Where is EPO produced?

A

Kidneys

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34
Q

What 2 things are required for EPO?

A
  1. Normal kidneys

2. Normal bone marrow micro-environment

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35
Q

Is anemia a diagnosis?

A

No. It is a labratory finding. It remains undiagnosed until you find a cause for it.

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36
Q

What are the 3 ways in which a patient can become anemic?

A
  1. Losing red cells
  2. Not making enough red cells
  3. Both
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37
Q

What is the morphology of an anemic patient’s red blood cells?

A

Small without much hemoglobin. Microcytosis=small red cells. Hypochromic=loss of color bc of low hemoglobin.

Lots of variation in size and shape. Anisocytosis=varying size. Poikilocytosis=varying shape.

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38
Q

In regards to anemic red blood cells on a peripheral blood smear, what is the rule of thumb for the area of central pallor?

A

If the diameter of the enlarged central pallor area is greater than 1/3 of the red cell’s diamter, the cell is hypochromic aka lacking hemoglobin.

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39
Q

What is another characteristic (besides microcytic hypochromic) of anemic red cells?

A

Lots of variation in size and shape. Anisocytosis=varying size. Poikilocytosis=varying shape.

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40
Q

What form is dietary iron in?

A

Ferric (Fe3+). Must be reducted to ferrous (Fe2+) in the stomach before it can be taken up in the small bowel.

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41
Q

What 2 things are required for dietary iron to be reduced from Fe3+ to Fe2+?

A
  1. Low pH

2. Ascorbate

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42
Q

What molecule handles the transport of iron in the plasma?

A

Transferrin

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43
Q

What oxidizes ferrous iron in the plasma to its ferric state so it can be bound to transferrin?

A

Serum oxidases

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44
Q

Why would free iron in the plasma be a bad thing?

A
  1. Augment bacterial growth

2. Catalyze formation of superoxide radicals from oxygen

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45
Q

What are the 2 fates of iron bound to transferrin?

A
  1. Transferred to red cell precursors in the BM via transferrin receptor
  2. Transferred to ferritin for the iron storage pool
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46
Q

Where is the storage pool of iron located?

A

Bound to ferritin in macrophages located in the BM, liver, and spleen.

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47
Q

How is serum iron measured?

A

It is a direct measure of transferrin-bound iron.

48
Q

T or F. A measurement of transferrin-bound iron does not directly assess iron stores.

A

T

49
Q

What does the soluble transferrin receptor amount measure?

A

Measurement of the small number of transferrin receptor molecules that get sloughed off the storage pool cells and into the plasma.

50
Q

How is the amount of storage pool iron measured?

A

Measured by the trace amount of ferritin present in the serum. This value is directly proportional to the amount of storage pool iron in the body.

51
Q

T or F. Serum ferritin is the most useful measure of iron metabolism.

A

T: used for assessment of anemias of unknown etiology.

52
Q

What is the measurement of the total amount of transferrin in circulation called?

A

Total iron binding capacity

53
Q

Patients with poor iron intake show a reduced level of what?

A

Serum iron. Careful though, this can be seen in other conditions.

54
Q

What happens to the soluble transferrin receptor value when the iron storage pool is depleted?

A

It is increased bc when iron stores are depleted, macrophages increase the amount of transferrin receptors on their surface.

55
Q

With iron deficiency, what happens to the total iron binding capacity (TIBC) and serum ferritin levels?

A

TIBC: increased (bc transferrin production is increased)

Serum ferritin: decreased

56
Q

T or F. In anemias due to chronic blood loss, the combined flux of dietary iron and iron store mobilization is insufficient to keep up with the red cell loss.

A

T

57
Q

Describe the lab findings in a patient with an anemia due to chronic blood loss.

A

They are identical to the lab values seen when iron deficiency results from poor dietary intake.

58
Q

What is thalassemia?

A

Reduced globin production resulting from genetic mutations (alpha or beta).

59
Q

What is the morphology of red cells in Beta Thalassemia?

A
  1. Microcytosis, hypochromia (just like iron deficiency)

2. Frequent target cells (non-specific)

60
Q

What are the main differences in red cell morphology of beta thalassemia compared to iron deficiency?

A
  1. Smaller: MCV < 70 pL (normal=90-100 pL)…note this is not always true
  2. Presence of target cells on PBS
61
Q

What are target red cells also commonly seen in association with?

A

Liver disease. Remember: target cells are non-specific.

62
Q

What is the difference between homozygous and heterozygous beta globin chain mutations?

A

Homozygous: can be severe.
Heterozygous: can be mild and not clinically obvious.

63
Q

What is a reliable clue to let you know if a patient with a microcytic anemia has a thalassemia or an iron deficiency?

A

The NUMBER of red cells. In iron deficiency, the number of red cells is decreased. In thalassemias, the number of red cells is normal or increased.

64
Q

What test needs to be ordered to confirm that a patient has a thalassemia?

A

Hemoglobin Electrophoresis Test

65
Q

The beta globin locus is located on which chromosome?

A

Chromosome 11

66
Q

What are the 6 beta globin forms?

A
  1. Epsilon
  2. g-Gamma
  3. a-Gamma
  4. Psi-Beta
  5. Delta
  6. Beta
67
Q

Which 3 beta globin forms are expressed in utero?

A

Epsilon, g-gamma, and a-gamma.

68
Q

Which beta globin form is primarily expressed in the fetus and has a low level of expression after birth?

A

Delta (all the others besides beta are expressed in the fetus too)

69
Q

Which beta globin form is expressed in adults?

A

Beta

70
Q

What happens to the relative amount of delta globin if expression of a beta globin allele is impaired due to a mutation?

A

Increased, sometimes to high levels.

71
Q

What is the predominant adult form of hemoglobin?

A

Hemoglobin A: 2 alpha chains, 2 beta chains.

72
Q

What is hemoglobin A2 composed of?

A

2 alpha chains and 2 delta chains.

73
Q

To confirm beta thalassemia, what is seen on hemoglobin electrophoresis?

A

Increased Hemoglobin A2. Hemoglobin A2 forms bc of the increased expression of delta globin and migrates differently on electrophoresis than Hemoglobin A.

74
Q

In severe cases of beta thalassemia, what other form of hemoglobin is detected on electrophoresis?

A

Hemoglobin F (for fetal): 2 alpha chains, 2 gamma chains.

75
Q

The alpha globin locus is located on what chromosome?

A

Chromosome 16

76
Q

What are the 4 forms of alpha globin?

A
  1. Zeta 2
  2. Zeta 1
  3. Alpha 2
  4. Alpha 1
77
Q

Which 2 forms of alpha globin are primarily expressed in the fetus? Adult?

A

Fetus: Zeta 1 and Zeta 2.
Adult: Alpha 1 and Alpha 2.

78
Q

A patient with a heterozygous alpha2 mutation?

A

Alpha thalassemia 1 trait. Results in almost no clinical/lab findings.

79
Q

A patient with homozygous alpha 1 mutations?

A

Alpha thalassemia 2 trait.

80
Q

A patient with alpha thalassemia 2 trait presents with what type of anemia?

A

Mild microcytic anemia.

81
Q

At birth, what type of Hgb do alpha thalassemia 2 trait patients have excess numbers of?

A

Hgb Bart’s (4 gamma chains)

82
Q

T or F. Alpha thalassemia 2 trait patients have a normal Hgb electrophoresis as adults.

A

T

83
Q

What tests are used to diagnose alpha thalassemia 2 trait?

A

PCR based: electrophoresis and/or sequencing.

84
Q

Alpha thalassemia 2 trait is seen in 3% of what ethnic group?

A

African Americans

85
Q

A patient with both alpha 1 alleles mutated and one alpha 2 allele mutation have what disease?

A

Hemoglobin H disease

86
Q

Hemoglobin H is composed of?

A

4 beta globin chains

87
Q

Hemoglobin H disease shows what in regards to lab findings?

A
  1. Variable degree of microcytic anemia

2. Hgb electrophoresis shows 15-30% Hgb H

88
Q

What can Hgb H disease be misdiagnosed as?

A

Iron deficiency

89
Q

A patient with no function allele of either alpha 1 or alpha 2?

A

Hgb Bart’s

90
Q

T or F. Hgb Bart’s is lethal in utero or shortly after birth.

A

T: fetus/baby dies before normal expression of beta globin can produce significant amounts of Hgb H.

91
Q

Where is Hgb Bart’s common?

A

Southeast Asia

92
Q

What are the biochemical requirements for DNA synthesis?

A

Ribonucleoside triphosphates have to be reduced to the deoxy form and UTP has to be methylated to TTP. Methylation requires B12 and folate.

93
Q

What are the 3 consequences of impaired DNA synthesis in regards to red cell production?

A
  1. Fewer cells are produced
  2. Normal/enhanced maturation of cytoplasm
  3. Impaired nuclear maturation
94
Q

T or F. Impaired DNA synthesis in red cell production holds up production after one or two cell divisions resulting in cells with large nuclei and chromatin that is not condensed into heterochromatin.

A

T

95
Q

If DNA synthesis is impaired in red cell production, what color are the resulting cells? What is the name for the appearance of these cells?

A

Red (instead of blue). As the cytoplasm continues to mature, RNA which stains blue is degraded and Hgb’s reddish color takes over. This is termed megaloblastic.

96
Q

What are the 4 causes of megaloblastic anemia?

A
  1. Impaired B12 uptake
  2. Impaired folate uptake
  3. Drug effect
  4. Intrinsic bone marrow dysfunction
97
Q

T or F. Most megaloblastic anemias can be diagnosed without a BM biopsy.

A

T

98
Q

What is a megaloblastic anemia due to impaired B12 uptake called?

A

Pernicious anemia

99
Q

What are the causes of impaired folate uptake?

A

Malabsorption or malnutrition.

100
Q

What 2 types of drugs can cause megaloblastic anemia?

A
  1. Nucleoside analogs (HAART)

2. Ribonucleotide reductase inhibitors (hydroxyurea)

101
Q

What intrinsic bone marrow dysfunction can cause a megaloblastic anemia?

A

Myelodysplastic syndrome

102
Q

T or F. Red cell production is regulated by organs outside the bone marrow and can be impaired by dysfunction of those organs.

A

T: ex. anemia as a result of renal failure bc the kidneys synthesize EPO.

103
Q

How is EPO production regulated?

A

Oxygen sensors

104
Q

Where are the oxygen sensors located that regulate EPO production?

A

Peritubular cells in the renal cortex. They secrete EPO

105
Q

What does hepcidin impair?

A

Iron store mobilization

106
Q

Hepcidin is secreted by what organ?

A

Liver

107
Q

What stimulates the production of hepcidin?

A

IL-6 that is produced in response to chronic inflammatory conditions. So infection and inflammation impair utilization of iron stores.

108
Q

What is increased in the bone marrow due to increased hepcidin production?

A

Increased bone marrow iron stores

109
Q

How is the transferrin saturation calculated?

A

Serum iron divided by TIBC.

110
Q

What 3 things happen in anemia of chronic inflammation in regards to iron transport?

A
  1. Iron not mobilized from storage
  2. Iron not absorbed well from GI tract
  3. Transferrin pulled out of circulation
111
Q

What happens to the transferrin saturation value in anemia of chronic inflammation?

A

Increased (bc TIBC is reduced).

112
Q

T or F. The net flux of iron through the system is reduced in anemia of chronic inflammation.

A

T

113
Q

What cell type is affected by anemia of chronic inflammation?

A

Red cell precursors bc there isn’t as much iron to bind to their transferrin receptors (even if macrophages are full of ferritin).

114
Q

If you suspect anemia of chronic inflammation, what must be ordered to confirm it?

A

Bone marrow biopsy bc CBC and iron labs do not rule out other bad things happening in the bone marrow like acute leukemia, lymphoma, metastases, or a large number of granulomas.

115
Q

In anemia of chronic inflammation/disease, what 4 things are seen in the labs and tests?

A
  1. Normocytic anemia
  2. Increased ferritin
  3. Reduced or normal serum iron
  4. Increased bone marrow iron stores
116
Q

T or F. AIDS, TB, RA, or any type of cancer can result in an anemia of chronic inflammation/disease.

A

T