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ACVP Phase II - Clinical Pathology > Harvey Chapter 3 Hematopoiesis (with Schalm's) AKG > Flashcards

Harvey Chapter 3 Hematopoiesis (with Schalm's) AKG Flashcards

1
Q

Primitive hematopoiesis - name the locations in where it occurs before it reaches the bone marrow and lymphoid organs.

A
  1. Starts in the yolk sac (outside of the body of embryo)
  2. Then moves within aorta-gonad-mesonephros (AGM) region of the embryo
  3. Shift to liver and spleen mid-gestation
  4. Then to bone marrow and lymphoid organs
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2
Q

The HSCs and associated endothelial cells (endothelium of yolk sac and dorsal aorta) are produced by common embryonic stem cells known as _____. These cells express what surface markers?

A

Hemangioblasts: VEGFR-2, CD34, CD133

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3
Q

Major hematopoietic organs in…

Bird:

Reptiles:

Amphibians:

Fish:

A

Bird: bone marrow

Reptiles: bone marrow +/- spleen

Amphibians: kidney, liver, spleen +/- bone marrow

Fish: kidney and/or spleen

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4
Q

The particular stromal cells that support the endothelium of the venous sinuses in the bone marrow are termed _______.

A

Adventitial stromal cells

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5
Q
A

A scanning electron micrograph of the cut surface of bone marrow showing a system of vascular sinuses originating at the periphery of the marrow (right side of field) and draining into a large vein (upper left corner). The large vein has several apertures in its wall, representing tributary venous sinuses. Hematopoietic tissue lies between the vascular sinuses.

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6
Q
A

A scanning electron micrograph from the extravascular space in rat bone marrow. Spherical hematopoietic cells are shown developing in close association with marrow stromal cells and their cytoplasmic processes.

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7
Q

Granulopoiesis occurs primarily on the surface of _______.

A

stromal cells

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8
Q

In addition to hematopoietic cells and developing blood cells, there are a number of accessory cells involved in regulating hematopoieis that reside within the extravascular space of mammalian bone marrow. What are these accessory cells?

A

Macrophages

NK cells

Mature lymphocytes

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9
Q

Hematopoietic stem cells (HSC) exhibit long-term self-renewal and differentiation. How often do they replicate?

A

Once every 8-10 weeks

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10
Q

______ are cells that form colonies in the bone marrow culture like HSCs, but do not have long-term self-renewal capacities.

A

Hematopoietic progenitor cells (HPCs)

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11
Q

HSCs and HPCs cannot be distinguished from mature lymphocytes morphologically. What surface marker can be used to label HSCs and HPCs that would differentiat them from from lymphocytes?

A

CD34 - some HSCs lack CD34 though (possibly primitive non-active/quiescent HSCs are negative CD34, and CD34 may be used to assess degree of activation); CD34 is also present on nonhematopoietic stem cells and vascular endothelial cells.

Stem cell antigen 1 (SCA-1)

c-kit (c-kit = receptor for SCF)

CD133

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12
Q

Frequency of HSCs in marrow is < _____% in mice and < _____% in cats.

Are HPCs present in higher or lower concentrations?

A

< .01% in mice

<.0001% in cats

HPCs >>> HSCs (< 2% of all nucleated bone marrow cells in adult dogs are CD34+, but up to 18% of CD34+ cells have been reported in neonatal pups)

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13
Q

Which cells are more numerous in the marrow: HSCs or HPCs?

A

HPCs

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14
Q

WHen measured in an in vitro cell culture assay, HPCs are referred to as _____. HPCs that rapidly proliferate, retain their ability to migrate, and form multiple subcolonies around a larger central colony in culture are called _______.

A

Colony-forming units (CFUs)

Burst-forming units (BFUs)

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15
Q

In mammals, all blood cells are produced in the ____ space of the bone marrow. In birds however, only leukocytes are produced in the ______ space of the bone marrow. Erythrocytes and thrombocytes are produced within the ____ space of the marrow.

A

Mammals - extravascular space

Birds - leukocytes in extravascular space; erythrocytes and thrombocytes in the vascular space

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16
Q

Marrow stromal cells, adipocytes, osteoblasts, chondrocytes, fibroblasts, and myoblasts all come from which stem cells?

A

Mesenchymal stem cells

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17
Q

List different stem cell markers:

Surface molecules

Transcription Factors

A

Surface molecules: CD34, stem cell antigen-1 (SCA-1), c-kit, CD133

Transcription factors: Oct4, Nanog, Sox-2

Dye efflux (flow cytometry)

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18
Q

List the appropriate chemokine that:

  • Produced by marrow endothelial cells and stromal cells
  • Forms a gradient to promote migration of HSCs/HPCs from blood to bone marrow. These cells express its receptor CXCR4.
  • Promotes expression of CXCR4 and other adhesion molecules on the surface of HSCs/HPCs
  • Induces transendothelial migration
A

CXCL12 = SDF-1 (stromal cell derived factor 1)

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19
Q

Homing of HSC HPCs to the marrow

Which molecules are:

  1. membrane-spanning, sugar-binding glycoproteins
  2. Bind to glycosylated ligands on HSCs/HPCs
  3. Promote loose, rolling-type adhesion b/w HSCs/HPCs and endothelial cells in blood
A

P- and E-selectin molecules

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20
Q

Homing of HSC/HPCs to the marrow

Which molecules:

  1. Are expressed on the surface of migrating cells
  2. Bind to counter receptors VCAM-1 on endothelial cells
  3. Are responsible for tight adhesion
A

Integrins –> α₄β₁-integrin (very late antigen-4, VLA-4)

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21
Q

In steady state conditions, quiescent HSCs can be found near _______, and osteoblasts help regulate their number. More active HSCs and HPCs can be found near ______ and likely have a homeostatic role during steady-state conditions.

A

endosteal and trabecular bone

vascular sinuses

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22
Q
  • Erythroid cells develop around ______
  • Megakaryocytes form adjacent to _______
  • Granulocyte develop adjacent to ______
A
  • macrophages
  • sinusoidal endothelial cells
  • Adventitial stromal cells (away from vascular sinuses)
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23
Q

Which two collagen types are produced by stromal cells in BM to provide a surface that HSCs and HPCs can adhere to:

A

Collagen types I and IV

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24
Q

List the three early-acting hematopoietic growth factors (HGFs) that are involved with triggering dormant (G0) primitive HSCs to begin cycling:

A
  1. Stem cell factor (SCF)
  2. fms-like tyrosine kinase ligand (Flt3L)
  3. TPO
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25
Q

List three intermediate-acting HGFs that have broad specificity and support proliferation of multipotent HPCs:

A
  1. IL-3 (multi-CSF)
  2. GM-CSF
  3. IL-4
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26
Q

List five late-acting HGFs that have restricted specificity, and have the most potent effects on committed progenitor cells and later stages of development when cell lines can be recognized morphologically.

A
  1. M-CSF (macrophage-CSF)
  2. G-CSF
  3. EPO
  4. TPO
  5. IL-5
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27
Q

Which HGF is considered an early and late-acting HGF that sitmualtes platelet production and maintains population of HSCs in osteoblastic niche.

A

TPO

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28
Q

Primitive RBCs enter blood as nucleated cells. In mammals, enucleation can eventually occur in circulating. The extruded nuclei circulate for a shor ttime and are surrounded by a small amount of cytoplasm. They have been called _____.

A

Pyrenocytes

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29
Q

Embryonal hemoglobin has a ___ oxygen affinity.

A

high

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30
Q

The earliest erythroid progenitor is called the _____ , which differentiates into the _____. The first morphologically recognizable erythroid cell is the _____.

A

Burst-forming unit erythrocyte (BFU-E)

Colony-forming unit erythrocyte (CFU-E)

Rubriblast

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31
Q

Primary growth factor involved in proliferation and differentiation of CFU-Es into rubriblasts

A

EPO

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32
Q
  • Early and late stages of erythroid development occur with intimate membrane apposition to central macrophages in “erythroid islands.”
  • Direct contact with macrophages enhances proliferation of erythroid precursors under basal conditions
  • Macrophages may also produce EPO - positive growth factor
  • Macrophages may also produce negative factors, mostly associated with inflammation- list these.
A
  • IL-1
  • TNF-a
  • TGF-b
  • IFN-alpha, IFN-beta, IFN-gamma
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33
Q

List the nutrients required for erythropoiesis

A
  1. Amino acids and essential fatty acids
  2. Copper (in form of ceruloplasm)
  3. Vitamin B6 (pyridoxine)
  4. Tetrahydrofolic acid (active form of folic acid - B9)
  5. B12
34
Q

In erythroid cells, what gives the cells a blue color vs red color when using Romanowsky-type stain?

A

Blue - ribosomes/polyribosomes

Red - hemoglobin

More red - means losing ribosomes and gaining more hemoglobin

35
Q

What is the main type of reticulocyte in cats compared to dogs?

A

Reticulocytes are generally not released from bone marrow of non-anemic cats until they mature to punctate-type reticulocytes. Consequently few to no aggregate reticulocytes (< 0.4%) but up to 10% punctate reticulocytes are found in blood from normal adult cats. The punctate reticulocyte takes 10-12 days to mature. If they form a regenerative response, aggregate reticulcoytes will get released, but will only last about a day before they mature into punctate reticulocytes. Punctate reticulocytes do NOT appear as polychromatophils when stained with Wright-Giemsa stain. Canines release immature aggregate-type reticulocytes that quickly mature into adult RBCs within 24 hours and the punctate reticulocytes are short lived.

36
Q

Inhibitors of erythropoiesis:

A
  • TGF-beta
  • TNF-alpha
  • IFN-y
  • IL-6 (enhances megakaryopoiesis and granulopoiesis)
  • TNF-related apoptosis ligand (TRAIL)
37
Q

EPO synthesis in adult mammals occurs primarily where?

What is an extrarenal source of EPO in adults that is the major site of EPO production in mammalian fetus?

A
  1. Within peritubular interstitial cells located within the inner cortex and outer medulla of the kidney.
  2. Liver

*macrophages and EP cells can also produce EPO in BM

38
Q

Other hormones can enhance growth of EP cells in vitro:

A
  1. Androgens
  2. Glucocorticoid hormones
  3. GH
  4. Insulin and insulin-like growth factors
  5. Thyroid hormone (T3)
39
Q

EPO has roles outside of hematopoiesis:

A
  • promote proliferation and migration of endothelial cells
  • enhance neovascularization
  • stimulate production of modulators of vascular tone
  • exert cardioprotective and neuroprotective effects
40
Q

Congenital Dyserythropoiesis - Poodle macrocytosis

A
  • Toys and Minis
  • not anemic, no reticulocytosis
  • marked macrocytosis (85-105 fL), +/- metarubricytosis w/ nuclear-cytoplasmic asynchrony, HJBs (large + multiple)
  • BM: looks like VB12 deficiency
    • nuclear bridging!
41
Q

Inherited selective malabsorption of cobalamin

A
  • Giant schnauzers, Border Collies, Beagle, cat
  • GI absorption, essential cofactor for methylmalonic-CoA mutase + methionine synthase → tetrahydrahydrofolate which is essential cofactor for NA synthesis
  • inhibition of nuclear maturation → megaloblastosis, neutropenia, hyperseg neuts
  • normocytic, normochromic w/ increased RDW
  • lack of receptor for intrinsic factor-cobalamin complex = cubilin
  • chronic NRA, acanthocytosis, increased RDW
  • Dx: serum cobalamin, methylmaolnic acid, total homocysteine
42
Q

This is a fatal condition in polled hereford calves. Affected calves have macrocytic normochromic anemia with mild reticulocytosis.

A

Congenital dyserythropoiesis with dyskeratosis

43
Q

Congenital dyserythropoiesis, polymyopathy, and cardiac disease in ________ is characterized by moderate anemia with spherocytes, schistocytes, dacryocytes, codocytes, and vacuolated RBCs seen in blood smears

A

English springer spaniels

44
Q

Which myeloid stages are capable of mitosis?

Which stage produces primary (reddish purple) cytoplasmic granules?

Which stage produces secondary (specific) granules?

A

Myeloblast

Promyelocytes - produce primary granules

Myelocytes - produce secondary (specific granules)

45
Q

Which myeloid stages fall under the post-mitotic (matruation and storage pool) pool?

A

Metamyelocytes

Bands

Segmented neutrophils

46
Q

What are the three most improtant cytokines in the production of neutrophils?

A

IL-3

GM-CSF

G-CSF

47
Q

WHich cytokine promotes granulopoiesis and thrombopoiesis during inflammation?

A

IL-6

48
Q

Which cytokine promotes terminal maturation of eosinophils? Which lymphocytes produce this cytokine?

A

IL-5; Th2

49
Q

IL-3, GM-CSF, and IL-5 inhibit _______

IL-12 and IFN-y inhibit ______

A

IL-3, GM-CSF, and IL-5 inhibit eosinophil apoptosis (POSITIVE)

IL-12 and IFN-y inhibit eosinophil production (NEGATIVE)

50
Q

Maturation of mast cells occurs where?

A

in TISSUES (not bone marrow); mast cells can also proliferate locally

51
Q

What is the major growth and differentiation factor for mast cells?

A
52
Q

It takes _____ (more/less) time to make monocytes than granulocytes.

A

less; and many monocytes are not stored in the marrow

53
Q

Not all macrophages and dendritic cells originate from monocytes in steady state conditions because these cells are capable of self-replication. What are examples in skin and CNS?

A

Langerhans cells (epidermal dendritic cells)

Microglia (macrophages in CNS)

54
Q

IL-3, GM-CSF, M-CSF and IL-___ are involved in monocyte production.

A

IL-34

55
Q

Exposure of ______ promotes development of M1-like macrophages.

Exposure of _____ promotes development of M2-like macrophages.

A

M-CSF + IFN-y –> M1

M-CSF + IL4 –> M2

56
Q

GM-CSF + IL4 + TNF-a produce _______ dendritic cells

A

‘inflammatory’ or ‘TNF-a and inducible iNOS-producing’ dendritic cells

57
Q

Monocyte progenitors + M-CSF + ______ –> osteoclasts

What inhibits osteoclast formation?

A
  • RANKL
  • IL3 + GM-CSF inhibits osteoclast formation
58
Q

Development of B and T lymphocyte progenitor cells is antigen _____.

A

INDEPENDENT

59
Q

Which IL cytokine is a big positive-growth factor for B-cells?

A

IL-7

60
Q

TGF-B, IFN-a, IFN-B, and IFN-y are ____ of B-cell lymphopoiesis.

A

inhibitors

61
Q

Plasma cells are dervied from B-cells. They can only be formed in lymphoid organs. T/F

A

False - B-cells can differentiate into plasmablasts and plasmablasts can develop into plasma cells in lymphiod tissue, as well as peripheral tissues or bone marrow

62
Q

______ attracts plasmablasts to bone marrow. and _____ + _____ promote plasma cell development by preventing apoptosis.

A

SDF-1; SDF-1 and IL-6

63
Q

T-cell progenitors are made in the ____ and mature in the _____.

A

bone marrow; thymus

64
Q

Most NK cells are produced, proliferate, and mature in the _____.

A

bone marrow

65
Q

What are hte positive growth facotrs for NK cells?

A

SCF; IL-2; IL-7; and IL-15

66
Q

Megakaryoblasts undergo ____ (nuclear reduplication without cell divisions).

A

endomitosis

67
Q

Positive growth factor for megakaryocytes is SDF-1 and ____.

A

FGF-4

*promote binding and localization of megakaryocytic progenitors in vascular niche (via adhesion molecules VCAM-1 and a4B1 integrin)

68
Q

Do non-mammalian species have megakaryocytes?

A

No - thrombocytes are nucleated and are produced via mitosis of precursors

69
Q

____ is the key stimulator of platelet production. The major site of its production is _____.

A

TPO - endothelial cells of the liver

70
Q

Platelets and megakaryocytes have ____ receptors to provide NEGATIVE-feedback by binding, internalizing and degarding ____.

A

TPO (c-Mpl receptors)

71
Q

Blood [TPO] is _____ in thrombocytopenia resulting from megakaryocytic hypoplasia.

Blood [TPO] is _____ with ongoing immune-mediated thrombocytopenia, becuase megakaryocytes are generally increased int he marrow and rapid platelet turnover is ocurring.

A

High

Low

72
Q

____ increases production of TPO by the liver and can contribute to thromobocytosis in some inflammatory conditions.

A

IL-6

73
Q

Platelet factor 4; TGF-B; IL-4; and TNF-alpha are ____ of megakaryocyte production.

A

inhibitors

74
Q

IN health, young platelets have large amounts of ____ on their surface, but become progressively ____ as they age. These aged platelets bind to hepatic ____ receptor, and are ingested by hepatocytes.

A

sialic acid

desilaylated

AMR receptor

75
Q

In ITP, auto-antibodies against ___ or ____ induce platelet phagocytosis and destruction by ____ macrophages. This is why ____ can be a component of ITP treatment in humans.

A
76
Q

This is a transcription factor that binds 3’ flanking region of EPO gene and stimulates EPO production. It is constitutively produced, but degraded by an oxygen dependent protease - so accumulates during hypoxia.

A

HIF-1

(hypoxia inducible factor)

77
Q

Glucocorticoids ___ ertyhroid progenitor proliferation and ____ differentiation.

A

stimulate; inhibit

78
Q

This is an anti-apoptotic protein that prevents apoptosis of hemoglobinizing rubricytes.

A

Bcl-xL

79
Q

This molecule is associated with EPO receptor and is responible for down stream signaling in erythroid progenitors via recruitment of STAT5

A

JACK 2

80
Q

What is the megakaryocyte and platelet receptor for TPO?

A

MPL

81
Q

What is the hepatocyte receptor for desialylated (aged) platelets?

A

AMR

ACVP Phase II - Clinical Pathology (14 decks)

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