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CMOD Week 7 > Hematopoiesis > Flashcards

Hematopoiesis Flashcards

1
Q

What is the normal range for WBC?

A

4.8-10.8 K/ul

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2
Q

What is the normal range for RBC? Male and female?

A

4.7-6.1 (male), 4.2-5.4 (female). All x10^6/ul

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3
Q

What is the normal range for Hgb? Male and female?

A

14-18 (male), 12-16 (female) g/dL

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4
Q

What is the normal range for Hct (hematocrit)? Male and female?

A

42-52% (male), 37-47% (female)

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5
Q

What is the normal range for MCV (average volume of RBC)?

A

80-100 fL

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6
Q

What is the normal range for RDW (Red Blood Cell Distribution Width. It is a measurement of the size of red blood cells)?

A

11.5-14.5%

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7
Q

What is the normal range for MCH (the average amount of hemoglobin in the average red cell)?

A

27-31 pg

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8
Q

What is the normal range for MCHC (mean cell hemoglobin concentration, which is the average concentration of hemoglobin in a given volume of blood. The MCHC is a calculated value derived from the measurement of hemoglobin and the hematocrit)?

A

32-36 %

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9
Q

What is the normal range for Plts?

A

150-400 K/ul

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10
Q

What is the normal range for MPV (mean platelet volume)?

A

7.4-10.4 fL

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11
Q

What is the normal percentage range for neutrophils in WBCS?

A

36-75%

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12
Q

What is the normal percentage range for lymphocytes in WBCS?

A

20-50%

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13
Q

What is the normal percentage range for monocytes in WBCS?

A

3-10%

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14
Q

What is the normal percentage range for eosinophils in WBCS?

A

0-4%

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15
Q

What is the normal percentage range for basophils in WBCS?

A

0-2%

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16
Q

How is hemoglobin measured?

A

by spectrophotometry.

Lyse the red cells, add cyanide to generate blue color, quantify it by % absorption

NOTE: Any turbidity in a blood specimen (such as excess lipoproteins after a fatty meal) will ALSO absorb non-blue light and result in artifactually high HgB measurement

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17
Q

How can red cells be measured by manual methods?

A

centrifugation- put anti coagulated blood in tube and spin down the cells. Can use a capillary tube (aka a spin hematocrit)

A/B= hematocrit, where A is the red part and B is the supernatant

NOTE: EDTA-containg tubes (lavender top) and citrate containing tubes (blue top), and heparin-containing tubes (green top)

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18
Q

How else can red cell be measured?

A

faster and more precisely via conductivity via the ‘coulter chamber” using DIRECT CURRENT

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19
Q

How does a coulter chamber work?

A

consists of a small container of fluid placed in a large container of the same fluid. The small container has a tiny aperture in it. Fluid is pumped at a precise rate into the large container, through the aperture, into the smaller container, and finally into a waster container. Since red cells outnumber other cells by a factor of about 1000, just counting all the cells will essentially give you the red cell count.

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20
Q

How is manual leukocyte differential measured?

A

done by visual inspection of 100 leukocytes, but only done on request because very laboring intensive

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21
Q

How can leukocytes be measured automated?

A

If you lyse the red cells in a blood specimen and then run the leukocytes through a coulter chamber, you can count the white cells and measure their volume similar to red cell measurements.

But if you change the setup by simultaneously measuring the resistance to radio frequency alternating current, you can measure what’s inside the cells (lobulate nuclei, for example vs spherical ones) instead of their size.

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22
Q

What is a drawback of the automated leukocyte measuring technique?

A

eosinophils and basophils are not well seperated from other populations

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23
Q

How can you separate eosinophils and basophils out then?

A

flow cytometer. Prior to the coulter chamber, the cells are hydrodynamically focused and run through a chamber in which they are hit by a laser. The amount of deflected light is the called the side scatter measurement and it provides a measure of the cytoplasmic granularity of the cells. This allows separation of basophils and eosinophils from neutrophils

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24
Q

Hematocrit is usually three times the value of hemoglobin. What might cause a smaller ratio?

A

fatty foods. Any turbidity in a blood specimen (such as excess lipoproteins after a fatty meal) will ALSO absorb non-blue light and result in artifactually high HgB measurement

So here, hemoglobin increases and hematocrit remains the same

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25
Q

How would small red blood cells affect hemoglobin and hematocrit?

A

they would both decrease

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26
Q

What might cause hematocrit to decrease?

A

red cells in a coulter counter may not be going through in a single file line and so the counter may count two RBCs clumped together as one, resulting in an artifically lowered red cell count, and thus, a lower hematocrit level

hemoglobin will not be affected

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27
Q

What is a reticulocyte?

A

immature red cell that is slightly bigger than mature ones and have a bluish tint caused by residual RNA

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28
Q

An increase in reticulocytes would result in what comment in a CBC?

A

polychromasia comment should be made

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29
Q

Can a hematology anayzer count reticulocytes?

A

Yes, very accuratley- can be used to assess whether an anemia is due to impaired red cell production

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30
Q

What is IPF?

A

immature platelet fraction-marketed by Sysmex as the platelet equivalent of reticulocyte count

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31
Q

What does a high IPF mean?

A

a thrombocytopenia is occurring due to rapid platelet consumption

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32
Q

What is a major problem with IPF?

A

it can always increase due to thrombocytopenias due to reduced platelet production- as well as the intended rapid platelet consumption

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33
Q

Current hematology analyzers have what capabilities?

A

automated spectrophotmetry, conductivity, and flow cytometry all in one

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34
Q

What things wont hematology analyzer count?

A

1) Bands- and other immature granulocytes (counted as neutrophils)
2) Blasts- may be counted as lymphocytes or monocytes
3) Red cell fragments- may not be detected, or counted as platelets
4) Platelet clumps- not always detected and may result in an artifactual thrombocytopenia

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35
Q

What are blasts?

A

early blood cell precursors which biologically similar to the earliest forms seen in bone marrow. These are small round cells with hypodense chromatin and none of the morphologic features associated with differentiation

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36
Q

The presence of blasts correlates to what diseases?

A

acute leukemias

37
Q

How do platelet clumps occur as a lab artifact?

A

occasional patients have antibodies to platelet antigens which are not exposed in vivo. They cause no problems at all. But in the presence of EDTA, these antigens may be exposed, causing platelets to clump. The hematology analyzer will call this thrombocytopenia (which must be caught). This is called pseudothrombocytopenia. If it is caught, citrate tubes can be used instead.

38
Q

After getting an automated leukocyte count in suspected pneumonia, what would you do?

A

order a manual count

39
Q

What are pluripotent stem cells?

A

1) Rare (1 in 20 million)
2) Cant be ID’d be morphology
3) Expresses receptors for growth factors
4) subset of blasts in bone marrow

40
Q

What cells derive directly from pluripotent stem cells?

A

Common myeloid progenitor cells and common lymphoid progenitor cells

41
Q

What cells derive directly from common myeloid cells?

A

burst forming units (BFUs) and colony forming units (GMEo and baso)

42
Q

Can you use a microscope to pick out BFUs from the bone marrow?

A

No. Cant distinguish from CFUs this way- most likely they don’t have any features associated with differentiation at all- aka they are “blasts”

43
Q

How are BFUs defined?

A

by the fact that if you dump a mixture of cells from bone marrow into a peri dish, certain growth factors cause their formation

44
Q

What is TPO?

A

thrombopoietin

45
Q

What is EPO?

A

erythropoietin

46
Q

What is the order of cell growth from blast to bands/neutrophils (aka granulopoiesis)?

What is the relative distribution of each in bone marrow?

A 
blasts (4%), 
promyelocyte (2-8%), 
myelocyte (10-13%), 
metamyelocyte (10-15%), 
bands and neutrophils (25-40%)

increase because cell division is associated with the growth process

last cell division is at myelocyte stage

47
Q

What is the major regulator of granulopoiesis?

A

GM-CSF

48
Q

Eythroblast production is stimulated by what?

A

hypoxia, as sensed by renal peritubular cells. **Thus, renal failure- productive anemia ***

49
Q

How are erythroblasts made in bone marrow?

A 
blasts,
pronormoblast
basophilic erythroblast, 
polychromatophilic erythroblast, 
normochromic erythroblast

there are typically 4-5 divisions per stage

50
Q

How are platelets made?

A

done via megakaryocytes (multiple divided nuclei- up to 16-32 haploid genomes)

They extend snakelike tubes called proplatelets into the fenestrated blood vessels int he bone marrow (aka sinuses), and mature platelets get cleaved one at a time from the ends of the proplatelets

51
Q

Where is TPO made?

A

liver in response to low platelet levels

52
Q

What does TPO do?

A

bind to platelets and megakaryocytes stimulating their production from immature precursors and platelet production from mature megakaryocytes

53
Q

How is heme made?

A

drop a porphyrin ring with a Fe2+ inserted in it into globin

54
Q

Where are porphyrin rings made?

A

mitochondria

55
Q

How is porphyrin made?

A

succinyl CoA and glycine needed

56
Q

How is glycine provided?

A

Via diet and a system that makes glycine in the liver using B12 and folate (heme is needed for CYP450 in the liver as well)

57
Q

What enzymes are used in porphyrin synthesis?

A

ALA synthetase and ferrochelatase

58
Q

What happens if these enzymes are defective?

A

a disease family called porphyrias develop (inherited)- patients must stay away from light and sun

59
Q

What are sideroblasts?

A

When ferrochelatase is defective, iron transport into mitochondria continues even without a porphyrin ring to put it in, leading to abnormal, overloaded red precursors called sideroblasts

60
Q

Dietary iron mostly exists in the oxidized state, but it most be reduced for hemoglobin use. How is this done?

A

reduced in the duodenum via duodenal reductase (cytochrome b) using vitamin C (aka ascorbate) and then taken up in small intestine

Thus, you can treat iron deficiency with vitamin C

61
Q

What happens once iron is taken up?

A

it is re-oxidized for transport and then taken up by cells via a transferrin receptor

62
Q

How does iron travel through blood? Freely?

A

No, via tranferrin, which only binds Fe3+, not Fe2+.

NOTE: free iron in blood= more bacterial growth and more superoxide radicals= BAD

63
Q

Where in the body are there massive reservoirs of iron?

A

macrophages in bone marrow, liver, and spleen

64
Q

Is the iron reservoir in macrophages in those tissue free?

A

No, bound to ferritin.

NOTE: Transferrin is also used to transfer this iron is dietary levels drop

65
Q

What transporters are used to shuttle iron through gut enterocytes?

A

DMT-1 (apical) and ferroportin (basement membrane)

66
Q

What are DMT-1 levels regulated by?

A

iron levels- more iron- more transcription

67
Q

What are ferroportin levels regulated by?

A

hepcidin (made in liver)

less iron= upregulation on enterocytes AND in iron reservoir tissues for mobilization

68
Q

Describe ferroportin regulation.

A

Increasing levels of transferrin bound iron increase hepcidin production, which INHIBITS ferroportin expression in macrophages and enterocytes and vice-versa.

Thus, high hepcidin= anemia.

69
Q

What is hemochromatosis?

A

When iron/transferrin levels are low, hepcidin is down-regulated, causing ferroportin to increase iron levels that are wrongly deposited to inappropriate tissues, causing damage.

70
Q

Hereditary hemochromatosis is caused by what?

A

Most caused by mutations of HFE

71
Q

What does globin synthesis require?

A

alpha and beta globin genes, and amino acids

72
Q

Important paradox: Although red cells are anuclear, they requires LOTS of DNA in order to replicate frequently during development

A

Important paradox: Although red cells are anuclear, they requires LOTS of DNA in order to replicate frequently during development

73
Q

Red cell replication requires what?

A

deoxynucelotide triphosphates, which need ribonucleotide reductase, thymidine (which requires folate and B12)

74
Q

How does folate circulate through the body? Significance?

A

as THF. THF can be methylated to form up to 4 different compounds used in different biosynthetic processes (i.e. the N-10-formyl form in purine synthesis and the N5, N10 methylene form in thymidine synthesis).

Thus, folate or B12 deficiency= anemia

75
Q

What else is needed for purine synthesis?

A

PRPP and gln, glu and asp (to accept methyl from N-10-formyl) and NAPDH (for methylation of THF to N-10-formyl THF)

76
Q

What else is needed for pyridime synthesis?

A

N5, N10- methylene THF transfers methyl to dUMP to form dTMP (using thmidylate synthase) resulting in dihydrofolate, which is recycled to THF via dihydrofolate reductase using NADPH, which is then cycled again to N5, N10 methylene THF as serine become glycine via serine hydroxymethyl transferase

77
Q

Why would B12 deficiency lead to anemia?

A

lack of B12 traps folate in the N5-methyl form (that is needed to convert homocysteine to methionine), making it unavailable for nucleotide synthesis

78
Q

Lack of B12 would also cause?

A

demyelination of some areas of the spinal cord, because it needed for production of sphingomyelin, a component of myelin

79
Q

Red cell production is regulated primarily via what?

A

erythrypoietin (Epo).

80
Q

What does Epo require to function?

A

normal kidneys, a normal bone-marrow microenvironment (i.e. no myelofibrosis), functional EPO-R receptor

81
Q

Describe the structure of Epo (on erythroid precursors) and Tpo (on mature or immature megakaryocytes).

A

They are both transmembrane dimers with two copies of a relatively inactive tyrosine kinase (Jak-2), which can then phosphorylate STATs, which dimerize and go to nucleus

82
Q

What is the receptor of Tpo called?

A

Mpl

83
Q

How can iron be measured in a lab?

A

two classes:

1) measurement of iron transport systems and
2) measurement of storage pool iron

84
Q

What are some ways to measure iron transport systems?

A

1) serum iron- measure of transferrin-bound iron
2) total iron binding capacity- total amount of transferrin in circulation
3) transferrin saturation (serum iron divided by transferrin levels)

85
Q

What are some ways to measure storage pool iron?

A

1) serum ferritin- trace amount of ferritin leak from reservoir in relation to total amount of pooled iron (don’t know why)

86
Q

T or F. Serum ferritin is the MOST useful initial measurement you can get of iron metabolism in patients with unexplained anemias.

A

TRUE.

87
Q

T or F. Bone marrow cellularity decreases with age.

A

T. Cells are replaced with fat.

88
Q

To a first approximation, the fraction of normal bone marrow cells taken up by hematopoietic cells is:

A

100-age

CMOD Week 7 (16 decks)

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