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CPR Exam 2 > Erythrocyte Biochemistry > Flashcards

Erythrocyte Biochemistry Flashcards

1
Q

What is the lifespan of RBCs?

A

120 days

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2
Q

When does the majority of Hb synthesis occur?

A

Before extrusion of the nucleus from the normoblast to become a reticulocyte (with a small amount made in the reticulocyte)

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3
Q

What are the subunits of fetal Hb?

A

Alpha2 gamma2

0.5%

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4
Q

What are the subunits of adult HbA?

A

Alpha2 beta2

97%

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5
Q

What are the subunits of adult HbA2?

A

Alpha2 delta2

3%

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6
Q

Describe heme

A

One per subunit (4 total)
Has iron atom (ferrous; Fe2+)
Carries O2
Hydrophobic

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7
Q

What is the conformational change that occurs in Hb upon oxygen binding?

A

Iron lies slightly outside the plane of porphyrin in heme
Upon O2 binding it moves into the plane of the heme
This 0.4A change pulls down the proximal histidine of Hb and changes interaction with associated globin chain

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8
Q

What is positive cooperativity?

A

Binding of one molecule of O2 to one heme facilitates the binding of an O2 to another heme

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9
Q

What is the percentage of O2 delivery in the tissues?

A

66%

98-32

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10
Q

What is the percentage of O2 delivery for myoglobin?

A

7%

98-91

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11
Q

What is the percentage of O2 delivery in a protein with 4 subunits like Hb but no cooperativity?

A

38%

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12
Q

What changes in the ODC are seen with exercise?

A

Drop in PO2 from 40 to 20 torr in exercising tissues corresponds to the steepest part of the ODC
Hb is very effective in providing oxygen to exercising tissues

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13
Q

What modulations occur by 2,3-BPG in the ODC?

A

Reduces O2 affinity so Hb gives up more O2 to tissues

Signal to Hb to let go of oxygen

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14
Q

What is the Bohr effect?

A

Stimulation of O2 release by CO2 and H (produced by actively respiring tissues)
Cause decrease in pH which decreases binding affinity of Hb for O2 and oxygen release is favored
CO2 and H are allosteric effectors of Hb

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15
Q

Describe sickle cell anemia

A

Mutation at aa position 6 in beta globin
Glutamic acid (neg charged) changes to valine (hydrophobic)
Causes polymerization of Hb (HbS)
Sickle shaped RBCs, impede circulation leading to hemolytic anemia
Pain, organ damage, stroke, increased infections, etc

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16
Q

What are some treatments being considered for sickle cell anemia?

A

Research ongoing to induce expression of HbF
Currently using hydroxyurea to induce HbF
Works but causes inflammation and is a toxic chemotherapeutic agent

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17
Q

Describe iron

A

Readily exchanges electrons; ideal catalyst for redox reactions
Exists in Fe2+ (ferrous) or Fe3+ (ferric) state
Plays a role in O2 transport (component of Hb and myoglobin)
Also in ETC (component of cytochromes)
Regulated by modulating its absorption

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18
Q

Describe stored iron distribution

A

27% (stored in cells that line the intestines, liver, spleen and bone marrow)
Ferritin - a protein that binds to ferric iron
Hemosiderin - product of ferritin breakdown

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19
Q

Binding of hepcidin to ferroportin causes what?

A

Internalization of ferroportin and its subsequent degradation in lysosomes (when iron levels are high)

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20
Q

What are the levels of hepcidin controlled by?

A

A complex signaling pathway involving the protein transferrin, its receptor and a protein called human hemostatic iron regulator protein (HFE)

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21
Q

When iron is high..

A

Hepcidin expression is up, ferroportin levels are down and iron absorption is low

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22
Q

When iron levels are low..

A

Hepcidin expression is down, ferroportin levels are up and iron absorption is high

23
Q

If iron absorption levels are too low what disease state will occur?

A

Iron deficiency

24
Q

If iron absorption levels are too high what disease state will occur?

A

Fe overloading

25
Q

What are the different reasons why iron deficiency can occur?

A

Insufficient dietary iron, insufficient absorption, excessive blood loss via menstruation, overuse of aspirin, ulcers of GI tract (blood loss)

26
Q

What can iron deficiency cause?

A

Hypochromic microcytic anemia

27
Q

What is the Tx for iron deficiency?

A

Dietary iron supplementation

28
Q

What is the clinical definition for iron overload (hereditary hemochromatosis or HH)?

A

Increased absorption of iron which then accumulates in the heart, liver and pancreas
Iron overload causes liver cirrhosis, hepatocellular carcinoma, diabetes, arthritis, and heart failure

29
Q

What is the genetic definition for iron overload?

A 
Autosomal recessive (incidence is 1/250)
Mutations in hereditary hemochromatosis gene (HFE)
30
Q

How much iron is present in someone with iron overload?

A

15g (normal is 3-5g)

31
Q

RBC production is dependent on what?

A

Folate (folic acid) and vitamin B12 (cobalamin)

32
Q

What does folate and vitamin B12 deficiency cause?

A

A severe anemia called megaloblastic macrocytic anemia

Occurs due to diminished DNA synthesis in developing RBC in bone marrow

33
Q

Describe megaloblastic macrocytic anemia

A

Caused by deficiency of folate and vitamin B12
Characterized by large erythrocytes (MCV >100 fL; normal is 80-100)
Have normal Hb content in relation to size (MCHC; mean cell Hb content)

34
Q

What are the characteristics of RBCs seen in megaloblastic macrocytic anemia?

A

RBC volume increased
Blood smear shows macrocytic, normochromic cells
Also present are many oval macrocytes

35
Q

Describe the bone marrow during megaloblastic macrocytic anemia

A

Bone marrow shows large erythroblast (megaloblasts)

Also hyper-segmented neutrophils occur (more than 5 lobes; normal is 3-4)

36
Q

Describe the structure of folate

A

Exists in a number of derivative forms collectively known as folate
Has 3 parts (pteridine ring, PABA and glutamate residues)

37
Q

Folate can be reduced to dihydrofolate (DHF) by which enzyme?

A

Dihydrofolate reductase which uses NADPH

38
Q

DHF can be reduced to tetrahydrofolate (THF) by which enzyme?

A

Tetrahydrofolate reductase

39
Q

What is the active form of folate?

A

THF

40
Q

What is THF important for?

A

The synthesis of purines and the pyrimidine thymine

Serves a vital role in DNA synthesis

41
Q

Where is folate found?

A

In most foods including liver, eggs, milk, legumes and yeast
Especially abundant in leafy vegetables and in fruit (particularly citrus)

42
Q

What does a deficiency in folic acid lead to?

A

Decreased DNA synthesis which can lead to megaloblastic macrocytic anemia**

43
Q

Describe folate absorption

A

Absorbed in SI (jejunum)
Liver stores 5-10mg folate which can last 3-6 months
Most dietary sources have folate present in the DHF form
Once absorbed in the intestine folic acid is reduced to N5-methyl-THF which is the primary circulating form of THF in the bloodstream

44
Q

What are some sources of one carbon units for THF?

A

Serine, glycine, choline —> methylene THF
Histidine —> methenyl-THF
Formate —> formyl-THF

45
Q

What structures are made via synthesis using one carbon units from THF?

A

Serine
Methionine
TMP —> DNA
Purines

46
Q

What is methotrexate?

A

An anti-neoplastic agent
Inhibitor of DNA synthesis
Strong inhibitor of dihydrofolate reductase (binds to enzyme 100 fold more tightly than DHF)

47
Q

If vitamin B12 is not available what happens to folate?

A

Folate is stuck as N5-methyl-THF

Called the folate trap

48
Q

Vitamin B12 removes a methyl group from which structure?

A

N5-methyl-THF to make methyl-cobalamin (B12-CH3) and release THF (FH4)
Then cobalamin transfers methyl group of homocysteine to create methionine which makes S-adenosyl methionine

49
Q

Where is B12 found?

A

In animal products (not in plant products)

50
Q

Vitamin B12 deficiency can also cause which disease?

A

Megaloblastic macrocytic anemia* because of its impact on DNA synthesis

51
Q

85% of B12 deficiency is from the lack of a protein called?

A

Intrinsic factor

52
Q

Describe B12 absorption

A

Dietary B12 binds to R binder proteins
Proteases from the pancreas degrade R proteins in the duodenum releasing B12
Intrinsic factor carries B12 to ileum from where it is released into the blood stream
Intrinsic factor-cobalamin complex carried by transcobalamin II in blood
Intrinsic factor-cobalamin is taken up by cells via receptor mediated endocytosis

53
Q

What is pernicious anemia?

A

Vitamin B12 deficiency due to lack of intrinsic factor
A type of megaloblastic macrocytic anemia
Results from failure to absorb vitamin B12 resulting form unavailability of IF

54
Q

How can pernicious anemia be diagnosed?

A

Test serum B12 and folate (folate deficiency vs B12 deficiency)
-serum folate <3ng/mL
-serum B12 <350pg/mL
In B12 deficiency it is important how the deficiency occurred (B12 diet or absorption?)
Gold standard was Schilling test

CPR Exam 2 (18 decks)

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