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Hematology and Oncology > EXAM #1: HEMOGLOBIN > Flashcards

EXAM #1: HEMOGLOBIN Flashcards

1
Q

What is the most abundant form of Hb in adult? What subunits does it have?

A

HbA

  • Tetramer
  • 2x alpha globins
  • 2x beta globins
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2
Q

How many oxygen binding sites does Hb have?

A

4, one per subunit

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3
Q

What happens to oxygen binding as oxygen levels increase?

A

Hb binds O2 more efficiency at higher O2 concentrations b/c of cooperative binding

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4
Q

How does myoglobin’s affinity for oxygen differ from Hb?

A

Myoglobin binds O2 with HIGH affinity at LOW oxygen concentrations

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5
Q

What is the effect of lower pH/ higher CO2/ lower O2 on oxygen binding?

A

Favors oxygen dissociation

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6
Q

What is the effect of higher pH/ lower CO2/ higher O2 on oxygen binding?

A

Favors oxygen binding

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7
Q

What is the effect of 2,3-BPG on oxygen binding?

A

Favors dissociation

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8
Q

What is Hb A2?

A

Hb with:

  • 2 alpha globins
  • 2 delta globins
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9
Q

What are the three Hb sub-types present in the early embryo? What are the subunits?

A

Hb Gower 1= 2-zeta and 2 epsilon
Hb Gower 2= 2 alpha and 2 epsilon
Hb Portland= 2 zeta and 2 gamma

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10
Q

What sub-type of Hb predominates as the embryo begins to age? What are the subunits?

A

Hb F= 2 alpha and 2 gamma

This is the major Hb of the fetus

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11
Q

When does an infant have a switch from predominantly Hb F to Hb A?

A

By 1 year old, the 98% of Hb is Hb A (vs. F in utero)

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12
Q

How does the oxygen affinity of Hb Gower 1,2, Portland, and F compare to Hb A?

A

V. high relative oxygen affinity

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13
Q

What is the purpose of increased oxygen affinity of the fetal and embryonic Hbs?

A

To “capture” oxygen diffusing from maternal circulation

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14
Q

What is the molecular basis of the higher affinity of Hb F for oxygen than Hb A?

A
  • Histidine in B-chain
  • Replaced with serine in gamma-chain

2,3-BPG binds to the Histidine in Hb A (Beta globin). Serine removes the positive charge that 2,3-BPG binds to, increasing the affinity of Hb F for oxygen.

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15
Q

What are the alpha-like globins? What chromosome are they encoded on?

A

Chromosome 16

  • alpha
  • zeta

Note that the pseudo genes are also encoded on chromosome 16–these cannot produce a functional protein product.

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16
Q

What are the beta-like globins? What chromosome are they encoded on?

A

Chromosome 11

  • Beta
  • Gamma
  • Delta
  • Epsilon
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17
Q

What is the control region located upstream to the alpha-like globins?

A

HS-40

Confers high level tissue specific expression of alpha-like globins

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18
Q

What is the control region located upstream of the beta-like globins?

A

LCR

Confers high level tissue specific expression of beta-like globins

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19
Q

What are hemoglobinopathies?

A

Disorders of hemoglobin

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20
Q

What are the two categories of hemoglobinopathies?

A

1) Structural variants–>Heinz bodies

2) Thalassemias

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21
Q

What is the definition of Thalassemia?

A

Imbalanced synthesis of alpha and beta globins i.e. reduced synthesis of one or more of the globin chains

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22
Q

What is a Heinz body?

A
  • Unstable Hb forms unstable complexes and is oxidized to methemoglobin
  • Methemoglobin form hemichrome
  • Hemichrome aggregates form Heinz bodies
23
Q

What are the three major Hb structural variants?

A

1) Hb S
2) Hb C
3) Hb E

24
Q

What is Hb S?

A

This is the Hb variant found in Sickle cell disease

25
Q

How does Hb S differ from Hb A?

A

Glutamate at position 6 in the Beta-globin gene is replaced with VALINE
- Valine is v. hydrophobic and polymerizes when deoxygenated

26
Q

What is the difference between Sickle Cell Trait and Sickle Cell Disease?

A

Trait= heterozygous mutation

Disease= homozygous mutation

27
Q

Explain how the valine substitution at position 6 contributes to the pathology of Sickle Cell Disease.

A
  • Valine is EXPOSED in deoxygenated Hb S
  • Exposed valine forms a hydrophobic patch
  • Hb S has a tendency to accumulate and stack

Stacked Hb forms the “Sickle” distortion of RBCs

28
Q

What are the negative consequences of having Sickle-shaped RBCs?

A
  • Clog the microcirculation
  • Reduced lifespan

Leads to hemolytic anemia

29
Q

What is the agent of choice for the management of sickle cell disease?

A

Hydroxyurea

30
Q

How does hydroxyura treat Sickle Cell Disease?

A
  • Antineoplastic agent
  • Increases Hb F
  • Hb F promotes solubility of Hb and suppresses the sickling of cells
31
Q

What is Hb C?

A

This is a Hb variant with the glutamate at position 6 substituted with LyCine and forms Crystals

32
Q

What is the pathology associated with Hb C?

A
  • Hb C has reduced solubility and Crystallizes in RBCs

- Makes RBCs INFLEXIBLE, which leads to extravascular hemolysis/ anemia

33
Q

What is Hb SC?

A

Disease caused by compound heterozygote of Hb S and Hb C; the disease course is milder than Hb S

34
Q

What is Hb E?

A
  • Hb variant with the glutamate at position 26 replaced by lysine
  • This mutant B-chain is NOT synthesized as efficiently as Hb A

–>Imbalanced chain synthesis; found in SE asia

35
Q

What is the clinical presentation of Hb E?

A

Mild thalassemia i.e. imbalance in the synthesis of alpha and beta globin chains causing:

  • Microcytosis
  • Hypochromia
  • MILD anemia
36
Q

What types of mutations lead to Thalassemias?

A

1) Deletion

2) Point mutation

37
Q

Generally, what is an alpha or beta thalassemia?

A

Disorder where either an alpha or beta globin chain is not being produced

38
Q

Generally, what is an alpha+ or beta+ thalassemia? What about alpha or beta0?

A
  • Disorder where an alpha or beta chain is being produced in REDUCED QUANTITIES
  • vs. no quantities
39
Q

Why are alpha-thalassemias manifest in both fetal and adult life?

A

Hb requiring alpha-globins are found throughout life:

  • Embryonic= Gower 2 (a2e2)
  • Fetal= (a2g2)
  • Adult= HbA and HbA2
40
Q

Describe the phenotype of a patient with one defective alpha gene and three functional alpha genes.

A

No clinical signs

41
Q

Describe the phenotype of a patient with two defective alpha genes and two functional alpha genes.

A

Mild anemia

42
Q

Describe the phenotype of a patient with three defective alpha genes and one functional alpha gene.

A

Severe deficiency that leads to formation of:

1) Gamma tetramers i.e. Hb-Barts in the fetus
2) Beta tetramers i.e. Hb H in the adult

Both are POOR oxygen carriers**

43
Q

Describe the phenotype of a patient with four defective alpha genes and one functional alpha gene.

A

This is LETHAL and results in Hb Barts hydrops fetalis syndrome

44
Q

How is Hb-constant spring formed?

A

This is a POINT MUTATION that leads to alpha-thalassemia

  • stop codon converted to codon for glutamine
  • read-through occurs and increases alpha-globin chain length

Specifically, T is replaced by a C

45
Q

What would you expect to see in patients expressing Hb-constant spring?

A

mRNA is very UNSTABLE; thus, only 1-2% of the Hb is Hb-constant spring; thus, this behaves like alpha+

46
Q

What is Hb-lepore?

A

Hb with part beta and part delta globin in one globin chain

47
Q

How is Hb-lepore formed?

A
  • Recombination events delete part of Beta and Delta globin

- A fusion protein is produced that has both parts

48
Q

Describe the case where a point mutations gives rise to a Beta+ thalassemia.

A
  • Point mutations ( A sub for T) generates an inappropriate splice site that is SOMETIMES recognized
  • Result is reduced message and too little Beta-globin
49
Q

What are the advantages to the use of electrophoresis in the analysis of Hb variants?

A

Useful for neonatal screening

  • Cheap
  • Easy
50
Q

What are the disadvantages to the use of electrophoresis in the analysis of Hb variants?

A
  • Insensitive

- Difficult to use in premature infants

51
Q

How is restriction fragment length polymorphism used to identify individuals who carry particular Hb mutations?

A

1) Take blood sample
2) Expose to PCR primers
3) Amplify B-globin gene
4) Expose to MstII restriction enzyme

  • Normal= 550 bp
  • Mutant HbS= 700 bp
52
Q

What is the structural cause for the positive cooperatively seen with oxygen binding?

A
  • O2 binds alpha subunits first
  • Binding of O2 to the second alpha globin causes a conformational change that rotates valine from the oxygen binding site on beta-globin
53
Q

What are the structural variants of Hb that alter oxygen affinity? What is the mutation and effect?

A

Hb-Helsinki=

  • B-subunit mutation of Lysine for Methionine at 2,3 BPG binding site
  • INCREASED oxygen affinity

Hb-Kansas

  • B-subunit mutation of asparagine for thereonine at a1B1 contact site
  • DECREASED oxygen affinity
54
Q

What are the structural variants of Hb that readily form Methemoglobin?

A

Hb M-Boston
- Alpha mutation (Distal histidine for tyrosine)

Hb M-Hyde Park
- B mutation (Proximal histidine for tyrosine)

Hematology and Oncology (38 decks)

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