hematology exam 1 - globin chain synthesis, ODC, RBC metabolism

globin chain synthesis phases

1. embryonic

2. fetal

3. birth

4. 1 year old

5. adult

embyronic phase of globin chain synthesis

globin gene activation progresses from ζ to α gene and from the ε gene to the γ, δ, and β genes

ζ and ε chains are only present in the embryonic stage of development and are produced for 3 months after conception

type of Hb:

• Gower 1 + 2, Portland

  • Gower 1: ζ₂, ε₂ subunits

  • Gower 2: α₂ subunits, ε₂ subunits

  • Portland: ζ₂ subunits, γ₂ subunits

  • DO NOT TRANSPORT OXYGEN

fetal phase of globin chain subunits

type of Hb:

• fetal Hb (Hgb F or Hgb Portland) → α₂, γ₂

  • γ chain production occurs actively from the 3rd month of development to one year after birth

  • 90-95% of total Hb levels before birth

  • Hgb F makes up 60% of Hb in newborns

  • Hgb F can carry oxygen, and levels decrease after 1-yr post birth

  • Hgb F is the main type of Hb produced by the liver and spleen

birth

type of Hb present

• Hgb F (α₂, γ₂) → around 50-85% of total Hb

• Hgb A (adult Hb) → α₂, β₂ → around 10-40% of total Hb

• HbA2 → α₂, δ₂ → <1% of total hb

α is always present

γ chain production occurs actively from the 3rd month of development to one year after birth

1 year old globin chain synthesis phase

type of Hb present:

• HbF → α₂, γ₂ = <2%

• HbA → α₂, β₂ = >95%

• HbA2 → α₂, δ₂ = 3.5%

adult globin chain synthesis phase

α is always present and the constant component in adult Hb

3-6 months after birth, γ chain production declines and β chain production increases to make Hgb A or adult HgB

Hgb A → 80-85% of Hb one year after birth

the majority of adult hemoglobin is HbA (α₂β₂), representing 95-98% of all adult Hb

Hgb A₂ (HbA2, α₂δ₂) is 3-5% of adult Hb, produced around 3-5 wks of pregnancy

Hgb F represents <2% of adult Hb

globin chain synthesis graph

hemoglobin-oxygen dissociation curve

measurement of Hb’s affinity for oxygen

• oxygen affinity is expressed as p50, where 50% of Hb is saturated with oxygen

• in an avg human, p50 = 26 mmHg

measure the Hb-O2 saturation vs the partial pressure of oxygen = oxygen dissociation curve (ODC)

beginning of the curve

• fully staurated Hb molecule containing full oxygen with a high oxygen lvl tension

• as it travels, it releases oxygen to the surrounding tissues that need oxygen

partial pressure of oxygen O2

factors that can affect oxygen affinity

increases → oxygen affinity increases

pH

factors that can affect oxygen affinity

• decrease (increase in H+) = Bohr effect, conformational change in the amino acids of Hb causing it to enter the T state (tensed) where oxygen binds less easily

• increase (decrease in H+) = oxygen affinity increases

partial pressure of carbon dioxide (PCO2)

factors that can affect oxygen affinity

• increase = oxygen affinity decreases for the same reason as pH, tissues are more acidic

2,3-BPG

factors that can affect oxygen affinity

molecule in RBCs that binds to Hb

• decreases oxygen affinity

• increased concentration of BPG in situations where oxygen is less available, such as high altitude and chronic lung diseases (cuz im assuming that it wants to deliver the oxygen to tissues and doesn’t want to keep it with RBC)

temperature

factor that can affect oxygen affinity

• increase = oxygen affinity reduces

  • Hb tends to release oxygen more efficiently in warmer temps

ODC right and left shifts

right shift

• Hb has less affinity for oxygen and releases the oxygen more compared to normal curve

  • cells are 50% saturated at 40 mmHG

  • can be caused by

    • anemia

    • rise in body temp

    • increase in 2,3-DPG

    • acidosis

left shift

• Hb has a higher affinity for oxygen and doesn’t like to release oxygen to the tissues

  • cells are 75% saturated at 40 mmHg and will release about 12% of oxygen to the tissues

  • caused by

    • decrease in body temp

    • lower lvls of 2,3-DPG

    • alkalosis

    • higher lvls of methemoglobin and carboxyhemoglobin (by forcing hemoglobin into its relaxed R state)

    • blood transfusions (decrease 2,3-DPG)

    • higher hemoglobin F levels

carboxyhemoglobin

abnormal hemoglobin

iron is in the 2+ state

no oxygen will be delivered to the tissues because Hb has a higher affinity for carbon monoxide compared to oxygen (200x stronger binding)

methemoglobin

abnormal Hb

iron state is Fe3+ and has been oxidized

iron in this state can no longer bind to oxygen

sulfhemoglobin

abnormal Hb

iron is in the 2+ state

iron is not able to carry oxygen and can’t be reversed unless the RBCs are taken out of circulation

100x higher affinity for oxygen and competes with hemoglobin for oxygen

glycolytic pathway

90-95% of cell’s glucose consumption is metabolized by this pathway

glucose metabolized by this pathway to lactate or pyruvate = net gain of 2 moles of ATP per mole of glucose

• if NADH is available in the cell, pyruvate is reduced to lactate

• lactate or pyruvate formed is transported from cell to plasma and metabolized elsewhere in body

ATP necessary to maintain erythrocyte shape, flexibility, and membrane integrity and to regulate intracellular cation concentration

glycolysis generates NADPH, reduces glutathione and protects cell from oxidative injury

• keep iron in Hb in the oxidated state (Fe 2+) and prevent hemoglobin iron from reducing (Fe3+) because in reduced state, iron CANNOT carry oxygen

what happensif no glucose for RBC

ATP for cation pumps is no longer available

cells can’t maintain normal intracellular cation concentration

cells become sodium and calcium loaded and potassium depleted

• even though Na+ should be higher outside, K+ should be higher inside

cell accumulates water and changes from bioconcave disc to a sphere and is removed from circulation

Rapoport-Luebering pathway

controls the amount of 2,3-BPG produced

• affects the oxygen affinity of Hb

• key enzyme: BPG-synthase

part of the glycolytic pathway, bypasses the formation of 3-phosphoglycerate and ATP from 1,3-biphosphoglycerate (1,3-BPG)

instead, 1,3-BPG forms 2,3 BPG

erythrocyte sacrifices one of its two ATP producing steps in order to form 2,3-BPG

methemoglobin reductase pathway

EMP shunt

essential to maintain heme iron in the reduced state (ferrous) Fe++

1. methemoglobin (Hb with iron in oxidized ferric state, Fe3+) is generated simultaneously with the oxidative compounds discussed as O2 dissociates from heme iron

   1. cannot bind oxygen

2. methemoglobin reductase w/ NADH produced by glycolytic pathway fxns to reduce the ferric iron in methemoglobin, converting it back to ferrous hemoglobin

3. W/O this sys: 2% of methemoglobin formed daily eventually builds up to 20-40%

   1. certain oxidant drugs can interfere w/ this process and cause even higher levels of methemoglobin = cyanosis

hexose-monophosphate shunt

provides NADPH and glutathione to reduce oxidants that would shift the balance of oxyhemoglobin to methemoglobin

glutathione reductase, G6PD