HEMOGLOBINOPATHIES

• are disorders affecting the structure, function, or production of hemoglobin.

  Hemoglobinopathies
• Normal hemoglobins are tetramers of two α-like

  and two β-like

  globin polypeptide chains
• α-like: _ amino acids

  141
• β-like: _amino acids

  146
• After 8 weeks of fetal life the embryonic

  hemoglobins, (ζ2ε2), (α2ε2),

  and(ζ2γ2), are formed.

  Gower-1, Gower-2, Portland
• At 9 weeks of fetal life, the major hemoglobin is

  _(α2γ2)

  Hb F
• appears at ~1 mo of fetal life but does

  not become the dominant hemoglobin until after birth,

  when Hb F levels start to decline.

  HbA
• Major adult Hb:(≥_%)

  HbA

  95
• Minor adult Hb: HbA2 (α2δ2)

  (≤ 3.5%)
• predominates during most of the

  gestation.

  HbF
• HbF constitutes a small fraction of

  the total Hb in adult red cells (0.3-1.2%) in

  which it is largely restricted to a small subset of

  circulating RBCs (0.2-7%) referred to as F cells.
• highly soluble

  hemoglobin tetramer
• individual globin chains

  insoluble
• Unpaired globin precipitates, forming _that

  damage the cell.

  inclusions
• (dysfunctional hemoglobins that are

  unable to transport oxygen)

  Dyshemoglobins
• form and may accumulate to toxic

  levels, after exposure to certain drugs or

  environmental chemicals or gasses.

  Dyshemoglobins
• The offending agent modifies the structure of the

  hemoglobin molecule, preventing it from binding

  oxygen.

  DYSHEMOGLOBINS
• formed by the reversible oxidation of heme iron to the ferric state (Fe3+)

  Methemoglobin (MetHb)
• Normally, a small amount of methemoglobin is

  continuously formed by oxidation of iron during the normal

  oxygenation and deoxygenation of hemoglobin.
• methemoglobin reduction systems, predominantly the

  NADH-methemoglobin reductase pathway, normally limit

  its accumulation to only 1% of total hemoglobin
• cannot carry oxygen because the oxidized ferric

  iron cannot bind it.

  Methemoglobin
• An increase in the methemoglobin level

  results in decreased delivery of oxygen to the tissues.
• Individuals with methemoglobin levels less than 25% are

  generally asymptomatic.
• the methemoglobin level increases to more than 30% of

  total hemoglobin, cyanosis (bluish discoloration of skin and

  mucous membranes) and symptoms of hypoxia (dyspnea,

  headache, vertigo, change in mental status) occur.
• Levels of methemoglobin greater than 50% can lead to coma and death.
• An increase in methemoglobin, _ can

  be acquired or hereditary.

  methemoglobinemia
• An increase in methemoglobin, called methemoglobinemia, can be acquired or hereditary.

  The acquired form, also called toxic methemoglobinemia,

  occurs in normal individuals after exposure to an exogenous

  oxidant, such as nitrites, primaquine, dapsone, or benzocaine.
• As the oxidant overwhelms the hemoglobin reduction systems, the level of methemoglobin increases, and the patient may exhibit cyanosis and symptoms of hypoxia.
• is formed by the irreversible oxidation of hemoglobin

  by drugs (such as sulfonilamides, phenacetin, nitrites, and

  phenylhydrazine) or exposure to sulfur chemicals in industrial or environmental settings.

  Sulfhemoglobin
• SULFHEMOGLOBIN is formed by the addition of a sulfur atom to the pyrrole ring of heme and has a greenish pigment.
• Sulfhemoglobin is ineffective for oxygen transport, and patients with elevated levels present with cyanosis
• Sulfhemoglobin cannot be converted to normal Hb A; it persists for the life of the cell.
• results from the combination of carbon monoxide (CO) with heme iron.

  Carboxyhemoglobin (COHb)
• The affinity of carbon monoxide for hemoglobin is 240 times that of oxygen.
• Carbon monoxide has been termed the silent killer because it is an odorless and colorless gas, and victims may quickly become hypoxic.
• Once one molecule of carbon monoxide binds to hemoglobin, it shifts the hemoglobin-oxygen dissociation curve to the left, further increasing its affinity and severely impairing release of oxygen to the tissues
• Hemoglobins with altered amino acid sequences that result

  in deranged function or altered physical or chemical

  properties

  Structural hemoglobinopathies
• HbS, hemoglobin sickling

  Abnormal hemoglobin polymerization
• High affinity


  polycythemia
• Low affinity

  cyanosis, pseudo-anemia