Normal/abnormal hemoglobin structure

Question 1

Oxygen binding properties of hemoglobin

Answer 1

• Heme groups do NOT bind O2 with equal affinity
• Hb does not bind O2 efficiently at LOW O2 conc
  
  • as O2 levels increase, Hb becomes more efficient at binding O2
• IN CONTRAST, myoglobin binds O2 with HIGH affinity at low O2 conc and exhibits hyperbolic O2 binding curve

Question 2

describe the significant of Hb F

Answer 2

• Embryo lacks functional circulatory system in early development
  
  • Hb grower 1, grower 2 and portland must capture O2 from mother and have a VERY HIGH oxygen affinity
• Hb F has higher oxygen affnity than Hb A
  
  • allows OXYGEN FLOW FROM MOTHER TO FETUS
    
    • a histidine residue in the Beta-chain required for 2,3 BPG binding is replaced with serine in the gama-chain

Question 3

Hb S

Answer 3

• Structural variant found in SICKLE CELL DISEASE
  
  • GLUTAMATE replaced with VALINE at position six of the beta-globin chain
  • DEOXYGENATED HBS POLYMERIZES
    
    • leads to distorted shape of red blood cells
      
      • misshapen cells blocks microcircualtion
      • cells lyse readily –> chronic hemolytic anemia
• Heterozygotes have sickle cell trait
• homozygotes have sickle cell disease

Question 4

describe the tx of sickle cell disease

Answer 4

HYDROXYUREA (HU)

• Antineoplastic agent
• INCREASED EXPRESSION OF Hb F –> promotes hemoglobin solubility
• Reduces
  
  • sickling, painful crises, hospitalization

Question 5

Hb C

Answer 5

Hb C disease

• Glutamate replaced with LYSINE at position six of Beta-globin chain
• Hb C does NOT POLYMERIZE and cells DO NOT sickle
• Hb C LESS SOLUBLE than HbA and PRECIPITATES
  
  • less flexible red cells have reduce lifespan –> hemolytic anemia

Question 6

Hb E

Answer 6

• Glutamate at position twenty sixe of Beta-globin chain is replaced with Lysine
  
  • mutant Beta-globin chains is NOT SYNTHESIZED EFFECTIVELY
    
    • imbalanced alpha and beta-globin chain synthesis –> mild thalassemia develops
• heterozygotes are asymptomatic
• homoxygotes show microcytosis, hypochromia and typically mild anemia

Question 7

Thalassemias

Answer 7

• REDUCED SYNTHESIS OF EITHER TYPE OF CHAIN REDUCES AMOUNT OF FUNCTIONAL TETRAMER FORMED
  
  • results in anemia
• Most common
  
  • α-thalassemias and β-thalassemias
  • α+-thalassemias and β+-thalassemias

Question 8

Alpha thalassemias

Answer 8

• Two genes for alpha-globin on chromosome 16
• alpha globin chains found in embryonic, fetal and adult hemoglobins
  
  • alpha-thalassemias manifest during devleopment and in adult life

carrier STATES

• 3 functional alpha globin genes/1 defective gene –> no clinical signs
• 2 functional/1 defective –> mild thalassemic anemia
• 1 functional/3 defective –> severe alpha-globin chain deficiency
  
  • Hb H = form later in development, poor oxygen carriers (short life span)
  • Bart’s hemoglobin = form in fetus, Poor oxygen carriers
• 4 defective alpha-globin genes
  
  • alpha-thalassemia
  • only EMByONIC HEMOGLBINS
  • lethal condition = hemoglobin bart’s hydrops fetalis syndrome

Question 9

review thalassemias…