Abnormal hemoglobin

Question 1

What is the defect in sickle cell hemoglobin?

Answer 1

6th position in beta chain, GLU–>VAL point mutation

Question 2

How does sickling occur in sickle cell disease?

Answer 2

Val in Hbs assoc in HBS aggreation. In the deoxy form, erythrocytes assume abnormal shapes, there is lysis of sickle cels.
consequence: anemia–>acidosis from stasis–>lower pH shift curve to right–>more O2 release and more sickling occurs

Question 3

How do sickle cells cause faso-occlusion and painful crisis?

Answer 3

repeated sickling causes stiffness, stuck in microvasculature, RBCs behind non flexible RBC give up O2 and sickle, blockade is formed as more RBCs with Hbs give up O2 and sickle.

Question 4

describe hemoglobin C

Answer 4

• HbC inherited as autosomal recessive and causes a mild hemolytic anemia; it is a benign hemoglobinopathy; it may not be diagnosed until adulthood.
• Involves a change of Glu6 -> Lys6 in the b-chain.
• HbC is less soluble than HbA; HbC can precipitate in red cells to form crystals. RBC with HbC are less deformable and have shorter survival.
• Presence of HbC is associated with resistance to malaria in parts of Africa.
• Homozygotes may have some abdominal and joint pain, an enlarged spleen, and mild jaundice; they -do not have severe crises as in sickle cell disease.
• In the US: HbC trait affects 1 to 3% of African Americans. Also reported in people of Hispanic and Sicilian ancestry.

Question 5

describe hemoglobin E

Answer 5

• The most common Hb variant in the world - prevalent among SE Asians, but not in Han Chinese or Japanese
• Involves a change of b-chain Glu26  Lys26, low levels of HbE
• Heterozygous state is asymptomatic–causes microcytosis (small RBC, low MCV) without anemia
• Homozygous state–more severe microcytosis and hypochromia (pale color), but little anemia. HbE should be considered when working up an unexplained microcytosis in the affected ethnic groups
• Synthesized inefficiently compared with HbA and is associated clinically with a mild form of b-thalassemia

Question 6

What are Heinz bodies?

Answer 6

• denatured hemoglobin precipitates in RBCs

- bite like deformities bc heinz bodies torn out of RBCs during passage in spleen and some membrane taken out

Question 7

What are example of unstable hemoglobins?

Answer 7

Hb Koln:The more bulky side chain of Met (replacing Val) distorts FG segment in Hb, breaking several heme contacts with amino acids
Hb Hammersmith: big Phe replaced by small Ser, the side chain of Ser is too short to reach the heme group (phe to see mutation).Breaks apart heme pocket, lets in water which oxidizes the central Fe atom

-Associated with Heinz bodies

Question 8

What is methemoglobinemia?

Answer 8

-If MetHb is greater than 1% of Hb.
-causes: acquired or toxic by drugs
hereditary via NADH cytochrome b5 reductase deficiency or Hb M-abnormal glbin with His–>Tyr mutation (stabilizes Fe3+ form instead of Fe2+) –>cyanosis

Question 9

Increased O2 affinity in Hb can be caused by mutations that:

Answer 9

-That involves amino acids that are contact points between a1- and b2-chains
-That involve salt bridges that are formed at the COOH-terminal region
-That involve the amino acids that form the binding pocket for 2,3-DPG
results: increase EPO, impaired O2 delivery but benign clinical course, treatment not indicated
Eg. Hb Hiroshima and Ranier

Question 10

Describe decreased O2 affinity Hg.

Answer 10

• change in residue involving alpha1beta2 contacts that destabilize the oxy form
• Hb reluctant to pick up O2 from the lung with high P50
• no need to intervene medically, O2 delivery to tissue is adequate
• may result in anemia and/or cyanosis if very low affinity
  e. g. Hb Kansas

Question 11

What is Hemoglobin C Harlem?

Answer 11

-has double amino acid substitution that confers malarial resistance

Question 12

What are defective hemoglobins that contribute to thalassemia?

Answer 12

Hb Gun Hill: deletion mutation in beta chain–>beta thal
Hb Wayne: frameshift in alpha chain–>alpha thal
Hb Grady: insertion mutation in alpha–>alpha thal
Hb Constant Spring: stop codon mutation in alpha chain–>alpha thal
Hb Lepore: translocation error, delta beta fusion error–>beta thal