Heme #14: Disorders Of Hemoglobin

Front 1

What is the structure of Hemoglobin?

How many oxygen's are carried in 1 Hb molecule?

Back 1

Made up of 1 a-like globins, and 2 b-like globins. Each globin has a heme ring which carries an Iron.

Each Hb molecule = 4 oxygens

Front 2

What are the two types of alpha genes? What is"zeta" globin? What chromosome is it located on?

What are the five beta-like genes? What chromosome is it located on?

Back 2

α-1, α-2, and zeta (which is alpha chain transiently expressed early in embryogenesis). Chromosome 16.

Epsilon, Gamma, Alpha, Delta, and Beta. Chromosome 11.

Front 3

What combination of globins makes up Hb Gower 1, Hb Gower 2, and Hb Portland?

Where in development are these Hb's found?

Back 3

Embryonic Hb-

Gower 1 = Zeta + Epsilon
Gower 2 = Alpha + Epsilon
Portland = Zeta + Gamma (present at embryo transition to fetus)

Front 4

During fetal life, what is the Hb made up of?

What is the Infant (adult) Hb comprised of (note: there are 2)?

Back 4

Hb F = Alpha + Gamma

Hb A= Alpha + Beta
Hb A2= Alpha + Delta

Front 5

What 2 types of Hb's form when there is no alpha-globin around? (note: both are pathologic)

Back 5

Hb H = B4 (just beta's)

Hb Barts = G4 (just gamma's)

Front 6

A genetic defect in the production of hemoglobin is termed ______.

A genetic defect in the function of hemoglobin is termed _______.

Back 6

Thalassemia = defective globin

Hemoglobinopathy= defective function of Hb

Front 7

What is the "heterozygote advantage"?

Back 7

Sickle cell and thalassemias are most common in areas where Malaria is also present because it is thought to have a protective function.

Merozoites infect RBCs and need 7-10 days to replicate. In people with sickle cell/thalassemia, there is shorter RBC lifespan. So parasite can't go through reproduction (b/c RBC is destroyed).

Front 8

What is the pathogenesis of α-Thalassemia? Include in your discussion "ineffectual erythropoiesis".

Back 8

Genetic defect where decreased/abnormal α chains produced.

Excess gamma and beta chains dimerize. They precipitate in the RBC and damage membrane --> hemolysis. The bone marrow tries to compensate by producing RBCs but they die early ("ineffectual erythropoiesis")

Front 9

How is α-thalassemia classified?

Back 9

Based on the NUMBER OF MISSING/INACTIVE alpha-genes (normally four copies of the gene).

--/-- = Hb Barts - hydrops fetalis (death in utero). Gamma 4
a-/--= Hb H- Beta 4- very sick requires transfusion therapy
aa/-- = mild microcytosis and anemia (no therapy needed)
aa/a- = Mild microcytosis but no anemia

Front 10

What population do we tend to see alpha thalassemia's in?

What is "alpha thalassemia trait"?

Back 10

Prevalent in Asian and African populations.

Alpha thalassemia trait = loss of one or two alpha genes (not associated with anemia, but MCV and MCH are low).

Front 11

What is the RBC count like in alpha thalassemia? Why?

Back 11

RBC count is extrememly high (>5.5 x 10^6). This is because Hb is deffective, so body compensates by making more RBC (the problem is not in RBC production but rather in Hb production).

Front 12

What is Hb constant spring (describe pathogenesis)?

What phenotype do children have? Where is it found?

Back 12

It is an α-Thalassemia variant. Mutation in termination codon which causes ribosomes to be unstable. Allows ribonuclease to chew up mRNA (making half life shorter) - resulting in decreased ability for alpha chains to tetremerize.

Asian kids, have thalassemic phenotype.

Front 13

In β-thalassemia, what types of Hb's would you expect to be elevated?

What is the problem with α-4 globins?

Back 13

β-thal --> no β so alpha chains tetramerize or combine with gamma and delta --> increased Hb F and Hb A2

α-4 binds oxygen with high affinity (but doesn't let it go). It precipitates in cell --> damage --> hemolysis --> ineffectual erythropoiesis

Front 14

β-Thalassemic phenotype includes Sekeletal deformities, wasting, gout, and increased metabolic rate.

It also includes endocrine deficiencies, cirrhosis, and cardiac failure. Explain how all these occur?

Back 14

Excess HbF --> reduced O2 delivery (because of high affinity) --> increased marrow expansion -->

1. skull deformity- thinning of long bones and increased medullary hematopoiesis
2. increased metabolic rate - RBCs are turning over so much that patient has wasting appearance
3. Gout- increased cell turnover


Children who develop anemia undergo transfusion or have increased Fe absorption by active bone marrow --> Iron loading. Deposits in pituitary gland, liver, and stiffens myocardium leading to abnormalities.

Front 15

How are β-thalassemias classified?

Back 15

Based on CLINCAL SEVERITY (not # of deleted genes)

1. Thalassemia trait - no anemia (1 normal)
2. Thalassemia minor - mild microcytic anemia (2 slightly functional genes)

3. Thalassemia intermedia - moderate microcytic, mostly compensated
4. Thalassemia major - severe anemia, needs transfusion (no functional gene product)

Front 16

Looking at this smear, what thalassemia do you suspect this individual has?

Back 16

Thalassemia minor (cells are mildly microcytic and there is some loss of pallor). There is at least one functional Beta gene or two partially functioning genes.

Front 17

Looking at this smear, what thalassemia do you suspect this individual has?

Back 17

Thalassemia trait (cells mildly microcytic, not too much difference from normal smear). This person probably doesn't have anemia.

Front 18

Looking at this smear, what thalassemia do you suspect this individual has?

Back 18

Thalassemia major (the cells are microcytic, flimsy, flat, and shredded. there is a nucleated RBC - indicating that the bone marrow is working extra hard to pump out RBCs).

This person probably has severe anemia requiring transfusion and probably 2 non-functional beta genes.

Front 19

Clinical presentation of β-thalassemia

Back 19

Most present within first year of life (or by 6 months, when they will switch to Adult Hb and don't have protective Hb F).

Growth retardation, pallor
Icterus (jaundice), grey-brown pigment (from bilirubin deposits in skin)
Muscle wasting
Hepatosplenomegally
Skull changing (frontal bossing, overbite)- due to increased medullary hematopoiesis

Front 20

Why does deletion of all alpha chain genes cause death in the fetus, but deletion of all the β-genes do not appear clinically untill >4 months of life?

Back 20

Fetuses have gamma chains to mop up extra alpha chains and maintain balance (i.e. HbF). With loss of alpha chains- you only have beta and gamma left so they make tetramers- non viable.

Front 21

What is standard of care for diagnosing Thalassemias?

Back 21

Standard of care = Hb electrophoresis.

You can also do DNA probing for specific mutations, send CBC, and iron studies.

Front 22

How does RDW help distinguish Iron-deficiency anemia from a thalassemia?

How does Red cell count help distinguish the two? What about the Mentzer Index?

Back 22

Both are microcytic hypochromic anemias. But fe-deficiency produces wide range of cell sizes (anisocytosis) since body will use up any available Fe to make a reticulocyte.
In Thalassemia- genetic defect affects all cells, so they will all be small.

Red cell count in thal is increased. Decreased in Fe deficiency (because doesn't have tools to make RBC).

Mentzer Index is MCV/red cell count. In Thal, this is decreased <12 since Red cell count is high. In Fe deficiency it is increased >13.

Front 23

What therapy is available for Thal trait? What about Thal major?

Back 23

Thal trait- no therapy needed (they are not anemic but might just have some slight changes in rbc MCV)

Thal major- regular blood transufsions with iron chelators (to avoid overload). Genetic counseling, splenectomy, bone marrow transplant.

Front 24

Will a patient who has a two α chain deletion and has β0 thal have MORE or LESS severe disease than β0 thal alone?

Back 24

Less severe (since there are still some alpha's left to bind to Beta). With Beta 0 thal, there is a complete imbalance between a and B chains.

Front 25

What is Hb lepore? What phenotype do children have?

Back 25

Hb variant from the fusion of a delta-globin and beta globin. (It essentially renders B nonfunctional- so presents as a B-thalassemia).

Homozygotes have thal major. Heterozygotes have thal minor.