3.18.14* Thalassemias and Hemoglobinopathies

Question 1

the causes of iron overload

Answer 1

hemochromatosis
siderblastic anemia
thalassemia intermedia
chronic liver disease

Question 2

hemoglobin types and structures

Answer 2

Hb A- a2B2
Hb A2- a1d2
Hb F- a2y2

(a genes are on chromosome 16 and others are on chromosome 11)

Question 3

alpha thalassemia

Answer 3

(caused by loss of any of the four alpha genes)
alpha thalassemia trait (1 or 2): results in low MCV and MCH with high RBC. Not usually associated with anemia
Hb H (3): moderately severe (hb 7-11) microcytic, hypochromic anemia with splenomegaly. Called Hb H disease because hemoglobin H (B4) can be detected by electrophoresis.

Question 4

Hb H disease

Answer 4

Hb H (3): moderately severe (hb 7-11) microcytic, hypochromic anemia with splenomegaly. Called Hb H disease because hemoglobin H (B4) can be detected by electrophoresis. PBS will also show target cells and poikilocytosis. Special stain can reveal “golf ball” cells cause by precipitations of B chains.

Question 5

Beta thalassemia major

Answer 5

little or no B chain produced due to point mutations. Excess a chains precipitate in erythroblasts and mature RBCs causing severe ineffective erythropoesis and hemolysis.

Hb F 98%, Hb A2 2%

Question 6

Clinical features of beta thalassemia major?

Answer 6

severe anemia is apparent at 3-6 months with liver and spleen enlargement due to excessive red cell destruction. Expansion of bones due to intense marrow hyperplasia leads to thalassaemic facies and thinning of cortex of many bones with tendency to fractures and bossing of the skull.

Question 7

What disease is the major cause of transfusional iron overload?

Answer 7

thalassemia major. This is because regular transfusion when infants have low hepcidin levels.

Question 8

PBS of thalassemia major

Answer 8

microcytic, hypochromic cells, target cells, nucleated RBCs (normoblasts), Howell-Jolly bodies are seen,.

Question 9

Howell-Jolly bodies

Answer 9

cluster of DNA seen in RBC

Question 10

beta thalassemia trait (minor)

Answer 10

hypochromic microcytic (low MCV and NCH) but high RBC and mild anemia (10-12). A raised Hb A2 (> 3.5%) confirms diagnosis.

Question 11

thalasemia intermedia

Answer 11

moderate thalassemia (hb 7-10)

Question 12

alpha and beta trait thalassemia

Answer 12

beneficial because there is not as much alpha to precipitate in the RBC.

Question 13

Sickle cell disease

Answer 13

due to inheritance of sickle B-globin gene making Hb S (a2Bs2) which forms crystals when exposed to low oxygen tension. The red cells sickle and may block different areas of microcirculation. The sickle B-globin gene has a substitution of valine for flutamic acid in position 6 of the beta chain (Go Vols).

Question 14

Hb S

Answer 14

gives up oxygen easily compared to Hb A (curve shifted to the right)

Question 15

Sickle cell trait

Answer 15

benign with only hematuria cause by minor infarcgts of renal paillae. Hb S 25-45%.

Question 16

Patient with thalassemia is SOB with swollen neck veins. What are you concerned with?

Answer 16

heart failure due to iron overload from transfusions. Thrombosis is increased

Question 17

when does fetal hb switch to adult hb?

Answer 17

3-6 weeks after birth

Question 18

how many beta chains are there?

Answer 18

1 per chromosome 11 (two total)

Question 19

Hgb Bart’s

Answer 19

gamma 4

Question 20

Q. Genetic cause of alpha thalassemia

a. Deletion of alpha genes
b. Point mutation in alpha gene that decreases alpha chains
c. Point mutation in alpha gene that increases alpha chains
d. Increased methylation of alpha gene promoter

Answer 20

A

Question 21

Patient with anemia and expanded bony structure of face. How do you diagnose beta thalassemia?

a. Decreased Hgb A seen by electrophoresis
b. increased beta chains on hb electrophoresis
c. genetic analysis of chromosome 16
d. Increased hb A2 or fetal hb

Answer 21

D

Question 22

What is the cause of hemolysis in beta thalassemia

Answer 22

too many alpha chains leads to aggregation and alpha hemochromes that develop under the RBC membrane leading to autoimmune hemolysis, activation of thrombosis and RBC degredation. Beta thalassemia has a lot of RBC destruction in the marrow.

Question 23

clinical features of beta thalassemia

Answer 23

a. expanded mandible/maxilla
b. expanded bone marrow (due to hyper-erythropoiesis)
c. severe osteoporosis
d. hepatosplenomegaly
d. ischemia ulcerations

Question 24

PBS of beta thal

Answer 24

hyperchromatic, microcytic
normoblasts
target cells
fragments
basophilic stipling
howell-jolly bodies

Question 25

PBS of thal trait

Answer 25

microcytosis target cells (looks a lot like iron deficiency anemia, distinguishable with some basophilic stipplling**)

Question 26

What is characteristic of a thalassemia CBC?

Answer 26

slightly decreased Hgb Low MCV/MCH increased RBC

Question 27

How does beta thal lead to iron overload?

Answer 27

many people get transfusions which increases iron. Also because ineffective erythropoiesis, their hepcidin is always low because they need a lot of iron, iron absorption is very increased

Question 28

how much iron is in 1 cc prbc?

Answer 28

1 mg

Question 29

where does iron accumulate in iron overload/ beta thalassemia?

Answer 29

a. liver- can lead to hemochromatosis, cirrhosis and hepatocarcinoma. b. heart c. endocrine cells- hypogonadism and pituitary insufficiency, pancreas leading to diabetes

Question 30

How does iron overload lead to osteopenia?

Answer 30

a. bone marrow expansion due to hyper-erythropoiesis | b. endocrine disfunction

Question 31

How do you prevent iron overload

Answer 31

give iron chelators

Question 32

How do you diagnose beta thalassemia?

Answer 32

electrophoresis showing increased A2 and hb F

Question 33

How do you diagnose alpha thalasemia?

Answer 33

Lab: low MCV/MCH elevated RBC normal ferritin (this is presumptive, actual diagnosis needs DNA screening)

Question 34

PBS finding in alpha thal

Answer 34

microcytosis target cells HbH inclusion bodies look like "golf balls"

Question 35

polychromasia

Answer 35

high RBC count

Question 36

Hgb E disorder

Answer 36

Point mutation beta globin gene leading to unstable mRNA. Beta chain is transcribed but decreased production.

Question 37

Hgb Lepore

Answer 37

Delta/beta fusion with marked decrease non-alpha chains

Question 38

Hereditary persistence of fetal hemoglobin

Answer 38

Marked decrease in beta chain formation compensated by marked increase fetal hgb

Question 39

Hgb Constant Spring

Answer 39

Base substitution terminal codon alpha gene with marked reduction in alpha genes