Topic 4: Thalassemias

Question 1

what are thalassemias?

Answer 1

a group of inherited blood disorders in which the body makes abnormal forms of hemoglobin

patients with thalassemia produce an inadequate amount of either alpha or beta globin chains

as a result, hemoglobin synthesis is insufficient and the oxygen-carrying capacity of RBCs is reduced

both forms cause the destruction of red blood cells (RBCs), leading to anemia

Question 2

what is heme made out of?

Answer 2

iron and porphyrin

Question 3

what are the components of Hb?

Answer 3

heme and globin

4 heme and 4 globin chains

Question 4

what is HbA2 and in which thalassemia is it seen?

Answer 4

two alpha and two delta chains

it is seen in higher concentrations in beta thalassemia

Question 5

what is alpha thalassemia?

Answer 5

decrease in alpha chain production resulting in anemia of varying degrees

Question 6

what causes alpha thalassemia?

Answer 6

deletion of one or more alleles

alpha globin gene actually has four alleles – two on each chromosome 16

alleles are co-dominantly expressed so you use all four genes to make alpha chains

the severity of the disease depends on the number of deleted alleles

Question 7

what chromosome is alpha globin gene on?

Answer 7

16

4 alpha globin chains; 4x4=16

Question 8

what happens if you don’t have enough alpha chains around?

Answer 8

1. can’t make enough Hb
2. unpaired beta (if you’re an adult) or gamma (if you are a fetus) chains clump together in little tetramers

harder to deal with alpha thalassemia because you can’t replace alpha chains; with beta thalassemia you can replace B chains with gamma or delta chains

Question 9

what happens to the B or gamma tetramers formed in alpha thalassemia?

Answer 9

the spleen removes cells with these clumps from circulation which only worsens the anemia

beta chain tetramers in adults = HbH or H bodies

gamma chain tetramers in babies = Hb Barts

Question 10

what is B thalassemia?

Answer 10

disease caused by a defect in the production of beta globin

Question 11

what chromosome is the B globin gene encoded on?

Answer 11

11

there’s only 2 B alleles, not 4 like alpha globin

Question 12

what are the types of mutations that can happen in B thalassemia?

Answer 12

B0 = beta globin production is completely gone

B+ = decrease in the production in beta globin

B+ is less severe

Question 13

what happens to the alpha chains in B thalassemia?

Answer 13

free excess alpha globin cannot be integrated into hemoglobin and will either remain soluble or aggregate with other alpha globin molecules in the blood

soluble alpha globins are a big problem because they stick to the RBC membrane and cause membrane damage, leading to apoptosis in the marrow or phagocytosis and destruction in the spleen

Question 14

What determines the severity of beta thalassemia?

Answer 14

Both the severity of the mutation (complete or partial) and the zygosity (homozygous vs heterozygous) determine the severity of beta thalassemia

Question 15

what are the clinical manifestations of thalassemias?

Answer 15

1. decreased Hb production
2. extra medullary hematopoiesis
3. hemolysis

Question 16

why do thalassemia patients have decreased Hb production?

Answer 16

a patient with thalassemia is not producing sufficient alpha or beta globin chains

so hemoglobin synthesis will be inadequate and oxygen-carrying capacity will be affected

Question 17

why do thalassemia patients have extra medullary hematopoiesis?

Answer 17

in severe cases of thalassemia, the body tries its best to make red blood cells anywhere it can, including places that are not typically sites of bone marrow production, such as the calvarium of the skull

Question 18

why does thalassemia cause hemolysis?

Answer 18

Hemolysis primarily occurs in the spleen

Abnormal RBCs are phagocytosed and removed from circulation

This, along with extramedullary hematopoeisis, leads to hepatosplenomegaly

Question 19

what are the clinical symptoms of thalassemia?

Answer 19

• pallor
• jaundice
• dyspnea
• tachycardia
• bilirubin stones in gallbladder = hemolysis

Question 20

What are the three mechanisms by which patients with thalassemia can be anemic?

Answer 20

• poor production of hemoglobin
• ineffective hematopoiesis
• hemolysis

can all contribute to anemia in thalassemia

Question 21

what is needed for a definitive diagnosis of thalassemia?

Answer 21

hemoglobin electrophoresis

hemoglobin electrophoresis is necessary for definitive diagnosis because it reveals the presence and amount of alpha and beta globin chains (as well as gamma and delta chains)

Question 22

what does the CBC of a patients with alpha or beta thalassemia show?

Answer 22

low Hb

low mean cell hemoglobin concentration (MCHC) = hypo chromic

low MCV = microcytic

Question 23

how is the RBC count in MILD thalassemia effected?

Answer 23

usually increased

big difference between thalassemia and IDA where RBC count is low

Question 24

how is the RDW effected in MILD thalassemia?

Answer 24

low end of normal with means RBCs are microcytic BUT uniform in size

Question 25

how is the hemoglobin in severe thalassemia effected?

Answer 25

drastically decreased

Question 26

how is the RDW in severe thalassemia effected?

Answer 26

elevated which means there’s a big range of cells sized present

some RBCs are slightly microcytic, and some RBCs are severely microcytic

Question 27

what does the blood smear of mild thalassemia look like?

Answer 27

RBCs are hypochromic

target cells are frequently seen

Question 28

what does the blood smear of severe thalassemia look like?

Answer 28

you can see variations in RBC size if thalassemia is severe

nucleated blood cells

hypochromic RBCs

Question 29

do mild cases of alpha and beta thalassemia require treatment?

Answer 29

no

patients are asymptomatic and can survive with a very mild anemia

Question 30

when is a transfusion required for thalassemia?

Answer 30

HbH disease and thalassemia major

Question 31

what is the complication with transfusions for thalassemia?

Answer 31

may cause iron overload unless iron chelation is used

a unit of packed RBCs has way more iron than the normal daily requirement

Question 32

when can a transplant be used to treat thalassemia?

Answer 32

thalssemia major may be treated definitively with stem cell transplant

Question 33

what’s the complication associated with a stem cell transplant for thalassemia?

Answer 33

graft vs. host disease

a condition in which the immune cells within the donated tissue (graft) attacks the tissue of the host

Question 34

What is the main treatment of thalassemia major?

Answer 34

blood transfusions

Question 35

What bone marrow abnormality can be seen in thalassemia major?

Answer 35

Hyperplastic bone marrow

Question 36

Which lab values can differentiate thalassemia from iron-deficiency anemia?

Answer 36

Red Blood Cell Distribution Width (RDW)

RDW is elevated in iron-deficiency anemia but is normal in thalssemia

In thalassemia, the RDW is normal, most likely because the synthesis of RBCs is chronically deficient

in IDA, RDW is high because as the disease progresses, RBCs become more microcytic, so older RBCs will still be normocytic, thus the variation in size