8/7- Thalassemias and Hemoglobin Disorders Flashcards Preview

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Flashcards in 8/7- Thalassemias and Hemoglobin Disorders Deck (37):
1

What is a hemoglobinopathy?

Mutations that affect the structure of beta or alpha chains

2

What are thalassemias?

Mutations that affect the balance of production of alpha and beta chains such that not enough alpha or beta chains exist

- Imbalance of alpha and beta globins production

- It's the ratio that is important

3

Case)

- 34 yo black man is referred for microcytic RBCs

- Hx unremarkable and no family hx of anemia

- CBC shows hematocrit of 39% with MCV of 79, low retic count

- Microcytic RBCs with some hypochromia on smear

- Ferritin is 120 ng/mL

- Hemoglobin electrophoresis is normal

Which is the most likely diagnosis?

A. G6PD deficiency

B. Alpha thalassemia minor 

C. Beta thalassemia minor

D. Sickle trait

E. Anemia of chronic disease

Which is the most likely diagnosis? 

A. G6PD deficiency 

B. Alpha thalassemia minor 

C. Beta thalassemia minor 

D. Sickle trait 

E. Anemia of chronic disease

4

Most alpha thalassemias result from what kind of mutations?

Gene deletions

5

Most beta thalassemias result from what kind of mutations?

Point mutations (more than 400 known)

6

What is the typical beta/alpha ratio?

1.2 (?)

7

Damage in thalassemia is due to the chain in excess or scarcity?

Damage is done by globin chain that is in excess

- alpha chain is incredibly unstable

8

Alpha thalassemias result from what?

- Result?

- Ratio?

- Pathophysiology?

- Most commonly from gene deletions resulting in decreased alpha chain production and excess beta chains

- beta/alpha ratio is increased

- Red cell membrane damage is due to excess beta chains which can associate das tretramers (B4 or hemoglobin H)

9

Beta thalassemias result from what?

- Result?

- Ratio?

- Pathophysiology?

- Most commonly from point mutations that affect mRNA production for beta chain synthesis

- beta/alpha ratio is decreased (beta chain synthesis is decreased and there is an excess of alpha chains)

- Alpha chains do not associate, but oxidize and precipitate and are very toxic to the RBC membrane (so unstable they do not form a tetramer recognizable on electrophoresis)

10

Epidemiology/geography of thalassemias?

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11

Which thalassemia type presents earlier?

Alpha

- Alpha Hb is switched to adult form early in life

- Alpha thalassemia will be present at birth

- Most severe alpha thalassemia results in hydrops fatalis (stillbirth)

- Beta thalassemias don't present until you attempt full expression of the beta chain somewhere between 6 mo of age and 1 yr 

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12

What is seen in alpha thalassemia (aa/a3.7)

- Normal iron studies

- Normal Hb electrophoresis

- Trait is common in black Americans (30%)

- Normal or borderline low Hb

- Very mild: hypochromic microcytic

- Silent carrier?

13

What is seen in alpha thalassemia (a3.7/a3.7)

- Mild anemia

- Microcytosis

- 1-3% of black Americans

- No need for genetic counseling

- Pts are warned to check iron studies before accepting a diagnosis of iron deficiency

14

Case)

- Pt from China

- 60 yo woman presenting with pallor and microcytic anemia

- Ferritin is 1000 ng

- Hematocrit is 28%, MCV 65

- Retics 4.2 

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Thalassemia

- On PBS: see marked hypochromia and microcytosis with some tear drops and normal platelets

15

What is this? 

Q image thumb

Golf Ball RBCs (Weatherall)

- Micro Heinz bodies of precipitated beta tetramer or Hemoglobin H

- New methylene blue or crystal violet

16

Pathophysiology of Hemoglobin H disease?

- Children at birth have tetramers of gamma, "Barts"

- Within a few motnhs, they mostly have adult hemoglobin and the beta chain excess forms beta tetramers, or Hemoglobin H

17

What happens when both chromosomes have gene deletions (no functioning alpha genes)?

Hydrops Fetalis- Stillborn

- Development of the fetus is affected by the very high O2 affinity of tetramers of fetal gamma chains (Bart's)

- The placenta is huge 

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18

Which produces more globin, alpha 1 or alpha 2?

Alpha 2 produces more globin than alpha 1

19

Relative amounts of globin produced by genes? Certain mutation effects?

- Just 1 functioning gene = HbH disease

- No functioning genes = Hydrops featlis with Hb Bart's 

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20

What is Hemoglobin Constant Spring?

- Stop codon mutation that results in a long globin that is unstable (hemoglobin being made but unstable)

- Acts somewhat like a 2 gene mutation

21

Another chart describing genotypes of alpha thalassemias

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22

Case)

- 30 yo man presents with anemia with hematocrit of 30, Hb of 10, and MCV of 60

- PBS show microcytosis and hypochromia and some basophilic stippling

- Iron studies are normal

- Greek ethnicity

- Hemoglobin electrophoresis is normal except for increased A2 of 5.5%

Which of the following is the most likely diagnosis?

A. Sickle cell disease

B. Alpha thalassemia

C. Beta thalassemia minor

D. G6PD deficiency

Which of the following is the most likely diagnosis?

A. Sickle cell disease 

B. Alpha thalassemia 

C. Beta thalassemia minor?

D. G6PD deficiency

23

What is this?

Q image thumb

Beta thalassemia minor

- Hematologically: microcytic hypochromic RBCs with a lot of targeting and some basophilic stippling

- Cells are uniformly small so the red blood cell size distribution width (RDW) is normal

- Iron deficiency is marked by the variability of iron available to the red blood cell so the cells are small, but more variable in size, the RDW is increased

24

Genes behind beta thalassemia minor? major?

Chromosomes involved?

Minor: One normal beta gene on chromosome 11 and a thalassemic beta mutation on the other

Major: Two genes affected

25

Again, what is the underlying mutation mechanism that typically results in beta thalassemias?

Typical beta thalassemic mutations affect mRNA splicing, or sometimes transcription initiation

26

Cellular pathogenesis of beta thalassemia?

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27

What is this?

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Beta Thalassemia Major

- More extreme targeting, microcytosis

- Marrow is greatly expanded and nucleated reds circulate (leak out from expanded marrow); increased after splenectomy

28

Which of these is with splenectomy? without?

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Left: pre-splenectomy

Right: post-splenectomy 

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29

What is this showing? 

Q image thumb

Marrow expansion with extramedullary hematopoesis

- Wads of hematopoeitic tissue hanging off the spine

30

What is this showing? 

Q image thumb

Hair on end

- Diploe is expanded

- Can be seen in thal major and sometimes in other congenital hemolytic anemias such as sickle cell dz

31

What is this showing? 

Q image thumb

Chipmunk facies characteristic in beta thal major

32

What is this showing?

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Extramedullary hematopoeisis causing massive splenomegaly (in beta thal major)

33

Chronic transfusions result in what? Management?

Chronic transfusions produce iron overlaod; managed with iron chelation

- If not compliant, iron overload results in cardiomopathy, liver problems, and diabetes 

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34

What is this?

Q image thumb

Iron stain in a heart of a pt with transfusional iron overload

35

Overview of beta thalassemias

- βthal minor: microcytic, hypochromic anemia; hemoglobin electrophoresis reveals increased A2, sometimes F

- βthal major: alpha chain excess results in in-effective erythropoiesis, marrow expansion, myeloid metaplasia

- β thal major: transfusions, iron chelation

- β thal major: Role of BMT

36

Examples of hemoglobinopathies?

- High Affinity Hemoglobins—Polycythemia

- Unstable hemoglobins—Heinz body hemolytic anemia

- M hemoglobins/Congenital Methemoglobinemia (enzymopathy)

- Sickle Cell Disease

37

What is this showing? What is causing it? 

Q image thumb

Cyanosis here is really Met hemoglobin

- Pts with M hemoglobin may be more slate colored

- Cyanosis due to hypoxia may be bluer (observed when there is more than 5 g/dL of deoxyHb)

- Cyanosis is seen when there is 1.5 gm/dL of methemoglobin