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Flashcards in Thalassemia Deck (54):
1

What 2 types of abnormal Hgb can patients with alpha-thal have and what chains are each one made of?

1. Hgb H: 4 beta chains
2. Hgb Bart's: 4 gamma chains

2

What types of Hgb are increased in beta-thal?

Increased Hgb F or Hgb A2.

3

What are the 3 classifications of thalassemia?

1. Major
2. Intermediate
3. Minor

4

Thalassemia majors involve what genes?

Beta genes on chromosome 11. The other 2 categories involve both beta and alpha genes.

5

Beta-thal is most common in patients with what kind of heritage?

Mediterranean.

6

Why is anemia seen in Beta-thal?

Unpaired alpha chains form hemichromes (and inclusion bodies?) that induce apoptosis in erythroblasts. Basically the hemichromes alter the functionality of the RBC, it sucks, so it is murdered.

7

What molecule is on the outside of normal RBCs?

Choline containing phospholipids.

8

What molecule is on the inside of normal RBC membranes?

Phosphatidylserine

9

What enzyme normally maintains RBC membranes?

Flipase

10

What 4 factors related to thalassemia RBCs lead to a hypercoagulable state?

1. Membrane damage by alpha hemichromes and oxidant stress
2. Phosphatidylserine exposed out of membrane
3. Increase in free plasma hemoglobin
4. Increase in platelet activation

11

What therapy reduces thrombotic complications in thalassemia?

Transfusions

12

What 2 things does the exposure of phosphatidylserine on the outside of RBCs induce?

1. Apoptosis: serves as the recognition site
2. Increases thrombin production

13

What's the advantage of being a carrier of a Hgb mutation?

Decreases susceptibility to malaria.

14

Hydrops fetalis is characterized by an inability to produce which globin chain? Outcome?

Alpha chain. Not a viable pregnancy: death occurs in utero.

15

What are the 3 forms of adult hemoglobin and what chains comprise each of them?

1. Hgb F: 2 alpha + 2 gamma
2. Hgb A2: 2 alpha + 2 delta
3. Hgb A: 2 alpha + 2 beta

16

What is responsible for the thinning and deformity of bones seen in beta-thal?

Result of bone marrow expanding within the bones i.e. osteopenia, jacked up grill, weird face.

17

What are some other signs and symptoms of beta-thal?

1. Significant hepatosplenomegaly
2. Hemachromatosis (from the hemolytic anemia)
3. Ulcers on legs

18

What must be given in conjunction with transfusions for a beta-thal patient?

Iron chelation therapy to prevent iron overload.

19

Is there a physiologic mechanism for getting rid of excess iron?

No. Reason why iron absorption is so regulated.

20

What are the 2 causes of iron overload in beta-thal patients?

1. Repeated transfusions
2. Increased iron absorption

21

Why is there an increase in iron absorption in beta-thal patients?

The decrease in RBCs sends a hypoxia signal to the bone marrow telling it to expand. Thus, iron absorption is increased to fuel this BM expansion (via decreased hepcidin).

22

How can you reduce the thrombotic complications in beta-thal patients?

Transfusions. However, more transfusions lead to increased iron loading.

23

Why are there problems with endocrine organs in beta-thal patients?

Iron deposition causes organ damage. Hypogonadism and pituitary insufficiency.

24

What are the 3 causes of osteopenia in beta-thal patients?

1. Bone marrow expansion
2. Endocrine dysfunction
3. Iron chelators

25

What is the difference between B0 and B+ thalassemias?

B0: no beta chains at all
B+: few beta chains expressed thus some Hgb A

26

What is basophilic stippling?

RBCs on PBS show blue dots. The blue dots are RNA that hasn't been degraded.

27

What are the 6 diseases in which basophilic stippling is seen?

1. Thalassemia trait and major
2. Hemolytic anemia
3. Myelodysplastic syndrome/sideroblastic anemia
4. Megaloblastic anemia
5. Pyrimidine 5' nucleotidase deficiency
6. Heavy metal poisoning: lead, zinc, arsenic, silver, mercury

28

What are 5 things used in the diagnosis of beta-thal?

1. Family Hx
2. CBC
3. Blood smear
4. Physical exam
5. HPLC or Hgb electrophoresis

29

Can HPLC of hemoglobin be used to diagnose alpha-thal?

No. Those hemoglobins will not be picked up.

30

What is used to diagnose alpha-thal if the mutation is known?

PCR

31

What is used to diagnose alpha-thal if the mutation is unknown?

Restricted fragment length polymorphism analysis

32

For which thalassemia patients are BM transplants recommended?

Nobody effing knows. Deal with it. Suggested for beta-thal majors early in the course of the disease.

33

What are the 3 prognostic indicators for a BM transplant in thalassemia patients?

1. Portal fibrosis
2. Hepatomegaly
3. Inadequate chelation

34

What is Hereditary Persistence of Fetal Hemoglobin?

Big decrease in beta globin synthesis. There's an increase in gamma chain synthesis to compensate thus Hgb F is formed. HPFH may result from a co-deletion of delta and beta genes.

35

What is Hemoglobin E disease caused by?

Homozyguos point mutations of Glu26Lys on beta globin gene produces an unstable mRNA.

36

Patients with Hemoglobin E disease will clinically resemble patients with which thalassemia?

Beta-thal minor

37

What is E/Beta-thalassemia?

Patient has one beta globin gene carrying a beta-thalassemia gene and one carrying the Hemoglobin E point mutation.

38

Is E/Beta-thal worse or better than Hemoglobin E disease?

Better usually. Clinically will resemble thalassemia minor or intermediate depending on the beta-thal mutation present.

39

On electrophoresis or HPLC, Hgb E moves in the same location as what other hemoglobin?

Hgb A2

40

What patient populations is Hemoglobin E and E/Beta-thal diseases most common in?

Southeast Asians. 1/4 Cambodian births. 1/9 Thai/Laotian births. Very common in US immigrant families.

41

What is Hemoglobin Lepore disease?

Patient has normal alpha chains but a delta/beta hybrid fusion chain. This results in a drastic reduction in the non alpha chains causing a thalassemia intermediate to major phenotype in the clinic (in homozygotes).

42

What is Hemoglobin S/Beta-thal disease?

Patients have sickle cell hemoglobin and a beta-thal gene.

43

How do you make the diagnosis of Hgb S/beta-thal?

HPLC. Note: these patients do not have Hgb A.

44

How many copies of the alpha globin gene are there?

4

45

What causes Alpha-Thalassemia?

Any combination of alpha globin gene deletions.

46

What are the 4 types of alpha-thal?

1. Hgb Bart's: all 4 genes lost
2. Hgb H: 3 genes lost
3. Alpha-thal Trait: 2 genes lost
4. Silent carrier: 1 gene lost

47

Loss of all 4 alpha globin genes results in what?

Death. This is Hgb Bart's (4 gamma chains) and the fetus dies in utero. Also known as hydrops fetalis. At least one alpha globin gene is required for life.

48

What is the pathophysiology of Hgb H?

Precipitation of beta globin tetramers as red cells age. Decreased RBC deformability leads to hemolysis. Hgb H has very high oxygen affinity and won't unload oxygen in the tissues. Hypersplenism (10%). Leg ulcers. Gallstones. Pts rarely need transfusions or splenectomy. Rare iron overload.

49

Red cells in alpha-thal silent carriers show what?

Normal to microcytic with minor anemia. Also, globin chain synthesis ratio of alpha:beta is 0.8-0.9.

50

Red cells of alpha-thal trait patients show what?

Microcytic RBC indices. Normal or mild anemia. Globin synthesis ratio of alpha:beta is 0.7-0.8.

51

T or F. Alpha-thal patients show lots of target cells in their PBS but these target cells are not specific for alpha-thal.

T: target cells are seen in other diseases too.

52

What is Hemoglobin Constant Spring?

Single base substitution in the terminal codon of the alpha chain causing the mRNA to copy another 31 amino acids yielding an unstable mRNA. This leads to a significant decrease in the translation of the alpha globin gene.

53

Patients that are homozygous for Hemoglobin Constant Spring clinically resemble patients with what type of alpha-thal?

Moderately severe alpha-thal

54

In what patient population is Hemoglobin Constant Spring most common?

Southeast Asians