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Flashcards in Hemaglobinopathies Deck (65):
1

What comprises 70% of the RBC?

hemoglobin

2

Where are the beta globin genes located?

short arm of chromosome 11

3

What genes are located within the "beta globin gene cluster"?

genes for beta, delta, gamma-A, gamma-G and epsilon globin

4

What controls expression of the "Beta Globin Gene Cluster"?

A single locus control region

5

T/F: All globin genes on chromosome 11 are continuously expressed. 

F: genes are differently expressed throughout development

6

What results from rearrangement, deletion or changes to the genes within the Beta Globin Gene Cluster?

gene expression during improper stages of development

7

What genes are within the Alpha Globin Gene Cluster?

Zeta 1 and 2

Alpha 1 and 2

8

What does gamma gene expression yield?

Hgb F

9

What does expression of the delta gene yield?

Hgb A2

10

What does expression of the beta gene yield?

Hgb A

11

What are the components of the tetrameric hgb protein?

Products of B1, B2 genes

Products of any 2 of the 4 alpha genes

12

What are the 4 functions of hgb?

1. O transport

2. CO2 transport

3. pH regulation

4. NO sump

13

NO is inhibited by (3):

hypoxia

activated WBCs

Sickled RBCs

14

What activates sickled RBCs?

hypoxia

15

What is ultimately activated by hypoxia (via a few different pathways)?

VCAM-1

16

What is inactivated by NO (either directly or indirectly)?

VCAM-1

17

In the presence of Heinz bodies, what will be impaired?

Vasodilation, due to removal of NO

18

Explain how beta-like globin gene switching progresses during development.

1. Initially, epsilon is expressed.

2. As epsilon expression decreases, gamma (A +G) are expressed.

3. Just before birth, gamma expression declines and beta expression increases.

(4. Delta is expressed a little bit, starting around birth)

19

What happens to unstable hgb (such as Heinz bodies) within the RBC?

it precipitates

20

Sickle cell is commonly seen in people of what descent?

African

Mediterranean

21

What are two types of Sickle Cell variants (non-carriers)?

Sickle Cell Anemia
    -Hb SS
    -Hb SB0 Thalassemia
Hb SB+ Thalassemia
Sickle Hb SC (mildest)

22

T/F: Hb SC has partially normal hgb

F: no normal hgb

23

What percent of AA are Hgb-AS heterozygous? 

8%

24

If a patient has more symptomatic sickle cell, he/she is higher risk for:

early death

25

What is the cardinal feature of sickle cell disease?

unpredictable pain

26

What sickle cell symptom often signals life-threatening complications? What are these?

Acute pain ("precedes 22% of SCD deaths")

Chest syndrome, stroke, sepsis, organ failure

27

What is the specific substitution occurs in the beta-S protein?

Val substituted for Glu (at 6)

28

What abnormality is present in the beta-C protein?

Lys is substituted for Glu (6)

29

What does the abnormal shape of sickled RBCs cause?

1. sluggish blood flow and occlusion 

2. reperfusion injuries (underperfused tissues are exposed to inflammatory cytokines)

3. Endothelial and tissue damage due to oxygen radicals

30

What structural change causes decreased solubility in Hgb S? 

 single amino acid substitution at 6th position of beta chain

31

What factors affect the solubility of Hgb S?

Oxygenation

pH

Temperature (more crises in winter)

32

How does polymerization occur in Hgb S?

 1. intermolecular binding of contiguous hydrophobic (valine) molecules occurs when hgb is deoxy

2. hydrophobic regions on neighboring chains bind (this is strengthened by electrostatic forces)

3. Fibers grow, forming stacks and helical filaments 

33

T/F: Hgb S polymerization is reversible.

T: Most hgb reverts (however, 5-7% will be permanent)

34

Should you give a patient in SC crisis oxygen?

No--it suppresses EPO production

35

T/F: Hgb will polymerize if oxygenated.

F: deoxygenated

36

What is the most important factor in the soluble (non-polymerized) phase of Hgb S?

intracellular concentration of Hgb S

(really didn't understand the context of this--edit if you knew what big-picture point she was making)

37

What can block polymerization of Hgb S? How?

Hgb F; copolymerizes with hgb S in an orientation trans to the subunit containing val/hydrophobic region  

38

What protein improves severity of SCD in direct proportion to its concentration (when conc >10%)?

Hgb F

39

How does hydroxyurea treat SCD?

increases Hgb F production, which decreases SCD crises by 40%

40

What cell structures are affected by hydroxyurea?

RBC adhesion molecules (decreases them)

41

4 main ways sickled RBC are different from normal RBC:

1. rigid

2. dehydrated

3. adhere abnormally to vascular endothelium and macrophages

4. increase whole-body viscosity

42

In SCD, hemolysis may be located:

intravascular

Extravascular

43

What are common SCD crisis triggers?

1. hypoxemia

2. infection

3. climate change (cold)

4. stress

5. dehydration

6. hyperviscosity 

7. acidosis

44

Possible Contributory Factors in SCD Vaso-Occlusion:

  • Hb S polymer
  • Sickle cell deformability
  • Sickle blood viscosity
  • Fraction of dense sickle cells
  • Sickle cell-endothelial cell adherence
  • Endothelial cell activation
  • Hemostatic activation
  • Platelets
  • White blood cells
  • Vascular tone/architecure

45

What are 3 major manifestations of SCD?

1. vasc occlusion

2. infection

3. anemia

4. inflammation

46

What are common symptoms of SCD seen in very young children?

dactylitis (due to vasc occlusion)

acute sequestration crisis

47

What conditions often occur secondary to anemia in SCD?

priapism 

leg ulcers

pulmonary hypertension

(due to hemolysis and NO scavenging)

48

What conditions often occur secondary to vaso-occlusion in SCD?

acute/chronic organ failure

retinopathy

chest syndrome

"painful events"

(due to tissue ischemia, infarction)

49

What conditions often occur secondary to infection in SCD?

pneumonia

chest syndrome

bacteremia 

sepsis

50

Why is infection common in SCD?

asplenia, making the patient susceptible to encapsulated bacteria and viruses (+ fever)

51

What are some acute pain syndromes related to SCD?

chest syndrome

cholecystitis 

hand-foot syndrome (dactylitis)

pain crises

priapism 

splenic infarction

bone infarction

52

What are some chronic pain syndromes related to SCD?

1. arthritis

2. avasc necrosis

3. leg ulcers

4. vertebral body collapse

5. osteopenia

6. vit D deficiency

7. boen infarction

 

53

How long do blood cells live in SCD?

14 days--then they release their contents into blood stream

(*this short lifespan means new RBC must be produced at a faster rate)

54

What scavenges NO in the blood?

free Hgb

55

What 3 lab values would be abnormal in anemia of SCD?

LDH (elevated)

Bilirubin (elevated)

Reticulocytes (elevated)

56

What factors contribute to avascular necrosis in SCD?

older age

mild anemia (alpha deletion, Hgb SC, S-Thal)

57

How renal problems progress in SCD?

-Proteinuria occurs (RBC fragments?)

-Tubular endothelium becomes congested

-Growth factors are induced, which results in fibroblast prolif and matrix synth

-Renal fibrosis results in renal failure

58

What are common ocular problems in SCD -" Hgb C"?

hemorrhage

retinitis proliferans

neovascularization

retinopathy (periph)

damage to retinal vasculature

 

(this was badly worded slide; if you know what she was getting at, fix--or delete)

59

T/F: High Hgb F is the best way to prevent SCD-associated leg ulcers. 

F: "Negative correlation with Hb level and Hb F value"

60

Leg ulcers are most common in (men/women/children) and in (SA, SS, SC).

Men

SS

61

What are common fetal complications when the mother has SCD?

1. placenta infarctions

2. fetal demise

62

How do you treat pain associated with SCD?

opiates

63

How do you treat anemia associated with SCD?

blood transfusion

64

How do you treat severe vasc occlusion associated with SCD?

blood exchange

65

How does ICAGEN improve anemia in SCD?

blocks RBC ATPase