L2_Sickle Cell Anemia 1

Question 1

How is anemia defined?

Answer 1

is a decrease in number of red blood cells (RBCs) or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin deficiency.

Question 2

In what chromosome does the sickle cell mutation occur?

Answer 2

11

Question 3

Describe the mutation that takes place for HbS? reside, nucleic acid, amino acid

Answer 3

Residue 6 of beta globin. GAG (GLU) to GTG (VAL)

Question 4

What happens in deoxygenated HbS?

Answer 4

14 stranded Hb polymers form and push the cell into the sickled shape.

Question 5

In ISCs, do the HbS polymers return to monomers in the oxygenated sate?

Answer 5

Yes, it is defects in the spectrin/actin cytoskeleton that keep it locked into place

Question 6

What other cellular factors play a role in the severity of sickle cell disease?

Answer 6

altered leukocytes, blood vessel endothelial cells, and plasma factors

Question 7

What chromosome is the alpha cluster on?

Answer 7

16

Question 8

Describe the source of erythropoiesis during developement

Answer 8

yolk sac- early embryonic development
fetal liver- midway through first trimester
Bone Marrow- Birth

Question 9

Describe the course of expression in the beta locus

Answer 9

epsilon- embryonic
Ggamma and Agamma - fetal
Beta - birth
All controlled by locus control region

Question 10

How does HbF expression correlate with sickle cell severity?

Answer 10

The higher the HbF expression leads to decreased HbS polymerization, the less severe the sickle cell is.

Question 11

What other two chromosomes are related to sickle cell severity, what are their biomarkers, and what do they play a role in

Answer 11

Chromosome 2 marker BCL11A and chromosome 6 marker HBS1l-MYB are trans acting factors that play a role in the switch from gamma to beta

Question 12

What percentage of cells does HbF normally represent?

Answer 12

0.1-1% but can be brought up to ~20%

Question 13

What haplotype is the worst? the best?

Answer 13

Worst is Bantu, best is Arab-Indian

Question 14

Describe the cycle of ischemia-reperfusion

Answer 14

Vassoocclusion leads to ischemia, ischemic cells produce xanthine oxidase, when blood flow returns , xanthine oxidase converts Oxygen into superoxide radicals, this causes expression of NFkB which is a transcription factor that up regulates, cytokines, leukocytes, adhesion molecules and leads to further vassooclusion

Question 15

What does double jeopardy refer to?

Answer 15

Sickle Cell RBCs contain 3x as much ROS compared to normal cells, they also contain less reduced glutathione (GSH) which is an antioxidant, this all leads to increased oxidative stress.

Question 16

Is GSH an enzyme? what does it help do?

Answer 16

No, it helps scavenge H2O2 which decreases the amount of OH- radicals which are the most dangerous.

Question 17

Is there a known antioxidant for OH-?

Answer 17

No

Question 18

What converts O2- radicals to H2O2?

Answer 18

Superoxide dimutase

Question 19

Describe the role of methemoglobin in oxidative stress of sickle cells.

Answer 19

The binding of O2 to Hb can cause the iron to be oxidized into its ferric state. producing superoxide radical and methemoglobin. Methemoglobin has a decreases affinity for heme. much of the released hemin and iron build up. The free iron can then be used to convert H2O2 to OH-. The conversion to methemoglobin happens at a much higher rate in sick cell RBCs

Question 20

Describe HbS interaction with NO?

Answer 20

Released cell free HbS binds NO limiting its vasodilatory, anti-inflammatory, and antithrombotic properties.

Question 21

What two molecules/enzymes help reduce H2O2

Answer 21

GSH and catalase

Question 22

Explain how H2O2 has effects on proteins in the sickle cell

Answer 22

They oxidize cysteine molecules to an irreversible oxidation state which causes permanent damage

Question 23

What is one enzyme that is directly effected by cysteine modifications and what does its malfunction do the SS RBCs

Answer 23

Scramblase. Increased scramblase activity results in phosphatidyl serine on the the outer leaflet (bad) this negative charge leads to increased clotting and macrophage activation.

Question 24

Describe the molecular basis of the formation of ISC membrane (2 major reasons)

Answer 24

1. B-actin disulfide bridges (caused by ROS and RNS) leads to actin protofilaments that disassemble slowly. 2. diminish a-spectrin ubiquitination creates ternary complexes that disassemble slowly

Question 25

What can be used to help reverse some of the oxidative damage that occurs in SS RBCs?

Answer 25

N-acyl-Cyteine (NAC)

Question 26

Describe a few reasons for dehydration of sickle cells.

Answer 26

Lowering GSH increases ROS species which cause oxidative damage to the gardos channel (Ca2+ dependent) which leads to K+ efflux and dehydration. Oxidative damage leads to locking of sickle cells which induces sickling induce leak channels, dehydration leads to further polymerization and water loss.

Question 27

What does hydroxyurea help do?

Answer 27

Increase HbF

Question 28

What are the targets are some of the drugs under research?

Answer 28

effect K leakages, effect NO levels (statins, inhaled NO),effect oxidative stress (NAC), effect adhesion (Statins), effect inflammation, effect HbF levels (hydroxyurea)

Question 29

What are 3 current biomarkers that have been identified?

Answer 29

1. 20 monocyte proteins (increase is bad correlated with 5 yr crisis rate) 2. Apolipoprotein A-1 (decrease is bad lead associated with pulmonary hypertension) 3. microRNA mir144 (increase bad and leads to low antioxidant activity)