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► Med Misc 19 > "Molecular & Cellular Princ Med CC: Sickle Cell Disease I Steven Goodman" SANA > Flashcards

"Molecular & Cellular Princ Med CC: Sickle Cell Disease I Steven Goodman" SANA Flashcards

1
Q

A to T conversion in the __1__ globin chain within chromosome 11 causes a single ___2____ change in residue 6 of __1 again__ globin.

A
  1. Beta

2. amino acid

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2
Q

What is the activity of HbS in solution?

A

It forms polymers, that when sickled in the blood cause hemolysis and vasooclusion.

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3
Q

What are ISCs?

A

Irreversible sickled cells. ISCs play an important role in vasooclusion.

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4
Q

Can a RBC be sickled even when HbS is depolymerized?

A

Yes

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5
Q

What are the contributing factors to vasoocclusion in sickle cell disease?

A
  1. Sickled RBCs
  2. Activation of endothelial cells and leukocytes
  3. Plasma factors/expression of adhesion proteins
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6
Q

Describe the evolution of hemoglobin from conception to birth.

A

Embryonic –> fetal and alpha (gestation) –> alpha and beta (birth)

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7
Q

What three chromosomes have been implicated in identifying the severity of sickle cell disease a person has?

A

11 (beta globin cluster), 2 (trans-acting BCL11A), 6 (HBS1L-MYB). Variants that result in higher fetal Hb are less severe

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8
Q

What is BCL11A?

A

A transcription factor (repressor) of gamma globin.

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9
Q

What does higher circulating fetal Hb mean for a patient with sickle cell disease?

A

Altered transcriptional regulation of the gamma to beta switch –> Higher circulating Hb –> decreased polymerization of Hbs
Normal HbF - 0.1-1%, altered, up to 20%. Higher HbF seen in Arab-Indian and Senegalese patients.

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10
Q

The Bantu people have the most severe sickle cell disease. Why?

A
  1. Least amount of gamma globin

2. Least response to treatment with hydroxyurea

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11
Q

Ischemia caused by vascooclusion in SCD causes what?

A

Metabolic changes which lead to bursts of reactive oxygen species production when reperfusion is attained.

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12
Q

During ______ cells increase expression of xanthine oxidase.

A

ischemia

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13
Q

Upon reperfusion after an ischemic event, what chemical converts oxygen into a superoxide radical (ROS)? What cells are the radicals coming from?

A

xanthine oxidase

ROS coming from endothelial cells, adherent leukocytes and xanthine oxidase attached to endothelial surface

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14
Q

The production of ROS (radical oxygen species) causes activation of what other events?

A
  1. NFkb activation
  2. Inflammation and release of inflammatory cytokines
  3. Activation of leukocytes
  4. Increased expression of adhesion molecules on the surface of the endothelial cells and leukocytes, further vascular plugging
  5. Decreased NO availability resulting in abnormal endothelial dependent vaso-dilation
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15
Q

T/F: Sickle RBCs contain 3x as much oxygen radicals compared to normal RBCs.

A

True

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16
Q

Do sickle RBCs have more or less glutatione? Why?

A

Sickle RBSs have lows levels of reduced glutatione (GSH). The level of GSH is inversely proportional to cell density. Thus, sickled cells are very dense.

17
Q

When oxygen is bound to heme Fe, the iron can be oxidized to the III state. What is formed when this happens?

A

superoxide

methemoglobin (metHb)

18
Q

Superoxide is converted to ____ by SOD, superoxide dismutase. SOD is increased in sickle cell disease patients.

A

H2O2

19
Q

H2O2, converted from superoxide, sits on RBS surfaces in sickle cell disease, and is then converted to what toxic chemical by hemin, also known as free heme (Fe III)?

A

OH-. This reaction is increased in sickle cell patients.

20
Q

What explains why there are high levels of H2O2 in sicke cell disease?

A

GPX (glutathione peroxidase) and catalase activity are low in sickle cell disease. Normally GPX and PRDX2 (peroxiredoxin 2) are the H2O2 scavengers.

21
Q

In the RBC, what is the most important of non-enzymatic antioxidants?

A

Reduced glutathione (GSH)

22
Q

Why is circulating OH-, produced from H2O2 and free heme, a bad thing?

A

OH- reacts with proteins, lipids, and DNA and is a toxic oxidant. There are no known enzymes that neutralize OH-.

23
Q

How is the level of phosphydityl serine on the outer leaflet of the sickle RBC membrane related to the pathophysiology of SCD?

A

Oxidative stress –> flippase inhibited in RBC membrane, and scramblase activated –> puts PS (negative charge) on outside of RBC membrane –> PS can associate with Ca2+ and clotting factors and increase hypercoagulation and thrombosis. PS patches also serve as recognition for macrophages, which is why sickled RBCs have a shorter lifespan. Finally, PS also increases binding of RBCs to endothelium of blood vessels.

24
Q

What factors lead to the variance in clinical severity and outcome in SCD?

A 
Changes in proteins
Posttranslational modifications (PTMs) such as the formation of cysteine oxiforms
25
Q

What is the molecular basis for the irreversibly sickled RBC (ISCs)?

A

Cysteine modification and oxidative stress. Oxidative stress –> cysteine oxiforms –> disulfide bridge in beta-actin and decreased spectrin ubiquitination –> locked and botched assembly of the RBC membrane skeleton

26
Q

Part of the reason sickle RBCs get so dense is activation of a leak channel. Walk me through the steps leading to this channel forming, beginning with the deoxygenation event and sickling.

A
  1. Deoxygenation
  2. Polymerization/sickling
  3. Activation of sickling-induced leak channel
  4. Transient increase in intracellular free Ca2+ and loss of intracellular K+ and Mg2+.
  5. Activation of Ca2+-dependent Gardos channel and KCL co-transport channel with resultant loss of K+, Cl- and water.
  6. Dehydration means MCHC (mean corpuscular hemoglobin concentration)
  7. High MCHC stimulates HbS polymerization and further K+ and dehydration.
27
Q

What is NAC?

A

An antioxidant (n-acetylcysteine) which can raise intracellular GSH levels and block formation of ISCs. It is currently in clinical trials to study its efficacy as a therapy.

28
Q

How can biomarkers of sickle cell severity lead to future personalized medicine for sickle cell disease?

A

Biomarkers can predict sickle cell phenotype early in life, which can aid in choice of treatment.

► Med Misc 19 (32 decks)

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