Sickle Cell

Question 1

When does HbS polymerize? In the oxygenated or deoxygenated state?

Answer 1

In the deoxygenated state

Question 2

What is the primary cause of HbS polymerization? What other factors increase the likelihood of polymerization?

Answer 2

Deoxygenated state; fever, acidosis, dehydration

Question 3

When is sickle cell disease diagnosed? What is given following diagnosis?

Answer 3

As a newborn- give antibiotics prophylactically because of the risk of sepsis

Question 4

What is sickle cell trait (AS)?

Answer 4

Heterozygous for disease; asymptomatic

Question 5

What is homozygous sickle cell anemia (SS)?

Answer 5

Homozygous for disease; most severe

Question 6

What is HbSC disease?

Answer 6

One parent is AS and the other is AC;HbC doesn’t usually sickle but increases the viscosity of HbS; milder

Question 7

What is sickle beta thalassemia?

Answer 7

One parent is AS and the other is alpha thalassemia (doesn’t produce any beta chains); severity depends on if thalassemia produces no HbA

Question 8

What is a major cause of death in kids with sickle cell disease?

Answer 8

Bacterial sepsis

Question 9

Sickle cell patients are immunocompromised because of vaso-occlusion to spleen. What is a complication of their inability to mount an immune response?

Answer 9

Purpura fulminas- skin necrosis that may result in amputation because circulation is so poor

Question 10

What is the first vaso-occlusive episode seen in sickle-cell patients as infants? How does it change over time? How should they be treated?

Answer 10

First: hand-foot syndrome (swelling of hands and feet)
Over time these episodes spread throughout the body
Treat with narcotics

Question 11

How can stroke occur in children with sickle cell disease?

Answer 11

Vaso-occlusion of arterial vessels to the brain

Question 12

What is the treatment for children with sickle cell who have a stroke? How can it be prevented?

Answer 12

Treatment: RBC transfusions and maybe BM transplant
Prevention: transcranial doppler

Question 13

What is acute chest syndrome?

Answer 13

Unique to sickle cell disease; diffuse and bi-lateral loss of space in lungs with an unknown cause

Question 14

What is the most common cause of death for sickle cell patients over the age of 5?

Answer 14

Acute chest syndrome

Question 15

How is acute chest syndrome treated?

Answer 15

Antibiotics, oxygenation, incentive spirometry

Question 16

What is acute splenic sequesteration crisis?

Answer 16

Sudden enlargement of the spleen due to acute vaso-occlusion in sickle cell patients

Question 17

What is the potentially life threatening effect of splenic sequesteration crisis? How is it treated?

Answer 17

Hypovolemic shock; fluids and transfusion

Question 18

What is currently the only cure for sickle cell disease?

Answer 18

BM transplant

Question 19

What is the correlation between the number of crises/ year and the severity of disease?

Answer 19

Greater than 3= severe
1-3= moderate
1= mild

Question 20

Where does erythropoeisis begin? How does it transition as the fetus develops? What are the different structures seen for the beta chain?

Answer 20

Begins in yolk sac (epsilon chains)–> liver (gamma)–> at birth to BM (beta)

Question 21

What gene is located on chromosome 6 and how is it related to the transition from HbF to HbA?

Answer 21

MYB- results in decreased gamma synthesis

Question 22

What gene is located on chromosome 2 and how is it related to the transition from HbF to HbA?

Answer 22

BCL- transcriptional repressor and gamma globin silencer

Question 23

Generally, variants of sickle cell disease that have more HbF are more or less severe?

Answer 23

Less severe

Question 24

The polymerization of HbS leads to vaso-occlusion and ischemia. What is enzyme is increased in response? How does this lead to a cyclic effect?

Answer 24

Xanthine oxidase; when oxygen returns the xanthine oxidase released free radicals leading to NFkB activation, which leads to inflammation the release of cytokines and activation of WBC which then bind to RBC and occlude a vessel

Question 25

Sickle cell RBCs have more or less GSH? What is GSH?

Answer 25

Less- GSH is an antioxidant

Question 26

What does the high ROS and RNS in sickle cells cause?

Answer 26

Auto-oxidation of HbS into the metHb and O2- which then can increase OH-

Question 27

The presence of ROS/RNS sulfinic acid gets oxidized what acid? This has effects on what enzyme?

Answer 27

Sulfonic acid; scrambalase

Question 28

What is the consequence of damage to scrambalase?

Answer 28

Can’t maintain symmetry of the membrane and phosphatidyl serine gets placed on the outer leaflet where can associate with clotting factors

Question 29

What is different about beta-actin in irreversible sickle cells? What effect does this have on actin?

Answer 29

Beta-actin has a disulfide bridge that joins the two cystines causing actin to depolymerize less quickly

Question 30

What enzymatic activity does alpha-spectrin have? How is this effected in irreversible sickle cells?

Answer 30

E2-E3 ubiquitin ligase; inhibited in sickle cells

Question 31

What is the Gardis channel?

Answer 31

Activated by influx of Ca which occurs in polymerized HbS; results in the loss of K, Cl, and Mg from the cell leading to dehydration

Question 32

What is the two step model for dense irreversible sickle cell formation?

Answer 32

1. low GSH means can’t clear ROS/RNS and get oxidative damage to gardos channel leading to cell dehydration
2. oxidative damage to B-actin and lower ubiquination by spectrin