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Flashcards in Sickle Cell Disease Deck (38):

What is a thalassemia?

Inherited autosomal recessive blood disorder characterized by abnormal formation of hemoglobin


What does it mean to have sickle cell trait?

Means you are an heterozygote and carry the mutant ß globin gene


What is the genetic explanation of SCD? What does this cause?

Glu6Val missense mutation in the β chain → disrupts secondary structure → hydrophobic interaction with AAs on the interface with other subunit to hide Val from solvent when it T-state → new shape reduces deoxyhemoglobin solubility → T-state aggregation → Hb forms long inflexible chains: sickled RBCs


What are the 2 ways of detecting SCD?

1. Electrophoretic analysis of HbS
2. Screening for the hbS mutation


Describe how electrophoretic analysis of HbS works.

The substitution of the negatively charged Glu with the neutral Val alters the electrical
property of the hemoglobin molecule such that it migrates more slowly toward the anode when placed in an electric field.


Does the electrophoretic analysis of HbS correspond to SDS page?

No! The protein is in its globular form


Describe how genetic screening of HbS works.

Used to be done with Southern blot, but now we use PCR w/ digestion of the DNA by restriction enzymes followed by gel electrophoresis


What are restriction enzymes? What are the ones used in SCD detection?

They are nucleases that recognize specific sequences.
The mutation in the ß globin gene changes the recognition site for particular restriction enzymes


How can you interpret the result of PCR for SCD detection?

- 3 smaller fragments: HbA
- 2 larger fragment: HbS


What is the lifespan of a normal RBC vs sickled?

90-120 days vs 10-20 days


What brings T-state tetramers together? What does this produce?

Hydrophobic interactions that produce HbS strands: 10/4 fiber (10 strands around a core of 4 strands)


Explain the 2 step process of HbS aggregation and fiber formation

1. The T-state HbS reversibly associate w/ each other
2. A critical nucleation mass is obtained, which nucleates the formation of other fibers, which in turn nucleates the formation of other fibers: this is irreversible.


What is the molecular threshold for sickle cell crisis?

The second step of HbS aggregation and fiber formation


What does the first step of HbS aggregation and fiber formation depend on? What does this mean?

Concentration dependent: decrease in T-state HbS = longer time for the step 1 to occur (could reach the lungs in time to avoid a crisis)


Explain the biochemical rationale for hydroxyurea use

The chemotherapeutic agent 5-azacytidine increases HbF by altering DNA methylation --> lowers HbS levels and prevents aggregations by preventing the mucleation mass from being reached


What do butyrates do to SCD patients?

They increase HbF levels and work synergistically with hydroxyurea


What is an additional benefit of taking hydroxyurea?

It produces nitric oxide, which acts as a potent vasodilator to:
1. Prevent vaso-occulsion
2. Prevent Hydroxyurea's rxn with T-HbS to form metHbS
3. Reacts with hydroxyurea to form HbSNO, which delays the onset of aggregation


Explain the biochemical rationale for cyanate use

It reacts with the N-termini of the alpha units, which are then unable to bind H+/CO2 (salt bridges and carbamate formation would stabilize the T-state)


Is cyanate still used to treat SCD?



Explain the biochemical rationale for hydration therapy use

Increase RBC volume to decrease HbS concentration


What can SCD patients do to avoid an SCD crisis?

Avoidance of situations that stabilize the T-state:
- Elevated temperatures
- Low O2 levels (eg: high altitude)
- Rapid temperature changes
-Dehydration: increases RBC concentration
- Very low temperatures (causes vasoconstriction)
- Stress


What happens to the 2,3-BPG concentration in response to anemia associated with SCD? Why? What is the result?

Concentration increases considerable to promote better delivery of O2 to the tissues
This complicates the situation because the higher levels stabilize the T-state


Would trying to decrease the concentration of 2,3-BPG in SCD patients be a good way to help them in theory?

Yes, but has not been tested


What are the 7 different genotypes of SCD?

1. HbSS (the most common form): homozygote for the S globin with usually a severe or moderately severe phenotype and with the shortest survival. It is typically associated with vascular obstruction and ischemia.
2. HbSA: heterozygote, is also known as sickle cell trait. Individuals with sickle cell trait are usually healthy, however if the individual’s parent also has another abnormal hemoglobin gene (thalassemia, hemoglobin C, hemoglobin D, hemoglobin E) they are likely to have SCD.
3. HbSc - intermediate
4. HbSB0 - Severe
5. HbSB+ - milder
6. HbS+F -asymptomatic
7. HbSE - Mild


What is ischemia?

Insufficient blood supply to the organs


What are some major complications of SCD?

• Damage to organs because of O2 deprivation
• Stroke
• Lack of blood in lungs: acute chest syndrome, COPD, pulmonary embolism
• Jaundice: sickle cells do not live as long as normal red blood cells and, therefore, they are dying faster than the liver can filter them out. Bilirubin (which causes the yellow color) from these broken down cells builds up in the system causing jaundice.
• Blindness
• Priapism: painful erection that can lead to impotence
• By the age of 5: asplenic: no spleen
• Susceptibility to develop bacterial infections because the spleen is not protecting them


Why are SCD patients given prophylactic antibiotics (penicillin)?

To prevent bacterial infections. They are more susceptible to these because of the lack of spleen (or decreased performance of the spleen)


What is the difference between acute and chronic transfusion therapies?

Acute: for episodic events or a needed medical intervention
Chronic: may be needed if complications due to SCD have occurred


What is the difference between simple and exchange transfusions?

- Simple: transfusing healthy RBCs
- Exchange: removing and replacing the patient's BV by pheresis to reduce the concentration of HbS without increasing the hematocrit


What is a negative side effect of transfusions?

Iron overload in vital organs which can be very dangerous


What is hypoxia?

Deficiency in the amount of oxygen reaching the tissues


Why do heterozygous patients have a lower rate of fiber formation and precipitation?

Because they have a lower concentration of HbS in their blood


Is decreasing erythrocyte volume to ease passage through capillaries a potential treatment for SCD patients?



Does the missense mutation in SCD patients affect Hb's affinity for H+?



Does HbS polymerization dependent on how long the HbS molecules are in the T-state?



Does HbS polymerization dependent on how long the HbS molecules are in the R-state?



What happens when the conditions are right for sickling to occur?

There is a lag between the conditions and the onset


Does HbS in the R-state have a lower affinity for O2 than HbA in the R-state?