Clinical Correlation: Sickle Cell Anemia

Question 1

what is the genetic cause for sickle cell anemia?

how is this genetic disease inherited?

Alpha or beta hemoglobin?

Answer 1

a glutamic acid aa is substituted for a valine

• therefore going from a acidic, negatively charged polar aa to a non polar one
• at position 6 on the beta subunit of Hg

autosomal recessive

Question 2

how does the mutation form filaments?

where do they form?

does the filament formation happen more in the lungs or the tissues?

Answer 2

the non polar valine creates a hydrophobic motif that enables binding btwn beta chains of 2 deoxygenated HbS tetramers (aggregate bc hydrophobic)

*only exposed in the T (deoxyHb) form on the outer surface of the Hg tetramer

this allows formation of fibrous polymeric filaments of deoxyHb

more in the tissues because thats where the T state predominates

Question 3

the sickle shape and the filament precipitation ultimately causes?

what causes the filaments to dissociate

Answer 3

vaso-occlusion which leads to the peripheral pain and many other complications

• also see domino effect of more filaments climbing and therefore more deoxygenated blood which leads to a forward cycle
• exposure to oxygen in the lungs causes filaments to dissociate

Question 4

describe a sickle cell crises

Answer 4

• slow blood flow in capillaries can lead to crises bc longer time allows filaments to polymerize and further blockage
• oxygen deprivation and dehydration can contribute

Question 5

how does one diagnose sickle cell anemia? what are the 2 options?

Answer 5

1) Newborn screening
use high pressure liquid chromatography

which is a cation exchange (so the column is neg and catches pos charge)

different hB subunts have different charges on surface and will interact with the column.

But the affinity for the negatively charged column will be higher as val has replaced glutamic acid. therefore hbs elutes LATER

2) isoelectric focusing:
separate proteins based on charge and do gel electrophoreses. get hb to move through until it reaches an isoelectric point. can see the acid group missing

Question 6

how is sickle cell unique.

what can trigger the disease?

hallmark physical sign?

Answer 6

first time a disease linked to molecular abnormality

triggers include cold air, infections, dehydration, anesthesia, etc.

delayed growth and puberty

Question 7

what is the prevalence of sickle cell?

Answer 7

8-10% of AA cary the trait and

70-80k americans have it

Question 8

PiSCES study

PROPS study

Answer 8

pain on a daily basis- ER visit is tip of the iceberg

penicillin prophylaxis in sickle cell

Question 9

what are the top 3 complications of sickle cell and how do you treat them?

Answer 9

1) actue chest syndrome: new infiltrate in CXR with chest pain and fever that progresses rapidly (12 hrs)
tx: oxygen, antibiotics, steriods, etc.
2) splenic sequestration: sometimes the spleen disappears by 11 mths but if pt has spleen, vasoocclusion prevents blood from leaving and rapidly enlarges. person goes into hypoglemic shock bc not enough blood circulating
tx: IVF hydration and blood transfusion

3) stroke : get stenosis in brain and blood supply slows down
- can use transcranial doppler to screen for blood velocity

standard of care: give transfusion that is continual and indefinite.

Question 10

what are 3 good treatment options

what direction is the new research going in?

Answer 10

1) hydroxyurea- FDA approved medication. increases hbf levels (fetal) in a reverse manner and increases nitric oxide which is a vasodilator
2) bone marrow transplant: by day 100 you are good to go. new approach is to lower toxicity of iron
3) blood transfusion
- new research looks as neutrophils that adhere to the wall of the vessel bc it may activate sickled cells as a first step.