Sickle Cell Disease

Question 1

What are the factors that influence Hb S polymerization?

Answer 1

1. decreased oxygen tension/saturation
2. decreased pH, right shift in O2 curve
3. Decreased intracellular hydration, right shift
4. increase temperature, right shift.

inhibited by HbF

Question 2

What is the genetic cause of sickle cell?

Answer 2

Hb S: glu–>val substitution of beta globin, 6th position

Hb C: glu–>lys, same position

Question 3

Describe how polymerization affects RBC cell.

Answer 3

1. membrane damage due to fragmentation and oxidant damage
   - exposure of cryptic protein seq–>adherence to vascular endothelium, PS–>prothrombotic, membrane rigidity
2. intracellular dehydration due to loss of K+ and water–>deformation, increase blood viscosity, decreased blood flow

Question 4

What are the common genotypes of the sickle cell disease?

Answer 4

Sickle cell anemia: Hb SS
Sickle-C disease: Hb SC
S B+ thalassemia: Hb SB+
S B0 thalessemia: Hb SB0
other combinations rare

Question 5

What is the mechanism that produces the signs and symptoms of sickle cell disease?

Answer 5

VASCULAR OCCLUSION
less dense RBC adheres to vascular endothelium (post capillary venule)–>partial obstruction–>dense cells lodge behind and occlude–>hypoxia causes sickling in trapped cells–>obstruction spreads retrograde–>log jam

-causes acute pain and organ damage

Question 6

What are some clinical features of sickling disorders?

Answer 6

• chronic hemolytic anemia
• intermittent acute events called crises
• increased susceptibility to bacterial infections
• specific organ syndromes due to ischemia/infarc/necrosis

Question 7

What are major causes of morbidity and mortality in sickling disease?

Answer 7

• acute chest syndrome: adult respiratory distress syndrome,
• stroke
• infection

Question 8

List the organ damage syndromes associated with sickling disease.

Answer 8

1. acute chest syndrome
2. proliferative sickle retinopathy
3. auto-splentectomy due to ischemic necrosis
4. cholelithiasis: due to increased bill from hemolysis
5. avascular necrosis of bone
6. renal insufficiency

Question 9

What are the general therapeutic approaches to sickle cell disease?

Answer 9

• transfusion
• supportive care: IV hydration, pain management, infection prophylaxis, end organ complication management
• hydroyurea: ribonuclease reductase inhibitor to increase Hb F production and decrease membrane damage
• other Hb F modulating agents
• bone marrow transplantation: select patients
• gene therapy: more in future