Lecture 15

Question 1

Sickle Cell Disease

Answer 1

• Most common genetic disorder in US
o 100,000 Americans living w/ SCD
o 1000 babies w/ SCD born each year
 1/500 AA babies born
• 3 million Americans have sickle cell trait
o ½ African Americans
• Sickle cell life span 10-20 days, normal 120 days
• Affected: African American, Mediterranean, Arabians, Indians

Question 2

SC Mutation

Answer 2

• SCD caused by single point mutation
o Beta chain of HbA
o GAT->GTT, Glu->Val
• Although caused by a single point mutation, SCD is a multigenic disorder
o there is phenotypic diversity not accounted for by hemoglobin genotype
o other genetic polymorphisms and differences in gene product function contribute to the complexity of phenotypic expression
o multiple environmental, psychological, and social factors affect the disease course
o variable clinical severity w/in and b/w patients

Question 3

Hemoglobins in normal adults

Answer 3

o HbA – 96-98%, HbF ~1%, HbA2 <3.5%
• Primary function of Hb is to pick up O2 in pulmonary circulation and transport/deliver to tissues
o Tasks facilitated by the allosteric nature of the Hb molecule
o HbS not normally present and has a decrease in solubility when deoxygenated causing vaso-occlusion

Question 4

Sickle Cell Trait

Answer 4

Not a disease
o	8% of AA
o	Not a mild form of sickle cell disease
o	Absence of sickle pain episodes
o	Normal life expectancy
o	100M ppl worldwide

Question 5

SCD Types

Answer 5

• SCD can be different combinations of mutations
o HbSS – sickle cell anemia
o Hb S/B thalassemia
o Hb SC

Question 6

Clinical Manifestations of SCD

Answer 6

o Anemia
 Reduced life span of red blood cells in the circulation
 Hemolysis w/ decreased availability of nitric oxide (NO)
o Vaso-occlusion
o Vasculopathy – changes in the blood vessel wall
• Every organ in body can be affected (strokes, loss of vision, pulmonary hypertension, gallbladder stones, liver/kidney failure, bone infarcts, leg ulcers, priapism)
• Sickle cell retinopathy (more common in adults)
• Chronic kidney disease is common in SCD

Question 7

Painful Episode

Answer 7

o Most common clinical complication
o Vaso-occlusion
 Skeletal, soft tissue, various organs
o Adversely affects QOL
o Variable frequency
o Unpredictable
o Often can not identify a precipitating cause
o Believe patient – no biomarkers to monitor
o Oral and IV narcotic analgesia often required issues of dependence

Question 8

Stroke

Answer 8

o Cerebrovascular occlusion – more common at young ages
 10% of children w/ HbSS
 Vasculopathy
• Large intracranial blood vessels
o Hemorrhagic – more common in adults
o Transfusion can decrease recurrence risk

Question 9

Acute Chest Syndrome

Answer 9

o	Progressive respiratory tract symptoms and signs
	Chest pain, fever, hypoxia, infiltrates
o	Causes
	Infection
	Fat emboli (from bone marrow)
	In situ sickling
	Pulmonary infarction
o	May be life threatening

Question 10

Priapism

Answer 10

o Sustained painful erection
o Treated acutely w/ aspiration
o Surgical shunting is required if no resolution
o Can lead to permanent scarring and impotence if not promptly treated

Question 11

Pulmonary Hypertension

Answer 11

o Right side if heart needs to work harder to pump blood to the lungs
o Can lead to chronic and progressive shortness of breath, hypoxia, dyspnea, and heart failure
o Difficult to treat

Question 12

Splenic Infarction

Answer 12

o Occurs in majority of HbSS patients in early childhood
o Risk for life-threatening bacterial infections
o Prevent w/ vaccinations and prophylactic antibiotics

Question 13

SCD Treatments

Answer 13

o Immunizations – prevent childhood infections, sepsis
o Penicillin prophylaxis-in children
o Hematopoietic stem cell transplantation
 Potentially curative
 Not available to most patients
o Chronic red blood cell transfusion
 Labor intensive
 Significant side effects and not used for uncomplicated pain crisis
o Therapies to increase fetal hemoglobin
 Hydroxyurea
 Decreases painful episodes, hospitalization, chest syndrome and extends life
 Barriers to use
o L-glutamine powder

Question 14

How did SCD become a chronic adult disease

Answer 14

 1973 life expectancy was 14 years of age
 Dramatic increase in life expectancy in pts cared for at a comprehensive sickle cell center
• Median life expectancy is increasing w/ medical advances
o Male SS = 42 yrs, females=48 yrs
o Male SC=60 years, females=68 yrs
 Post HU likely even better
 Bone marrow transplant leads to cure in those treated