Sickle Cell Disease (complete) Flashcards
Explain the molecular bases for sickle cell disease.
- Both Beta-globin genes are mutated
- At least one w/ Beta6 glu –> val and the other abnormal in the same or different way
- Called sickle disease w/ two glu–> val
What is the mode of inheritance of sickle cell disease?
Autosomal recessive
How does the sickle cell mutation lead to the phenotype?
- HbSS are easily lysed
- Don’t last long
- Normal looking w/ O2
- When O2 is released, create the sickle shape — cells clump together
- Can only last a few cycles (fewer than normal)
Describe the geographic distribution of sickle cell disease
- Most common in African, Indian, Middle Eastern, and Mediterranean pop’n
- Think: around equator
Describe a situation where people heterozygous for sickle cell disease may have a survival advantage.
Reduced risk of morbidity and mortality of malaria
Describe findings on CBC for pts w/ sickle cell disease
RI: increased
WBC: increased
Platelets: increased
RDW: increased
What are other abnormal chemistry findings in pts w/ sickle cell disease? Why?
Total/indirect bilirubin: increased
LDH: increased
AST: increased
All released from lysed RBCs
Describe findings on peripheral blood smear for pts w/ sickle cell disease
- Sickle forms
- Schistocytes
- Polychromasia
- Anisocytosis
- Poikilocytosis
- Howell-Jolly bodies
What are schistocytes?
“Broken” irregular cells
http://en.wikipedia.org/wiki/Schistocyte
What is polychromasia?
- Blue-colored cells
- Represent reticulocytes
http://en.wikipedia.org/wiki/Polychromasia
What is anisocytosis?
Variation in RBC size
http://en.wikipedia.org/wiki/Anisocytosis
What is poikilocytosis?
Variation in RBC shape
http://en.wikipedia.org/wiki/Poikilocytosis
What are Howell-Jolly bodies?
Small purple dots w/in RBCs
Seen in pts w/o a functional spleen
What is sickle trait?
Occurs in a person w/ 1 sickle gene and 1 NORMAL gene
What are the consequences of sickle trait?
- Normal gene produces Beta-globin chains in normal quantities
- This protects against development of sickle cell disease
What are the major variants of sickle cell disease?
1) Sickle Cell Anemia
2) Sickle B(0) thalassemia
3) Sickle- Hb C
4) Sickle B(+) thalassemia
5) Sickle Cell Trait
Describe sickle cell anemia. Include Beta-globin gene types, normal Hb amount, normal retic count, size of RBC, clinical severity.
B-globin genes: S+S
Hb count: 6-9 (nl: 14=16g/dl)
Retic count: 5-30% (nl: 1-2%)
RBC size: Normal
Clinical Severity: 4+ (worst)
Describe Sickle B(0) Thalassemia. Include Beta-globin gene types, normal Hb amount, normal retic count, size of RBC, clinical severity.
B-globin genes: S+B(0)
Hb count: 6-9 (nl: 14=16g/dl)
Retic count: 5-30% (nl: 1-2%)
RBC size: Small
Clinical Severity: 4+ (worst)
Describe Sickle Hb C. Include Beta-globin gene types, normal Hb amount, normal retic count, size of RBC, clinical severity.
B-globin genes: S+C
Hb count: 10-12 (nl: 14=16g/dl)
Retic count: 3-5% (nl: 1-2%)
RBC size: Normal
Clinical Severity: 2+ (mid)
Describe Sickle B(+) Thalassemia. Include Beta-globin gene types, normal Hb amount, normal retic count, size of RBC, clinical severity.
B-globin genes: S+B(+)
Hb count: 11-13 (nl: 14=16g/dl)
Retic count: 3-5% (nl: 1-2%)
RBC size: Small
Clinical Severity: 2+ (mid)
Describe Sickle Cell Trait. Include Beta-globin gene types, normal Hb amount, normal retic count, size of RBC, clinical severity.
B-globin genes: normal+S
Hb count: 14-16 (nl: 14=16g/dl)
Retic count: 1-2% (nl: 1-2%)
RBC size: Normal
Clinical Severity: 0 (not severe)
Describe the deoxygenated state of HbS
HbS polymerizes into 14-strand helical fibers
These distort shape — membrane is damaged
Describe the reoxygenated state of HbS
- Polymers dissolved
- Normal shape achieved
What happens to HbS after several deoxy-reoxy cycles?
- Cell becomes irreversibly sickled
- Then lysed/destroyed
What happens to HbS shape in presence of other Hb?
- Normal Hb or HbC interfere w/ polymerization process
- Lessens tendency for RBC sickling/membrane injury
- Lessens disease
What are the signs and symptoms of sickle cell disease?
1) Chronic hemolytic anemia
2) Chronic RBC adhesion/vascular occlusion
3) Acute RBC adhesion/occlusion
Describe chronic hemolytic anemia as it relates to sickle cell disease
- Sickle RBC is fragile/rigid —> chronic RBC destruction
- Sickle RBCs only last 20 days —> ^RI, ^WBC, ^platelets, ^RDW
Describe chronic RBC adhesion/vascular occlusion as it relates to sickle cell disease
- RBCs extra sticky b/c of membrane injury/retention of adhesion molecules at cell surface
- Cell adhesion —> vaso-occlusion, vessel wall injury, endothelial remodeling —> vessels narrow —> chronic organ damage
Which organs are chronically damaged due to chronic RBC adhesion in sickle cell disease?
1) Spleen
2) CNS
3) Lungs
4) Kidney
5) Retina
6) Femoral/humeral heads
7) Skin
Describe the chronic damage on the spleen in sickle cell disease
- Large # of RBCs trapped —> splenic sequestration, chronic circulation occlusion
- Causes tissue death (autoinfarction)
- Compromises spleen’s killing of bacteria
Describe the chronic damage on the CNS in sickle cell disease
- Large blood vessels damaged by sickle RBCs
- 10% of kids w/ HbSS have stroke
- Adults more likely to have hemorrhages from progressive vessel weakening —> rupture
Describe the chronic damage on the lungs in sickle cell disease
Damage to vessel in lungs —> ^ pressure in pulm arteries
Causes strain of R side of heart (30-40% of pts)
Most common cause of death for sickle cell disease
Describe the chronic damage on the kidney in sickle cell disease
Tubules damaged by chronic vaso-occlusion —> inability to concentrate urine
Leads to dehydration, blood in urine, glomeruli enlargement, protein in urine
In 10% of pts
Describe the chronic damage on the retina in sickle cell disease
Retinal vessel damage —> retinal detachment/blindness
Describe the chronic damage on the femoral/humeral heads in sickle cell disease
Avascular necrosis —> chronic pain/joint deterioration
Can require joint replacement surgeries
Describe the chronic damage on the skin in sickle cell disease
Can cause ulcers, often on ankles
Microvascular ischemia and poor healing
Describe acute RBC adhesion/occlusion
AKA: sickle cell crisis
hypoxia, dehydration, inflammation, infection —> sickle RBCs damaged —> sudden vaso-occlusion
Leads to pain crisis (b/c of reversible ischemia)
Resolves when cause resolves
What does RBC adhesion/occlusion cause?
1) Splenic sequestration
2) Hand-foot syndrome
3) Acute chest syndrome
4) Acute multi-organ failure
5) Priapism
6) Bone infarction
Describe acute chest syndrome in pts w/ sickle cell disease
Sickle RBCs trapped in lung circulation
Damages vessels —> fluid leaks out —> cannot oxygenate blood
What is priapism?
Sickle RBCs trapped in penis, painful sustained erections
Explain the relationship between aplastic crisis and parvovirus B19
Parvovirus B19 causes aplastic crisis —> fifth disease
Infection is usually quick — pts may need a transfusion
What are the consequences of fifth disease?
Infects RBC precursors —> arresting their development
What are some therapies used to treat pts w/ sickle cell disease?
1) Folic acid
2) Penicillin
3) Bone marrow transplantation
4) Hydroxyurea therapy
5) Transfusion therapy
Why is folic acid used as a treatment for pts w/ sickle cell disease?
In response to developmental delays caused by anemia
Why is penicillin used as a treatment for pts w/ sickle cell disease?
Sepsis! used as prophylactic
Splenic death can kill kids w/ HbSS
Why is bone marrow transplantation used as a treatment for pts w/ sickle cell disease?
Leads to >90% disease-free survival
Only 20% of eligible pts have a donor (matched full sibling w/o HbSS)
Why is hydroxyurea therapy used as a treatment for pts w/ sickle cell disease?
- An oral chemotherapy agent —> induces production of HbF
- HbF interferes w/ HbS polymerization
- Improves anemia
- Reduces acute pain crises
- Reduces mortality
Why is transfusion therapy used as a treatment for pts w/ sickle cell disease?
- Most people don’t require these
- Used if anemia is worsening
- May reverse process
Can lead to iron overload
Describe iron chelation therapy
Binds excess iron
Used for pts who receive multiple transfusions
Why is iron chelation challenging for some pts?
- Most common agent (deferoxamine) is infused sq in abdomen
- Requires 8-12 hrs, 5-7 times/week
Explain how newborn screens can be used to diagnose sickle cell disease
- All infants born in US are screened for hemoglobinopathies
- Uses heel stick
- Parental ed and prophylactic penicillin can be used ASAP to prevent early deadness
