Sickle Cell Disease

Question 1

Explain (1) the molecular bases for sickle cell disease and (2) how specific mutation leads to the phenotype. (3) Describe the mode of inheritance.

Answer 1

SCD is (3) an autosomal recessive genetic disorder of hemoglobin in which (1,2) both of the Beta-globin genes are mutated, at least 1 with the characteristic single amino acid substitution of sickle cell (Beta6 glu val) and 1 that is abnormal. If the other gene also has the sickle cell mutation, the disease is called Sickle Cell Anemia (HbSS). Sickle cell disease also occurs if the other gene is abnormal (HbC) or there is a underproduction of normal Beta globin chain (B-thalassemia).

Question 2

Describe the geographic distribution of sickle cell disease and a situation where people heterozygous for sickle cell disease may have a survival advantage.

Answer 2

Most common in African, Indian, Middle Eastern and Mediterranean populations (around equatorial region of the world). When carried as a genetic TRAIT (heterozygous state- 1 gene normal, 1 gene mutated) the presence of the abnormal hemoglobin likely reduces the morbidity and mortality of malaria, providing carriers with survival advantage

Question 3

Describe the findings on the CBC and peripheral blood smear in patients with sickle cell disease

Answer 3

Blood smear: sickle cells, schistocytes (broken cells), polychromasia (blue colored retic’s), anisocytosis (size of RBCs varies), poikilocytosis (shape of RBCs varies). Howell-Jolly bodies seen in pts without a spleen (purple dots in RBCs). Target cells and Hgb C crystals (seen in HbSC disease). Microcytosis (with low MCV) and target cells found in HbSβ0 thalassemia and HbSβ+ thalassemia

Question 4

Describe what “sickle trait” is and the consequences of having sickle cell trait.

Answer 4

Sickle cell trait occurs in a person with 1 sickle gene and one NORMAL gene. The normal gene produces Beta-globin chains in normal quantities and protects against the development of sickle cell disease. People with sickle cell trait do NOT develop sickle cell disease

Question 5

Describe major variants of sickle cell disease, including sickle beta-thalassemia and SC disease.

Answer 5

Look at graph: 
HbSS
HbSB0
HbSC
HbSB+
Sickle Cell Trait

Question 6

Describe the precipitating factors and pathophysiologic process by which hemoglobin S causes sickling

Answer 6

Deoxygenated state: sickle hemoglobin polymerizes into 14-strand helical fibers which distore the shape of the RBC into a sickle form and membrane is damaged. When reoxygenated, the polymers dissolve and the RBC returns to its normal shape. After several deoxy-reoxy cycles, the cell becomes IRREVERSIBLY sickled and is lysed/destroyed. The presence of other hemoglobins (ie: HgbC or some normal HgbA) interferes with the polymerization process and lessens the tendency for RBC sickling and membrane injuryattenuates disease

Question 7

Describe the signs and symptoms, both acute and chronic, of the consequences of sickling

Answer 7

1. Chronic hemolytic anemia: sickle RBC is fragile/rigid chronic RBC destruction. Sickle RBC’s survive only 20 days. Can also have aplastic crisis (sudden drop in hemoglobin due to bone marrow’s inability to produce RBCs (ie: infection, medications, vitamin deficiency-folic acid), presentation is low retic count. Growth retardation/delay (related to anemia and increased metabolic rate from increased RBC production). Bilirubin gallstones (from chronic bilirubin elevation).
2. Chronic RBC adhesion/vascular occlusion: even when not sickled, the RBCs in sickle cell disease are extra sticky due to membrane injury and retention of adhesion molecules of the surface. Adhesion of cells to microvasculature transient vaso-occlusion, vessel wall injury, endothelial remodeling vessels narrow chronic organ damage especially to the spleen, CNS, lungs, kidney, retuna, femoral/hemoral heads and skin
3. Acute RBC adhesion/occlusion: sickle cell crisis: under conditions of hypoxia, dehydration, inflammation, infection or other stresses, the RBCs sickle and blood cells become acutely damaged and constricted, which promotes sudden vaso-occlusion “pain crisis” (pattern of pain is unique to each individual, but in arms, legs, chest and ABD). Pain is due to reversible ischemia and resolves when inciting factors improve.

Question 8

chronic organ damage due to RBC adhesion/vascular occlusion: spleen—

Answer 8

when large # of RBCs are trapped: splenic sequestration, chronic occlusion of spleen’s microcirculation: autoinfarction (destruction) of spleen by age 5. This also compromises the spleens ability to kill organisims (pneumococcus, meningococcus, hemophilis) which can lead to sepsis. Reduced risk if children use prophylactic penicillin.

Question 9

chronic organ damage due to RBC adhesion/vascular occlusion: CNS—

Answer 9

large blood vessels of CNS can be damaged by sickle RBCs. 10% of children with HbSS has a large vessel stroke. Risk detected by transcranial Doppler (increased blood velocity= increased risk for stroke). Risk reduced with blood transfusions. Adults are more likely to have hemorrhages from progressive weakening and rupture of vessels.

Question 10

Lung—

Answer 10

damage to vessels in lungs increase pressure in pulmonary arteries (PAH), which strains the R side of the heart (30-40% of patients). Most common cause of death in adults with sickle cell disease.

Question 11

chronic organ damage due to RBC adhesion/vascular occlusion: Kidney—

Answer 11

Tubules damaged by chronic vaso-occlusion resulting in the inability to concentrate urine to avoid dehydration, blood in urine, enlargement of the glomerulus and protein in urine. 10% of pts develop renal insufficiency.

Question 12

chronic organ damage due to RBC adhesion/vascular occlusion: Retina—

Answer 12

retinal vessel damage retinal detachment and blindness

Question 13

chronic organ damage due to RBC adhesion/vascular occlusion: femoral/humeral heads—

Answer 13

avascular necrosis chronic pain and progressive join deterioration (requires hip and shoulder replacement).

Question 14

chronic organ damage due to RBC adhesion/vascular occlusion: Skin ulcers—

Answer 14

microvascular ischemia and poor healing (most often on ankles).

Question 15

Examples of acute RBC adhesion/occlusion

Answer 15

1. Splenic sequestration
2. Hand-foot syndrome: in infants, swelling of hands and feet, early manifestation of HbSS
3. Acute chest syndrome: sickled RBCs trapped in lung circulation, damages vessels, fluid leaks out, cannot oxygenate blood.
4. Acute multi-organ failure syndrome: acute renal failure and liver failure.
5. Priapism: RBCs trapped in penis, painful sustained erections
6. Bone infarction: ischemia of bone that can lead to necrosis.