Sickle Cell Disease I Flashcards
INTRODUCTION AND PATHOGENESIS
What is Sickle cell disease?
Sickle cell disease (SCD) and its variants are genetic disorders of mutant haemoglobin (Hb).
Sickle Cell Disease results when someone inherits two abnormal Hb genes and at least one of the genes is HbS. Inheritance is by autosomal recessive and follows simple Mendelian principle:
•Which means when one parent is homozygous for the βs-gene and the other is normal then all the offspring has equal chance of having either a trait AS or normal AA genotype
What is Sickle cell anaemia and consesquences of the disease?
Sickle cell anaemia is the term used for homozygous presence of two abnormal beta s gene.
*The major consequence of this sickle shape is that RBCs become much less deformable; therefore, they obstruct the microcirculation. Tissue hypoxia occurs, which promotes further sickling.
*Sickle-shaped RBCs are rapidly haemolyzed and have a life span of only 10-20 days (vs the normal 120 days).
Patients who are homozygous for the HbS gene have full-blown sickle cell anemia. Patients who are heterozygous for the HbS gene are carriers of the condition.
Can carriers display clinical manifestations is sickle sell?
Under stressful conditions, carriers may display some clinical manifestations (e.g, severe hypoxia). If both members of a couple are carriers, they have a 25% risk of producing a child who is homozygous for the HbS gene.
What varies from individual to individual in sickle cell?
Morbidity, frequency of crisis, degree of anaemia, and the organ systems involved vary considerably from individual to individual
Epidemiology of SCD
•Sickle cell disease is widespread in Africa.
•In several sections of Africa, the prevalence of sickle cell trait (heterozygote) is as high as 30%.
•Many children are not diagnosed, especially in rural areas, and death is often attributed to malaria or other co-morbid conditions.
•Incidence at birth is determined by gene frequency,
• in Africa= 25-40%,
•Nigeria 25% for the gene, 3% for homozygous.
•Prevalence at later ages is determined by patients’ survival
Sickle cell gene is also found, with much less frequency, in eastern Mediterranean and Middle East populations, and to a lesser extent in India.
•In the US: is present in approximately 8% of black Americans.
•The expected incidence of sickle cell anemia in the United States is 1 in 625 persons at birth.
•The actual prevalence is less because of early mortality.
•More than 2 million people in the United States, nearly all of them of African American ancestry, carry the sickle gene.
Where did Hbs likely originate from?
Hbs- gene probably originated by:
•Multiple independent mutations in Africa. DNA polymorphism of the beta S gene suggests that it arose from 5 separate mutations:
•The ancestry of the first 4 cases of Hbs were traced to West Africa, one mutation in Saudi Arabia/ India.
•The most common of these is an allele found in Benin in West Africa. Other haplotypes are found in Cameroon, Senegal and Bantu africa, as well as in India and the Middle East.
HbS: What is the…
Abnormal aa
Position
Normal aa?
Abnormal aa: Valine
Position: 6
Normal aa: Glutamic Acid
HbC: What is the…
Abnormal aa
Position
Normal aa?
Abnormal aa: Lysine
Position: 6
Normal aa: Glutamic Acid
HbE: What is the…
Abnormal aa
Position
Normal aa?
Abnormal aa: Glutamine
Position: 26
Normal aa: Glutamic Acid
HbE: What is the…
Abnormal aa
Position
Normal aa?
Abnormal aa: Glutamine
Position: 121
Normal aa: Glutamic Acid
Hb Oarab: What is the…
Abnormal aa
Position
Normal aa?
Abnormal aa: Lysine
Position: 121
Normal aa: Glutamic Acid
PATHOGENESIS OF HAEMOGLOBIN S
- Hb S arises from a point mutation substituting thymine for adenine in the sixth codon of the beta-chain gene, GAG to GTG.→ coding for valine instead of glutamine in position 6 of the Hb beta chain.
- The resulting Hb has the physical properties deoxy conditions.
- Under deoxy conditions (which inititiates the sickling process), Hb S undergoes marked decrease in solubility, increased viscosity, and polymer (a slow and gradual polymer formation, with a parallel array of filaments) formation at concentrations exceeding 30 g/dL.
*Cytoplasm forms a gel-like substance containing Hb crystals called tactoids. The gel-like form of Hb is in equilibrium with its liquid-soluble form.
*These properties are responsible for the profound clinical expressions of the sickling syndromes. The sickling is reversible with reoxygentation, but repeated and prolonged sickling damages the membrane causing an irreversibly sickled rbc.
What are the factors that influence the equilibrium of the gel-like form of Hb and the liquid-soluble form / factors affecting sickling ?
- Oxygen tension : Polymer formation occurs only in the deoxy state. If oxygen is present, the liquid state prevails.
- Concentration of haemoglobin S
* The normal cellular Hb concentration is 30 g/dL.
* Gelation of Hb S occurs at concentrations greater than 20.8 g/dL. - The presence of other haemoglobins: Normal adult haemoglobin (Hb A) and foetal haemoglobin (Hb F) have an inhibitory effect on gelation & polymerization.
- These and other Hb interactions affect the severity of clinical syndromes.
- Hb SS produces a more severe disease than sickle cell Hb C (Hb SC), Hb SD, Hb SO Arab, and Hb with one normal and one sickle allele (Hb SA).
What happens after recurrent episodes of sickling?
After recurrent episodes of sickling,
membrane damage occurs and the cells are no longer capable of resuming the biconcave shape upon reoxygenation.
Thus, they become irreversibly sickled cells (ISCs). 5-50% of RBCs permanently remain in the sickled shape
- When RBCs sickle, they gain Na+ and lose K+. * Membrane permeability to Ca2+ increases, possibly due, in part, to impairment in the ATPase dependent Ca2+ pump.
- The intracellular Ca2+ concentration is 4 times the reference level. The membrane becomes more rigid, however, these changes are not found consistently. Also, whether calcium is solely responsible for membrane rigidity is not clear.
- The lipid bilayer is perturbed. The outer leaflet’s increased amounts of phosphatidyl ethanolamine, containing phosphatidyl serine, may contribute to thrombosis, acting as a catalyst for plasma clotting factors.
Why is there increased adherence of Sickle cells?
Sickle cells express very late antigen (VLA)-4 on the surface. which interacts with the endothelial cell adhesive molecule, (VCAM)-1, increasing adhesion
VCAM-1 is up regulated by hypoxia and inhibited by nitric oxide. Hypoxia also decreases nitric oxide production, thereby adding to the adhesion of sickle cells to the vascular endothelium. Nitric oxide is a vasodilator.
Free Hb is an avid scavenger of nitric oxide. Because of the continuing active haemolysis, there is free Hb in the plasma, and it scavenges nitric oxide. This makes it less available and contributes to vasoconstriction.
