SCA Flashcards
Genetic Disorder: SCD is an inherited condition, which means it is passed down from parents to children through genes. Specifically, it is an autosomal recessive disorder, meaning a child must inherit abnormal genes from both parents to have the disease.
Hemoglobin (Hb): Hemoglobin is a protein in RBCs that carries oxygen. It contains
four chains (two alpha and two beta) and includes
Normal adult hemoglobin (HbA),
some HbA2
fetal hemoglobin (HbF).
What Causes of SCD
Mutation: SCD is caused by a mutation in the 6th codon of the beta-globin gene, changing glutamic acid to valine.
Impact of SCD:
RBC Lifespan: In SCD, RBCs live only 10-20 days instead of the normal 120 days, causing the bone marrow to struggle to produce enough new RBCs.
Shape and Function: Sickle-shaped RBCs are stiff and sticky, leading to blockages in small blood vessels. This blockage causes ischemia (reduced blood flow), severe pain, and organ damage over time.
Inheriting one HbS gene and one normal gene usually results in Sickle Cell Trait, which is often asymptomatic (no symptoms)
In Africa Nigeria the percentage with SCD is?
2-3%
Sickle Cell Disease Pathogenesis
Pathogenesis of Sickle Cell Disease (SCD) involves how the disease develops and progresses due to the abnormal sickle hemoglobin (HbS).
Explain the Mechanism of Sickle Cell Disease (SCD)
SCD is caused by a point mutation in the β-globin gene, where glutamic acid is replaced by valine at the 6th position.
This mutation produces hemoglobin S (HbS) instead of normal hemoglobin A (HbA).
Polymerization Process:
Under low oxygen conditions, HbS molecules stick together, forming long chains or polymers.
This polymerization changes the RBC from a flexible biconcave disc into a rigid, sickle (crescent) shape.
- Initial Cellular Changes
Viscous Gel Formation:
As HbS molecules polymerize, the RBC cytosol (the liquid inside the cell) changes from a liquid to a viscous gel.
This gel formation marks the beginning of cellular rigidity.
Deoxygenation-Reoxygenation Cycles:
Repeated cycles of deoxygenation (losing oxygen) and reoxygenation (gaining oxygen) cause the HbS polymers to grow and shrink, stressing the RBC membrane.
- Membrane Damage and Ion Influx
Herniation and Membrane Damage:
As HbS polymers grow, they push against and eventually herniate through the cell membrane, damaging its structure.
This damage allows an abnormal influx of calcium ions (Ca2+) into the cell.
Activation of Ion Channels:
The increased Ca2+ activates ion channels, leading to an efflux of potassium (K+) and water (H2O) out of the cell
These changes result in the RBC becoming dehydrated, dense, and rigid.
Irreversibly Sickled Cells:
With repeated sickling episodes, RBCs become increasingly deformed.
Some cells become irreversibly sickled, maintaining their sickle shape even when oxygenated.
These cells are particularly prone to destruction by the spleen, leading to chronic hemolysis.
- Chronic Hemolysis
Extravascular Hemolysis:
Irreversibly sickled cells are rapidly sequestered and destroyed by macrophages in the spleen (extravascular hemolysis).
Intravascular Hemolysis:
The mechanical fragility of sickled cells also leads to their rupture within blood vessels (intravascular hemolysis).
- Microvascular Occlusion
Increased Adhesion:
Sickled RBCs express higher levels of adhesion molecules, making them sticky and prone to adhering to blood vessel walls.
Inflammatory mediators, released during inflammation, further increase the expression of adhesion molecules on endothelial cells.
Stagnation and Sickling:
Adhesion of sickled cells to the endothelium slows blood flow, particularly in microvascular beds (small blood vessels).
Stagnation in these areas leads to prolonged low oxygen conditions, causing more sickling and occlusion.
Cycle of Occlusion and Ischemia:
The cycle of sickling, vascular occlusion, and hypoxia (low oxygen) creates a feedback loop, leading to repeated blockages and tissue damage.
- Role of Nitric Oxide (NO)
NO Depletion:
Free hemoglobin (Hb) from lysed sickle cells binds to and inactivates nitric oxide (NO), a potent vasodilator and inhibitor of platelet aggregation.
Reduced NO levels lead to increased vascular tone (narrowing of blood vessels) and enhanced platelet aggregation.
Contribution to Vascular Occlusion:
The depletion of NO exacerbates the tendency for sickled RBCs to block small blood vessels.
This further contributes to the cycle of sickling, ischemia, and organ damage.
What are the Factors Affecting the Rate and Degree of Sickling
- Hemoglobin Composition
Heterozygotes (Sickle Cell Trait - SCT):
Individuals with SCT have a mix of hemoglobin types: about 40% HbS and 60% normal hemoglobin A (HbA).
HbA interferes with the polymerization of HbS, preventing sickling under normal oxygen conditions.
Sickling in SCT only occurs under extreme hypoxia (very low oxygen levels).
Hemoglobin F (HbF):
HbF, or fetal hemoglobin, inhibits the polymerization of HbS more effectively than HbA.
Infants with high levels of HbF are typically asymptomatic because HbF prevents sickling.
Symptoms of SCD usually begin to appear around 6 months of age as HbF levels naturally decline.
- Mean Corpuscular Hemoglobin Concentration (MCHC)
High MCHC:
An increased concentration of HbS within RBCs (high MCHC) promotes HbS aggregation and polymerization.
Dehydration of RBCs raises MCHC, further facilitating the sickling process as cells lose water and become more concentrated with HbS.
- Intracellular pH
Decreased pH (Acidosis):
Lower intracellular pH reduces the oxygen affinity of hemoglobin, leading to more deoxygenated HbS at any given oxygen level.
This increase in deoxygenated HbS enhances its tendency to polymerize and form sickle shapes.
Clinical features of SCD
Onset:
Symptoms are typically present from birth but are rare before 3-6 months of age due to protective levels of HbF.
Main Symptoms:
Pain: Episodes of pain, especially in the joints, due to vascular occlusion.
Anemia: The rate of erythropoiesis (production of new RBCs) cannot keep pace with the rate of hemolysis (destruction of RBCs).
Infection: Increased susceptibility to infections, including minor ones and severe, life-threatening conditions such as septicemia, pneumococcal meningitis, and osteomyelitis.
What are the different typeset of Sickle Cell Crises
Vaso-occlusive Crisis:
Episodes of severe pain due to blockage of blood flow by sickled cells.
Hyperhemolytic Crisis:
Rapid destruction of RBCs leading to severe anemia.
Splenic Sequestration Crisis:
Common in children. Sickle cells get trapped in the spleen, causing a rapid drop in hemoglobin (Hb) levels and spleen enlargement. Symptoms include abdominal pain, shock, shortness of breath (dyspnea), and rapid heartbeat (tachycardia).
Aplastic Crisis:
Often triggered by infection with parvovirus B19, leading to temporary cessation of RBC production in the bone marrow
List the Factors Associated with Increased Risk of Crisis
Strenuous Exercise:
Increases oxygen demand and can exacerbate sickling.
Dehydration:
Leads to increased MCHC and promotes sickling.
Emotional Stress:
Can trigger physiological changes that promote sickling.
Air Travel:
Hypoxia at high altitudes can induce sickling.
Sudden Changes in Temperature:
Can cause vasoconstriction and promote sickling.
Pyrexia (Fever):
Increases metabolic demand and oxygen consumption.
Infection:
Can trigger immune responses and inflammation, promoting sickling.
Anesthetics:
Certain anesthetics can lower oxygen levels and promote sickling.
Pregnancy/Labor:
Increases metabolic and oxygen demands, heightening the risk of crises.
What are the tests that are done to test for SCD?
Full Blood Count (FBC):
Basic blood test to check for anemia and other abnormalities.
Solubility Test:
Screening test that detects the presence of HbS by its reduced solubility in a high-phosphate buffer.
Sickling Test:
Involves exposing a blood sample to a deoxygenating agent to induce sickling of RBCs.
Hemoglobin Electrophoresis:
Separates different types of hemoglobin, allowing identification of HbS.
High-Performance Liquid Chromatography (HPLC):
Highly precise method to quantify different hemoglobin types, including HbS.
Molecular Testing:
Techniques like Restriction Fragment Length Polymorphism (RFLP) and DNA sequencing to identify specific genetic mutations.
Morphology of SCD
Irreversible Sickle Cells:
Characteristic sickle-shaped RBCs visible under a microscope.
Reticulocytosis:
Elevated number of immature RBCs, indicating increased erythropoiesis.
Target Cells:
RBCs with a bullseye appearance, seen in various hemoglobinopathies.
Howell-Jolly Bodies:
Nuclear remnants in RBCs, typically seen due to asplenia (non-functional spleen).
Marrow Hyperplasia:
Bone marrow hyperactivity to compensate for chronic hemolysis, leading to:
Erythroid Expansion: Changes in bone structure, particularly in the skull and facial bones.
Extramedullary Hematopoiesis: Blood cell production occurring outside the bone marrow.
Increased Hemoglobin Breakdown: Leading to pigment gallstones and hyperbilirubinemia.
How’s SCD managed?
Pain Management:
Analgesia: Pain relief during sickle cell crises.
Hydroxyurea: Daily medication to reduce pain crises and need for transfusions.
Fluid and Oxygen Therapy:
IV Fluids: To maintain hydration and reduce sickling.
Oxygen Therapy: To improve oxygen levels and reduce sickling.
Infection Prevention:
Antibiotics: Prevent infections, particularly in children (e.g., penicillin).
Vaccinations: To protect against infections.
Observation and Support:
Monitoring Vital Signs: Regular checks during acute episodes.
Emotional Support: Addressing psychological aspects of chronic illness.
Acute Episode Management:
ICU Admission: For severe crises.
Blood Transfusion: To manage severe anemia or complications.
Emergency Splenectomy: If spleen enlargement and trapping of RBCs occur.
Advanced Treatments:
Bone Marrow/Stem Cell Transplant: Replacing defective marrow with healthy donor marrow.
Gene Therapy: Experimental treatments to correct the genetic defect.
Experimental Therapies:
Nitric Oxide: To reduce vessel clumping and improve blood flow.
Drugs to Boost Fetal Hemoglobin: Increase HbF to prevent sickling.
Statins: To reduce inflammation and improve blood flow.
