L4 | Sickle Cell Anemia: HBB Mutation & Hemoglobin

Sickle Cell Anemia

• It involves a point mutation in HBB (β-globin).
• It's an autosomal recessive condition.
• It has a polymerization of deoxygenated hemoglobin, leading to red cell distortion, hemolytic anemia, microvascular obstruction, and ischemic tissue damage.

Hemoglobin

• Normal adult red cells mainly contain HbA (α2β2), along with small amounts of HbA2 (α2δ2) and fetal hemoglobin (HbF; α2γ2).
• Glu-Val is an important consideration.
• Sickle hemoglobin is denoted as HbS; (α2βs2).

Epidemiology

• 70,000 to 100,000 individuals in the United States have sickle cell anemia.
• The high prevalence of sickle cell trait in certain African populations stems from its protective effects against falciparum malaria.
• About 300,000 infants are born annually worldwide with the severe homozygous form (HbSS disease), with over half occurring in Nigeria, India, and the Democratic Republic of Congo.

Sickle Cell Anemia and Malaria

• Metabolically active intracellular parasites consume oxygen and decrease intracellular pH, promoting sickling of AS red cells.
• These distorted, stiff cells may be cleared more rapidly by splenic and hepatic phagocytes, keeping parasite loads low.
• Sickling impairs the formation of membrane knobs containing a protein made by the parasite called PfEMP-1.

Pathogenesis

• HbS molecules tend to stack into polymers when deoxygenated; this process converts the red cell cytosol from a freely flowing liquid into a viscous gel.
• With continued deoxygenation, HbS molecules assemble into long needlelike fibers within red cells, producing a distorted sickle or holly-leaf shape.

Pathophysiology

• Sickling causes cumulative damage to red cells through several mechanisms
• Severe derangement in membrane structure causes an influx of Ca2+ ions, which induce the cross-linking of membrane proteins and activate an ion channel that leads to the efflux of K+ and H2O.
• Repeated sickling episodes cause red cells to become dehydrated, dense, and rigid
• Sickled red cells are mechanically fragile, leading to intravascular hemolysis.
• Microvascular occlusions depend on membrane damage and local factors like inflammation or vasoconstriction, which slows or arrests red cell movement through microvascular beds.
• Enhanced platelet aggregation may contribute to red cell stasis, sickling, and thrombosis in some instances.
• Variables like the interaction of HbS with other hemoglobin types affect the rate and degree of sickling; 40% of hemoglobin is HbS, and the rest is HbA, which interferes with HbS polymerization.
• Red cells in heterozygous individuals only sickle if exposed to prolonged, severe hypoxia.
• HbF inhibits the polymerization of HbS even more than HbA.
• Infants with sickle cell disease do not become symptomatic until around 5 or 6 months of age, when HbF levels normally fall.

Clinical Features

• Moderately severe hemolytic anemia (hematocrit 18% to 30%) is associated with reticulocytosis and hyperbilirubinemia, along with the presence of irreversibly sickled cells.
• Vaso-occlusive crises (pain-crises) affect bones, lungs, liver, brain, spleen, and penis; in children, it can mimic osteomyelitis.
• Acute chest syndrome is a particularly dangerous type of vaso-occlusive crisis involving the lungs.
• Dactylitis in children (< 5 years) is typically the earliest manifestation of sickle cell disease.

Clinical features and Complications

• Priapism
• Stroke can be common in children
• Sickle cell hepatopathy
• Organ infarctions, particularly affecting the spleen
• Avascular necrosis
• Acute hemolytic crisis, including Splenic sequestration and Aplastic crisis
• Venous Thromboembolism
• Infections like (Pneumonia, Meningitis, Osteomyelitis, Staphylococcus aureus, Sepsis) can occur

Chronic Complications

• Chronic pain can occur
• Avascular necrosis
• Functional asplenia
• Sickle Retinopathy
• Sickle Nephropathy
• Sickle cell chronic lung disease
• Cardiomyopathy
• Pulmonary Hypertension
• The current estimated life expectancy for patients with SCD in the US is 54 years.

Further Complications

• The morbidity of SCD is progressive throughout life.
• Most complications early on occur in acute recurrent episodes.
• Growth and puberty are delayed due to increased metabolic demands from ongoing hemolytic anemia.
• In adulthood, organ damage is prominent in addition to acute complications and acute pain episodes, acute chest syndrome, and ischemic stroke which can occur at any life stage.

Diagnosis

• Newborn screening
• High-performance liquid chromatography is used to detect the presence of hemoglobin variants
• Hemoglobin electrophoresis (Confirmation)
• When SCD is not identified via screening, it may be diagnosed as part of evaluating a normocytic anemia in a clinic, evaluating severe atraumatic pain in the emergency department, or in prenatal testing.

Treatment

• Hydroxyurea can be used
• Crizanlizumab, L-glutamine, and voxelotor (2017) have been used
• Hematopoietic stem cell transplant with a matched sibling donor can be used for severe disease.
• Gene therapy trials have had some success

Hydroxyurea

• It is a ribonucleotide reductase inhibitor that induces fetal hemoglobin production.
• HbF inhibits HbS polymerization, reducing red cell rigidity and hemolysis, which improves anemia.
• It increases nitric oxide, decreases red cell adhesion, and decreases leukocytes.
• First-line therapy for all individuals with HbSS and HbSβO beginning at 9 months of age.
• It is also used for HbSC and HbSβ+ -thalassemia, that have recurrent acute pain episodes, ACS, or hospitalizations.

Additional drugs

• L-glutamine is an oral amino acid supplement that decreases reactive oxygen species in RBCs, thereby reducing sickling and RBC adhesivity.
• Crizanlizumab is a monoclonal antibody directed against P-selectin, an adhesion molecule found on activated platelets and endothelial cells that may partially mediate vaso-occlusion.
• Voxelotor stabilizes the oxygenated state of Hb in SCD by promoting HbS binding to oxygen, decreasing sickle Hb polymerization and related hemolysis.
• Gene therapy: increase HbF production by decreasingexpression of BCL11A, a suppressor of the γ-globin gene thatencodesHbF.