An important class of hereditary hemoglobin diseases known as sickle cell disease (SCD) is defined by the production of sickle hemoglobin (HbS), a faulty form of hemoglobin. Red blood cells with low oxygen tension or deoxygenation take on a sickle form thanks to HbS. All conditions related to red blood cell sickling are called sickle cell diseases.
Categorization of sickle cell illness
Anemia Sickle Cell (SS)
• This condition is known as homozygous, meaning that one faulty gene each from both parents causes both β-globin chains to be aberrant or defective.
• Because no HbA is created and HbS makes up more than 70% of hemoglobin, these patients present clinically early in life.
• Recessive autosomal condition.
Sickle Cell Trait (AS)
This heterozygous condition results in one parent's gene being faulty for HbS (abnormal) and the other parent's gene being faulty for HbA (normal).
• These patients lack any notable clinical characteristics and have both HbA and HbS in their red blood cells. The percentage of HbS might range from 25 to 40% and go unnoticed.
Additional Sickling Syndromes (Compound Heterozygous): These conditions are characterized by distinct defects in both β-globin chains (e.g., HbSC, HbS-β-thalassemia).
ANEMIA SICKLE CELL
Definition
The homozygous state (SS) of sickle cell anemia is brought on by a mutation in the β-globin gene. The hallmarks of this hemolytic anemia include a shortened life span, extensive acute and chronic organ damage, and vaso-occlusive illness.
Patients with sickle cell anemia mostly have red blood cells that contain HbS, or more than 70% of hemoglobin. It has been proposed that HbS protects against malaria caused by falciparum.
Etiopathogenesis: • The aberrant hemoglobin known as sickle hemoglobin (HbS) is the cause of sickle cell anemia.
• In HbS, codon 6 of the β-globin gene has an adenine (A) to thymidine (T) substitution (GAG→GTG). This point mutation modifies the solubility or stability of hemoglobin by substituting a valine molecule for the typical glutamic acid residue. The structural formula α2β2 S (α2β2 6Glu-Val) defines the resulting HbS, which is accountable for the disease's traits.
It is covered under the ensuing subsections: The four main areas of study are the molecular causes of sickling, variables that contribute to sickling, the mechanism of red cell destruction, and the pathophysiology of microvascular occlusions.
The Sickling Mechanism (Molecular Basis)
• HbS molecules aggregate and polymerize when there is little oxygen tension or deoxygenation. The red cell cytoplasm initially changes from a freely flowing liquid to a viscous gel as a result of aggregation of HbS. Aggregated HbS molecules within red blood cells might form long, needle-like threads or pseudocrystalline formations called tactoids if deoxygenation persists. The length of these pseudocrystalline structures increases beyond the red cell's diameter. This causes the red cell to take on the shape of an extended sickle, crescent moon, or holly leaf. Sickle cells do not change form when moving through the splenic circulation, unlike regular red blood cells. Stasis and vascular occlusion are made more likely by this.
Elements That Influence Sickling
• Amount of other hemoglobins: Adult hemoglobin (HbA) reduces sickling and interferes with HbS polymerization.
About 40% of hemoglobin in sickle cell trait (heterozygous) is HbS and 60% is HbA. These people continue to be asymptomatic carriers, and only in cases of extreme hypoxia do their red blood cells become sick.
On the other hand, people who are homozygous for HbS but do not have HbA experience severe sickle cell anemia.
- Fetal hemoglobin (HbF): It lowers sickling and stops HbS from polymerizing.
Therefore, when the HbF level starts to approach adult levels, babies up to six months old do not show any symptoms.
- Hemoglobin C: Individuals with HbS and HbC (called HbSC illness) have increased sickling because it promotes sickling by preventing ion exchange across the RBC membrane.
• Transit time in the microvasculature: Deoxygenated HbS cannot aggregate in the microvasculature because of its typically relatively short transit time.
– Sickleing occurs when blood flow slows down when red blood cells are exposed to hypoxia for longer periods of time. When there is inflammation, blood flow is seen to slow down.
• Mean corpuscular hemoglobin concentration (MCHC): Increased MCHC is caused by intracellular dehydration and higher HbS concentrations, which promote sickling.
Red Cell Damage Mechanism
Red cell destruction from sickling is caused by multiple ways.
• Expanding HbS Past Membrane: As HbS polymers enlarge, they poke through the cell membrane, which is only partially covered by the lipid bilayer.
• Dehydration: Red blood cells that have been sickled repeatedly grow more and more dehydrated, becoming stiff and thick. Eventually, the most seriously damaged cells become irreversibly sickled cells (ISC), an irreversible, nondeformable end-stage. Even when completely oxygenated later, these ISC are not able to return to normal and maintain the sickle shape.
• ISC percentage: The proportion of irreversibly sickled cells (ISCs) is correlated with the extent of hemolysis. Erythrophagocytosis in the spleen, liver, or bone marrow eliminates the injured ISCs. Therefore, hemolysis is primarily extravascular; nevertheless, a small amount of intravascular hemolysis can also be caused by mechanically fragile sickled cells.
Impaired cation homeostasis: The membrane's structural alterations result in the influx of (Ca2+)ions, which open an ion channel and release K+ and H2O.
The Microvascular Occlusions' Pathogenesis
Occlusion of the microvasculature is one of the most concerning clinical characteristics of sickle cell anemias. Though the precise etiology is unknown, a number of theories have been considered.
• Flexibility: When sickle cells move through the microvasculature, they have trouble altering their form. The small blood vessels may get blocked by the accumulation of these stiff cells.
• Slowing factors: Damage to the cytoskeletal structure of red blood cells and other variables (such as inflammation) that slow or stop the flow of red blood cells via microvascular beds may be responsible for occlusion.
The submembrane cytoskeleton's persistent distortion is the reason for this irreversibility.
• Increased adhesion molecule expression: Sickle cells have unusually high levels of adhesion molecule expression. Adhesion molecule expression on endothelial cells may be upregulated during inflammation by chemical mediators secreted from leukocytes. In inflammatory microvasculature, these mediators promote the adherence and stagnation of these sticky sickle cells. Low oxygen tension as a result promotes microvascular blockage and sickling.
• Nitric oxide inactivation: Nitric oxide (NO) is a strong vasodilator and platelet aggregation inhibitor. Free hemoglobin that has been released by lysed sickle cells binds and inactivates NO. NO inactivation causes sickling and microvascular stasis by constricting the arteries and encouraging platelet aggregation.
Features of the Clinic
As life progresses, sickle cell disease's clinical appearance alters. A protective role for HbF is present during the first six months of life. After six months of age, symptoms start to show up when the HbF goes away. Children and infants often come with acute conditions such as stroke, splenic sequestration, acute chest syndrome, and severe infection. In children, generalized growth and development impairment is caused by chronic hypoxia. Adults who have sustained organ damage present.
The primary causes of the clinical characteristics include infections, persistent organ damage, crises (painful events that occur frequently), and chronic hemolytic anemia.
A. Hemolytic Anemia Chronica
Hemolysis is a lifelong condition for the patients, although most of them have mild anemia. Although sickled red blood cells are mechanically brittle, they can also produce intravascular hemolysis. Hemolysis is primarily extravascular. Increased amounts of unconjugated (indirect) bilirubin from chronic hemolytic anemia put people at risk for pigmented bilirubin gallstones.
Crises in Cholelithiasis
Crises are any new symptoms or episodes that appear suddenly in people with sickle cell anemia. Several crises can often make sickle cell anemia worse throughout its extended course. Four categories of crises arise. These could result in cholecystitis.
1. Sickling crises, also known as an infarctive, painful, or vaso-occlusive crisis: Vaso-occlusive crises are the most typical and distinctive feature of sickle cell disease. Hypoxic damage and infarction result from sickled red cell blockage of the microcirculation. Clinically, it manifests as acute, excruciating pain in the afflicted area, such as excruciating pain in the muscles, bones, or thoracic cavity. These kinds of crises can be brought on by fever, infection, and dehydration—conditions that encourage illness—or they might occur for no apparent reason at all. Usually, it affects the lungs, liver, spleen, and bones.
• Bone: Acute osteomyelitis may mimic bone involvement in children. They show up as dactylitis of the hands, feet, or both, or as the hand-foot syndrome.
• Lung: Acute chest syndrome, which is characterized by fever, cough, chest discomfort, and pulmonary infiltration, is a potentially fatal presentation. Sometimes a straightforward lung infection starts them.
• Spleen: Acute abdominal pain that lasts for four to five days may be the initial indication of abdominal visceral infarcts brought on by four to five-day vaso-occlusive crises. Autosplenectomy, or total involution of the spleen with diminished or absent splenic function, is the result of recurrent splenic infarction. 2. Hemolytic crisis: This is an uncommon kind that manifests as a sharp rise in hemolysis along with an abrupt drop in reticulocytosis and hemoglobin levels.
3. Aplastic crisis: An acute parvovirus B19 infection of erythroid progenitor cells may cause a temporary stop to bone marrow erythropoiesis.
