Causes and pathogenesis of sickle cell anemia
Last reviewed: 23.04.2024
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The main defect in this pathology is the production of HbS as a result of spontaneous mutation and deletion of the β-globin gene on chromosome 11, which leads to the replacement of valine with glutamic acid in the position of the VIP-polypeptide chain (a 2, β 2, 6 val). Deoxygenation causes the deposition of deoxygenated molecules of anomalous hemoglobin in the form of monofilaments, which, as a result of aggregation, turn into crystals, thereby changing the erythrocyte membrane, which ultimately is accompanied by the formation of sickle cells. It is believed that the presence in the body of the sickle cell anemia gene gives the patient a certain degree of resistance to malaria.
The carriage of the sign of sickle cell anemia (heterozygous form, AS)
The presence of the sickle cell anemia gene in the heterozygous state is usually accompanied by a benign course of the disease. Among African Americans, about 8% of heterozygotes for HbS. Separate erythrocytes of carriers of anomalous sign contain a mixture of normal hemoglobin (HbA) and sickle-shaped hemoglobin (HbS). The share of HbS is from 20 to 45%. With such a proportion under physiological conditions, the process of "crescent" does not occur. The condition of carriage of the symptom of sickle cell anemia does not affect life expectancy. Carriers should avoid situations that may be accompanied by hypoxia (flights on airplanes, scuba diving).
[Pathogenesis of sickle-cell anemia
Substitution of glutamic acid with valine results in the appearance of neutral neutral charge at pH 8.6 in HbS, instead of the negative electrical charge characteristic of HbA, and this strengthens the bond of one hemoglobin molecule to the other. Charge change leads to the development of structural instability in the entire HbS molecule and to a decrease in the solubility of the reduced (giving up oxygen) form of HbS. It was found that HbA, which gave oxygen, is soluble in water less than HbA, saturated with oxygen. The solubility of HbS, which gave up oxygen, is reduced by a factor of 100. Inside the erythrocyte, hemoglobin passes into the gel state, and at a reduced partial pressure of oxygen it precipitates in the form of tactoid-spindle-shaped pointed crystals. Tactoids stretch erythrocytes, giving them a crescent shape and contributing to their destruction. The appearance of sickle-shaped erythrocytes significantly increases the viscosity of the blood, which in turn reduces the rate of blood flow and leads to the clogging of small capillaries. In addition to hypoxia, the formation of a gel inside the erythrocyte is facilitated by acidosis (a decrease in pH from 8.5 to 6.5 reduces the degree of affinity of hemoglobin to oxygen) and an increase in temperature (up to 37.0 ° C).
The formation of sickle cells is important in the further pathogenesis of the disease. S-erythrocyte loses its plasticity, undergoes hemolysis, blood viscosity increases, rheological disturbances occur, as sickle erythrocytes get stuck in capillaries with subsequent thrombosis (occlusion) of vessels. In the blood supply of tissues due to thrombosis, infarcts occur accompanied by hypoxia, which in turn contributes to the formation of new sickle-cell erythrocytes and hemolysis.
Pathophysiology of sickle-cell anemia
Point mutation in the 6th codon of the β-globin gene (replacement of valine with glutamic acid) leads to a change in the properties of the protein globin molecule.
- Hb S has a more negative charge than HbA, and as a result, a different electrophoretic mobility.
- The deoxy form of Hb S is less soluble, that is, after transfer of the oxygen atom, Hb S polymerizes by changing the shape of the red blood cells (in the form of a sickle); The polymerization of Hb S is partially reversible.
- Crescent erythrocytes stick together, adhere to the surface of the vascular endothelium, which disrupts the rheological properties of the blood, resulting in vaso-occlusive crises and strokes, and rapidly break down, leading to hemolysis.
Hematologic features of sickle cell anemia:
- anemia - of medium severity to severe, normochromic, normocytic;
- Sickness test positive;
- reticulocytosis;
- neutrophilia (often enough);
- the number of platelets is often increased;
- morphology of erythrocytes of peripheral blood:
- sickle cells;
- high polychromasia;
- normoblasts;
- target red blood cells;
- Jolly's body (possibly);
- ESR is low (crescent erythrocytes can not form "coin pillars");
- Electrophoresis of hemoglobin - Hb S moves slower than HbA.