Causes and pathogenesis of sickle cell anemia

The main defect in this pathology is the production of HbS as a result of a spontaneous mutation and deletion of the β-globin gene on chromosome 11, which leads to the replacement of valine with glutamic acid in the VIP position of the polypeptide chain (a ₂, β ₂, 6 val). Deoxygenation causes the deposition of deoxygenated molecules of abnormal hemoglobin in the form of monofilaments, which, as a result of aggregation, turn into crystals, thereby changing the membrane of erythrocytes, which, ultimately, is accompanied by the formation of sickle cells. It is believed that the presence of the sickle cell gene in the body gives the patient a certain degree of resistance to malaria.

Carrier of sickle cell trait (heterozygous form,AS)

The presence of the sickle cell gene in a heterozygous state in a person is usually accompanied by a benign course of the disease. Among African Americans, approximately 8% are heterozygotes for HbS. Individual red blood cells of carriers of the abnormal trait contain a mixture of normal hemoglobin (HbA) and sickle hemoglobin (HbS). The proportion of HbS is from 20 to 45%. With such a proportion, the process of "sickle" does not occur under physiological conditions. The state of carriage of the sickle cell trait does not affect life expectancy. Carriers should avoid situations that may be accompanied by hypoxia (flying on airplanes, scuba diving).

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Pathogenesis of sickle cell anemia

Substitution of glutamic acid with valine results in HbS acquiring a neutral charge at pH 8.6 instead of the negative electric charge characteristic of HbA, which strengthens the bond between one hemoglobin molecule and another. The charge change results in structural instability of the entire HbS molecule and a decrease in the solubility of the reduced (oxygen-releasing) form of HbS. It has been established that HbA that has released oxygen is less soluble in water than HbA saturated with oxygen. The solubility of HbS that has released oxygen decreases by 100 times. Inside the erythrocyte, hemoglobin becomes a gel, and at reduced partial pressure of oxygen, it precipitates in the form of tactoids - spindle-shaped pointed crystals. Tactoids stretch the erythrocytes, giving them a sickle shape and promoting their destruction. The appearance of sickle-shaped erythrocytes significantly increases blood viscosity, which in turn reduces the blood flow rate and leads to blockage of small capillaries. In addition to hypoxia, acidosis (a decrease in the pH from 8.5 to 6.5 reduces the affinity of hemoglobin for oxygen) and an increase in temperature (up to 37.0 °C) contributes to the formation of gel inside the erythrocyte.

The formation of sickle cells is important in the further pathogenesis of the disease. The S-erythrocyte loses its plasticity, undergoing hemolysis, blood viscosity increases, rheological disorders occur, since sickle-shaped erythrocytes get stuck in the capillaries with subsequent thrombosis (occlusion) of the vessels. In the blood-supplied areas of tissue, as a result of thrombosis, infarctions occur, accompanied by hypoxia, which in turn contributes to the formation of new sickle-cell erythrocytes and hemolysis.

Pathophysiology of sickle cell anemia

A 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 globin protein molecule.

• Hb S has a more negative charge than Hb A and, as a result, a different electrophoretic mobility.
• The deoxy form of Hb S is less soluble, that is, after the transfer of an oxygen atom, Hb S polymerizes, changing the shape of the erythrocytes (in the form of a sickle); the process of Hb S polymerization is partially reversible.
• Sickle-shaped erythrocytes stick together, adhere to the surface of the vascular endothelium, which disrupts the rheological properties of the blood, leading to vaso-occlusive crises and strokes, and are quickly destroyed, leading to hemolysis.

Hematological features of sickle cell anemia:

• anemia - moderate to severe, normochromic, normocytic;
• sickle cell test is positive;
• reticulocytosis;
• neutrophilia (quite common);
• platelet count is often elevated;
• morphology of peripheral blood erythrocytes:
  • sickle cells;
  • high polychromacy;
  • normoblasts;
  • target red blood cells;
  • Jolly bodies (possibly);
• ESR is low (sickle-shaped red blood cells cannot form rouleaux);
• hemoglobin electrophoresis - Hb S moves more slowly than Hb A.