Pathogenesis of hereditary spherocytosis (Minkowski-Schoffar disease)

The primary defect in hereditary spherocytosis is instability of the red blood cell membrane due to dysfunction or deficiency of a red blood cell skeletal protein. The most common defect is spectrin and/or ankyrin, but other skeletal proteins may also be deficient: band 3 protein, band 4.2 protein. Spectrin deficiency is common (75-90%). The severity of the disease, as well as the degree of spherocytosis (as assessed by osmotic resistance and red blood cell morphometry) depend on the degree of spectrin deficiency. Homozygous patients with spectrin levels up to 30-50% of normal develop severe hemolytic anemia, often transfusion-dependent. Ankyrin deficiency is observed in approximately 50% of children whose parents are healthy. The risk of developing the disease in other children is less than 5%.

In patients with hereditary microspherocytosis, a genetically determined defect of erythrocyte membrane proteins (spectrin and ankyrin) was found: either a deficiency or a disruption of the functional properties of these proteins. The following defects of cell membrane proteins were established:

1. Spectrin deficiency - the degree of anemia and the severity of spherocytosis directly correlate with the degree of spectrin deficiency. Most patients have mild spectrin deficiency - 75-90% of the norm. Patients with spectrin levels of 30-50% of the norm have severe hemolytic anemia and are dependent on blood transfusions.
2. Functional deficiency of spectrin - lack of binding capacity to protein 4.1 (synthesis of unstable spectrin).
3. Segment 3 deficiency.
4. Protein deficiency 4.2 (rare).
5. Ankyrin (protein 2.1) deficiency - found in 50% of children with hereditary spherocytosis whose parents are healthy.

An abnormal protein of the erythrocyte membrane causes a disruption of cation transport - membrane permeability for sodium ions increases sharply, which contributes to an increase in the intensity of glycolysis and an increase in lipid metabolism, a change in cell volume and the formation of the spherocyte stage. The site of deformation and death of erythrocytes is the spleen. The forming spherocyte experiences mechanical difficulty when moving at the level of the spleen, since, unlike normal erythrocytes, spherocytes are less elastic, which complicates their deconfiguration when moving from the intersinus spaces of the spleen to the sinuses. Having lost elasticity and the ability to deform, spherocytes get stuck in the intersinus spaces, where unfavorable metabolic conditions are created for them (reduced concentration of glucose and cholesterol), which contributes to even greater damage to the membrane, an increase in the sphericity of the cell and the final formation of microspherocytes. With repeated passage of the splenic intersinus spaces, membrane sequestration reaches such a level that the erythrocytes die, being destroyed, are absorbed by the phagocytes of the spleen, participating in the fragmentation of erythrocytes. Phagocytic hyperactivity of the spleen, in turn, causes progressive hyperplasia of the organ and a further increase in its phagocytic activity. After splenectomy, the process is stopped, despite the fact that biochemical and morphological changes remain.

As a result of skeletal protein deficiency, the following disorders develop:

• loss of membrane lipids;
• a decrease in the ratio of the cell's surface area to its volume (surface loss);
• change in the shape of red blood cells (spherocytosis);
• acceleration of sodium entry into the cell and its exit from the cell, which causes cell dehydration;
• rapid utilization of ATP with increased glycolysis;
• destruction of immature forms of red blood cells;
• sequestration of erythrocytes in the system of phagocytic macrophages of the spleen.

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