Pathogenesis of hereditary spherocytosis (Minkowski-Shoffard disease)

The primary defect in hereditary spherocytosis is the instability of the erythrocyte membrane due to impaired function or deficiency of the skeletal protein of erythrocytes. The most characteristic defect is the spectrin and / or ankyrin, but there may also be a deficiency of other skeletal proteins: protein band 3, protein band 4.2. Usually (75-90%) there is a lack of spectrin. The severity of the disease, as well as the degree of spherocytosis (according to the assessment of osmotic resistance and morphometry of erythrocytes) depend on the degree of deficiency of the spectrin. In homozygous patients with a level of spectrin of up to 30-50% normal, marked hemolytic anemia develops, often transfusion-dependent. Ankyrin deficiency occurs in about 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 in the proteins of the erythrocyte membrane (spectrin and ankyrin) was found: either a deficiency or a violation of the functional properties of these proteins. The following defects of the cell membrane proteins were established:

1. Deficiency of spectrin - the degree of anemia and the severity of spherocytosis directly correlate with the degree of deficiency of the spectrin. In most patients, a slight deficit of spectrin is revealed - 75-90% of the norm. Patients with a level of spectrin of 30-50% of the norm have severe hemolytic anemia and are dependent on blood transfusions.
2. Functional deficiency of the spectrin is the absence of binding ability with protein 4.1 (synthesis of unstable spectrin).
3. Segment deficiency 3.
4. Deficiency of Protein 4.2 (rare).
5. Deficiency of ankyrin (protein 2.1) - found in 50% of children with hereditary spherocytosis, whose parents are healthy.

An abnormal protein of the erythrocyte membrane causes a disruption in the transport of cations - the permeability of the membrane for sodium ions sharply increases, which increases the intensity of glycolysis and enhances lipid metabolism, changes the cell volume and forms the stage of spherocytes. The place of deformation and death of erythrocytes is the spleen. The emerging spherocyte, when moving at the spleen level, experiences a mechanical impediment, as in contrast to normal red blood cells, the spherocytes are less elastic, which makes it difficult to deconfigure them when passing from the sinus spinal sinus spaces. Having lost elasticity and ability to deform, spherocytes get stuck in the intersynus spaces, where unfavorable metabolic conditions are created (reduced concentration of glucose and cholesterol), which contributes to even more damage to the membrane, increased sphericity of the cell and the final formation of microspherocytes. With repeated passage of splenic intersynus spaces membrane sequestration reaches such a level that the erythrocytes perish, being destroyed, they 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.

Due to skeletal protein deficiency, the following disorders develop:

• loss of lipid membranes;
• a decrease in the ratio of the surface area of the cell to its volume (loss of surface);
• change in the form of erythrocytes (spherocytosis);
• acceleration of sodium intake into the cell and its exit from the cell, which causes dehydration of the cell;
• rapid utilization of ATP with increased glycolysis;
• destruction of immature forms of red blood cells;
• sequestration of erythrocytes in the phagocytic macrophage system of the spleen.

[1], [2], [3]