Thalassemias

Thalassemia is a heterogeneous group of hereditary hypochromic anemias of varying severity, which are based on a disorder of the globin chain structure. Numerous types of thalassemia with a variety of clinical and biochemical manifestations are associated with a defect in any of the polypeptide chains (α, β, γ, 5). Unlike hemoglobinopathy, thalassemia does not have disorders in the chemical structure of hemoglobin, but there is a distortion of the quantitative ratios of HbA and HbF. In some types of α-thalassemia, tetrameric forms are found, such as HbH (β = 4), Hb Bart's (γ = 4). Synthesis of polypeptide chains may be completely absent, which is noted in β ⁰ type of β-thalassemia, or be characterized by partial deficiency (β ⁺ type).

The molecular pathogenesis of thalassemia syndrome is expressed in the excessive synthesis of α- or β-chains of hemoglobin. A correlation has been established between the excess of synthesized α-chains in β-thalassemia and the survival of erythroid cells. Reduced survival of erythroid cells with excessive synthesis of α-chains in the major form of β-thalassemia leads to ineffective erythropoiesis.

It has been shown that isolated hemoglobin chains, especially α-chains, are more labile and less resistant to denaturing effects compared to hemoglobin tetramer. Their oxidation and subsequent aggregation cause membrane damage. This process is accompanied by lipid peroxidation and erythrocyte membrane proteins by highly active free oxygen radicals formed during the autoxidation of isolated chains. Both processes cause the death of the erythroid cell.

Hydrops fetalis syndrome with Bart hemoglobin

Hydrops fetalis with Barth hemoglobin is the most severe form of α-thalassemia, caused by homozygous α-thalassemia-1 (all four genes, two on each chromosome, are affected) and thus no functional hemoglobin is produced except during the embryonic stage, when α-like chains are synthesized. Free β-globin forms tetramers called Barth Hb, which have a very high affinity for oxygen. Barth Hb does not release hemoglobin into the fetal tissues, resulting in tissue asphyxia, edema, congestive heart failure, and the clinical picture of hydrops fetalis.

Bart's hemoglobin is found almost exclusively in Southeast Asians, who have predominantly cis-deletion of the α-globin genes. Infants with hydrops fetalis are not viable, dying either in utero or in the first hours of life. On examination, the fetus is pale, edematous, with a massive and loose placenta. Petechiae are visible on the skin. There are defects in the development of the lungs. The heart is enlarged, hypertrophy of both ventricles is pronounced. The thymus gland is enlarged. The liver is enlarged more than the spleen. Ascites, pleural and pericardial effusion, often undescended testicles and gynospadias are determined. Hemosiderin deposits are found in various tissues and organs due to severe hemolysis in the fetus. The total hemoglobin level is 30-100 g / L. Hemoglobin composition: Bart's hemoglobin 70-100% with traces of Portland hemoglobin; HbH, HbA, HbA ₂, HbF are absent. In the blood there is severe erythroblastemia with hypochromic macrocytes, target cells, pronounced aniso- and poikilocytosis.

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Beta thalassemia

Beta-thalassemia (β-thal) is a heterogeneous group of diseases characterized by a decrease or absence of β-globin chain synthesis. Depending on the severity of the condition, 3 forms of β-thalassemia are distinguished: major, intermediate and minor. The severity of clinical manifestations is directly proportional to the degree of imbalance of globin chains.

Beta thalassemia

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Alpha thalassemia

Alpha thalassemia is a group of diseases common in Southeast Asia, China, Africa, and the Mediterranean. Two nearly identical copies of the α-globin gene are found on chromosome 16. In 80 to 85% of cases of α-thalassemia, one or more of these four genes are lost. In the remaining patients, these genes are retained but do not function.

The clinical manifestations of α-thalassemia correlate with the degree of impairment of α-globin chain synthesis, but they are usually less pronounced than in β-thalassemia. This is due, firstly, to the fact that the presence of four α-globin genes promotes the formation of an adequate number of α-chains until three or four genes are lost. A significant imbalance of hemoglobin chains occurs only if three of the four genes are affected. Secondly, β-chain aggregates (β1-tetramers are formed with α-chain deficiency) are more soluble than α4 _- tetramers, and therefore even in patients with significantly impaired α-globin synthesis in α-thalassemia, hemolysis is much weaker and erythropoiesis is more effective than in β-thalassemia.

Alpha thalassemia

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Hemoglobinopathy H

Hemoglobinopathy H - occurs due to the loss or dysfunction of three α-globin genes. The clinical picture is the same as in the intermediate form of β-thalassemia. The disease manifests itself by the end of the first year of life as moderate chronic hemolytic anemia (Hb 80-90 g / l); against the background of intercurrent diseases or when taking medications, hemolytic crises with a drop in hemoglobin levels to 40 g / l may develop, requiring blood transfusions. Delay in physical development, Mongoloid facial type, jaundice, hepatosplenomegaly may be noted. Blood tests - hypochromic anemia, reticulocytosis, microcytosis, aniso- and poikilocytosis, target erythrocytes. Most erythrocytes contain HbH, which is a β4 _- tetramer formed by excess β-chains and is detected by gel electrophoresis as the most mobile fraction. HbH precipitates mainly in mature erythrocytes, which is accompanied by moderate hemolytic anemia. During hemoglobin electrophoresis, the HbH level is 5-30%. Bart's hemoglobin is also determined in varying amounts. The HbA2 content _is reduced, HbF is in normal amounts or slightly increased (up to 3%).

Treatment of thalassemia

Indications for initiation of transfusion therapy:

• major form of β-thalassemia, hemoglobinopathy H with a hemoglobin level below 70 g/l;
• intermediate and major forms of β-thalassemia, hemoglobinopathy H with a hemoglobin level of 70-90 g/l with a pronounced delay in physical development, the presence of bone changes, and a significant increase in the spleen.

How is thalassemia treated?