Hemolytic anemias Hemoglobinopathies Part 2 Thalassemias Thalassemias are
Hemolytic anemias Hemoglobinopathies Part 2
Thalassemias • Thalassemias are a heterogenous group of genetic disorders – Individuals with homozygous forms are severely affected and die early in childhood without treatment – Heterozygous individuals exhibit varying levels of severity – The disorders are due to mutations that decrease the rate of synthesis of one of the two globin chains ( or ). The genetic defect may be the result of:
Thalassemias • A mutation in the noncoding introns of the gene resulting in inefficient RNA splicing to produce m. RNA, and therefore, decreased m. RNA production • The partial or total deletion of a globin gene • A mutation in the promoter leading to decreased expression • A mutation at the termination site leading to production of longer, unstable m. RNA • A nonsense mutation – Any of these defects lead to: • An excess of the other normal globin chain • A decrease in the normal amount of physiologic hemoglobin made • Development of a hypochromic, microcytic anemia
Thalassemias – Beta ( ) thalassemia • The disease manifests itself when the switch from to chain synthesis occurs several months after birth • There may be a compensatory increase in and chain synthesis resulting in increased levels of hgb F and A 2. The genetic background of thalassemia is heterogenous and may be roughly divided into two types: – 0 in which there is complete absence of chain production. This is common in the Mediterranean. – + in which there is a partial block in chain synthesis. At least three different mutant genes are involved: » +1 – 10% of normal chain synthesis occurs » +2 – 50% of normal chain synthesis occurs » +3 - > 50% of normal chain synthesis occurs
Thalassemias • The clinical expression of the different gene combinations (1 from mom and 1 from dad) are as follows: – 0/ 0, +1/ +1, or 0/ +1, +2, or +3 = thalassemia major, the most severe form of the disease. » Imbalanced synthesis leads to decreased total RBC hemoglobin production and a hypochromic, microcytic anemia. » Excess chains precipitate causing hemolysis of RBC precursors in the bone marrow leading to ineffective erythropoiesis » In circulating RBCs, chains may also precipitate leading to pitting in the spleen and decreased RBC survival via a chronic hemolytic process. » The major cause of the severe anemia is the ineffective erythropoiesis.
Thalassemias » The severe, chronic anemia early in life leads to marked expansion of the marrow space and skeletal changes due to the increased erythropoiesis. » Untreated individuals die early, usually of cardiac failure (due to overwork and hemochromatosis). » Individuals may have massive splenomegaly leading to secondary leucopoenia and thrombocytopenia. This can lead to infections and bleeding problems. » Lab findings include: - hypochromic, microcytic anemia - marked anisocytosis and poikilocytosis - schistocytes, ovalocytes, and target cells - basophilic stippling from chain precipitation - increased reticulocytes and nucleated RBCs
Thalassemias - serum iron and ferritin are normal to increased and there is increased saturation - chronic hemolysis leads to increased bilirubin and gallstones - hemoglobin electrophoresis shows increased hgb F, variable amounts of hgb A 2, and no to very little A
Thalassemia major
Thalassemias » Therapy – transfusions plus iron chelators to prevent hemochromatosis and tissue damage from iron overload; Gene therapy? – +2, or 3 homozygous = thalassemia intermedia – Heterozygosity of 0, or + = thalassemia minor » Mild hypochromic, microcytic anemia » Patients are usually asymptomatic with symptoms occurring under stressful conditions such as pregnancy – thalassemia may also be found in combination with any of the hemoglobinopathies (S, C, or E) leading to a mild to severe anemia depending upon the particular combination.
Thalassemia minor
Thalassemias – Alpha ( ) thalassemia • The disease is manifested immediately at birth • There are normally four alpha chains, so there is a great variety in the severity of the disease. • At birth there are excess chains and later there are excess chains. These form stable, nonfunctional tetramers that precipitate as the RBCs age leading to decreased RBC survival. • The disease is usually due to deletions of the gene and occasionally to a functionally abnormal gene.
Thalassemias • • The normal haploid genotype is / If one gene is deleted, the haploid phenotype is thal 2 If both genes are deleted, the haploid phenotype is thal 1 Since one gets two genes from each parent, there are four types of thalassemia: – / thal 2 = silent carrier – / thal 1, or thal 2/ thal 2 = thal trait with mild anemia – thal 1/ thal 2 = hemoglobin H disease ( 4 = hgb H) Hgb H has a higher affinity for O 2 and precipitates in older cells. Anemia may be chronic to moderate to severe.
Thalassemias – thal 1/ thal 1 = hydrops fetalis which is fatal with stillbirth or death within hours of birth. Hemoglobin Barts ( 4) forms and has such a high affinity for O 2 that no O 2 is delivered to the tissues. – Hgs S/ thalassemia – symptomless to moderate anemia – Delta/beta ( / ) thalassemia – both and chains are absent with no or little compensatory increase in chain synthesis. This leads to 100% hgb F and mild hypochromic, microcytic anemia – Hereditary persistence of hgb F – are a group of heterogenous disorders with the absence of and chain synthesis which is compensated for by an increase in chain synthesis leading to 100% hgb F. Since hgb F has an increased affinity for O 2, this results in polycythemia.
Thalassemias – Hemoglobin Constant Spring – formed by a combination of two structurally abnormal chains (each elongated by 31 amino acids at the COOH end) and two normal chains. • The abnormal chains are inefficiently synthesized resulting in an thal 1 like phenotype (excess chains) • Homozygous individuals have mild hypochromic, microcytic anemia similar to a mild a thalassemia. – Hemoglobin Lepore – a normal chain plus a - hybrid (N-terminal , and C-terminal ). – There is ineffective synthesis of the hybrid chain leading to chain excess and the same problems seen in thalassemia.
Thalassemias » Homozygous individuals have a mild to severe hypochromic, microcytic anemia » Heterozygous individuals are asymptomatic.
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