Hemolytic anemias - Hemoglobinopathies

1. Hemolytic anemias - Hemoglobinopathies Part 2

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:

3. Thalassemias • A mutation in the noncoding introns of the gene resulting in inefficient RNA splicing to produce mRNA, and therefore, decreased mRNA 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 mRNA • 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

4. WORLD DISTRIBUTION OF THALASSEMIAS

5. 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 A2. • 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

6. ALPHA AND BETA THALASSEMIAS

7. 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.

8. 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 leukopoenia 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

9. 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 A2, and no to very little A

10. Thalassemia major

11. 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.

12. Thalassemia minor

13. 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.

14. 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 O2 and precipitates in older cells. Anemia may be chronic to moderate to severe.

15. 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 O2 that no O2 is delivered to the tissues. • Hgb S/  thalassemia – symptomless to moderate anemia

16. ALPHA THALASSEMIAS

17. THALASSEMIAS • 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 O2, this results in polycythemia.

18. 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.

19. Thalassemias • Homozygous individuals have a mild to severe hypochromic, microcytic anemia • Heterozygous individuals are asymptomatic.