1. H EMOLYTIC ANEMIAS - H EMOGLOBINOPATHIES Part 2

2. T HALASSEMIAS 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. T HALASSEMIAS 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. T HALASSEMIAS 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

6. ALPHA AND BETA THALASSEMIAS

7. T HALASSEMIAS 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. T HALASSEMIAS 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. T HALASSEMIAS - 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. T HALASSEMIA MAJOR

11. T HALASSEMIAS 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. T HALASSEMIA MINOR

13. T HALASSEMIAS 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. T HALASSEMIAS 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.

15. T HALASSEMIAS  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. 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 O 2, this results in polycythemia.

18. T HALASSEMIAS 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. T HALASSEMIAS Homozygous individuals have a mild to severe hypochromic, microcytic anemia Heterozygous individuals are asymptomatic.