5 4- Hereditary persistence of fetal Hb (HPHF) (Hb F in adults)
6 5- Acquired Hemoglobinopathies A- Met-Hb due to toxic exposure.B- Sulf-Hb due to toxic exposure.C- CarboxyHb due to CO.D- Hb-H in erythroleukemia.E- Elevated Hb-F in states of erythroid stress & BM dysplasia.
7 ThalassemiaThis is an inherited disorder of α or β globin chain biosynthesis.Causes reduced production of Hb tetramers causing hypochromia µcytosis. The latter is leading to ineffective erythropoiesis & hemolytic anemia.Normal Hb consists of 2α and 2β chains.Two clusters of genes encode for globin synthesis (β genes on chromosome 11 & α genes on chromosome 16).An unbalanced accumulation of α or β chains results
8 α- ThalassemiaDecreased α-chain production relative to β-chain production forming β4 (Hb-H inclusion bodies).RBCs bearing inclusion bodies are rapidly removed from the circulation by RES cells thus shortening RBC survival.
9 S & SDeletion of 1 gene (-α/αα) & 2 genes (-/αα; -α/-α) are virtually asymptomatic.Deletion of 3 genes (--/-α) producing Hb H disease (Hb Barts).Moderate hypochromic microcytic anemia & splenomegaly.Hb= 8-10 g/dL, special stain shows Hb H inclusions.Hb electrophoresis shows Hb H. Hb H tends to precipitate during oxidative stress & under increased temperature as in infections causing hemolysis.
10 Deletion of 4 genes (--/--) is the most severe form that is incompatible with life leading to intrauterine death of the fetus (hydrops fetalis).
11 β- ThalassemiaDecrease in β-chain production relative to α-chain production.Common in Mediterranean, Asian & African populations (areas endemic with malaria).Trait --- asymptomatic.Clinical anemia ---- is seen in homozygous or compound heterozygous e.g. β thalassemia/Hb E.
12 Reduced β globin chain synthesis leads to accumulation of free α globin chains that precipitate in early erythroblast development since they are insoluble.These lead to ineffective erythropoiesis in BM & enhanced destruction in circulation.
13 Anemia, splenomegaly ± hypersplenism, osteoporosis, skeletal & soft tissue changes due to BM expansion, iron overload ( ↑GIT absorption & blood transfusion) deposit in liver, heart, pancreas, pituitary & other endocrine organs.
15 ℞α-thalassemia gene or 2 genes deletion may be asymptomatic and require no treatment.Hb H disease- Folic acid 1mg/day orallySplenectomy for progressive anemia.
16 β thalassemiaImproved outcome recently due to the use of aggressive blood transfusion support & effective iron chelation therapy.The only curative ttt by BM transplantation.
17 Blood transfusion– non-transfused pt survives only 2 y in homozygous state.-- Aim to maintain Hb at 11-13g/dL-- Pre-transfusion level>10g/dL-- extend life to 2nd decade, minimize bony abnormalities, and improve sexual development.-- Leukocyte-poor RBCs given to minimize allosenstization & not to prejudice future BMT.-- HB vaccine given for pt with –ve Ab test
18 Splenectomyif transfusion requirement > 1.5 normal (>200ml/kg/year)-- preceded by polyvalent pneumococcal vaccine (pediatric pt also given H influenza & N meningitides vaccine)
19 Iron chelation --- if not given pts will die of iron overload. --- Subcutaneous desferrioxamine g/d--- Oral defroperone, deferasirox--- S.C desferral h infusion 5-6x/w --- S/E visual disturbances, tinnitus, azotemia, proteinuria.Annual ophth & audiol exam needed.
20 --- Periodic estimation of iron burden (S Fe, TIBC & S Ferritin) --- Estimate of liver iron concentration--- Annual cardiac evaluation to detect early dis--- GTT, thyroid function test, cortisol determination--- Hormone replacement therapy
21 Stem cell transplantAllogeneic BMT for homozygous β thalassemia
22 Manipulation of globin chain gene expression with 5-azacytidine, hydroxyurea, erythropoietin,butyrate analogues to stimulate Hb F synthesis by γ globin chain augmentation
23 Experimental ttt --- gene therapy * For β globin alleles * Still investigational