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22 96% Hb A2 a22 3% Hb F a22 1% Hb A Chromosome 11-non-alpha globin -Both beta proteins work( β / β) -One works (trait/minor) (β/ β+, β/ β0) -Both affected, but not absent (intermedia) (β+/β+) -Absent (major) (β0/ β0,β+/β0) -One normal gene and one affected gene ( β / β + or β / β 0 ) -Often asymptomatic. -CBC :mild or no anemia, MCV and MCH are usually low, RBC count often high. -Hb electrophoresis or Hb HPLC: HbA2 > 3.5% of total hemoglobin) and usually HbF >1%. -An elevated HbA2 is considered diagnostic of -thalassemia trait. Iron Deficiency Anemia Thalassemia Minor p-value RBC (x 106 /μL) 4.7634 ± 0.4313 5.9662 ± 0.5929 <0.001 Hemoglobin(g/dl) 11.0095 ± 1.2102 11.8103 ± 1.1617 0.004 MCV (fL) 72.4432 ± 5.8923 62.2794 ± 4.4002 <0.001 MCH (pg) 23.2351 ± 2.7320 19.8669 ± 1.7002 <0.001 -Both affected, but not absent (β+/β+) -There is a moderate haemolytic anaemia -Some haemoglobin A is present -Varying increase in haemoglobin A2 -Distinct increase in haemoglobin F. Thalassemia Major β+/β0 or β0/β0. A decrease in the rate of production of β Imbalance with the normally produced α globin chains. α globin chains accumulates Modifiers May reduce the degree of globin chain imbalance and typically ameliorate the symptoms of thalassemia. -Co-inheritance of α thalassemia -Co-inheritance of determinants that increase gamma chain production -The presence of mild or silent -thalassemia alleles Hb F production advantages. Binding some of the excess alpha chains protect the RBCs provides additional Hb with oxygencarrying ability. Hb F production disadvantages increases oxygen affinity leading to hypoxia -It is characterize by severe anemia that can begin months after birth -Paleness -Delays in growth and development -Bone marrow expansion. -Untreated Beta Thalassemia major can lead to child death due to heart failure. Diagnostic work of suspected BTM Complete hemogram -Hemoglobin: usually <7 gm/dl. -MCV and MCHC are decreased unless recently transfused. -Reticulocyte count is increased unless recently transfused. -WBC ± increased -Leucopenia and thrombocytopenia indicates Hypersplenism. -Blood film: severe hypochromic microcytic anemia with anisocytosis and poikilocytosis, numerous target cells, nucleated red cells, and schistocytes may be seen. Moderate basophilic stippling is common Diagnostic work of suspected BTM Hemoglobin electrophoresis (HPLC) -Hb A decreased or absent. -Hb F invariably increased. -HbA2 usually normal VARIANT HEMOGLOBINS co-inherited with Beta -thalassemia The most common are Hemoglobin S, Hemoglobin E, and Hemoglobin C. -HbS/Beta-thalassemia -HbE/Beta –thalassemia -Hemoglobin C/Beta-thalassemia DNA testing -Presence of two severe beta Thalassemia mutations. -Absence of readily detectable forms of alpha Thalassemia. - Absence of determinants that increase gamma chain production Observation Phase (Variable) The decision to place a Thalassemia major patient on regular blood transfusion program is rarely urgent. Hb drop ≥ 1gm/ week lowest Hb less than 6.5g/dl on more than 2 occasions signs of ineffective erythropiesis Signs of Growth failure. β- THALASSEMIA MAJOR DIAGNOSED GENETIC COUNSELLING OBSERVATION PHASE BLOOD TRANSFUSION PROGRAM IRON CHELATION THERAPY MANAGEMENT OF IRON OVERLOAD COMPLICATIONS SPLENECTOMY BONE MARROW TRANSPLANATION -1 unit of blood contains approximately 200 mg of iron -Iron accumulates with repeated blood transfusion -iron absorption is increased Pituitary gland Heart • Iron overload results in non– transferrin-bound iron in the plasma Pancreas • Increased iron uptake into selective organs Gonadal • Generation of free hydroxyl radicals Liver Tissue damage What is the ideal iron chelator ? Heart failure is the leading cause of death in patients with ß-thalassemia major 60%mortality Iron cardiomyopathy Iron cardiomyopathy is preventable is treatable is reversible We are no more powerless to predict WHO is at risk ?? MRI T2* T2* - CARDIAC RISK RANGING Below a myocardial T2* of 20 ms, there was a progressive and significant decline in LVEF ( P<0·0001) High Intermediate Low -Success is related to the pre transplantation clinical conditions: -The presence of hepatomegaly -extent of liver fibrosis -magnitude of iron accumulation. -Disease-free survival is over 90% In HLA –Matched sibling donor transplant In children who lack the above risk factors. -Cord blood transplantation from a related donor. OPTIONS OFFERED FOR COUPLES AT GENETIC RISK MOST IDEAL Preconception Conception Preimplantation PGD Implantation Embryogenesis Prenatal PRENATAL DIGNOSIS ABORTION Fetal Growth Perinatal IN UTERO BMT Birth Childhood Postnatal BMT LEAST IDEAL BLOOD TRANSFUSION PROGRAM AND IRON CHELATION THERAPY -Remain Single -Avoid Another Carrier as Partner -Select as Usual but Remain Childless -PND at Cost of 25% Abortion -PGD if 1st PND Resulted in Abortion -PGD from Onset -PGD + HLA For Treating Affected Sibling THANK YOU