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Prof. Mervat Hesham 2010

Prof. Mervat Hesham 2010. Hemoglobinopathies. Definition of Anemia. Decrease in Hgb. Decrease in rbc decrease in hct below the normal for the age and sex. Different ways to classify anemia. *Mechanism of its production *Size and hemoglobin content of rbc.

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Prof. Mervat Hesham 2010

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  1. Prof. Mervat Hesham2010 Hemoglobinopathies

  2. Definition of Anemia Decrease in Hgb. Decrease in rbc decrease in hct • below the normal for the age and sex

  3. Different ways to classify anemia *Mechanism of its production *Size and hemoglobin content of rbc

  4. Classification according to mechanism 1- Blood loss acute and chronic 2- Excessive destruction of rbcs 3- Decreased production of rbcs

  5. decreased red cell production 1- Marrow failure *Diamond-Blackfan anemia * Aplastic crisis * Aplastic anemia 2- Impaired erythropoietin production * Anemia of chronic disease in renal failure *Chronic inflammatory diseases *Hypothyroidism *Severe protein malnutrition 3- Defect in red cell maturation *Nutritional anemia secondary to iron, folate, or vitamin B-12 deficiency * Sideroblastic anemias

  6. increased red cell destruction (hemolysis) • **Intracellular causes : • 1-Red cell membrane defects (eg, hereditary spherocytosis, elliptocytosis) • 2-Enzyme defects (eg, G-6-PD deficiency, pyruvate kinase deficiency) 3-Hemoglobinopathies (sickle cell , Thalassemias ) **Extracellular causes 1-Antibodies (autoimmune hemolytic anemia) 2-Infections, drugs, toxins 3-Thermal injury to red blood cells (with severe burns) 4-Mechanical injury (hemolytic-uremic syndrome, cardiac valvular defects)

  7. Hemoglobinopathy

  8. definition An inherited mutation of the globin genes leading to a qualitative or quantitative abnormality of globin synthesis

  9. Structural (qualitative) abnormalities are due to : • alterations in the polypeptide sequence changing the molecular structure and of the globin chains. (eg., Hb SS (Sickle cell disease); Hb SA (Sickle cell trait);Hb C disease; Hb SC disease; Hb E disease).

  10. • Quantitative abnormalities are secondary to : decreased rates of globin chain synthesis (beta-thalassemia; alpha-thalassemia). • The most common haemoglobinopathies are sickle cell disease/trait and thalassemia

  11. Hemoglobinopathy Genetics • Homozygous: Inheritance of two genes from each parent coding for the same type of abnormal hemoglobin, e.g., Hb SS • Heterozygous: Inheritance of genes from each parent which code for a different type of abnormal hemoglobin each, e.g., Hb SC

  12. Hemoglobin Hemoglobin is the oxygen carrying pigment of red blood cells. Structurally it contains 4 globular chains, each of which is wrapped around an iron-containing heme group.

  13. Hemoglobin structure α β β α heme

  14. Hemoglobins in normal adults α β α γ α δ β α γ α δ α HbA HbF HbA2 98% ~1% <3.5%

  15. Thalassemia

  16. Thalassemia Definition: • The most common chronic hemolytic anemia in Egypt and Mediterranean area • Syndromes in which the rate of synthesis of a globin chain is reduced • beta thalassemia - reduced beta chain synthesis • alphathalassemia – reduced alpha chain synthesis

  17. Types of HB • Hb A (Adult): 2  +2  • Hb F (Fetal): 2  +2  • Hb A2: 2  +2  • At birth: Hb F 70% • 6-12 m.: Hb A 98%

  18. Types of Thalassemia •  thalassemia: defect in synthesis of  chain: • Homozygous state: Thalassemia major • Heterozygous state: Thalassemia minor • Alpha thalassemia: defect in synthesis of  chain: • 4 HbH • 4  Bart’s Hb • 4  delta 4 Hb

  19. Pathophysiology • If  chain is affected, excess of  chains produced. • If  chain is affected, excess of  chains produced • Imbalance in chain synthesis causes 1- Decrease in total hemoglobin production 2- Ineffective erythropoiesis 3-Chronic hemolysis

  20. Excess  chains are unstable – precipitate within cell – precipitates bind to cell membrane, causing membrane damage • Excess  chains combine to form Hb H (four  chains) *High oxygen affinity – poor oxygen transporter * unstable

  21. Clinical Picture • Time of appearance: •  thalassemia: 6-12 month •  thalassemia: Incompatible with life (Hydrops foetalis) • Thalassemia minor: • Asymptomatic or- minimal pallor and mild splenomegaly • Thalassemia major: - severe pallor - jaundice (muddy face) - Dark urine - Mongoloid face - Splenomegaly - Hepatomegaly - growth retardation - Delayed puberty - Gall stone - Pathological fractures

  22. Laboratory Investigations • Peripheral blood exam: -Decreased RBC, hemoglobin, hematocrit - Microcytic hypochromic anemia (MCV, MCH, MCHC) - Anisocytosis and Poikilocytosis , Target cells -  reticulocytic count -  S. iron and S. Ferritin and decreased TIBC -  S. unconjugated bilirubin - decreased haptoglobin • Hb electrophoresis: - Major:  HbF - Minor:  HbA2 • B.M exam: - Erythroid hyperplasia • Alkaline denaturation test: - Resistant

  23. Radiological Investigations: • X-Ray skull: wide diploic space and Hair on end • appearance - Long bones: widen medullary cavities Trabeculations

  24. Normal Peripheral Smear

  25. Thalassemia

  26. Differential Diagnosis • From other microcytic hypochromic anemias: 1-Iron deficiency 2- Thalassemia syndrome 3-Anemia of chronic infection and inflammations 4-Sideroblastic anemias 5-Lead poisoning 6- B6 deficiency • From other hemolytic anemias By: • Facial appearance • Hb electrophoresis

  27. Treatment • Blood transfusion: when - Hb  6 gm% - Keep Hb  10. (hypertransfusion) - Keep Hb  12 (supertransfusion) • Iron chelating agent (Desferroxamine) • Folic acid • Antibiotics for Intercurrent infections • Splenectomy: - Hypersplenism - Pressure manifestations • Bone marrow transplantation

  28. Complications and treatment

  29. Alpha -Thalassemia

  30. Alpha -Thalassemia • Mutations can affect one or more of the  genes resulting in four levels of severity • When all four genes deleted – no a chains, hydrops fetalis or  -thalassemia Major (incompatible with life – infants are stillborn or die within a few hours ). • 3 of the four deleted, hemoglobin H Disease • 2 of the 4 deleted, a-thalassemia minor • 1 deletion, silent carrier

  31. Questions

  32. 1- The predominant hemoglobin present at birth in normal infant is: a- Hb - A . b- Hb – F. c- Hb – A2 d- Hb – portland • 2- B- thalassemia is characterized by the following except: a-microcytic hypochromic anemia .b-reticulocytosis . c-increased serum iron . d-increased total iron binding capacity .

  33. 3 – The main lines of treatment in B- thalassemia are : a- plasma transfusion . b- desferal . c-bone marrow aspiration . d- splenectomy . • 4-In thalassemia all are right except : a- Treating by iron chelating agent b- Hepatosplenomegally. c- Normocytic normochromic anemia. d- Protruded maxilla.

  34. Sickle cell anemia

  35. Sickle cell anemia • Definition:- AR chronic hemolytic anemia Abnormal HBS in which (Beta chain’s 6 th aa: valine is substituted for glutamic acid) • types: • homozygous • Heterozygous

  36. Pathophysiology • Sickle red blood cells become hard and irregularly shaped (resembling a sickle) • Become clogged in the small blood vessels and therefore do not deliver oxygen to the tissues. • Lack of tissue oxygenation can cause excruciating pain, damage to body organs and even death.

  37. Genetics Sickle cell is an autosomal recessive disease. Therefore, the child can only get Sickle cell if both parents are carriers, not if only one is and the other is normal. They have a 25% chance of getting it if both are carriers

  38. Early Symptoms • and Complications • Typically appear during infant's first year • 1st symptom: dactylitis and fever (6 mo-2 yrs) • Pain in the chest, abdomen, limbs and joints • Enlargement of the heart, liver and spleen nosebleeds • Frequent upper respiratory infections • Chronic anemia as children grow older • Over time Sickle Cell sufferers can experience damage to organs such as liver, kidney, lungs, heart and spleen • Can result in death

  39. Clinical pictures Of crisis • A) Vascular-occlusive crises These may be caused by infection, acidosis, dehydration or hypoxia occlusion of small bl./vessels Ht  infarction CNS  hemiplegia mesentery  abd. pain

  40. B) sequestration crisis destruction of RBC in liver and spleen  shock  HSM C) Aplastic crisis aplasia of BM D) hyperhemolytic crisis Acute hemolytic anemia

  41. Clinical Features of Sickle Cell Disease

  42. Laboratory Investigations 1- Peripheral blood exam  - Normocytic Normochromic -  Reticulocytic count - sickle shaped RBCs 2- Chemistry tests - Increased bilirubin - Increased LDH - Decreased haptoglobin

  43. 2- Sickling test Sodium metabisulfite added to blood ,Reduces oxygen tension and sickling Viewed microscopically 3- Hb electrophoresis: HbS and HBA2 4- BM exam: erythroid hyperplasia

  44. Sickle Cell Anemia – blood film SickleCells

  45. Treatment 1- Preventative – eliminate conditions that precipitate vaso-occulsion 1- during attacks  Rest in bed Hydration Sedation Antibiotics BI Transfusion 2- Between attacks - BI Transfusion - Iron chelating agents - Hydroxyurea to reduce intracellular sickling – reactivated fetal genes and elevated HbF 3- Marrow Stem Cell Transplantation 4- Gene Therapy Transplantation

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