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Anemias

Anemias. Body Contents of Iron. Structure of Hemoglobin. The Heme Group. Iron Absorption. Ferritin – a large protein for iron storage Hemosiderin – aggregated ferritin Iron storage sites: hepatocytes reticuloendothelial system muscle (minor)

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Anemias

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  1. Anemias

  2. Body Contents of Iron

  3. Structure of Hemoglobin

  4. The Heme Group

  5. Iron Absorption • Ferritin – a large protein for iron storage • Hemosiderin – aggregated ferritin • Iron storage sites: hepatocytes reticuloendothelial system muscle (minor) • Iron absorption – duodenum and jejunum Ferrous (Fe2+) >>> Ferric (Fe3+) • Transferrin – iron transport

  6. Pathway of Iron Absorption

  7. Daily Iron Intake and Absorption

  8. Iron Deficiency • Dietary intake of iron not adequate to meet normal requirements • Conditions producing an increased requirements of iron because of iron loss • Interference of iron absorption

  9. Therapy for Iron Deficiency • Oral therapy Drug of Choice – ferrous sulfate administered under fasting Side effects – heart burn, nausea, upper gastric discomfort, constipation, diarrhea antidote – deferoxamine • Parenteral therapy Drug – iron dextran injection, im or iv Side effects – im: long tern discomfort, local discoloration of skin, malignant changes iv: serious anaphylactic reactions

  10. Vitamin B12 and Folate Metabolism

  11. Vitamin B12 and Folate Metabolism

  12. Hematological Responses ofVitamin B12 and Folate Therapy

  13. Vitamin B12 (Cobalamin)

  14. Vitamin B12 Absorption • Release from food • Binds to intrinsic factor • Absorbed through ileum • Transport to blood • Binds transcobalamin II • Target tissue (bone marrow, liver)

  15. Intrinsic Factor/Vitamin B12 Complex

  16. Vitamin B12 Deficiency • Gastric achlorhydria and decreased intrinsic factor due to gastric atrophy and gastric surgery • Panacreatic disorders • Antibodies to intrinsic factor/vitamin B12 complex • Bacterial overgrowth and intestinal parasites prevent vitamin B12 from reaching the ileum • Damaged ileal mucosa • Congenital defects in transcobalamin II

  17. Vitamin B12 Therapy • Oral preparations to supplement deficient diet to prevent vitamin B12 deficiency • Cyanocobalamin injection given by intramuscular and subcutaneous routes, never intravenously

  18. Folate (pteroylglutamic acid)

  19. Folate Absorption • Release from food • Hydrolyzed, reduced and methylated • Absorbed through duodenum and jejunum • Transport to blood – folate binding protein • Target tissues • Liver to bile reabsorption (enterohepatic cycle)

  20. Folate Deficiency • Malnutrition • Acute and chronic alcoholism • Defect in folate enterohepatic cycle • Small intestinal diseases • Defects in folate binding protein • Vitamin B12 deficiency

  21. Folate Therapy • Oral preparations Folic acid – drug of choice • Folic acid injection Problems with absorption • Do NOT use folic acid to treat vitamin B12 deficiency

  22. Hematopoiesis

  23. Hematopoietic and LymphopoieticGrowth Factors • Glycoproteins produced by marrow cells and peripheral tissues • Active at low concentrations • Act on more than one committed stem cells • Synergism • Networking • Act on several points during cell proliferation and differentiation

  24. Erythropoietin • Stimulates proliferation, maturation and hemoglobin formation by CFU-E • Stimulates the release of reticulocytes • Acts synergistically with IL-3 and GM-CSF • A glycoprotein (34 kDa) • Binds to the erythropoietin receptor and activates signal transduction processes • Produced primarily by the kidney • Deficiency in anephric patients

  25. Erythropoietin Therapy • Recombinant erythropoietin (epoetin alpha) • Administered parenterally; half-life ~10 h • 50-100 units/kg; 3 times weekly for patients with chronic renal failure • Titrate dosage by hematocrit measurements • No significant allergic reactions • Mild adverse effects – lower dosage • Iron, vitamin B12/folate deficiency

  26. Myeloid Growth Factors(Colony-stimulating Factors) • Glycoproteins that stimulate the proliferation of one or more myeloid cell lines • Recombinant GM-CSF, G-CSF, IL-3, M-CSF (CSF-1), SCF, thrombopoietin are available • GM-CSF and G-CSF are used for treatments of neutropenia • Administered subcutaneously or intravenously • Short half-life • Adverse effects – bone pain, malaise, flulike symptoms, more seriously vessel defects

  27. Sickle Cell Anemia • Hemoglobin HbA (adult) – α2β2 HbF (fetal) – α2γ2 • Sickle Cell Hemoglobin – a single E6V mutation in the β chain HbA (adult) – α2β2s

  28. Normal vs Sickled Erythrocytes

  29. DeoxyHb Fibers in Sickle Erythrocyte

  30. Inter-molecular Contacts of HbS fibers

  31. Defects of Sickled Erythrocytes • More rigid and adhesive – lodged in micro-vasculatures resulting in vascular occlusion • Microinfarction – kidney, impaired its ability to concentrate urine and produce erythropoietin • Altered ability to activate complement and defective granulocyte function - infections • Splenic sequestration of sickled erythrocytes results in hemolytic anemia and splenomegaly

  32. Treatments of Sickle Cell Disease • Gene therapy • Prevention of infections - penicillin in children • Supportive managements of vaso-occlusive crises – pain killers, chronic heparin therapy • Hydroxyurea increases HbF levels to 15-20%, reducing frequency of vaso-occlusive crises • Prophylactic use, not for treatments of crises • Cytotoxic, side effects include GI effects (nausea, vomiting, diarrhea), dermatologic effect (macular papular rash, pruritus) and risk of secondary neoplasm (leukemia) with prolonged use • Hydroxyurea + Erythropoietin therapy?

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