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 B 12 and Folate Metabolism

12. Hematological Responses of Vitamin B 12 and Folate Therapy

13. Vitamin B 12 (Cobalamin)

14. Vitamin B 12 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 B 12 Complex

16. Vitamin B 12 Deficiency Gastric achlorhydria and decreased intrinsic factor due to gastric atrophy and gastric surgery Panacreatic disorders Antibodies to intrinsic factor/vitamin B 12 complex Bacterial overgrowth and intestinal parasites prevent vitamin B 12 from reaching the ileum Damaged ileal mucosa Congenital defects in transcobalamin II

17. Vitamin B 12 Therapy Oral preparations to supplement deficient diet to prevent vitamin B 12 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 B 12 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 B 12 deficiency

22. Hematopoiesis

23. Hematopoietic and Lymphopoietic Growth 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 B 12 /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) – α 2 β 2 HbF (fetal) – α 2 γ 2 Sickle Cell Hemoglobin – a single E6V mutation in the β chain HbA (adult) – α 2 β 2s

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?