1. Anemia • Blood Loss • Acute • Chronic • IN-creased destruction (HEMOLYTIC) • DE-creased production

2. Features of All Anemias • Pallor, where? • Tiredness • Weakness • Dyspnea, why? • Palpitations • Heart Failure (high output), why?

3. Blood Loss • Acute • Trauma • Chronic • Lesions of gastrointestinal tract, gynecologic disturbances. The features of chronic blood loss anemia are the same as iron deficiency anemia, and is defined as a situation in which the production cannot keep up with the loss.

4. Hemolytic • Hereditary • MEMBRANE disorders: e.g., spherocytosis • ENZYME disorders: e.g., G6PD deficciency • HGB disorders (hemoglobinopathies) • Acquired • MEMBRANE disorders (PNH) • ANTIBODY MEDIATED, transfusion or autoantibodies • MECHANICAL TRAUMA • INFECTIONS • DRUGS, TOXINS • HYPERSPLENISM

5. Impaired Production • Disturbance of proliferation and differentiation of stem cells: aplastic anemias, pure RBC aplasia, renal failure • Disturbance of proliferation and maturation of erythroblasts • Defective DNA synthesis: (Megaloblastic) • Defective heme synthesis: (Fe) • Deficient globin synthesis: (Thalassemias)

6. Modifiers • MCV, microcytosis, macrocytosis • MCHC, hypochromic • RDW, anisocytosis

7. Hemolytic Anemias • Life span LESS than 120 days • Marrow hyperplasia (M:E), EPO+ • Increased catabolic products, e.g., bilirubin, serum HGB, hemosiderin

8. Hemolysis • INTRA-vascular (vessels) • EXTRA-vascular (spleen)

9. M:E Ratio normally 3:1

10. Sickle Cell Disease • Classic hemoglobinopathy • Normal HGB is α2 β2: β-chain defects (Val->Glu) • Reduced hemoglobin “sickles” in homozygous • 8% of American blacks are heterozygous

11. Clinical features of HGB-S disease • Severe anemia • Jaundice • PAIN (pain CRISIS) • Vaso-occlusive disease: EVEREWHERE, but clinically significant bone, spleen (autosplenectomy) • Infections: Pneumococcus, Hem. Influ., Salmonella osteomyelitis

14. THALASSEMIAS • A WIDE VARIETY of diseases involving GLOBIN synthesis, COMPLEX genetics • Alpha or beta chains deficient synthesis involved • Often termed MAJOR or MINOR, depending on severity, silent carriers and “traits” are seen • HEMOLYSIS is uniformly a feature, a microcytic anemia • A “crew cut” skull x-ray appearance may be seen

16. Paroxysmal Nocturnal Hemoglobinuria (PNH) • ACQUIRED, NOT INHERITED like all the previous hemolytic anemias were • ACQUIRED mutations in phosphatidylinositol glycan A (PIGA) • It is “P” and “N” only 25% of the time GlycosylphosPhatidylInositol

17. Immunohemolytic Anemia • All of these have the presence of antibodies and/or compliment present on RBC surfaces • NOT all are AUTOimmune, some are caused by drugs

18. Coombs Test • DIRECT: Patient’s CELLS are tested for surface Ab’s • INDIRECT: Patient’s SERUM is tested for Ab’s.

19. Direct anti-globulin test

20. HEMOLYSIS/HEMOLYTIC ANEMIAS DUE TO RBC TRAUMA • Mechanical heart valves breaking RBC’s • MICROANGIOPATHIES: • TTP • Hemolytic Uremic Syndrome

21. NON-Hemolytic Anemias:i.e., DE-creased Production • “Megaloblastic” Anemias • B12 Deficiency (Pernicious Anemia) • Folate Deficiency • Iron Deficiency • Anemia of Chronic Disease • Aplastic Anemia • “Pure” Red Cell Aplasia • OTHER forms of Marrow Failure

22. MEGALOBLASTIC ANEMIAS • Differentiating megaloblasts (marrow) from macrocytes (peripheral smear, MCV>94) • Impaired DNA synthesis • For all practical purposes, also called the anemias of B12 and FOLATE deficiency • Often VERY hyperplastic/hypercellular marrow

23. Decreased intake • Inadequate diet, vegetarianism • Impaired absorption • Intrinsic factor deficiency • Pernicious anemia • Gastrectomy • Malabsorption states   • Diffuse intestinal disease, e.g., lymphoma, systemic sclerosis

24. Ileal resection, ileitis   • Competitive parasitic uptake   • Fish tapeworm in • Fish tapeworm infestation     • Bacterial overgrowth in blind loops and diverticula of bowel • Increased requirement • Pregnancy, hyperthyroidism, disseminated cancer

25. Vit-B12 Physiology • Oral ingestion • Combines with INTRINSIC FACTOR in the gastric mucosa • Absorbed in the terminal ileum • DEFECTS at ANY of these sites can produce a MEGALOBLASTIC anemia

26. Please remember that ALL megaloblastic anemias are also MACROCYTIC (MCV>94 or MCV~100), and that not only are the RBC’s BIG and hyperplastic/hypercellular, but so are the neutrophils, and neutrophilic precursors in the bone marrow too, and even more so, HYPERSEGMENTED!!!

27. PERNICIOUS ANEMIA • MEGALOBLASTIC anemia • LEUKOPENIA and HYPERSEGS • JAUNDICE • NEUROLOGIC posterolateral spinal tracts • ACHLORHYDRIA • Can’t absorb B12 • LOW serum B12 • Flunk Schilling test, i.e., can’t absorb B12, using a radioactive tracer

28. FOLATE DEFICIENCY MEGALOBLASTIC AMEMIAS • Decreased Intake: diet, etoh-ism, infancy • Impaired Absorption: intestinal disease • DRUGS: anticonvulsants, BCPs, CHEMO • Increased Loss: Hemodialysis • Increased Requirement: Pregnancy, infancy • Impaired Usage

29. APLASTIC ANEMIAS • ALMOST ALWAYS involve platelet and WBC suppression as well • Some are idiopathic, but MOST are related to drugs, radiation • FANCONI’s ANEMIA is the only one that is inherited, and NOT acquired • Act at STEM CELL level, except for “pure” red cell aplasia

30. APLASTIC ANEMIAS

31. APLASTIC ANEMIAS • CHLORAMPHENICOL • OTHER ANTIBIOTICS • CHEMO • INSECTICIDES • VIRUSES • EBV • HEPATITIS • VZ

32. MYELOPHTHISIC ANEMIAS • Are anemias caused by metastatic tumor cells replacing the bone marrow extensively

34. Fe Deficiency Anemia • Due to increased loss or decreased ingestion, almost always, in USA, nowadays, increased loss is the reason • Microcytic (low MCV), Hypochromic (low MCHC) • THE ONLY WAY WE CAN LOSE IRON IS BY LOSING BLOOD, because FE is recycled!

35. Fe Transferrin Ferritin (GREAT test) Hemosiderin

36. +++ ++ Fe Fe Regulation of iron absorption Gut lumen Heme Fe DMT1 Enterocyte Ferritin ++ +++ Fe Fe MTP1 Enterocyte precursor Plasma transferrin Transferrin Receptor HFE Hepcidin

37. Gastrointestinal absorption 1 mg/day Functional iron Blood, marrow, myoglobin 2 grams Storage iron Liver, RES 1 gram Plasma transferrin 2 mg Daily physiologic loss 1 mg

38. Clinical Fe-Defic-Anemia • Adult men: GI Blood Loss • PRE menopausal women: menorrhagia • POST menopausal women: GI Blood Loss

39. 2 BEST lab tests: • Serum Ferritin • Prussian blue hemosiderin stain of marrow (also called an “iron” stain)

41. Iron stores Erythron iron

42. Serum transferrin receptor Storage iron = 107 mg Storage iron = 335 mg Storage iron = 1,102 mg Serial measurement of sTfr during phlebotomy in 3 individuals Goodnough, Skikne, Brugnara. Blood, 2000; 96: 823 - 833

43. Ratio of serum transferrin receptor to ferritin as a measure of total body iron Cook, Flowers, Skikne. Blood 2003; 101: 3359 - 64

44. Serum ferritin and total body iron Kaltwasser, Gottschalk. Kidney Int. 1999; 55(suppl): S49 - S56

45. Treatment of iron def anemia • Oral iron is the preferred initial treatment • Recommended daily dose is 150-200mg/day of elemental iron • 325 mg of ferrous sulfate contains 65 mg of elemental iron • One table three times a day • Administer iron on an empty stomach with half a glass of OJ or 250mg ascorbic acid

46. Serum iron after oral iron in patients with iron deficiency 80 60 Serum iron 40 20 1 2 3 4 Hours WH Crosby, Arch Int Med; circa 1970

47. Safety of intravenous iron Sodium ferric gluconate in sucrose (Ferrlecit) Available in Europe > 30 years 2.7 x 106 doses/year in Germany + Italy in 1995 Iron dextran (Imferon until 1992, InFed since 1992) 3 x 106 doses/year in US in 1996 Faich, Strobos. Am J Kidney Dis 1999: 33(3):464-70

48. Safety of intravenous iron Reported severe adverse reactions (1976 - 1996): SFGS 3.3 severe allergic reactions/106 doses, no fatalities ID 8.7 severe allergic reactions/106 doses, 31 fatalities Faich, Strobos. Am J Kidney Dis 1999: 33(3):464-70

49. Safety of intravenous iron Other theoretical risks: iron overload sepsis acceleration of atherosclerosis Faich, Strobos. Am J Kidney Dis 1999: 33(3):464-70

50. Medicare warning :( Recombinant human erythropoietin is approved only for treatment of anemia caused by renal failure or by cancer treatment and for certain hematologic malignancies. Sodium ferric gluconate in sucrose is approved only for treatment of anemia in patients on hemodialysis and for patients who have had a severe reaction to iron dextran.