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Hema intro anemia

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Hema intro anemia

  1. 1. INTRODUCTION TO HEMATOLOGY Erlinda E. Samson-Cruz, MD, FPCP, FPSHBT
  2. 2. HEMATOLOGY <ul><li>study of circulating blood components and blood forming tissues </li></ul><ul><li>Blood </li></ul><ul><ul><li>5 to 7 % of total BW </li></ul></ul><ul><li>function </li></ul><ul><ul><li>deliver nutrients, hormones and O2 to tissues </li></ul></ul><ul><ul><li>to collect and dispose of the wastes from cellular metabolism </li></ul></ul><ul><ul><li>to deliver specialized cells to tissues for protection against external environment </li></ul></ul><ul><ul><li>to prevent leakage of blood in blood vessels </li></ul></ul>
  3. 3. Elements of blood <ul><li>Fluid elements </li></ul><ul><ul><li>Water </li></ul></ul><ul><ul><li>Electrolytes </li></ul></ul><ul><ul><li>Proteins </li></ul></ul><ul><li>Cellular elements </li></ul><ul><ul><li>RBC </li></ul></ul><ul><ul><li>WBC </li></ul></ul><ul><ul><li>Platelets </li></ul></ul>
  4. 4. Cellular elements <ul><li>with an area of central pallor about a third of the diameter of the cell </li></ul><ul><li>shape of a normal red cell resembles a disc that is thinner in the centre </li></ul><ul><li>Normal red cells </li></ul>
  5. 5. Cellular elements <ul><li>Scanning electron micrograph of a red cell </li></ul><ul><li>showing that it is disc shaped with central thinning </li></ul>
  6. 6. Cellular elements <ul><li>Normal white cells </li></ul>
  7. 7. Cellular elements <ul><li>Normal neutrophil and normal small lymphocyte </li></ul><ul><li>Neutrophils </li></ul><ul><ul><li>have two to five lobes </li></ul></ul><ul><ul><li>cytoplasm is very pale blue and contains small lilac-staining granules, called neutrophilic granules </li></ul></ul>
  8. 8. Cellular elements <ul><li>Normal eosinophil </li></ul><ul><li>Eosinophils </li></ul><ul><ul><li>granules stain orange and usually pack the cytoplasm </li></ul></ul><ul><ul><li>nucleus is most often bilobed </li></ul></ul><ul><ul><li>cytoplasm is weakly basophilic so when it is visible it stains pale blue </li></ul></ul>
  9. 9. Cellular elements <ul><li>Normal basophil </li></ul><ul><li>Basophil </li></ul><ul><ul><li>cytoplasm is packed with large purple granules which often almost obscure the lobulated nucleus </li></ul></ul>
  10. 10. Cellular elements <ul><li>Normal small lymphocyte </li></ul><ul><li>Lymphocyte </li></ul><ul><ul><li>cell is round with very scanty cytoplasm </li></ul></ul><ul><ul><li>cytoplasm is moderately blue or basophilic </li></ul></ul><ul><ul><li>high nucleocytoplasmic ratio </li></ul></ul>
  11. 11. Cellular elements <ul><li>Normal large lymphocyte </li></ul><ul><li>Large lymphocyte </li></ul><ul><ul><li>less condensed chromatin and more voluminous irregular cytoplasm than a small lymphocyte </li></ul></ul><ul><ul><li>cytoplasm is weakly or moderately basophilic </li></ul></ul>
  12. 12. Cellular elements <ul><li>Normal large granular lymphocyte </li></ul><ul><li>Large granular lymphocyte </li></ul><ul><ul><li>large lymphocytes containing a small number of azurophilic (light purple) granules </li></ul></ul><ul><ul><li>cytoplasm is usually weakly basophilic </li></ul></ul><ul><ul><li>nucleolus may be visible </li></ul></ul>
  13. 13. Cellular elements <ul><li>Normal monocyte </li></ul><ul><li>Monocyte </li></ul><ul><ul><li>largest normal white cell found in the blood </li></ul></ul><ul><ul><li>irregular lobulated nucleus and opaque grey-blue cytoplasm containing fine azurophilic (light purple) granules </li></ul></ul><ul><ul><li>cytoplasm is sometimes vacuolated </li></ul></ul>
  14. 14. Cellular elements <ul><li>Neutrophil band cell </li></ul><ul><li>Neutrophil band cells or band forms </li></ul><ul><ul><li>cells of neutrophil lineage with non-segmented nuclei </li></ul></ul><ul><ul><li>less mature than segmented neutrophils </li></ul></ul><ul><ul><li>increased number of band cells is referred to as a 'left shift' </li></ul></ul>
  15. 15. Cellular elements <ul><li>Normal platelets </li></ul><ul><li>Platelets </li></ul><ul><ul><li>small anuclear cytoplasmic fragments </li></ul></ul><ul><ul><li>small purple-staining granules </li></ul></ul><ul><ul><li>seen between the red cells in a blood film </li></ul></ul>
  16. 16. PRINCIPLES OF HEMATOLOGIC DIAGNOSIS <ul><li>History </li></ul><ul><ul><li>Present illness </li></ul></ul><ul><ul><li>Exposure to drugs or chemicals </li></ul></ul><ul><ul><li>Past med history </li></ul></ul><ul><ul><li>Family history </li></ul></ul><ul><ul><li>Review of symptoms </li></ul></ul><ul><li>Physical Examination </li></ul><ul><ul><li>clues to the mechanisms of hematologic disease/ anemia may be provided </li></ul></ul>
  17. 17. PRINCIPLES OF HEMATOLOGIC DIAGNOSIS <ul><li>Peripheral blood measurements </li></ul><ul><ul><li>CBC </li></ul></ul><ul><ul><li>PBS </li></ul></ul><ul><ul><li>Reticulocyte count </li></ul></ul><ul><ul><li>Iron studies </li></ul></ul><ul><li>B one marrow aspirate or biopsy </li></ul>
  18. 18. LABORATORY EVALUATION <ul><li>COMPLETE BLOOD COUNT </li></ul><ul><ul><li>Hemoglobin </li></ul></ul><ul><ul><li>Hematocrit </li></ul></ul><ul><ul><li>RBC count </li></ul></ul><ul><ul><li>red cell indices </li></ul></ul><ul><ul><li>WBC count with cell differential </li></ul></ul><ul><ul><li>Platelet count </li></ul></ul><ul><ul><li>reticulocyte count </li></ul></ul>
  19. 19. LABORATORY EVALUATION <ul><li>RBC indices </li></ul><ul><li>MCV in fl </li></ul><ul><ul><ul><li>= hct/rbc ct x 1000 </li></ul></ul></ul><ul><li>MCH in pg per cell </li></ul><ul><ul><ul><li>= hgb/rbc ct x 1000 </li></ul></ul></ul><ul><li>MCHC in grams per liter </li></ul><ul><ul><ul><li>hgb/hct x 100 </li></ul></ul></ul><ul><li>average volume of individual red cells </li></ul><ul><li>hgb content per red cell </li></ul><ul><li>hgb concentration of the red cells </li></ul>
  20. 20. LABORATORY EVALUATION <ul><li>PERIPHERAL BLOOD SMEAR  </li></ul><ul><li>information about defects in red cell production </li></ul><ul><ul><li>anisocytosis </li></ul></ul><ul><ul><li>poikilocytosis </li></ul></ul><ul><ul><li>polychromasia </li></ul></ul><ul><li>wbc immaturity or abnormality </li></ul><ul><li>platelet number and morphology </li></ul>
  21. 21. LABORATORY EVALUATION <ul><li>Anisocytosis </li></ul><ul><ul><li>variations in cell size </li></ul></ul><ul><li>Anisochromasia </li></ul><ul><ul><li>variation in staining from cell to cell </li></ul></ul><ul><ul><li>Ida pt </li></ul></ul>
  22. 22. LABORATORY EVALUATION <ul><li>Poikilocytosis </li></ul><ul><ul><li>means an increased variability in red cell shape </li></ul></ul><ul><li>Classification of poikilocytes </li></ul>
  23. 23. LABORATORY EVALUATION <ul><li>Polychromasia </li></ul><ul><li>indicates the presence of increased numbers of red cells with a bluish tinge superimposed on the red colour of haemoglobin </li></ul><ul><li>increased numbers of polychromatic cells correlates with an increased reticulocyte count </li></ul><ul><li>polychromatic cells are often larger than mature red cells and may then be referred to as polychromatic macrocytes </li></ul>
  24. 24. LABORATORY EVALUATION <ul><li>RETICULOCYTE COUNT  </li></ul><ul><li>key to the initial classification of anemia </li></ul><ul><ul><li>patient's reticulocyte count is compared with the expected reticulocyte response </li></ul></ul><ul><li>Normally red cell production rate increases to 2-3x normal within 10 days following the onset of anemia </li></ul><ul><li>In established anemia, a reticulocyte response less than two to three times normal indicates an inadequate marrow response </li></ul>
  25. 25. LABORATORY EVALUATION <ul><li>Reticulocytes </li></ul><ul><ul><li>young red cells newly released from the bone marrow </li></ul></ul><ul><li>identified by staining with a supravital dye that precipitates the residual ribosomal RNA </li></ul><ul><li>precipitates appear as blue or black punctate spots </li></ul><ul><li>residual RNA is metabolized over the first 24 to 36 h of the reticulocyte's lifespan in circulation </li></ul><ul><li>reticulocyte count ranges from 1 to 2% and reflects the daily replacement of 0.8 to 1.0% of the circulating red cell population </li></ul>
  26. 26. RETICULOCYTE COUNT 1 st CORRECTION <ul><li>adjusts the reticulocyte count based on the reduced number of circulating red cells </li></ul><ul><li>provides an estimate of the retic ct corrected for anemia </li></ul><ul><li>corrected retic </li></ul><ul><li>= retic % x (actual hgb or hct /ideal hgb or hct ) </li></ul><ul><li>Example </li></ul><ul><li>retic ct 9% </li></ul><ul><li>hemoglobin 7.5 g/dL </li></ul><ul><li>hematocrit 23% </li></ul><ul><li>corrected retic count </li></ul><ul><li>= 9 x (7.5/15) [or x (23/45)] </li></ul><ul><li>= 4.5% </li></ul>
  27. 27. RETICULOCYTE COUNT 2 nd CORRECTION <ul><li>for longer life of prematurely released reticulocytes in the blood </li></ul><ul><li>produces the reticulocyte production index </li></ul><ul><li>maturation time correction factor </li></ul>
  28. 28. RETICULOCYTE COUNT 2 nd CORRECTION <ul><li>necessary to convert the corrected reticulocyte count to an index of marrow production </li></ul><ul><li>provides an estimate of marrow production relative to normal </li></ul><ul><ul><li>+polychromatophilic macrocytes </li></ul></ul><ul><ul><ul><li>divided by 2 to account for the prolonged reticulocyte maturation time </li></ul></ul></ul><ul><ul><li>-polychromatophilic cells </li></ul></ul><ul><ul><ul><li>second correction is not required </li></ul></ul></ul>
  29. 29. LABORATORY EVALUATION <ul><li>TESTS OF IRON SUPPLY AND STORAGE  </li></ul><ul><li>Serum iron </li></ul><ul><ul><li>normal serum iron ranges from 9 to 27 umol/L (50 to 150 ug/dL) </li></ul></ul><ul><li>TIBC </li></ul><ul><ul><li>normal TIBC is 54 to 64 umol/L (300 to 360 ug/dL) </li></ul></ul><ul><li>Percent transferrin saturation </li></ul><ul><ul><li>derived by dividing the serum iron level (× 100) by the TIBC </li></ul></ul><ul><ul><li>transferrin saturation ranges from 25 to 50% </li></ul></ul><ul><li>Serum ferritin </li></ul><ul><ul><li>to evaluate total-body iron stores </li></ul></ul>
  30. 30. Bone marrow aspiration
  31. 31. Bone marrow aspiration
  32. 32. Sites of BMA
  33. 33. LABORATORY EVALUATION <ul><li>BONE MARROW EXAMINATION  </li></ul><ul><li>Cellularity </li></ul><ul><li>M/E ratio 3-4:1 </li></ul><ul><li>Morphology of cells </li></ul><ul><li>assessment of iron stores or iron in developing red cells </li></ul><ul><li>bone marrow aspirate and needle biopsy maybe useful in the diagnosis of a marrow disorder </li></ul>
  34. 34. How to examine a bone marrow aspirate
  35. 35. Bone marrow aspirate <ul><li>Macroscopic view of bone marrow film </li></ul><ul><li>   </li></ul><ul><li>Normal bone marrow fragment in an adult </li></ul>
  36. 36. Bone marrow aspirate <ul><li>Megakaryocytes in bone marrow </li></ul><ul><li>without any associated megakaryocytes </li></ul>
  37. 37. Bone marrow aspirate <ul><li>Normal mature megakaryocyte in the bone marrow </li></ul><ul><li>megakaryocyte is the largest normal bone marrow cell </li></ul><ul><li>has a large lobulated nucleus and its cytoplasm contains fine azurophilic granules </li></ul><ul><li>Normal megakaryocyte </li></ul>
  38. 38. Bone marrow aspirate <ul><li>Bone marrow iron stain, iron deficiency </li></ul><ul><li>Bone marrow iron stain, normal </li></ul>
  39. 39. SITES OF HEMATOPOIESIS <ul><li>NORMAL CONDITIONS </li></ul><ul><li>Fetal sites of Hematopoiesis </li></ul><ul><ul><li>Yolk sac </li></ul></ul><ul><ul><ul><li>3-12 wks AOG </li></ul></ul></ul><ul><ul><li>Liver </li></ul></ul><ul><ul><ul><li>5-6 weeks upto 6 months AOG to 2 weeks after birth </li></ul></ul></ul><ul><ul><li>Spleen </li></ul></ul><ul><ul><ul><li>4-8 months AOG </li></ul></ul></ul><ul><ul><li>Bone marrow </li></ul></ul><ul><ul><ul><li>5 months AOG </li></ul></ul></ul><ul><ul><ul><li>primary site by 7 months </li></ul></ul></ul>
  40. 40. SITES OF HEMATOPOIESIS <ul><li>Post natal sites of hematopoiesis </li></ul><ul><ul><li>At birth </li></ul></ul><ul><ul><ul><li>all BM cavities are hematopoietic </li></ul></ul></ul><ul><ul><li>After 20 years </li></ul></ul><ul><ul><ul><li>axial skeleton </li></ul></ul></ul><ul><li>Gross morphologic changes </li></ul><ul><ul><li>Red marrow </li></ul></ul><ul><ul><li>Yellow marrow </li></ul></ul>
  41. 41. SITES OF HEMATOPOIESIS <ul><li>DISEASE </li></ul><ul><li>Fetal hematopoietic sites </li></ul><ul><ul><li>Extramedullary site can serve as the primary sites of blood cell development </li></ul></ul><ul><ul><li>Liver, spleen </li></ul></ul><ul><li>Adult medullary sites </li></ul><ul><ul><li>to help meet the demand for increased blood cell production </li></ul></ul>
  42. 42. Hematopoiesis <ul><li>process by which the formed elements of the blood are produced </li></ul><ul><li>Stem cells are capable of producing red cells, all classes of granulocytes, monocytes, platelets, and the cells of the immune system </li></ul>
  43. 43. Hematopoiesis <ul><li>stem cells develop into differentiated cell types through incompletely defined molecular events that are intrinsic to the stem cell </li></ul><ul><li>Following lineage commitment hematopoietic progenitor and precursor cells come increasingly under the regulatory influence of growth factors and hormones </li></ul>
  44. 44. HEMATOPOIESIS PLURIPOTENT STEM CELL MYELOID MULTIPOTENT STEM CELL LYMPHOID MULTIPOTENT STEM CELL LYMPHOCYTES BFU-EYTHROID MEG PROGENITOR CFU-MEG GRAN/MONO PROGENITOR CFU-GM EO PROGENITOR CFU-Eo E PROGENITOR CFU-E RBC PLATELET MONOCYTE NEUTROPHIL BASOPHIL EOSINOPHIL
  45. 45. ERYTHROPOIESIS
  46. 46. ERYTHROPOIESIS <ul><li>critical elements </li></ul><ul><ul><li>EPO production </li></ul></ul><ul><ul><li>iron availability </li></ul></ul><ul><ul><li>proliferative capacity of the bone marrow </li></ul></ul><ul><ul><li>effective maturation of red cell precursors </li></ul></ul>
  47. 47. ERYTHROPOIESIS <ul><li>regulated process of red cell production </li></ul><ul><li>regulated by erythropoietin (EPO) the hormone required for the maintenance of committed erythroid progenitor cells that, in the absence of the hormone, undergo apoptosis </li></ul>
  48. 48. ERYTHROPOIETIN <ul><li>produced and released by peritubular capillary lining cells within the kidney </li></ul><ul><li>small amount is produced by hepatocytes </li></ul><ul><li>stimulus for EPO production </li></ul><ul><ul><li>Impaired O2 delivery to the kidney resulting to decreased red cell mass </li></ul></ul><ul><ul><li>impaired O2 loading of the hemoglobin molecule </li></ul></ul><ul><ul><li>impaired blood flow to the kidney </li></ul></ul>
  49. 49. Physiologic regulation of red cell production
  50. 50. Anemia classification
  51. 51. HYPOPROLIFERATIVE ANEMIAS
  52. 52. HYPOPROLIFERATIVE ANEMIAS <ul><li>normocytic and normochromic red cells </li></ul><ul><li>inappropriately low reticulocyte response </li></ul><ul><li>includes: </li></ul><ul><ul><li>acute and chronic inflammation </li></ul></ul><ul><ul><li>renal disease </li></ul></ul><ul><ul><li>hypometabolic states such as protein malnutrition and endocrine deficiencies </li></ul></ul><ul><ul><li>early iron deficiency </li></ul></ul><ul><ul><li>anemias from marrow damage </li></ul></ul>
  53. 53. ANEMIA OF CHRONIC DISEASE <ul><li>one of the most common forms of anemia seen clinically </li></ul><ul><li>includes the following: </li></ul><ul><ul><li>inflammation </li></ul></ul><ul><ul><li>infection </li></ul></ul><ul><ul><li>tissue injury </li></ul></ul><ul><ul><li>cancer </li></ul></ul><ul><li>features: </li></ul><ul><ul><li>low serum iron </li></ul></ul><ul><ul><li>increased red cell protoporphyrin </li></ul></ul><ul><ul><li>hypoproliferative marrow </li></ul></ul><ul><ul><li>transferrin saturation in the range of 15 to 20%, </li></ul></ul><ul><ul><li>normal or increased serum ferritin </li></ul></ul>
  54. 54. Cytokines effect
  55. 55. ANEMIA OF CHRONIC DISEASE <ul><li>Cytokines effect </li></ul><ul><li>IL-1 </li></ul><ul><ul><li>directly decreases erythropoietin production in response to anemia </li></ul></ul><ul><ul><li>IL-1 acting through accessory cell release of IFN-g suppresses the response of the erythroid marrow to erythropoietin — an effect that can be overcome by increased erythropoietin administration </li></ul></ul><ul><li>TNF </li></ul><ul><ul><li>acting through the release of IFN-g by marrow stromal cells, also suppresses the response to erythropoietin </li></ul></ul><ul><li>Hepcidin </li></ul><ul><ul><li>made by the liver </li></ul></ul><ul><ul><li>increased in inflammation and acts to suppress iron absorption and iron release from storage sites </li></ul></ul>
  56. 56. TREATMENT <ul><li>Treat underlying disease </li></ul><ul><li>If reversals are not possible </li></ul><ul><ul><li>Transfusions </li></ul></ul><ul><ul><li>Erythropoietin </li></ul></ul><ul><ul><ul><li>cancer up to 300 U/kg three times a week </li></ul></ul></ul><ul><ul><ul><li>Hgb levels of 10 to 12 g/dL are usually reached within 4 to 6 weeks if iron levels are adequate </li></ul></ul></ul><ul><ul><ul><li>only about 60% of patients may respond </li></ul></ul></ul>
  57. 57. ANEMIA OF RENAL DISEASE <ul><li>due to a failure to produce adequate amounts of erythropoietin </li></ul><ul><li>reduction in red cell survival </li></ul><ul><li>normocytic and normochromic RBC </li></ul><ul><li>Reticulocytes are decreased </li></ul><ul><li>normal serum iron, TIBC, and ferritin levels </li></ul><ul><li>Assessment of iron status provides information to distinguish the anemia of renal disease from the other forms of hypoproliferative anemia and to guide management </li></ul>
  58. 58. ANEMIA OF RENAL DISEASE <ul><li>EPO </li></ul><ul><ul><li>50-150 u/kg/wk iv or sc 1 to 3 x a wk </li></ul></ul><ul><ul><li>11-12 g/dl target hgb </li></ul></ul><ul><ul><li>Increase hgb by 1 to 2 g/dl over 4 week period </li></ul></ul><ul><li>Iron supplement </li></ul><ul><ul><li><20 TS and < 100 ug/l serum ferritin </li></ul></ul><ul><ul><ul><li>Give iron 50-100mg IV twice per week </li></ul></ul></ul><ul><ul><li>>50 TS and 800 ug/l serum ferritin </li></ul></ul><ul><ul><ul><li>Withhold iron </li></ul></ul></ul>
  59. 59. ANEMIA OF ENDOCRINE DISORDERS <ul><li>Anemia of Hypothyroidism </li></ul><ul><li>Thyroid hormones </li></ul><ul><li>+ effect on erythropoiesis </li></ul><ul><li>controlling cellular oxygen requirements through their effects on the metabolic rates of the tissues </li></ul><ul><li>Hypothyroidism </li></ul><ul><ul><ul><li>Normocytic or slightly macrocytic anemia </li></ul></ul></ul><ul><ul><ul><li>Reponse of BM to decreased tissue oxygen consumption that occurs in hypothyroidism </li></ul></ul></ul><ul><ul><ul><li>Normal BM but rate of hematopoiesis is low bec of diminished release of EPO from kidney </li></ul></ul></ul><ul><ul><ul><li>10% with macrocytosis </li></ul></ul></ul>
  60. 60. ANEMIA OF ENDOCRINE DISORDERS <ul><li>Anemia of Hypopituitarism </li></ul><ul><li>Androgen </li></ul><ul><li>direct effect on BM stimulating production of EPO </li></ul><ul><li>making marrow cells responsive to EPO </li></ul><ul><li>GH </li></ul><ul><li>trophic effect on the BM </li></ul><ul><li>Hypopituitarism </li></ul><ul><ul><li>Normochromic normocytic </li></ul></ul><ul><ul><li>Reduced retic ct </li></ul></ul><ul><ul><li>Low EPO levels </li></ul></ul><ul><ul><li>Hypocellular marrow </li></ul></ul>
  61. 61. ANEMIA OF ENDOCRINE DISORDERS <ul><li>Anemia of Hyperparathyroidism </li></ul><ul><li>PTH </li></ul><ul><li>Suppress erythropoiesis by </li></ul><ul><ul><li>renal calcification (decreased EPO formation) </li></ul></ul><ul><ul><li>marrow sclerosis ( decreased proliferation of erythroid precursors) </li></ul></ul>
  62. 62. ANEMIA OF ENDOCRINE DISORDERS <ul><li>TREATMENT </li></ul><ul><ul><li>Correction of underlying endocrine disorder </li></ul></ul>
  63. 63. Hypoproliferative Anemias: Treatment <ul><li>Transfusions </li></ul><ul><li>Thresholds for transfusion based on the patient's symptoms </li></ul><ul><li>patients without serious underlying cardiovascular or pulmonary disease can tolerate hemoglobin levels above 8 g/dL and do not require intervention until the hemoglobin falls below that level </li></ul><ul><li>Erythropoietin (Epo) </li></ul><ul><li>useful in anemias in which endogenous EPO levels are inappropriately low </li></ul><ul><li>Iron status must be evaluated and iron repleted to obtain optimal effects </li></ul><ul><li>Longer-acting preparations of EPO can reduce the frequency of injections </li></ul>
  64. 64. APLASTIC ANEMIA
  65. 65. DEFINITION <ul><li>Aplastic anemia </li></ul><ul><ul><li>pancytopenia with bone marrow hypocellularity </li></ul></ul><ul><li>Acquired aplastic anemia </li></ul><ul><ul><li>abrupt onset of low blood counts in a previously well young adult </li></ul></ul><ul><ul><li>seronegative hepatitis or a course of an incriminated medical drug may precede the onset </li></ul></ul>
  66. 66. DEFINITION <ul><li>Constitutional Aplastic anemia </li></ul><ul><ul><li>Fanconi's anemia </li></ul></ul><ul><ul><li>Dyskeratosis congenita </li></ul></ul><ul><ul><ul><li>frequently associated with typical physical anomalies and the development of pancytopenia early in life, can also present as marrow failure in normal-appearing adults </li></ul></ul></ul><ul><li>Iatrogenic marrow aplasia </li></ul><ul><ul><li>marrow hypocellularity after intensive cytotoxic chemotherapy for cancer </li></ul></ul>
  67. 67. EPIDEMIOLOGY <ul><li>2 cases per million persons annually in Europe and Israel </li></ul><ul><li>5 to 7 per million In Thailand and China </li></ul><ul><li>men and women are affected with equal frequency </li></ul><ul><li>biphasic age distribution </li></ul><ul><ul><li>major peak in the teens and twenties </li></ul></ul><ul><ul><li>second rise in the elderly </li></ul></ul>
  68. 68. ETIOLOGY <ul><li>ACQUIRED </li></ul><ul><li>Idiopathic </li></ul><ul><li>Secondary </li></ul><ul><ul><li>Radiation  </li></ul></ul><ul><ul><ul><li>Marrow aplasia is a major acute sequela of radiation </li></ul></ul></ul><ul><ul><ul><li>Radiation damages DNA </li></ul></ul></ul><ul><ul><ul><li>MDS and leukemia are late effects of irradiation </li></ul></ul></ul>
  69. 69. ETIOLOGY <ul><li>Secondary </li></ul><ul><ul><li>Chemicals  Benzene </li></ul></ul><ul><ul><ul><li>notorious cause of bone marrow failure </li></ul></ul></ul><ul><ul><ul><ul><li>aplastic anemia, acute leukemia, and blood and marrow abnormalities </li></ul></ul></ul></ul><ul><ul><ul><li>occurrence of leukemia is roughly correlated with cumulative exposure </li></ul></ul></ul><ul><ul><ul><li>employment history is important </li></ul></ul></ul>
  70. 70. ETIOLOGY <ul><li>Secondary </li></ul><ul><ul><li>Drugs </li></ul></ul><ul><ul><ul><li>Dose dependent effect </li></ul></ul></ul><ul><ul><ul><li>Idiosyncratic reactions </li></ul></ul></ul><ul><ul><li>Infections  </li></ul></ul><ul><ul><ul><li>Hepatitis is the most common preceding infection </li></ul></ul></ul><ul><ul><ul><li>Rarely IM, EBV </li></ul></ul></ul>
  71. 71. ETIOLOGY <ul><li>Secondary </li></ul><ul><ul><li>Immunologic Diseases  </li></ul></ul><ul><ul><ul><li>transfusion-associated graft-versus-host disease </li></ul></ul></ul><ul><ul><ul><li>eosinophilic fasciitis </li></ul></ul></ul><ul><ul><ul><li>systemic lupus erythematosus </li></ul></ul></ul><ul><ul><li>Pregnancy  </li></ul></ul><ul><ul><ul><li>Rarely may occur and recur during pregnancy and resolve with delivery or with spontaneous or induced abortion </li></ul></ul></ul>
  72. 72. ETIOLOGY <ul><li>Secondary </li></ul><ul><ul><li>Paroxysmal Nocturnal Hemoglobinuria  </li></ul></ul><ul><ul><ul><li>acquired mutation in the PIG-A gene in a hematopoietic stem cell resulting to clone of progeny deficient in glycosylphosphatidylinositol-linked cell surface membrane proteins </li></ul></ul></ul><ul><ul><ul><li>aplastic anemia/PNH syndrome is selection of the deficient clones, because they are favored for proliferation in the peculiar environment of immune-mediated marrow destruction </li></ul></ul></ul>
  73. 73. ETIOLOGY <ul><li>INHERITED </li></ul><ul><li>Fanconi's anemia </li></ul><ul><ul><li>autosomal recessive disorder </li></ul></ul><ul><ul><li>congenital developmental anomalies </li></ul></ul><ul><ul><li>progressive pancytopenia </li></ul></ul><ul><ul><li>increased risk of malignancy </li></ul></ul><ul><ul><li>Chromosomes susceptibility to DNA cross-linking agents </li></ul></ul><ul><ul><li>features </li></ul></ul><ul><ul><ul><li>short stature </li></ul></ul></ul><ul><ul><ul><li>cafe au lait spots </li></ul></ul></ul><ul><ul><ul><li>anomalies involving the thumb, radius, and genitourinary tract </li></ul></ul></ul>
  74. 74. ETIOLOGY <ul><li>INHERITED </li></ul><ul><li>Dyskeratosis congenita </li></ul><ul><ul><li>characterized by mucous membrane leukoplasia </li></ul></ul><ul><ul><li>dystrophic nails </li></ul></ul><ul><ul><li>reticular hyperpigmentation </li></ul></ul><ul><ul><li>development of aplastic anemia during childhood </li></ul></ul><ul><li>Shwachman-Diamond syndrome </li></ul><ul><ul><li>marrow failure with pancreatic insufficiency and malabsorption </li></ul></ul>
  75. 75. PATHOPHYSIOLOGY <ul><li>Bone marrow failure results from severe damage to the hematopoietic cell compartment </li></ul><ul><li>Aplastic anemia does not appear to result from defective stroma or growth factor production </li></ul><ul><li>replacement of the bone marrow by fat is apparent in </li></ul><ul><ul><li>the morphology of the biopsy specimen </li></ul></ul><ul><ul><li>magnetic resonance imaging (MRI) of the spine </li></ul></ul><ul><li>cells bearing the CD34 antigen, are greatly diminished </li></ul>
  76. 76. CLINICAL FEATURES <ul><li>History </li></ul><ul><li>Abrupt/ insidious onset </li></ul><ul><li>Bleeding is the most common early symptom </li></ul><ul><li>Symptoms of anemia are also frequent </li></ul><ul><li>restriction of symptoms to the hematologic system </li></ul>
  77. 77. CLINICAL FEATURES <ul><li>Physical Examination  </li></ul><ul><li>Petechiae, ecchymoses, retinal hemorrhages </li></ul><ul><li>Pallor of the skin and mucous membranes </li></ul><ul><li>Lymphadenopathy and splenomegaly are highly atypical </li></ul><ul><li>Cafe au lait spots and short stature suggest Fanconi's anemia </li></ul><ul><li>peculiar nails and leukoplakia suggest dyskeratosis congenita </li></ul>
  78. 78. CLINICAL FEATURES <ul><li>Fanconi's anaemia </li></ul><ul><li>Hands of patient with Fanconi's anaemia showing hypoplastic thumbs </li></ul>
  79. 79. CLINICAL FEATURES <ul><li>Abdomen of patient with Fanconi's anaemia showing abnormal depigmented skin </li></ul><ul><li>as in many such patients the skin abnormality worsened following bone marrow </li></ul><ul><li>Abnormal skin in Fanconi's anaemia </li></ul>
  80. 80. LABORATORY STUDIES <ul><li>Blood  </li></ul><ul><li>smear shows large erythrocytes and a paucity of platelets and granulocytes </li></ul><ul><li>MCV is commonly increased </li></ul><ul><li>Reticulocytes are absent or few </li></ul><ul><li>lymphocyte numbers may be normal or reduced </li></ul>
  81. 81. LABORATORY STUDIES <ul><li>Bone Marrow  </li></ul><ul><li>usually readily aspirated but appears dilute on smear </li></ul><ul><li>fatty biopsy specimen may be grossly pale on withdrawal </li></ul><ul><li><25% cellularity and shows mainly fat </li></ul><ul><li>Residual hematopoietic cells should have normal morphology </li></ul>
  82. 82. LABORATORY STUDIES <ul><li>Trephine biopsy in Fanconi's anaemia </li></ul><ul><li>oil </li></ul><ul><li>Trephine biopsy in AA, acquired </li></ul><ul><li>lpo </li></ul>
  83. 83. LABORATORY STUDIES <ul><li>Ancillary Studies  </li></ul><ul><li>Chromosome breakage studies of peripheral blood using diepoxybutane (DEB) or mitomycin C should be performed on children and younger adults to exclude Fanconi's anemia </li></ul><ul><li>Chromosome studies negative in typical aplastic anemia </li></ul><ul><li>Flow cytometric assays have replaced the Ham test for the diagnosis of PNH </li></ul><ul><li>Serologic studies may show evidence of viral infection, especially Epstein-Barr virus and HIV </li></ul><ul><li>Posthepatitis aplastic anemia is typically seronegative </li></ul>
  84. 84. DIAGNOSIS <ul><li>pancytopenia with a fatty, empty bone marrow </li></ul><ul><li>bone marrow in constitutional aplastic anemia is indistinguishable morphologically from the aspirate in acquired disease </li></ul><ul><li>diagnosis can be suggested by family history, abnormal blood counts since childhood, or the presence of associated physical anomalies </li></ul>
  85. 85. PROGNOSIS <ul><li>natural history of severe aplastic anemia is rapid deterioration and death </li></ul><ul><li>major prognostic determinant is the blood count </li></ul><ul><ul><li>severe disease is defined by the presence of 2 of 3 parameters: </li></ul></ul><ul><ul><ul><li>absolute neutrophil count <500/uL </li></ul></ul></ul><ul><ul><ul><li>platelet count <20,000/uL </li></ul></ul></ul><ul><ul><ul><li>corrected reticulocyte count <1% </li></ul></ul></ul><ul><ul><li>Survival of patients who fulfill these criteria is about 20% at 1 year after diagnosis with only supportive care </li></ul></ul><ul><ul><li>very severe disease </li></ul></ul><ul><ul><ul><li>defined by an absolute neutrophil count <200/u </li></ul></ul></ul><ul><ul><ul><li>fare even more poorly </li></ul></ul></ul>
  86. 86. TREATMENT <ul><li>can be cured by replacement of the absent hematopoietic cells by stem cell transplant </li></ul><ul><li>can be ameliorated by suppression of the immune system to allow recovery of the patient's residual bone marrow function </li></ul>
  87. 87. TREATMENT <ul><li>Bone Marrow Transplantation  </li></ul><ul><ul><li>best therapy for the young patient with a fully histocompatible sibling donor </li></ul></ul><ul><ul><li>allogeneic transplant from fully matched siblings, long-term survival rates for children are 80% </li></ul></ul>
  88. 88. TREATMENT <ul><li>Immunosuppression  </li></ul><ul><li>ALG or antithymocyte globulin (ATG) induces hematologic recovery in about 50% of patients </li></ul><ul><li>addition of cyclosporine to either ALG or ATG has further increased response rates to about 70% and especially improved outcomes for children and for severely neutropenic patients </li></ul>
  89. 89. TREATMENT <ul><li>ATG is given at 40 mg/kg per day for 4 days </li></ul><ul><ul><li>anaphylaxis is a rare but occasionally fatal complication </li></ul></ul><ul><ul><li>ATG binds to peripheral blood cells; therefore, platelet and granulocyte numbers may fall further during active treatmen </li></ul></ul><ul><ul><li>Serum sickness, a flulike illness with a characteristic cutaneous eruption and arthralgia, often develops about 10 days after initiating treatment </li></ul></ul><ul><ul><li>Most patients are given methylprednisolone, 1 mg/kg per day for 2 weeks, to ameliorate the immune consequences of heterologous protein infusion </li></ul></ul><ul><li>ALG is administered at 3.5 mg/kg per day for 5 days </li></ul><ul><li>Cyclosporine is administered orally at an initial dose of 12 mg/kg per day in adults (15 mg/kg per day in children), with subsequent adjustment according to blood levels obtained every 2 weeks </li></ul>
  90. 90. TREATMENT <ul><li>Supportive Care  </li></ul><ul><li>infection in the presence of severe neutropenia must be aggressively treated by prompt institution of parenteral, broad-spectrum antibiotics </li></ul><ul><li>Granulocyte transfusions using G-CSF-mobilized peripheral blood have been effective in the treatment of overwhelming or refractory infections in a few patients </li></ul><ul><li>Hand washing, the single best method of preventing the spread of infection </li></ul><ul><li>Total reverse isolation does not reduce mortality from infections </li></ul>
  91. 91. TREATMENT <ul><li>Supportive Care </li></ul><ul><li>transfusions once or twice weekly in order to maintain the platelet count >10,000/uL </li></ul><ul><li>Menstruation should be suppressed either by oral estrogens or nasal follicle-stimulating hormone/luteinizing hormone (FSH/LH) antagonists </li></ul><ul><li>Aspirin and other nonsteroidal anti-inflammatory agents inhibit platelet function and must be avoided </li></ul><ul><li>Red blood cells should be transfused to maintain a normal level of activity, usually at a hemoglobin value of 70 g/L (90 g/L if there is underlying cardiac or pulmonary disease) </li></ul>

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