Haematopoiesis & Approach to anaemia


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Haematopoiesis & Approach to anaemia

  1. 1. Haematopoiesis& Approach to Anaemia<br />Dr (Brig) YD Singh<br />MBBS, MD, FIACM, DIT<br />Professor (Internal Medicine)<br />SKN Medical College & Gen Hospital<br />Pune 411 041<br />
  2. 2. Haematopoiesis (1)<br />Process by which formed elements of blood <br />Produced & Regulated through series of steps <br />Pluripotent haematopoietic stem cell<br />Capable of producing red cells,<br />All classes of granulocytes, monocytes, platelets<br />Mechanism to become committed to a given lineage <br />Not fully known <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  3. 3. Haematopoiesis (2)<br />Following lineage commitment<br />Haematopoietic progenitor & precursor cells <br />Come under regulatory influence of growth factors and hormones.<br />For red cell production<br />Erythropoietin (EPO) is regulatory hormone<br />EPO is required for Maintenance of <br />Committed Erythroid progenitor cells <br />In absence of EPO hormone <br />Undergo programmed cell death (apoptosis)<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  4. 4. Factors Regulating RBCProduction<br />24-Sep-11<br />Dr (Brig) YD Singh<br />Regulated process of RBC production is Erythropoiesis <br />
  5. 5. RBC Characteristics<br />Mature red cell is 8 micron in diameter<br />Anucleate , Biconcave & discoid in shape<br />Extremely pliable<br />Needs to traverse microcirculation easily<br />Membrane integrity maintained by <br />Intracellular generation of ATP<br />Average RBC lives 100–120 day<br />1% of all circulating RBC daily replaced<br />Erythron:Organ for red cell production<br />Pool of marrow erythroid precursor cells & large mass of mature circulating RBCs<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  6. 6. RBCs : Normal Indices<br />Mean cell volume (MCV)<br />(Haematocrit x10) / (RBC count x 106) =90 ± 8 fL<br /> Mean Cell Haemoglobin (MCH)<br />(Hb x 10) / (red cell count x 106) = 30 ± 3 pg <br />Mean cell Hb concentration (MCHC)<br />(Hb x 10) / hematocrit or MCH/MCV = 33 ± 2% <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  7. 7. Leukocytes<br />All Leukocytes derived from <br />Common Stem cell in Bone marrow<br />3/4th of nucleated cells of bone marrow<br />Committed to production of Leukocytes<br />Mediate Inflammatory / Immune Responses<br />Include Neutrophils, T & B Lymphocytes <br />Natural Killer (NK) cells, Monocytes<br />Eosinophils & Basophils<br />These cells have specific functions<br />Antibody production by B Lymphocytes<br />Destruction of bacteria by Neutrophils<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  8. 8. Granulocytes Development (1)<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  9. 9. Granulocytes Development (2)<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  10. 10. Neutrophils<br />24-Sep-11<br />Dr (Brig) YD Singh<br />Neutrophil band with Döhle body<br />Normal Neutrophil<br />
  11. 11. 24-Sep-11<br />Dr (Brig) YD Singh<br />Eosinophil<br />Large bright orange granules<br /> usually bilobed Nucleus<br />Basophil<br />Large purple-black granules <br /> fill the cell & obscure nucleus<br />
  12. 12. Normal Bone Marrow<br />24-Sep-11<br />Dr (Brig) YD Singh<br />Low Power View<br />
  13. 13. Bone marrow<br />24-Sep-11<br />Dr (Brig) YD Singh<br />Normoblast<br />with dividing Nucleus<br />Eosinophil Cell<br />Fat Cell<br />Erythrocyte Cell<br />Normoblast Cell<br />Myelocyte dividing<br />Myelocyte Cell<br />Myelocyte Cell<br />Fat Cell<br />Fat Cell<br />
  14. 14. Bone Marrow: Erythroid Hyperplasia<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  15. 15. Bone Marrow: Myeloid Hyperplasia<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  16. 16. Anaemia: Introduction<br />Serum Hblevel or haematocrit < expected value for age & sex<br />WHO criteria<br />Adult men <br />Blood Hbconcentration <13 g/dLor <br />Hematocrit <39% <br />Adult women <br />Blood Hbconcentration <12 g/dL) or <br />Hematocrit <37% <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  17. 17. Anaemia: Types <br />Iron-Deficiency Anemia<br />Vitamin B12 Deficiency Anemia<br />Folate-Deficiency Anemia<br />Anemia of Chronic Disease<br />Haemolytic Anaemia <br />AplasticAnemia<br />Myelodysplastic Syndromes <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  18. 18. Anaemia: Mechanisms<br />3 major physiologic mechanisms of anemia<br />Marrow production defects (Hypoproliferation)<br />Reflects absolute or relative marrow failure <br />Erythroid marrow not proliferated appropriately<br />Can result from <br />Marrow damage<br />Iron deficiency<br />Inadequate erythropoietin stimulation <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  19. 19. Anaemia: Mechanisms<br />Ineffective erythropoiesis (RBC maturation defects)<br />Nuclear maturation defects associated with macrocytosis & abnormal marrow development <br />Cytoplasmic maturation defects associated with microcytosis and hypochromia, usually from defects in hemoglobin synthesis <br />Decreased erythrocyte survival: blood loss or hemolysis<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  20. 20. Anaemia: Symptoms & Signs (1)<br />Often recognized by abnormal results on screening lab tests <br />Signs and symptoms depend on<br />Level of anaemia <br />Time course over which it developed<br />Acute onset Anaemia <br />Chronic Anaemia<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  21. 21. Anaemia: Symptoms & Signs (2)<br />Acute anaemia (nearly always due to blood loss or haemoptysis) <br />If Loss of 10–15% of total blood volume<br />Hypotension <br />Decreased organ perfusion <br />Loss of >30% of blood volume <br />Postural hypotension <br />Tachycardia <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  22. 22. Anaemia: Symptoms & Signs (3)<br />Loss of >40% of blood volume <br />Hypovolemic shock <br />Confusion <br />Dyspnoea <br />Diaphoresis <br />Hypotension <br />Tachycardia <br />Haemolytic Anaemia <br />Presentation depends on mechanism that leads to RBC destruction<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  23. 23. Anaemia: Symptoms & Signs (3)<br />Chronic or progressive anaemia <br />Presentation depends on age of patient <br />Adequacy of blood supply to critical organs<br />Possible Symptom / Sign <br />Fatigue and Loss of stamina <br />Breathlessness (specially on exertion)<br />Pale skin and mucous membranes (Pallor) <br />Palpitation (Tachycardia, after physical exertion) <br />Forceful heartbeat (Heaving Apex beat)<br />High Volume pulse & Systolic flow murmur <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  24. 24. Anaemia: Symptoms & Signs (4)<br />In patients with coronary artery disease <br />Anginal episodes may appear or <br />Increase in frequency and severity <br />In patients with carotid artery disease <br />Light-headedness <br />Dizziness may develop<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  25. 25. Anaemia: DD (1)<br />Hypoproliferativeanaemias(75% of cases) <br />Marrow damage <br />Infiltration/fibrosis <br />Aplasia<br />Iron deficiency (mild to moderate) <br />Decreased stimulation <br />Inflammation <br />Metabolic defect (Hypothyroidism) <br />Renal disease <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  26. 26. Anaemia: DD (2)<br />Maturation disorder <br />Cytoplasmic defects <br />Iron deficiency (severe) <br />Thalassemia<br />Sideroblastic<br />Nuclear defects <br />Folate deficiency , Vitamin B 12 deficiency <br />Drug toxicity <br />Methotrexate & Alkylating agents <br />Alcohol <br />Refractory anemia<br />Myelodysplasia<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  27. 27. Anaemia: DD (3)<br />Haemolysis / Haemorrhage <br />Blood loss <br />Intravascular haemolysis <br />Metabolic defect <br />Membrane abnormality <br />Haemoglobinopathy <br />Autoimmune defect <br />Fragmentation haemolysis <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  28. 28. Anaemia: Diagnostic Approach (1)<br />02 questions need to be answered:<br />Type of Anaemia & Cause of Anaemia<br />Careful history <br />Nutritional history <br />Related to diet, drugs or alcohol <br />Family history of anaemia (Genetic)<br />Geographic backgrounds and ethnic origins<br />G 6 PD deficiency <br />Haemoglobinopathies<br />Middle Eastern, Mediterranean, or African origin<br />Exposure to toxic agents or drugs <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  29. 29. Anaemia: Diagnostic Approach (2)<br />Physical examination <br />May provide clues to mechanisms / cause of anaemia <br />Infection <br />Blood in the stool <br />Splenomegaly & Lymphadenopathy<br />Petechiae suggest platelet dysfunction. <br />Laboratory assessment <br />Including review of past laboratory measurements to determine time of onset <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  30. 30. Anaemia: Diagnostic Approach (3)<br />Physiologic classification / Type of anaemia<br />Reticulocyte index <2.5 & Normocytic, Normochromic anaemia <br />Hypoproliferative<br />Marrow damage: <br />Infiltration / fibrosis <br />Aplasia<br />Decreased stimulation:<br />Inflammation<br />Metabolic defect<br />Renal disease <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  31. 31. Anaemia: Diagnostic Approach (4)<br />Reticulocyte index <2.5 & microcytic or macrocyticanemia<br />Maturation disorder <br />Cytoplasmic defects: <br />Iron deficiency, <br />Thalassemia, Sideroblastic<br />Nuclear defects: <br />Folate deficiency<br />Vitamin B deficiency<br />Drug toxicity<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  32. 32. Anaemia: Diagnostic Approach (5)<br />Reticulocyte index ≥2.5 <br />Haemolysis / Haemorrhage <br />Blood loss <br />Intravascular haemolysis <br />Metabolic defect <br />Membrane abnormality <br />Haemoglobinopathy <br /> Autoimmune defect <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  33. 33. AnaemiaAlgorithm<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  34. 34. Normal Blood Smear (Wright’s stain)<br />24-Sep-11<br />Dr (Brig) YD Singh<br />Normal RBCs, single Neutrophil & few platelets seen<br />
  35. 35. Reticulocytes (Supravital Stain)<br />24-Sep-11<br />Dr (Brig) YD Singh<br />Reticulocyte count is key to initial classification of anemia<br />Reticulocytes are RBCs recently released from marrow<br />
  36. 36. Severe Iron Def Anaemia(Wright’s stain)<br />24-Sep-11<br />Dr (Brig) YD Singh<br />Microcytic & Hypochromic RBCs smaller than nucleus of a <br />Lymphocyte + marked variation in size (Anisocytosis) & <br />shape (Poikilocytosis)<br />
  37. 37. Macrocytosis<br />24-Sep-11<br />Dr (Brig) YD Singh<br />RBCs larger than small Lymphocyte & well haemoglobinized. Macrocytes are oval-shaped (Macroovalocytes) <br />
  38. 38. Howell-Jolly bodies <br />24-Sep-11<br />Dr (Brig) YD Singh<br />In absence of functional spleen, nuclear remnants are not expelled from RBCs & remain as small homogeneously staining blue inclusions on Wright stain <br />
  39. 39. Red cell changes in myelofibrosis<br />24-Sep-11<br />Dr (Brig) YD Singh<br />A Teardrop-shaped RBC & a Nucleated RBC is seen. These forms are seen in Myelofibrosis with Extramedullary Haematopoiesis <br />
  40. 40. Red cell changes in Thalassemia & Liver disease <br />24-Sep-11<br />Dr (Brig) YD Singh<br />Target cells have a bull’s-eye appearance & are seen in Thalassemia & Liver disease <br />
  41. 41. Red cell changes in Sickle Cell Disease <br />24-Sep-11<br />Dr (Brig) YD Singh<br />Sickle shaped cells are seen in Sickle Cell disease <br />
  42. 42. Anaemia: Lab Tests<br />CBC <br />Erythrocyte count <br />Haemoglobin & Haematocrit<br />Reticulocyte count <br />Erythrocyte indices <br />Mean cell volume (MCV) <br />Mean cell haemoglobin <br />Mean cell haemoglobin concentration <br />Leukocyte count <br />Cell differential <br />Nuclear segmentation of Neutrophils<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  43. 43. Anaemia: Lab Tests<br />Platelet count <br />Cell morphology <br />Cell size <br />Anisocytosis (variations in cell size) <br />Poikilocytosis (variations in cell shape) <br />Polychromasia<br />Iron supply studies <br />Serum iron <br />Total iron-binding capacity (TIBC) <br />Serum ferritin, marrow iron stain <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  44. 44. Hypoproliferative Anaemia: Key Tests<br />Serum iron & iron-binding capacity <br />Serum ferritin, to assess iron stores <br />Evaluation of renal & thyroid function <br />Marrow biopsy or aspirate<br />Detect marrow damage or infiltrative disease <br />Anemia of chronic inflammation shows<br />Low serum iron & Normal or low TIBC <br />Low percent transferrin saturation <br />Normal or high serum ferritin<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  45. 45. Hypoproliferative Anaemia: Key Tests<br />Mild to moderate iron deficiency anaemia: <br />Low serum iron level & High TIBC <br />Low percent transferrin saturation <br />Low serum ferritin level <br />Marrow damage by drug, infiltrative disease (Leukaemia / Lymphoma / Aplasia)<br />Peripheral blood and <br />Bone marrow morphology <br />Infiltrative disease or fibrosis <br />Marrow biopsy will likely be required <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  46. 46. Maturation disorders Anemia: Tests <br />Vitamin B12 <br />Folate<br />Serum iron and iron-binding capacity <br />Serum ferritin to assess iron stores <br />Haemoglobin electrophoresis <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  47. 47. Haemolytic Anemia: Tests <br />Haemoglobin electrophoresis <br />Screen for red cell enzymes <br />Direct or indirect anti-globulin test <br />Cold agglutinin titre <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  48. 48. Anaemia Classification<br />Based on defect in RBC production <br />Marrow production defects: Hypo-proliferation <br />Maturation defects: Ineffective Erythropoiesis<br />Decreased survival: Blood Loss / Haemolysis <br />Classification by MCV <br />Microcytic: MCV <80 fL <br />Normocytic: MCV 80–100 fL<br />Macrocytic: MCV >100 fL<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  49. 49. Complications: Anaemia<br />High-output Cardiac Failure <br />End-organ ischemia or infarct <br />Myocardial infarction <br />Stroke <br />Hypovolumic shock <br />Death <br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  50. 50. Management Pearls: Anaemia <br />Anaemia may be Multi-factorial <br />Finding one cause does not mean that no other forms of anaemia are present <br />Iron deficiency may occur with folate / B12 def<br />Producing Dimorphic anaemia<br />Iron deficiency often means <br />Occult blood loss<br />Worms infestation<br />Nutritional<br />24-Sep-11<br />Dr (Brig) YD Singh<br />
  51. 51. Treatment Approach: Anaemia<br />Mild to Mod Anaemia<br />Initiate treatment when sp diagnosis is made <br />Selection of treatment <br />Determined by cause of anaemia <br />Cause may be multi-factorial <br />Evaluate iron status before starting treatment<br />Rarely anaemia may be so severe <br />RBC transfusions required before specific diagnosis is made<br />24-Sep-11<br />Dr (Brig) YD Singh<br />