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Hemolytic anemia


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Hemo: Referring to blood cells
Poiesis: “The development or production of”
The word Hemopoiesis refers to the production & development of all the blood cells:
Erythrocytes: Erythropoiesis
Leucocytes: Leucopoiesis
Thrombocytes: Thrombopoiesis.
Begins in the 20th week of life in the fetal liver & spleen, continues in the bone marrow till young adulthood & beyond!

Published in: Health & Medicine, Technology

Hemolytic anemia

  1. 1. HEMOLYTIC ANEMIAPresented byDr. PANKAJ
  2. 2. Normal Red CellsNo nucleusBiconcave discsCenter 1/3 pallorPink cytoplasm (Hb filled)Cell size 7- 8 µ - capill.Negative charge100-120 days life
  3. 3. The Factory – Bone MarrowSternum, pelvis, vertebrae, longbones, skull bones, Tibia (paed)From stem cells (pleuripotent)75% of marrow for WBC25% of BM for Red cellsErythrod / Granulocyte Ratio 1:3Large white areas are
  4. 4. drpankajyadav05@gmail.comHemoglobin (Hb)
  5. 5.
  6. 6. HEMOPOIESIS• Hemo: Referring to blood cells• Poiesis: “The development or production of”• The word Hemopoiesis refers to the production &development of all the blood cells:– Erythrocytes: Erythropoiesis– Leucocytes: Leucopoiesis– Thrombocytes: Thrombopoiesis.• Begins in the 20th week of life in the fetal liver & spleen,continues in the bone marrow till young adulthood &beyond!
  7. 7. Sites of erythropoiesis• Mesoblastic stage-in the yolk sacStarts at 2 weeks of intrauterine life• Hepatic stage-2-7 monthsBoth liver and spleen• Myeloid
  8. 8. Myeloid stage• Occurs in bone marrow• Starts at 5 months of fetal life and takes overcompletely at birth• Red bone marrow of all bone.• Late adult life, red marrow of flat
  9. 9. SITES OF HEMOPOIESIS• Active Hemopoieticmarrow is found, inchildren throughout the:– Axial skeleton:• Cranium• Ribs.• Sternum• Vertebrae• Pelvis– Appendicular skeleton:• Bones of the Upper &Lower limbs• In Adults activehemopoietic marrow isfound only in:– The axial skeleton– The proximal ends of theappendicular
  10. 10. In adults extramedullary hematopoiesis may occur indiseases in which the bone marrow becomes destroyed orfibrosedIn children, blood cells are actively produced in the marrowcavities of all the bones.By age 20, the marrow in the cavities of the longbones, except for the upper humerus and femur, has becomeinactive .Active cellular marrow is called red marrow; inactive marrowthat is infiltrated with fat is called yellow
  11. 11. The bone marrow is actually one of the largest organs in thebody, approaching the size and weight of the liver. It is alsoone of the most active.Normally, 75% of the cells in the marrow belong to the whiteblood cell-producing myeloid series and only 25% arematuring red cells, even though there are over 500 times asmany red cells in the circulation as there are white cells.This difference in the marrow reflects the fact that theaverage life span of white cells is short, whereas that of redcells is
  12. 12. STEM CELLS• These cells have extensive proliferative capacity andalso the:– Ability to give rise to new stem cells (Self Renewal)– Ability to differentiate into any blood cells lines(Pluripotency)• They grow and develop in the bone marrow.• The bone marrow & spleen form a supporting system,called the• “hemopoietic microenvironment”
  13. 13. Stem cells• Totipotential stem cells- convert into any tissue type• Pluripotent stem cell- Pluripotent hematopoeiticstem cell• Committed stem cells- CFU E, CFU G, CFU M,
  15. 15. Hematopoietic stem cells (HSCs) are bonemarrow cells that are capable of producing alltypes of blood cells.They differentiate into one or another type ofcommitted stem cells (progenitor cells). These inturn form the various differentiated types of bloodcells.There are separate pools of progenitor cells formegakaryocytes, lymphocytes, erythrocytes, eosinophils, and basophils; neutrophils andmonocytes arise from a common
  16. 16.
  17. 17. PROGENITOR CELLS• Committed stem cells lose their capacity for self-renewal.• They become irreversibly committed.• These cells are termed as “Progenitor cells”• They are regulated by certain hormones or substancesso that they can:– Proliferate– Undergo
  18. 18.
  19. 19. ERYTHROPOIESIS15-20µm- basophilic cytoplasm,nucleus with nucleoli.14-17µm-mitosis, basophiliccytoplasm, nucleoli disappears.10-15µm-’POLYCHROMASIA’Hb appears, nucleus condenses.7-10µm- PYKNOTIC Nucleus.Extrusion, Hb is maximum.7.3µm- Reticulum of basophilicmaterial in the cytoplasm.7.2µm- Mature red cell with
  20. 20. Pronormoblast•15-20 microns•Mitosis present•Nucleus with multiplenucleoli•Basophilic cytoplasmwith polyribosomes•No
  21. 21. Basophilic erythroblast• Large nucleus• Basophiliccytoplasm• Active mitosis• Slight reduction
  22. 22. Polychromatophilic erythroblast• Chromatin lumps• Hb starts appearing• Reduced
  23. 23. Orthochromatic erythroblast• Small and pyknoticnucleus• Eosinophiliccytoplasm• Mitoses
  24. 24. Reticulocyte• Reticular nuclearfragments• Nucleus extruded• Slightly larger
  25. 25. ReticulocytesYoung erythrocytesContain a short network of clumped ribosomes and RER.Enter the blood streamFully mature with in 2 days as their contents aredegraded by intracellular enzymes.Count = 1-2% of red cellsProvide an index of rate of RBC
  26. 26. ProerythroblastorpronormoblastBasophilicerythroblastorEarlyNormoblastPolychromatophilic(or intermediate)Erythroblast orNormoblastDividingPolychromatophilicErythroblast orNormoblastOrthochromatic(Acidophilic)erythroblastOrLateErythroblastOrthochromaticerythroblastExtrudingNucleusReticulocyteReticulocyte(brilliant cresylblue dye)
  27. 27. DurationDifferentiation phase- from pronormoblast toreticulocyte phase- 5 daysMaturation phase: from reticulocyte to RBC-
  28. 28. Factor needed of Erythropoiesis1. Erythropoietin ( Released in response to Hypoxia)2. Vitamin B 6 (Pyridoxine)3. Vitamin B 9 (Folic Acid)4. Vitamin B 12 (Cobolamin)Essential for DNA synthesis and RBCmaturation5. Vitamin C  Helps in iron absorption (Fe+++ Fe++)6. Proteins  Amino Acids for globin synthesis7. Iron & copper  Heme synthesis8. Intrinsic factor  Absorption of Vit B 129.
  29. 29. Hormonal factors:Androgens: increase erythropoiesis by stimulating the production oferythropoietin from kidney.Thyroid hormones: Stimulate the metabolism of all body cells including the bone marrow cells,thus, increasing erythropoiesis. Hypothyroidism is associated with anemia while hyperthyroidism isassociated with polycythaemia.Glucocorticoids: Stimulate the general metabolism and also stimulate the bonemarrow to produce more RBCs. In Addison’s disease (hypofunction of adrenal cortex) anemiapresent, while in Cushing’s disease (hyperfunction of adrenal cortex)polycythaemia present.Factor needed of
  30. 30. Factor needed of ErythropoiesisHormonal factorsPituitary gland: Affects erythropoiesis both directlyand indirectly through the action of severalhormone.Haematopoietic growth factors: Are secreted bylymphocytes, monocytes & macrophages toregulate the proliferation and differentiation ofproginator stem cells to produce blood
  31. 31. Factor needed of ErythropoiesisState of liver & bone marrowLiver - Healthy liver is essential for normalerythropoiesis because the liver is themain site for storage of vitamin B12 , folicacid, iron & copper. In chronic liverdisease anemia occurs.Bone marrow - When bone marrow isdestroyed by ionizing irradiation or drugs,aplastic anemia
  32. 32. Regulation of erythropoiesisTissue
  33. 33. Erythropoietin• Glycoprotein with 165 amino acids, 4oligosaccharide chains and molecular weight of 34,000• Production- 85% by peritubular capillary bed interstitialcells(Kidney) and 15% by perivenous hepatocytes( Liver)• Also seen in brain, salivary glands, uterus, oviducts• Site of Action: BONE
  34. 34. Factors increasing erythropoietin secretion:(i) Hypoxia(ii) Androgens(iii) Growth Hormone(iv) Catecholamines(v) ProstaglandinsFactors inhibiting erythropoietin secretion:(i) Estrogen(ii)
  35. 35. Action of Erythropoietin:1. Formation of Pronormoblast from stem cell2. Speeds up the differentiation through variousstages of erythropoiesisMechanism of Action:• Formation of ALA synthetase• Activation of Adenylyl Cyclase• Synthesis of transferrin
  36. 36. Maturation factorsVitamin B12 and Folic acid:– Essential for DNA synthesis (Thymidine triphosphate)– Abnormal and diminished DNA– Failure of division and maturation– Macrocytic / Megaloblastic anemiaOther factors– Cobalt– Copper– Vitamin
  37. 37.
  38. 38. HEMOLYTIC ANEMIAHemolytic anemia = reduced red-cell
  39. 39. HAEMOLYTIC ANAEMIAS•The normal red cell life is 110-120 days afterwhich the senile cells are removed by bonemarrow and splenic macrophages.•Reduced red cell survival leads to increased redcell production due to erythropoietin drive that cancompensate for the reduced red cell life andmaintain a normal Hb level.•The mean red cell life is affected by molecularchanges in either the red cell membrane
  40. 40. •A haemolytic state exists when the in vivo survivalof the RBC is shortened.•Anaemia occurs if the onset of haemolysis issudden with no time for marrow compensation or insevere chronic haemolysis when the mean red celllife is very short.•The usual marrow response in acute hemolyticanemia is reflected by a reticulocyte index of 2–3,whereas in long-standing chronic hemolysis, theincrease in erythropoiesis is approximately
  41. 41. Correcting Retic CountRetic Index = Retic % x Patient HctNormal HctAbsolute Retic = Retic % x RBC/mm3Retic Production Index = Retic IndexDays in
  42. 42. CLINICAL FEATURESJaundice: generally mild and often not noticed by the patient.Anaemia: recent onset = acquiredlong-standing = possibly congenital.Haemoglobinuria: intravascular haemolysis.Urobilinogenuria: increased Hb catabolism.Splenic pain: spenomegaly or splenic infarction.Leg ulcers: intrinsic red cell disorders, e.g. sickle cell disease.Skeletal hypertrophy: severe congenital haemolytic anaemiasand
  43. 43. CLASSIFICATION OF HEMOLYTICANEMIASThe course of thediseaseacute chronicThe place of RBCdistractionintravascular extravascularThe whence acquired
  44. 44. Haemolytic anaemiaIntravascular vs. ExtravascularIntravascular• red cells lyse in thecirculation and releasetheir products into theplasma fraction.• Anemia• Decreased Haptoglobin• Hemoglobinemia• Hemoglobinuria• Urine hemosiderin• Increased LDHExtravascular• ingestion of red cells bymacrophages in theliver, spleen and bonemarrow• Little or no hemoglobinescapes into thecirculation• Anemia• Decreased Haptoglobin• Normal plasmahemoglobin• Increased
  45. 45.
  46. 46.
  47. 47. Evidence of Hemolysis• Low RBC survival with chromium taggingstudy• Unconjugated bilirubin• Plasma Hb• Decreased serum
  48. 48. Evidence of Erythropoiesis• Polychromasia• Increased reticulocyte• “Shift” macrocytosis• Hypercelluar
  49. 49. HEMOLYTIC ANEMIA• INTRACORPUSCULAR HEMOLYSIS– Membrane Abnormalities– Metabolic Abnormalities– Hemoglobinopathies• EXTRACORPUSCULAR HEMOLYSIS– Nonimmune–
  50. 50. Membrane Defect• Hereditary spherocytosis• Hereditary elliptocytosis• Hereditary pyropoikilocytosis• PNH (sensitivity to complement lysis --sugar water test, Ham’s test)• Hereditary stomatocytosis (possibly Rhnull)
  51. 51. Metabolic Defect(enzyme deficiency)• G6PD deficiency– Hexosemonophosphate shunt– Most common RBCenzyme defect, >50variants– X-linked– Low glutathione due tolow NADPH– Oxidative lysis, Heinzbodies, spherocytic– Primaquine, favabeans• Pyruvate kinasedeficiency– Glycolysis– Low RBC ATP level– Non-spherocytic• B12 and folate deficiency– Macrocytic– HJ bodies• Hemoglobinopathies– Poikilocytosis– Abnormal
  52. 52. Hemoglobin Abnormalities• Unstable hemoglobin disease• Sickle cell anemia• Other homozygous hemoglobinopathies(CC, DD, EE; Chapter 52)• Thalassemia major• Hemoglobin H disease• Doubly heterozygous disorders (such ashemoglobin SC disease and sicklethalassemia)
  53. 53. HEMOLYTIC ANEMIA - IMMUNE• Drug-Related HemolysisPENICILLIN,CEFTRIAXONE,CEFOTETAN,QUINIDINE,ALPHA-METHYLDOPA,LEVODOPA,PROCAINAMIDE,SULFA DRUGS• Alloimmune Hemolysis– Hemolytic Transfusion Reaction– Hemolytic Disease of the Newborn• Autoimmune Hemolysis– Warm Autoimmune (WAIHA)70-80%– Cold Autoimmune (CAIHA) 20-30%– Mixed 7-8%– Paroxysmal Cold Hemoglobinuria -
  54. 54. Warm vs. Cold AutoWARM• Reacts at 37 degC• Insidious to acute• Anemia severe• Fever, jaundice frequent• Intravascular not common• Splenomegaly• Hematomegaly• Adenopathy• None of theseCOLD• Reacts at roomtemperature• Often chronic anemia• 9-12 g/dL (less severe)• Autoagglutination• Hemoglobinuria,acrocyanosis andraynaud’s with coldexposure• No
  55. 55. EXTRACELLULAR DEFECTS• Fragmentation Hemolysis– DIC, TTP, HUS– Extracorporeal membrane oxygenation– Prosthetic heart valve– Burns—thermal injury– Hypersplenism– Venom - Snake, Spider,
  56. 56. Plasma Factors• Liver disease (Spur-cell )• Hypophosphatemia• Vitamin E deficiency in newborns• Abetalipoproteinemia• Infections– Malaria– Babesia– Clostridium– Gram negative endotoxin• Wilson
  57. 57. Etiologic and PathogeneticClassification of the HemolyticDisordersI. Inherited Hemolytic DisordersA. Defects in the erythrocyte membrane1. Hereditary spherocytosisD. Deficiencies of enzymes involved in the pentose phosphatepathway and in glutathione metabolism1. Glucose-6-phosphate dehydrogenase (G6PD)E. Defects in globin structure and synthesis1. Unstable hemoglobin disease2. Sickle cell anemia3. Other homozygous hemoglobinopathies (CC, DD, EE; Chapter52)4. Thalassemia major5. Hemoglobin H disease6. Doubly heterozygous disorders (such as hemoglobin SC diseaseand sickle thalassemia)
  58. 58. Etiologic and PathogeneticClassification of the HemolyticDisordersII. Acquired Hemoltyic AnemiasA. Nonimmune: due to1. Traumatic and microangiographic hemolytic anemias2. Infectious agents3.Chemicals, drugs, and venoms4. Physical agents5. Hypophosphatemia6. Spur-cell anemia in liver disease7. Vitamin E deficiency in
  59. 59. Etiologic and PathogeneticClassification of the HemolyticDisordersII. Acquired Hemoltyic AnemiasB. Immunohemolytic anemias1. Iso (allo) immune:transfusion of incompatible bloodHemolytic disease of the newborn2. Heteroimmune:Virus, bacterial infections, chemical, Drug-induced3. Autoimmune hemolytic anemiaIdiopathic (the essential cause is unknown)Secondary or symptomatic (in case of lymphoma, chronic lymphocytic leukemia,Other malignant disease, Immune-deficiency states, Systemic lupuserythematosus and other autoimmune disorders, Virus andmycoplasma infections)Autoimmune hemolytic anemia caused by warm-reactive antibodies (Coomb’spositive).Autoimmune hemolytic anemia caused by cold-reactive antibodiesCold hemagglutinin diseaseParoxysmal cold
  60. 60. Etiologic and PathogeneticClassification of the HemolyticDisordersII. Acquired Hemoltyic AnemiasC. Paroxysmal nocturnal
  61. 61. The Three Primary MeasuresMeasurement NormalRangeA. RBC count (RCC) 4- 5.7 millionB. Hemoglobin 12 to 17Hematocrit (PCV) 38 to 50A x 3 = B x 3 = C - This is the rule of thumbCheck whether this holds good in a given resultIf not -indicates micro or macrocytosis
  62. 62. The Three Derived IndiciesMeasurement NormalRangeA. RCC 4 to 5.7B. Hemoglobin 12 to 17C. Hematocrit 38 to 50MCV C ÷ A x 10MCH B ÷ A x 10MCHC (%) B ÷ C x
  63. 63. Hemolytic AnemiaAnemia of increased RBC destruction– Normochromic, normocytic anemia– Shortened RBC survival– Reticulocytosis – due to ↑ RBC destructionWill not be symptomatic until the RBC lifespan isreduced to 20 days – BM compensates
  64. 64. Findings in Hemolytic AnemiaReticulocyte count and RPI IncreasedSerum Unconjugated Bilirubin IncreasedSerum LDH 1: LDH 2 IncreasedSerum Haptoglobin DecreasedUrine Hemoglobin PresentUrine Hemosiderin PresentUrine Urobilinogen IncreasedCr 51 labeled RBC life span
  65. 65. drpankajyadav05@gmail.comTests to definethe cause of hemolysis1. Hemoglobin electrophoresis2. Hemoglobin A2 (βeta-Thalassemia trait)3. RBC enzymes (G6PD, PK, etc)4. Direct & indirect antiglobulin tests(immune)5. Cold agglutinins6. Osmotic fragility (spherocytosis)7. Acid hemolysis test (PNH)8. Clotting profile (DIC)
  66. 66. Peripheral
  67. 67. spherocytes- hereditary spherocytosis- acquired hemolyticanemia (e.g. AIHA)- physical or chemicalinjury-
  68. 68.
  69. 69. elliptocytes- heredirary elliptocytosis- iron def. anemia- myelofibrosis withmyeloid metaplasia- megaloblastic anemia- sickle cell anemia- normal (<10% of cells)
  70. 70.
  71. 71.
  72. 72. StomatocytesSlit like central pallor in RBC1. Liver Disease2. AcuteAlcoholism3. H Stomatocyosis4.
  73. 73.
  74. 74. acanthocytes(irregular surface spicules)irregularly spiculatedcellswith bulbous/roundedends of spicules- abetalipoproteinemia- liver
  75. 75. echinocytes(crenated cells, burr cells)regularly contracted cellswith smooth surfaceundulation- uremia- artifact- hyperosmolarity- discocyte-echinocytetransformation(may be associated with reducedATP of RBCs)
  76. 76. EchinocytesEvenly distributed spicules > 101. Uremia2. Peptic ulcer3. Gastric Ca4. PK-DCalled Burr
  77. 77. bite cellsRemoval (“bites”) ofmembrane by splenicmacrophages- G6PD
  78. 78. Heinz bodiesdenatured hemoglobin- G6PD
  79. 79. Heinz body preparation with Crystal violetUnstable
  80. 80.
  81. 81. drepanocytes(sickle cells)- sickle cell
  82. 82.
  83. 83. basophilic stipplingirregular basophilic granules(remnants of RNA)fine stippling:•increased production of RBCs(reticulocytosis)coarse stippling:•lead poisoning•impaired Hgb syntheisis•megaloblastic anemia•other sever
  84. 84. dacrocytes(teardrop cells)- thalassemia-
  85. 85. leptocytes(target cells)- liver disease(obstructive jaundice)- post splenectomy- hemoglobinopathies(hypochromic anemias)thalassemiaHgb C diseaseHgb H diseasebeta thalassemiarelative increase of cell membrane --> ―target‖formation
  86. 86.
  87. 87. rouleauxlined up RBCs in a row- multiple
  88. 88. sideroblast/siderocyteinorganic iron-containinggranules (Pappenheimerbodies)- sideroblastic anemiaabnormally trapped iron inmitochondria forming a ring aroundnucleus- post
  89. 89. Howell-Jolly bodyremnant of nuclear chromatinsingle:•megaloblastic anemia•hemolytic anemia•post splenectomymultiple:•megaloblastic anemia•other abnormal
  90. 90. Acanthocytes5-8 spikes of varying length, irregularintervalsCalled Spur Cells, Occur in A
  91. 91. schistocytes(cell fragments)indication of hemolysis- megaloblastic anemia- severe burns- traumatic hemolysis- microangiopathichemolytic anemia(helmet cells, triangular cells)“helmet cell”
  92. 92. Shistocytes1. MAHA2. Prostheticvalves3. Uremia4. Malignant HTFragmented, Helmet or triangle
  93. 93.
  94. 94. MAHAMicro Angiopathic
  95. 95. TRAUMATIC
  96. 96.
  97. 97. Normal BM High PowerE : G = 1 :
  98. 98.
  99. 99. Bone
  100. 100. Hyperactive BM – SkullHemolytic