Hemolytic Anemia Classification - By Thejus K. Thilak


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Hemolytic Anemia Classification - By Thejus K. Thilak

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  • Intravascular Hemolysis
  • Extravascular Hemolysis
  • Case History
  • Case History
  • Case History
  • Case History
  • Case History
  • Case History
  • Case History
  • Case History
  • Case History
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  • Hemolytic Anemia Classification - By Thejus K. Thilak

    2. 2. HEMOLYTIC ANEMIASHemolytic anemias = reduced red-cell life span
    3. 3. Hemolytic Anemia Definition:  Those anemias which result from an increase in RBC destruction Classification:  Congenital / Hereditary  Acquired
    4. 4. Mechanisms of hemolysis: - intravascular - extravascular
    5. 5. Inravascular hemolysis (1):- red cells destruction occurs in vascular space- clinical states associated with Intravascular hemolysis: acute hemolytic transfusion reactions severe and extensive burns paroxysmal nocturnal hemoglobinuria severe microangiopathic hemolysis physical trauma bacterial infections and parasitic infections (sepsis)
    6. 6. Inravascular hemolysis (2):- laboratory signs of intravascular hemolysis: indirect hyperbilirubinemia erythroid hyperplasia hemoglobinemia methemoalbuminemia hemoglobinuria absence or reduced of free serum haptoglobin hemosiderynuria
    7. 7. II. Extracorpuscular factorsA. Immune hemolytic anemias 1. Autoimmune hemolytic anemia - caused by warm-reactive antibodies - caused by cold-reactive antibodies 2. Transfusion of incompatible bloodB. Nonimmune hemolytic anemias 1. Chemicals 2. Bacterial infections, parasitic infections (malaria), venons 3. Hemolysis due to physical trauma - hemolytic - uremic syndrome (HUS) - thrombotic thrombocytopenic purpura (TTP) - prosthetic heart valves 4. Hypersplenism
    8. 8. Extravascular hemolysis :- red cells destruction occurs in reticuloendothelial system- clinical states associated with extravascular hemolysis : autoimmune hemolysis delayed hemolytic transfusion reactions hemoglobinopathies hereditary spherocytosis hypersplenism hemolysis with liver disease- laboratory signs of extravascular hemolysis: indirect hyperbilirubinemia increased excretion of bilirubin by bile erythroid hyperplasia hemosiderosis
    9. 9. Hemolytic anemia - clinical features: - pallor - jaundice - splenomegaly
    10. 10. Laboratory features:1. Laboratory features - normocytic/macrocytic, hyperchromic anemia - reticulocytosis - increased serum iron - antiglobulin Coombs’ test is positive2. Blood smear - anisopoikilocytosis, spherocytes - erythroblasts - schistocytes3. Bone marrow smear - erythroid hyperplasia
    11. 11. 3. PNH –laboratory features: - pancytopenia - chronic urinary iron loss - serum iron concentration decreased - hemoglobinuria - hemosiderinuria - positive Ham’s test (acid hemolysis test) - positive sugar-water test - specific immunophenotype of erytrocytes (CD59,CD55)4. Treatment: - washed RBC transfusion - iron therapy - allogenic bone marrow transplantation
    12. 12. Introduction Mean life span of a RBC-120days Removed Extravascularly by- Macrophages of RE system
    13. 13. Classification of Hemolytic AnemiasHereditary 1. Abnormalities of RBC interior a.Enzyme defects: G-6-PD def,PK def b.Hemoglobinopathies 2. RBC membrane abnormalities a. Hereditary spherocytosis etc. b. PNHAcquired c. Spur cell anemia 3. Extrinsic factors a. Hypersplenism b. Antibody: immune hemolysis c. Mechanical trauma: MAHA d. Infections, toxins, etc Ref : Harrison’s
    14. 14. Features of HEMOLYSIS Bilirubin LDH Reticulocytes, n-RBC Haptoglobulins +ve Urinary hemosiderin, Urobilinogen Blood Film Spherocytes No spherocytes FragmentationDCT +ve DCT –veAI Hemolysis H. Sherocytosis Malaria, Clostidium Hereditery enzymopathies Microangiopathic, Traumatic
    15. 15. Red Cell Membrane Defects1.Hereditary Spherocytosis  Usually inherited as AD disorder  Defect: Deficiency of Beta Spectrin or Ankyrin  Loss of membrane in Spleen & RES becomes more spherical Destruction in Spleen
    16. 16. Spherocytes
    17. 17.  C/F: Asymptomatic Fluctuating hemolysis Splenomegaly Pigmented gall stones- 50%
    18. 18. RBC Membrane
    19. 19. Complications Clinical course may be complicated with Crisis:  Hemolytic Crisis: associated with infection  Aplastic crisis: associated with Parvovirus infection
    20. 20.  Inv:  Test will confirm Hemolysis  P Smear: Spherocytes  Osmotic Fragility: Increased Screen Family members
    21. 21.  Management:  Folic Acid 5mg weekly, prophylaxis life long  Spleenectomy  Blood transfusion in Ac, severe hemolytic crisis
    22. 22. 2.Hereditary Elliptocytosis Equatorial Africa, SE Asia AD / AR Functional abnormality in one or more anchor proteins in RBC membrane- Alpha spectrin , Protein 4.1 Usually asymptomatic Mx: Similar to H. spherocytosis Variant: 3.SE-Asian ovalocytosis:  Common in Malaysia , Indonesia…  Asymptomatic-usually  Cells oval , rigid ,resist invasion by malarial parasites
    23. 23. Elliptocytosis
    24. 24. Red Cell Enzymopathies Physiology:  EM pathway: ATP production  HMP shunt pathway: NADPH & Glutathione production
    25. 25. 1. Glucose-6-Phosphate Dehydrogenase ( G6PD ) Deficiency  Pivotalenzyme in HMP Shunt & produces NADPH to protect RBC against oxidative stress  Most common enzymopathy -10% world’s population  Protection against Malaria  X-linked
    26. 26.  Clinical Features:  Acute drug induced hemolysis:  Aspirin, primaquine, quinine, chloroquine, dapsone….  Chronic compensated hemolysis  Infection/acute illness  Neonatal jaundice  Favism
    27. 27.  Inv:  e/o non-spherocytic intravascular hemolyis  P. Smear: Bite cells, blister cells, irregular small cells, Heinz bodies, polychromasia  G-6-PD level Treatment:  Stop the precipitating drug or treat the infection  Acute transfusions if required
    28. 28. 2. Pyruvate Kinase Deficiency  AR  DeficientATP production, Chronic hemolytic anemia  Inv; P. Smear: Prickle cells Decreased enzyme activity  Treatment: Transfusion may be required
    29. 29. AQUIRED
    30. 30. Autoimmune Hemolytic Anemia Result from RBC destruction due to RBC autoantibodies: Ig G, M, E, A Most commonly-idiopathic Classification  Warm AI hemolysis:Ab binds at 37degree Celsius  Cold AI Hemolysis: Ab binds at 4 degree Celsius
    31. 31. 1.Warm AI Hemolysis:  Can occurs at all age groups F>M  Causes:  50% Idiopathic  Rest - secondary causes: 1.Lymphoid neoplasm: CLL, Lymphoma, Myeloma 2.Solid Tumors: Lung, Colon, Kidney, Ovary, Thymoma 3.CTD: SLE,RA 4.Drugs: Alpha methyl DOPA, Penicillin , Quinine, Chloroquine 5.Misc: UC, HIV
    32. 32.  Inv:  e/o hemolysis, MCV  P Smear: Microspherocytosis, n-RBC  Confirmation: Coomb’s Test / Antiglobulin test Treatment  Correct the underlying cause  Prednisolone 1mg/kg po until Hb reaches 10mg/dl then taper slowly and stop  Transfusion: for life threatening problems  If no response to steroids  Spleenectomy or,  Immunosuppressive: Azathioprine, Cyclophosphamide
    33. 33. 2. Cold AI Hemolysis  Usually Ig M  Acute or Chronic form  Chronic:  C/F:  Elderly patients  Cold , painful & often blue fingers, toes, ears, or nose ( Acrocyanosis) Inv:  e/o hemolysis  P Smear: Microspherocytosis  Ig M with specificity to I or I Ag
    34. 34.  Other causes of Cold Agglutination:  Infection: Mycoplasma pneumonia, Infec Mononucleosis  PCH : Rare cause seen in children in association with cong syphilis
    35. 35.  Treatment:  Treatment of the underlying cause  Keep extremities warm  Steroids treatment  Blood transfusion
    36. 36. Non-Immune Acquired Hemolytic Anemia1. Mechanical Trauma A). Mechanical heart valves, Arterial grafts: cause shear stress damage B).March hemoglobinuria: Red cell damage in capillaries of feet C). Thermal injury: burns D). Microangiopathic hemolytic anemia (MAHA): by passage of RBC through fibrin strands deposited in small vessels  disruption of RBC eg: DIC,PIH, Malignant HTN,TTP,HUS
    37. 37. Acquired hemolysis2.Infection F. malaria: intravascular hemolysis: severe called ‘Blackwater fever’ Cl. perfringens septicemia3.Chemical/Drugs: oxidant denaturation of hemoglobin Eg: Dapsone, sulphasalazine, Arsenic gas, Cu, Nitrates & Nitrobenzene
    38. 38. Paroxysmal Nocturnal Hemoglobinuria Hematopoietic stem cell disorder Mutation of phosphatidylinositol glycan class A (PIG-A) gene Glycosylphosphatidylinositol (GPI) anchors membrane proteins Without GPI, unable to regulate completment activities on membrane Hemolysis is pH dependent Thrombosis can occur
    39. 39. Lab Tests for PNH Acidified serum lysis test (Ham’s test): PNH cells lyse due to complement activation in acidified serm Sugar water (sucrose hemolysis) test: RBCs sensitive to complement will lyse in sucrose and serum Flow cytometry: lack of CD59 on RBCs, or lack of CD59 or CD55 on granulocytes
    40. 40. Microangiopathy Schistocytes  Triangular or helmet shaped RBC fragments Destruction of RBC as they move through damaged blood vessels  Endocarditis  Hemangiosarcoma  Caval Syndrome – Heartworm Disease  Thrombosed IV catheter  Vasculitis  Hemolytic-uremic syndrome  DIC Schistocytes are also seen with osmotic fragility  Liver disease, iron deficiency, water intoxication, congenital, zinc toxicity
    41. 41. Young man of 19 Complains of giddiness weakness, pallorExamination reveals a spleen mild lemon yellow sclera
    42. 42. Laboratory Evaluation of Hemolysis Extravascular IntravascularHEMATOLOGICRoutine blood film Polychromatophilia PolychromatophiliaReticulocyte countBone marrow Erythroid Erythroidexamination hyperplasia hyperplasiaPLASMA OR SERUMBilirubin Unconjugated UnconjugatedHaptoglobin , Absent AbsentPlasma hemoglobin N/Lactate dehydrogenase (Variable) (Variable)URINEBilirubin 0 0Hemosiderin 0 +Hemoglobin 0 + severe cases
    43. 43. How shall you investigate to find out the cause of the problem?
    44. 44. Laboratory investigations:Severe normochromic, normocyticanemia (hemoglobin level of 6.4 g/dLReticulocyte count of 12.2%.Blood film:
    45. 45. Bilirubin level of 2.5 mg/dL,Lactate dehydrogenase (LDH) of2140 IU/L,Haptoglobin below 7 mg/dL
    46. 46. The direct antiglobulin test waspositive for complement (C3d) (++),and IgG (++-).Also was positive for agglutinins ofIgM type and had a titer of 1:1024.
    47. 47. complementDirect antiglobulin testdemonstrating the presence of autoantibodies (shownhere) or complement on the surface of the red bloodcell.
    48. 48. Serologies for humanimmunodeficiency virus, hepatitis Band C viruses, and Mycoplasmapneumoniae were negative.Rheumatoid factor and antinuclearantibodies were undetectable.
    49. 49. Prednisone therapy was started at a dose of 1 mg/kg intravenously, daily. Hemoglobin level rose to 11 g/dL, concomitantly with the improvement of hemolytic signs.
    50. 50. A reduction of positivity of bothdirect and indirect antiglobulin tests(polyvalent serum + ; C3d + ;IgG+ ), as well as a reduction ofcold agglutinin titers (1:128), wasobserved 8 weeks aftercorticosteroid therapy.
    51. 51. Three months later, corticosteroidswere tapered to a maintenancedose of 25 mg daily.Hemolysis recurred again with thefall of hemoglobin to 7 g/dL.
    52. 52. The direct antiglobulin test recurredpositive for polyvalent serum (+++),complement (+++), and IgG (+++),while cold agglutinin titers againbecame strongly positive (1:256).
    53. 53. Immunophenotyping of bonemarrow cells showed that 10% ofall the cells were CD20 and CD19positive.
    54. 54. CD20 is widely expressed on B-cells.CD20 could play a role in Ca2+influx across plasma membranes,maintaining intracellular Ca2+concentration and allowingactivation of B cells.
    55. 55. Hemoglobin value reached13.5 g/dL just before the third dose,although biochemical signs ofhemolysis remained substantiallyunaltered.
    56. 56. At the end of therapy, the hemolytic signs disappeared, the direct and indirect antiglobulin tests becamenegative, and cold agglutinin titers fell to 1:32 Immunophenotyping of bonemarrow cells showed the absence of CD20 and CD19 B cells.