HEMOLYTIC ANEMIA–Hereditary spherocytosis and      G6PD deficiency                                   Dr. Kalpana Malla    ...
Definition:• Anaemia due to increased red cell  destruction (and increased  erythropoiesis)
Classification:• INTRACORPUSCULAR HEMOLYSIS  – Membrane Abnormalities  – Haemoglobin defects  – Enzyme defects• EXTRACORPU...
Intracorpuscular defectsMembrane Defects• Microskeletal defects  – Hereditary spherocytosis**• Membrane permeability defec...
Intracorpuscular defects• Enzymopathies• Deficiencies in Hexose Monophosphate  Shunt  – Glucose 6-Phosphate Dehydrogenase ...
Intracorpuscular defectsHaemoglobin defects Haemoglobinopathies:   Sickle cell anemia Thalassemias:   β-thalassemia majo...
Extracorpuscular defects -IMMUNEAutoimmune Hemolysis  – Warm antibody  – Cold antibodyAlloimmune Hemolysis  – Hemolytic ...
Extracorpuscular defects -Nonimmune• M echanical• Infectious• Chemical• Thermal
General evidences of haemolysis:• Evidence of increased Hb breakdown:  - jaundice and hyperbilirubinemia - reduced plasma ...
• Evidence of compensatory erythroid  hyperplasia:   - Reticulocytosis   - Macrocytosis & polychromasia   - BM erythroid h...
HEREDITARYSPHEROCYTOSIS
ETIOLOGY•   Usually AD . Rarely AR•   25% have no F/H. New mutations•   Northern Europe most common•   Also seen in SE Asi...
RBC CYTOSKELETON• “Vertical” and “horizontal” interactions b/w  proteins and lipids• Lipid bilayer skeleton• Spectrin and ...
MOLECULAR PATHOPHYSIOLOGY      Deficiency in spectrin, ankyrin, protein 3            Lipid bilayer skeleton uncouplingMemb...
VARIOUS PRESENTATIONS•   Hemolytic d/s of newborn•   Hemolytic crisis : most common form•   Aplastic crisis•   Megaloblast...
CLINICAL CLASSIFICATION•   Trait•   Mild HS•   Moderate HS•   Moderately severe HS•   Severe HS
HS IN NEONATES•   Hemolytic d/s of newborn•   Prolonged neonatal jaundice•   May require PT/ exchange transf.•   Anemia pr...
HEMOLYTIC CRISIS• Pptd by viral inf : Infectious  mononucleosis• Exercise induced• Anemia,jaundice• Vomiting, abd pain, te...
APLASTIC CRISIS•   Less common, more serious•   Parvovirus B19•   Fever, chills•   Vomiting, diarrhea, myalgias•   Slapped...
PATHOGENESIS OF APLASTIC CRISIS• Parvovirus affects erythropoetic precursors -> arrests  cell cycle in G2 phase -> apoptos...
MEGALOBLASTIC CRISIS• Due to a secondary folate deficiency• In patients recovering from aplastic crisis• Hence supplement ...
COMPLICATIONS• Gall stones : young adults/ adolescence .• Gout, Leg ulcers• Chronic erythematous dermatitis of legs• Extra...
INVESTIGATIONS• Hb: 6-10g/dl• Increased retics• Indirect hyperbilirubinemia• MCV normal. MCHC increased (high  Hb)• PS: po...
INVESTIGATIONS• BM: erythroid hyperplasia• Decreased haptoglobin• Incubated Osmotic fragility test (deprive  RBC off gluco...
OSMOTIC FRAGILITY              100              80% Hemolysis              60              40              20             ...
Other conditions associated with       spherocytes on PS: •   Auto-immune hemolytic anemia •   Burns •   Wilson’s disease ...
Treatment:• If Hb > 10 gm/dl and retics < 10%- no Rx• If severe anemia, poor growth, aplastic  crises and age < 2 yrs- tra...
TREATMENT•   Splenectomy•   Folic acid 1 mg/day•   Blood transfusion SOS•   Cholecystectomy for gall stones
SPLENECTOMY• Indications:  Hypoplastic/aplastic crisis  Poor skeletal growth  Cardiomegaly
SPLENECTOMY• Recommended >5-6 yrs• Postsplenectomy sepsis with encaps org• Prophlactic vaccinations : Hib, Pneumo,  mening...
GLUCOSE-6-  PHOSPHATEDEHYDROGENASE  DEFICIENCY
• Two clinical syndromes:  - Episodic / induced hemolytic A  - Spontaneous chronic non-       spherocytic hemolytic A• Inh...
ETIOLOGY• X-Linked recessive• Evolutionary advantage of resistance  to falciparum malaria• 90 mutations of G6PD gene• Norm...
• Synthesis of G6PD determined by  X chromosome• Usually only males affected• Heterozygous females  (intermediate enzyme a...
FUNCTION OF G6PD• Regenerates NADPH, allowing regeneration  of glutathione• Protects against oxidative stress• Lack of G6P...
HbO2                      infections/ drugs  Hb                      O2                       H2O2         H2O            ...
PRECIPITATING FACTORS• Antimalarials: primaquine, quinine,  chloroquine• Antibiotics - nitrofuantoin, furazolidine,       ...
FAVA BEANS
TYPES• Type 1: mild (G6PD A-): Afro- americans• Type 2: moderately severe (G6PD B- and  G6PD Canton): SE Asia, Mediterrane...
CLINICAL FEATURES             Exposure to drug                  24-48 hr• Severe progressive anemia, cardiac failure      ...
TYPE 1• Mildest form (enzymes 8-15 % of normal)• Episodic form• Sensitive to strong oxidants• Usual doses of aspirin and C...
TYPE 2• Moderately severe• Episodic form• Fava exposure + oxidants• Neonatal Jaundice present• Hemolysis continuous with c...
TYPE 3• Chronic type• Spontaneous, without any ppt factor• If ppt factor given -> severe hemolysis with  hemoglobinuria• S...
INVESTIGATIONSDuring hemolysis :• Hb decreased• Elevated retics (5-15 %)• PS: Normocytic normochromic anemia• Polychromasi...
NEVER ASSESS G6PDLEVELS DURING ACUTE     HEMOLYSIS
WHY?• During acute hemolysis- all deficient cells  have been hemolysed• Young cells will be in circulation• Young survivin...
TREATMENT• Avoid the oxidants• Blood transfusion• Sodium bicarbonate to alkalinise urine in  severe Hburia… or else acid h...
Thank youDownload more documents and slide shows on The    Medical Post [ www.themedicalpost.net ]
Hemolytic anemia, Hereditary spherocytosis and G6PD deficiency
Hemolytic anemia, Hereditary spherocytosis and G6PD deficiency
Hemolytic anemia, Hereditary spherocytosis and G6PD deficiency
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Hemolytic anemia, Hereditary spherocytosis and G6PD deficiency

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Hemolytic anemia, Hereditary spherocytosis and G6PD deficiency

  1. 1. HEMOLYTIC ANEMIA–Hereditary spherocytosis and G6PD deficiency Dr. Kalpana Malla MD Pediatrics Manipal Teaching HospitalDownload more documents and slide shows on The Medical Post [ www.themedicalpost.net ]
  2. 2. Definition:• Anaemia due to increased red cell destruction (and increased erythropoiesis)
  3. 3. Classification:• INTRACORPUSCULAR HEMOLYSIS – Membrane Abnormalities – Haemoglobin defects – Enzyme defects• EXTRACORPUSCULAR HEMOLYSIS – Nonimmune – Immune
  4. 4. Intracorpuscular defectsMembrane Defects• Microskeletal defects – Hereditary spherocytosis**• Membrane permeability defects – Hereditary stomatocytosis• Increased sensitivity to complement – Paroxysmal nocturnal hemoglobinuria
  5. 5. Intracorpuscular defects• Enzymopathies• Deficiencies in Hexose Monophosphate Shunt – Glucose 6-Phosphate Dehydrogenase Deficiency**• Deficiencies in the EM Pathway – Pyruvate Kinase Deficiency
  6. 6. Intracorpuscular defectsHaemoglobin defects Haemoglobinopathies: Sickle cell anemia Thalassemias: β-thalassemia major HbH disease Double heterozygous disorders: Sickle cell β-thalassemia
  7. 7. Extracorpuscular defects -IMMUNEAutoimmune Hemolysis – Warm antibody – Cold antibodyAlloimmune Hemolysis – Hemolytic Transfusion Reaction – Hemolytic Disease of the NewbornDrug-Related Hemolysis
  8. 8. Extracorpuscular defects -Nonimmune• M echanical• Infectious• Chemical• Thermal
  9. 9. General evidences of haemolysis:• Evidence of increased Hb breakdown: - jaundice and hyperbilirubinemia - reduced plasma haptoglobin / haemopexin - increased plasma LDH e/o intravascular haemolysis haemoglobinaemia - haemoglobinuria - methaemalbuminaemia - haemosiderinuria
  10. 10. • Evidence of compensatory erythroid hyperplasia: - Reticulocytosis - Macrocytosis & polychromasia - BM erythroid hyperplasia - Radiological changes in bones• Evidence of damage to red cells: - Spherocytosis & increased fragility - Fragmented RBCs - Heinz bodies• Demonstration of shortened RBC life-span
  11. 11. HEREDITARYSPHEROCYTOSIS
  12. 12. ETIOLOGY• Usually AD . Rarely AR• 25% have no F/H. New mutations• Northern Europe most common• Also seen in SE Asia incl. India, Nepal
  13. 13. RBC CYTOSKELETON• “Vertical” and “horizontal” interactions b/w proteins and lipids• Lipid bilayer skeleton• Spectrin and Ankyrin : major components• Spectrin has α and β chains• Protein 3 also present• Deficiency in either of the 3 causes problem in the “vertical” interactions
  14. 14. MOLECULAR PATHOPHYSIOLOGY Deficiency in spectrin, ankyrin, protein 3 Lipid bilayer skeleton uncouplingMembrane loss in the form of microvesicles Surface area deficiency Spherocytosis Impaired passage through splenic cord Sequestration
  15. 15. VARIOUS PRESENTATIONS• Hemolytic d/s of newborn• Hemolytic crisis : most common form• Aplastic crisis• Megaloblastic crisis• HS in pregnancy
  16. 16. CLINICAL CLASSIFICATION• Trait• Mild HS• Moderate HS• Moderately severe HS• Severe HS
  17. 17. HS IN NEONATES• Hemolytic d/s of newborn• Prolonged neonatal jaundice• May require PT/ exchange transf.• Anemia progressing to CCF• Hydrops fetalis (rare)• Palpable spleen• Investigate parents
  18. 18. HEMOLYTIC CRISIS• Pptd by viral inf : Infectious mononucleosis• Exercise induced• Anemia,jaundice• Vomiting, abd pain, tender spleen• May happen also during recovery phase of aplastic crisis
  19. 19. APLASTIC CRISIS• Less common, more serious• Parvovirus B19• Fever, chills• Vomiting, diarrhea, myalgias• Slapped cheek apearance• Foll this - sudden pallor, jaundice, weakness
  20. 20. PATHOGENESIS OF APLASTIC CRISIS• Parvovirus affects erythropoetic precursors -> arrests cell cycle in G2 phase -> apoptosis.• Also transient neutropenia, thrombocytopenia (pancytopenia)• BM: giant pronormoblasts (hallmark)• Unused iron levels increase in serum• Hematocrit and retic count falls• Self limiting process. Self recovery after sometime
  21. 21. MEGALOBLASTIC CRISIS• Due to a secondary folate deficiency• In patients recovering from aplastic crisis• Hence supplement 1mg/day of F.A. to children with HS
  22. 22. COMPLICATIONS• Gall stones : young adults/ adolescence .• Gout, Leg ulcers• Chronic erythematous dermatitis of legs• Extramedullary hematopoesis• Hematologic malignancies : multiple myeloma, leukemia, hepatoma• Heart disease: CCF, cardiomyopathy
  23. 23. INVESTIGATIONS• Hb: 6-10g/dl• Increased retics• Indirect hyperbilirubinemia• MCV normal. MCHC increased (high Hb)• PS: polychromatophilia, spherocytes (usually >15-20% of cells), central pallor absent, hyperchromic,
  24. 24. INVESTIGATIONS• BM: erythroid hyperplasia• Decreased haptoglobin• Incubated Osmotic fragility test (deprive RBC off glucose overnight): increased fragility to hypotonic saline• Autohemolysis: spont cell breakdown after incubation for 48 hrs at 37C. Normally <4%, In HS >10-15%• Molecular and genetic analysis
  25. 25. OSMOTIC FRAGILITY 100 80% Hemolysis 60 40 20 0 0.3 0.4 0.5 0.6 NaCl (% of normal saline) Normal HS
  26. 26. Other conditions associated with spherocytes on PS: • Auto-immune hemolytic anemia • Burns • Wilson’s disease • Chemical injury • Infections • HDN due to anti-A
  27. 27. Treatment:• If Hb > 10 gm/dl and retics < 10%- no Rx• If severe anemia, poor growth, aplastic crises and age < 2 yrs- transfusion• If Hb < 10 gm/dl and retics > 10 % or massive spleen- splenectomy• Folic acid- 1 mg/day
  28. 28. TREATMENT• Splenectomy• Folic acid 1 mg/day• Blood transfusion SOS• Cholecystectomy for gall stones
  29. 29. SPLENECTOMY• Indications: Hypoplastic/aplastic crisis Poor skeletal growth Cardiomegaly
  30. 30. SPLENECTOMY• Recommended >5-6 yrs• Postsplenectomy sepsis with encaps org• Prophlactic vaccinations : Hib, Pneumo, meningococcus• Prophylactic penicillin V: <5yr: 125mgBD >5yr to adulthood: 250mg BD• Postsplenectomy Thrombocytopenia : self limiting• Partial spenectomy/embolisation if <5yrs
  31. 31. GLUCOSE-6- PHOSPHATEDEHYDROGENASE DEFICIENCY
  32. 32. • Two clinical syndromes: - Episodic / induced hemolytic A - Spontaneous chronic non- spherocytic hemolytic A• Inheritance of abnormal alleles of gene responsible for synthesis of G6PD molecules
  33. 33. ETIOLOGY• X-Linked recessive• Evolutionary advantage of resistance to falciparum malaria• 90 mutations of G6PD gene• Normal enzyme : G6PD B+• Variant: G6PD A+ (African-American) G6PD A -
  34. 34. • Synthesis of G6PD determined by X chromosome• Usually only males affected• Heterozygous females (intermediate enzyme activity) usually not symptomatic…unless random inactivation of normal X chromosome (rarely) Lyon’s hypothesis
  35. 35. FUNCTION OF G6PD• Regenerates NADPH, allowing regeneration of glutathione• Protects against oxidative stress• Lack of G6PD leads to hemolysis during oxidative stress- infection, medication, fava beans• Oxidative stress leads to Heinz body formation, extravascular hemolysis
  36. 36. HbO2 infections/ drugs Hb O2 H2O2 H2O Gl. Peroxidasemeth.Hb 2GSH GSSG Gl. ReductaseHeinz bodies NADP NADPH G6PD GG6P 6-PG maintains integrity of RBC membrane when deficient glycolysis haemolysis lactate
  37. 37. PRECIPITATING FACTORS• Antimalarials: primaquine, quinine, chloroquine• Antibiotics - nitrofuantoin, furazolidine, cotrimoxazole, Nalidixic acid, Chloramphenicol,• Others :• Vitamin K – large doses• Naphthalene (moth balls)• Benzene, Methylene blue• Probenecid• Acetyl salicylic acid (aspirin)• Fava beans• Septicemia and viral hepatitis in def. pts
  38. 38. FAVA BEANS
  39. 39. TYPES• Type 1: mild (G6PD A-): Afro- americans• Type 2: moderately severe (G6PD B- and G6PD Canton): SE Asia, Mediterranean• Type 3: chronic: North America and Europe OR• Episodic hemolytic anemia• Spontaneous chronic nonspherocytic hemolytic anemia
  40. 40. CLINICAL FEATURES Exposure to drug 24-48 hr• Severe progressive anemia, cardiac failure and jaundice• Favism: hemolysis after ingestion of fava beans
  41. 41. TYPE 1• Mildest form (enzymes 8-15 % of normal)• Episodic form• Sensitive to strong oxidants• Usual doses of aspirin and Co-trimox well tolerated• Young RBC have high conc of enzyme -> hence no neonatal jaundice• Hemolysis doesn’t continue after intial hemolysis as ageing G6PD cells dead and young ones have enzyme
  42. 42. TYPE 2• Moderately severe• Episodic form• Fava exposure + oxidants• Neonatal Jaundice present• Hemolysis continuous with continuous administration of drug• Assoc with viral hepatitis – severe jaundice• Encephalopathy sometimes
  43. 43. TYPE 3• Chronic type• Spontaneous, without any ppt factor• If ppt factor given -> severe hemolysis with hemoglobinuria• Severe neonatal jaundice -> kernicterus• Hemolysis after febrile episode• Enzyme level very very low
  44. 44. INVESTIGATIONSDuring hemolysis :• Hb decreased• Elevated retics (5-15 %)• PS: Normocytic normochromic anemia• Polychromasia, fragmented cells• Heinz bodies:- ppted hemoglobin- supravital staining• Hemoglobinuria• Indirect hyperbilirubinemia
  45. 45. NEVER ASSESS G6PDLEVELS DURING ACUTE HEMOLYSIS
  46. 46. WHY?• During acute hemolysis- all deficient cells have been hemolysed• Young cells will be in circulation• Young surviving cells may have normal levels of the enzyme• Hence falsely normal during acute episode• Assess 2-4 months later• Deficient G6PD levels will be evident• Usually affected have <10% of normal level
  47. 47. TREATMENT• Avoid the oxidants• Blood transfusion• Sodium bicarbonate to alkalinise urine in severe Hburia… or else acid hematin ppt in renal tubules
  48. 48. Thank youDownload more documents and slide shows on The Medical Post [ www.themedicalpost.net ]

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