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Hemolytic anemia, Hereditary spherocytosis and G6PD deficiency
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Hemolytic anemia, Hereditary spherocytosis and G6PD deficiency


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  • 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 [ ]
  • 2. Definition:• Anaemia due to increased red cell destruction (and increased erythropoiesis)
  • 3. Classification:• INTRACORPUSCULAR HEMOLYSIS – Membrane Abnormalities – Haemoglobin defects – Enzyme defects• EXTRACORPUSCULAR HEMOLYSIS – Nonimmune – Immune
  • 4. Intracorpuscular defectsMembrane Defects• Microskeletal defects – Hereditary spherocytosis**• Membrane permeability defects – Hereditary stomatocytosis• Increased sensitivity to complement – Paroxysmal nocturnal hemoglobinuria
  • 5. Intracorpuscular defects• Enzymopathies• Deficiencies in Hexose Monophosphate Shunt – Glucose 6-Phosphate Dehydrogenase Deficiency**• Deficiencies in the EM Pathway – Pyruvate Kinase Deficiency
  • 6. Intracorpuscular defectsHaemoglobin defects Haemoglobinopathies: Sickle cell anemia Thalassemias: β-thalassemia major HbH disease Double heterozygous disorders: Sickle cell β-thalassemia
  • 7. Extracorpuscular defects -IMMUNEAutoimmune Hemolysis – Warm antibody – Cold antibodyAlloimmune Hemolysis – Hemolytic Transfusion Reaction – Hemolytic Disease of the NewbornDrug-Related Hemolysis
  • 8. Extracorpuscular defects -Nonimmune• M echanical• Infectious• Chemical• Thermal
  • 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. • 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
  • 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. 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. 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. VARIOUS PRESENTATIONS• Hemolytic d/s of newborn• Hemolytic crisis : most common form• Aplastic crisis• Megaloblastic crisis• HS in pregnancy
  • 16. CLINICAL CLASSIFICATION• Trait• Mild HS• Moderate HS• Moderately severe HS• Severe HS
  • 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. 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. APLASTIC CRISIS• Less common, more serious• Parvovirus B19• Fever, chills• Vomiting, diarrhea, myalgias• Slapped cheek apearance• Foll this - sudden pallor, jaundice, weakness
  • 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. 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. 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. 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. 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. OSMOTIC FRAGILITY 100 80% Hemolysis 60 40 20 0 0.3 0.4 0.5 0.6 NaCl (% of normal saline) Normal HS
  • 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. 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. TREATMENT• Splenectomy• Folic acid 1 mg/day• Blood transfusion SOS• Cholecystectomy for gall stones
  • 29. SPLENECTOMY• Indications: Hypoplastic/aplastic crisis Poor skeletal growth Cardiomegaly
  • 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
  • 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. 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. • 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. 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. 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. 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. FAVA BEANS
  • 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. CLINICAL FEATURES Exposure to drug 24-48 hr• Severe progressive anemia, cardiac failure and jaundice• Favism: hemolysis after ingestion of fava beans
  • 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. 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. 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. INVESTIGATIONSDuring hemolysis :• Hb decreased• Elevated retics (5-15 %)• PS: Normocytic normochromic anemia• Polychromasia, fragmented cells• Heinz bodies:- ppted hemoglobin- supravital staining• Hemoglobinuria• Indirect hyperbilirubinemia
  • 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. TREATMENT• Avoid the oxidants• Blood transfusion• Sodium bicarbonate to alkalinise urine in severe Hburia… or else acid hematin ppt in renal tubules
  • 48. Thank youDownload more documents and slide shows on The Medical Post [ ]