hemolytic anemia, hereditary spherocytosis and g6pd deficiency
TRANSCRIPT
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HEMOLYTIC ANEMIA– Hereditary spherocytosis and
G6PD deficiency
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Dr. Kalpana MallaMD Pediatrics
Manipal Teaching Hospital
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Definition:
• Anaemia due to increased red cell destruction (and increased erythropoiesis)
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Classification:
• INTRACORPUSCULAR HEMOLYSIS– Membrane Abnormalities– Haemoglobin defects– Enzyme defects
• EXTRACORPUSCULAR HEMOLYSIS– Nonimmune – Immune
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Intracorpuscular defects
Membrane Defects • Microskeletal defects
– Hereditary spherocytosis**• Membrane permeability defects
– Hereditary stomatocytosis• Increased sensitivity to complement
– Paroxysmal nocturnal hemoglobinuria
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Intracorpuscular defects
• Enzymopathies • Deficiencies in Hexose Monophosphate
Shunt– Glucose 6-Phosphate Dehydrogenase
Deficiency**• Deficiencies in the EM Pathway
– Pyruvate Kinase Deficiency
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Intracorpuscular defects
Haemoglobin defects Haemoglobinopathies: Sickle cell anemia
Thalassemias: β-thalassemia major HbH disease
Double heterozygous disorders: Sickle cell β-thalassemia
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Extracorpuscular defects -
IMMUNE Autoimmune Hemolysis
– Warm antibody– Cold antibody
Alloimmune Hemolysis– Hemolytic Transfusion Reaction – Hemolytic Disease of the Newborn
Drug-Related Hemolysis
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Extracorpuscular defects -
Nonimmune • M echanical• Infectious• Chemical• Thermal
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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
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• 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
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HEREDITARY SPHEROCYTOSIS
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ETIOLOGY
• Usually AD . Rarely AR• 25% have no F/H. New mutations• Northern Europe most common• Also seen in SE Asia incl. India, Nepal
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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
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MOLECULAR PATHOPHYSIOLOGYDeficiency in spectrin, ankyrin, protein 3
Lipid bilayer skeleton uncoupling
Membrane loss in the form of microvesicles
Surface area deficiency
Spherocytosis
Impaired passage through splenic cord
Sequestration
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VARIOUS PRESENTATIONS
• Hemolytic d/s of newborn• Hemolytic crisis : most common form• Aplastic crisis• Megaloblastic crisis• HS in pregnancy
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CLINICAL CLASSIFICATION
• Trait• Mild HS• Moderate HS• Moderately severe HS• Severe HS
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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
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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
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APLASTIC CRISIS
• Less common, more serious• Parvovirus B19• Fever, chills• Vomiting, diarrhea, myalgias• Slapped cheek apearance• Foll this - sudden pallor, jaundice,
weakness
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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
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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
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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
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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,
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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
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OSMOTIC FRAGILITY
0
20
40
60
80
100
0.3 0.4 0.5 0.6
NaCl (% of normal saline)
% H
emol
ysis
Normal HS
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Other conditions associated with spherocytes on PS:
• Auto-immune hemolytic anemia• Burns• Wilson’s disease• Chemical injury• Infections• HDN due to anti-A
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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
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TREATMENT
• Splenectomy• Folic acid 1 mg/day• Blood transfusion SOS• Cholecystectomy for gall stones
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SPLENECTOMY
• Indications:Hypoplastic/aplastic crisisPoor skeletal growthCardiomegaly
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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
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GLUCOSE-6-PHOSPHATE
DEHYDROGENASE DEFICIENCY
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• 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
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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 -
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• 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
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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
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HbO2 infections/ drugs Hb O2 H2O2 H2O Gl. Peroxidase meth.Hb 2GSH GSSG Gl. Reductase Heinz bodies NADP NADPH G6PD GG6P 6-PG maintains integrity of RBC membrane when deficient glycolysis haemolysis lactate
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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• Diabetic ketoacidosis
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FAVA BEANS
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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
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CLINICAL FEATURESExposure to drug
24-48 hr
• Severe progressive anemia, cardiac failure and jaundice
• Favism: hemolysis after ingestion of fava beans
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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
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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
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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
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INVESTIGATIONSDuring hemolysis :• Hb decreased • Elevated retics (5-15 %)• PS: Normocytic normochromic
anemia• Polychromasia, fragmented cells• Heinz bodies:- ppted hemoglobin-
supravital staining• Hemoglobinuria• Indirect hyperbilirubinemia
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NEVER ASSESS G6PD LEVELS DURING ACUTE HEMOLYSIS
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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
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TREATMENT• Avoid the oxidants• Blood transfusion• Sodium bicarbonate to alkalinise urine
in severe Hburia… or else acid hematin ppt in renal tubules
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