Hereditary Defects Of Rbc Membrane And Hereditary Deficiencies

Front 1

Red Cell Membrane Chemical Structure

Back 1

• Carbohydrates: 8%
• Lipids: 40%
  • Proteins: 52%

Front 2

Glycophorin

Back 2

• Major integral membrane protein
• 20% total membrane protein
• Contains 60% carbohydrates; most of the membranes sialic acid
  • Many RBC antigen on this portion

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Spectrin

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• Peripheral protein
• 25-30% of the total membrane protein
• 75% of peripheral protein
• Forms microfilaments in the membrane
• Responsible for biconcave shape
  • Related to integrity of the RBC

Front 4

Hereditary Defects of the RBC Membrane

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• Hereditary Spherocytosis
• Hereditary Ovalocytosis (Elliptocytosis)
  • Other membrane defects

Front 5

Classification of Hereditary Defects of the RBC membrane

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• HS- microspherocytes
• HE- ellpitical RBCs
• Hereditary Stomatocytosis (hydrocytosis)- stomatocytes
• Hereditary xerocytosis (dessicocytosis)- dehydrated shrunken RBCs
  • HPP- thought to be a variant of HE; increase sensitivity to temperature

Front 6

Inheritance of Hereditary Spherocytosis

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• Autosomal dominant inheritance: 75%, homozygous incompatiable with life, heterozygous
  • Recessive: 25%

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Pathophysiology of HS

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• Spectrin deficiency
  • Dysfunction of spectrin, ankyrin, and protein 4.1

Front 8

Hereditary Spherocytosis (HS)

surface area/volume

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Loss of surface area, decreased surface to volume ratio

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Clinical and Laboratory Findings in HS

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• Anemia: mild to moderate
• Jaundice
  • Splenomegaly

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HS CBC

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MCHC >36fL

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HS Peripheral blood smear and BM

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• Spherocytosis
• Increased Polychromasia
• Increased reticulocyte count >5%
  • BM: erythroid hyperplasia

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HS Diagnostic Test

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• Osmotic Fragility: Increased
• Autohemolysis
  • Spectrin Assay

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HS treatment

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• Splenectomy: excellent response to splenectomy
  • Red cell transfusion

Front 14

Autohemolysis

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• Diagnostic test for HS
• Not routinely used (time consuming)
• Normal RBC incubated in own plasma hemolysis takes place
• In HS, the loss of mem and inability to maintain cation gradient, hemolysis much grtr
• 10-50% HS at 48 hrs, <5% Normal
  • Glucose can be added to drive/maintain cation pumps

Front 15

HE inheritance

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Autosomal dominant

Front 16

HE pathophysiology

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• Functional defect of protein assembly
• Impair spectrin dimer to tetrameter
• Quantitatively normal proteins
  • Decreased cell deformability; shortened survival

Front 17

Subtypes of HE

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• Common HE
• Spherocytic HE
  • Stomatocytic HE (SE Asian ovalocytosis), resistant to malaria invasion, Osmotic fragility usually normal

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Clinical Manifestation HE

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• Mild to moderate Anemia
• Jaundice
  • Splenomegaly

Front 19

HE laboratory results

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• Normal MCHC
• Retic <4%
• >25% ovalocytes
  • Osmotic fragility normal

Front 20

Treatment of HE

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Red cell transfusion in severe cases

Front 21

Hereditary Stomatocytosis

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• Failure of the Na+ and K+ pump; increase in intracellular water
• Elevated MCV
  • 10-30% stomatocytes

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Hereditary Pyropoikilocytosis (HPP)

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• Rare
• Severe anemia
• Micropoikilocytes
• Microspherocytes
• Schistocytes
• Few elliptocytes
• Osmotic fragility and autohemolysis markedly increased
  • Thermal sensitivity: fragment at 49C and 37

Front 23

Hereditary Xerocytosis

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• Autosomal dominant
• Inefficient Na-K pump
• Red cells dehydrated
• Decreased osmotic fragility
• High surface-volume ratio
  • High MCV and MCHC

Front 24

Hereditary Enzyme Deficiencies

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• Glucose-6-Phosphate Dehydrogenase Deficiency
  • Pyruvate Kinase Deficiency

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Most common erythocyte enzyme disorder

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G6PD deficiency

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G6PD deficiency

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• X-linked
• Gene mutation
• >400 genetic variants
  • Severe deficiency in Middle East

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Pathophysiology of G6PD

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• G6PD is need to maintain GSH
• Deficiency of enzyme
  • Decrease in NADPH
  • GSSG build up (hydrogen peroxide and oxidized glutathione)
    • Oxidized Hgb

Front 28

Target cells

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more resistant in osmotic fragility test

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Causes of G6PD deficiency

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• Denaturation of Hgb by various oxidative drugs and chemicals: Naphthalene, primaquine, sulfanilamide, others
• Heinz bodies formation
• Favism
  • Hemolytic episodes are usually self limiting

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Clincial Manifestations of G6PD

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• Variable intravascular hemolysis
• Hemoglobinuria
  • Jaundice

Front 31

G6PD Laboratory findings

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• N/N anemia
• Hgb: 3-4 g/dL
• Retics
• Polychromasia
• Bite cells
  • NRBCs

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G6PD other tests

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• Supravital stain for Heinz bodies
• Enzyme assay
• Fluorescent spot test
  • Ascorbate-cyanide test

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Most common G6PD variant

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G6PD B; class IV

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Compare G6PD-A adn G6PD med

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A: aging RBC effected, unusual hemolysis with drugs, no favism, mod. hemolysis, degree of hemolysis mod, no transfusion, no chronic hemolysis

Med: All RBC effected, Common hemolysis with drugs, occas favism, severe hemolysis, transfusion occas, no chronic hemolysis

Front 35

Prevalence of G6PD variant

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• G6PD B: most common
• G6PD A+ 20% A. American males
• G6PD A- 10 African american males
• G6PD canton: asians
  • G6PD med: caucasians

Front 36

G6PD ELP

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Normal: G6PD-B, Med

Fast: G6PD- A+, A-, Canton

Front 37

Pyruvate kinase deficiency

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• Autosomal Recessive
• Homo/Heterozygous
• Abnormal enzyme activity in RBC
• Deficiency of defect in PK- hemolytic anemia
  • Enzymopathy of the glycolytic pathway

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Clinical Manifestations PK

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• Variable anemia
• Jaundice
• Splenomegaly
  • Gallstones: common

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PK lab findings

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• N/N anemia
• Hgb: 6-12 g/dL
• Retics
• Polychromasia
  • NRBCs

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Diagnostic lab tests for PK

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• Enzyme assay
  • Fluorescent spot test

Front 41

Methemoglobin Reductase Deficiency

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• Increased level of methemoglobin
• Inherited autosomal recessive
• Cyanosis
  • Compensatory mild polycythemia may develop

Front 42

G6PD is associated with which pathway

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Hexose Monophosphate shunt

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Test for hereditary Spherocytosis

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• Hepranized venous blood
• 5.0 mL of 11 saline solution in tubes
• 50uL of well mixed blood mix; avoid foaming
  • Incubate 30 min, mix, centrifuge and estimate lysis 540nm

Front 44

Osmotic Fragility test for HS

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• RBC incubated in varying concentrations of a hypotonic solution of NaCl
• As NaCl decrease cells take on water to produce osmotic equilibrium
  • Normal cells begin to hemolyse at 0.5% NaCl
    • Spherocyte lysis completed by 0.4-0.5% due to inability to expand

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Methemoglobinemia Hb Electrophoresis

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N: Enzyme deficiency and toxic substance

Abnormal: Hb M disease

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Methemoglobinemia Hb Ezn Activity

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N: Toxic substance, Hb M disease

Low/Absent: Enzyme def

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Methohemoglobinemia MetHb Level

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Increase: Enzyme def, toxic substance, Hb M disease