04 Hemoglobin Hemoglobinopathies
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Transcript of 04 Hemoglobin Hemoglobinopathies
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Hemoglobinopathies
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Hemoglobinopathies (Qualitative)
Hereditary Disorders
Abnormal Hgb Structure
> 300 Types Abnormal Hgb (Hgb S Disorders - MostPrevalent
Molecular abnormalities in hemoglobinopathies Substitution of one amino acid for another (most common)
Substitution of more than one amino acid
Deletion of one or more amino acids Fusions of hemoglobin chains
Extension of an amino acid chain
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Possible Consequences of a
Hemoglobinopathy No detectable effect
Instability of Hgb molecule (Unstable Hgb)
Increase or a decrease in O2 affinity
Inability to maintain iron in its reduced
state (methemoglobinemia)
Dec solubility of hgb molecule
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Hemoglobin M Disease
Substitution at either proximal or distal histidine
loci (his tyr) iron-phenolate complex
Fe+++ state is incapable of binding O2
cyanosis
Methemoglobinemia
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Unstable Hemoglobinopathies
Mostly mutation in heme pocket region
H2O gains access to hydrophobic region
Result: heme instability, denaturation & releaseof heme from its binding site
Heinz Bodies evidence of an unstable hgbmutant
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Hemoglobinopathy Altering Oxygen
Affinity Increased O2 Affinity:
Stabilization of Oxy-
conformation = inc O2
affinity
Confirmed by left shift O2
Saturation Curve
Typically exhibit
erythrocytosis
Decreased O2 Affinity:
Stabilization of Deoxy-
conformation = dec O2
affinity
Confirmed by right shift
O2 Saturation Curve
Typically somewhat
anemic
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HEMOGLOBINOPATHIES
Hb E (GLULYSINE 26TH BETA)AGAR GEL E AT ACID Ph
UNSTABLE IN OXIDANT EXPOSURE
Very low MCV (55-65 fL) Few to many codocytes
Hb MA OR B- CHAIN MUTATION IN HIS TYR RESIDUE
OF HEME POCKETAutooxidation of iron to Fe3+) methemoglobin
(+) SCHUMMS TEST
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Hgb C-Harlem (C-Georgetown) double sub at B
chain
6th
valine for glutamic acid 73rd aspartic acid for asparagine (Korle Bu mutation)
Hgb D & G:
Group of beta & alpha chain variants that migrate in
an alkaline pH at the same electrophoretic position asHgB S
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Hgb O-Arab:
121st B chain lysine for glutamic acid
Mild hemolytic anemia; many codocytes
The only HgB to move just slightly away from
the point of application toward the cathode on
citrate agar at an acidic pH
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Clinically Significant Variant HemoglobinsHemoglobinopathy Alpha Beta Comments
Hemoglobin S a2bS
2 Normal Defective
Hemoglobin C a2bC
2 Normal Defective Hemolytic anemia, splenomegaly,
target cells are characteristic
Hemoglobin E a2bE2 Normal Defective Benign, common in SE Asia
Hemoglobin Constant
Spring
HCSpr Defective Normal Long alpha chain
Hemoglobin H b4 Absent Normal Paucity of alpha chains
Screening test: Heat instability testHemoglobin Barts g4 Absent Normal Not compatible with life
Hemoglobin M Normal Normal A group of abnormal hemoglobins in
which a single amino acid
substitution favors the formationof methemoglobin.
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HEREDITARY PERSISTENCE OF
Hb F PARTIAL/ TOTAL SUPPRESSION OF
BETA & DELTA CHAINS
Lab Dx:
ALKALI DENATURATION TEST
KLEIHAUER- BETKE (ACID
DENATURATION TEST)
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KLEIHAUER- BETKE (ACID
DENATURATION / Elution TEST) Principle:
Detects fetal-maternal hemorrhage
Blood smear + acid buffer (adult Hgb loses
Hgb into the buffer, only the stroma (cell
membrane) is left
Fetal RBCs unaffected & retain Hgb
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Fetal cells: bright pink
Adult cells: "ghost
cells
Cord blood is used as
the positive control
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Hemoglobinopathy S
AR
Chronic hemolytic
anemia Pallor,Jaundice, Dark urine,
HSM
Types:
Homozygous (Disease
or Anemia)
Heterozygous (Trait)
SC, SD, S-
THALASSEMIA
Homozygous: sickling
begins when O2
saturation < 85%
Heterozygous: sickling
begins when O2
saturation < 40%
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Hemoglobin S
Disorders Discovered 1904 man
from Grenada
Point Mutation
of B Globin Gene (146 aaof B globin chain)
Incidence: 8% in American Blacks
30% in Some African Confers resistance to P.
falciparum (Hgb S Trait)
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Complications
Hemolytic Crisis Hyperhemolytic crisis
Thrombotic crisis Heart infarction
CNS hemiplegia Mesentery abd. pain Sequestration crisis: Destruction of RBC in liver &
spleen shock HSM Aplastic crisis: Aplasia of BM
Hand-Foot Syndrome: children < 3 y/o w/ sickle cellanemia exhibit painful swelling in the hands and feet
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4 triggers of sickle cell crisis
Acidosis
Hypoxia
Infection
Fever
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Sickle Cell Anemia Lab Findings:
BM: erythroid hyperplasia
PBS: Marked poikilocytosis & anisocytosis
Drepanocytes
NRBCs Basophilic stippling
Pappenheimer bodies
Howell-jolly bodies
Moderate to marked polychromasia
Retic: 10-15%
High plt count & moderate neutrophilia
Low ESR
Low osmotic fragility test
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HEMOGLOBINOPATHY S LAB
DX:
PBS: SICKLE, BRONZE
ELLIPTOCYTES;
Normocytic
Normochromic
Reticulocytic count
BM exam: erythroid
hyperplasia
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HEMOGLOBINOPATHY S LAB
DX: SOLUBILITY TESTS (Na
DITHIONATE Test) Sickle Cell screening test
FALSE NEGATIVE in: Hgb
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Sickle Cell Disorders Diagnosis:
(+) SICKLING
PHENOMENON (Na
METABISULFIDETEST)
Sickledex - In Vitro
Sickling After Adding
Reducing Agt
Normal RBCs Sickled RBCs
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Sickle Cell Disorders Diagnosis:
Hgb Electrophoresis:ID Hgb S (Hb S- INC/Hb F- 1- 10% / Hb
A2- N) Sickle Cell
confirmation test
DNA Analysis -Prenatal Testing
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Treatment
During attacks: Rest in bed Hydration
Sedation
Antibiotics
Transfusion
Between attacks: Transfusion
Iron chelating agents
Splenectomy
Hydroxyurea
Butyrate
Increases proportion of HgB F inadults
Prognosis: Improve with age
Reactivate Fetal HemoglobinProduction using Hydroxyurea
Chemical inhibition of Hb Spolymerization
Increase in intracellular hydration
Altering RBC/Endothelial cellinteractions
BMT
Gene therapy
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HEMOGLOBINOPATHY C: Hb C
(GLU
LYSINE 6TH BETA) HGB C-A TRAIT:
ASYMPTOMATIC
Heterozygous HgBAC:
HgB C (30%)
HgB A (60%)
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HEMOGLOBINOPATHIES
HGB C-C DISEASE: NN anemia
Marked increased incodocytes (target cells)
Tetragonal crystals of HgBC on blood smear
Marked increase in retics
Homozygous HgB CC: Very little to no HgB A
HgB C (90%) HgB F (7%)
HgB A2 (3%)
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HgB SC lab findings:
NN anemia
HgB: 11 - 13 g/dL
Retic: 3 - 5%
PBS: Few sickle cells,codocytes, & intraerythrocyticcrystalline structures
Moderate hemolytic anemia
Moderate splenomegaly
Sodium dithionite test (+)
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WWW Sites of Interest
Joint Center for Sickle Cell and Thalassemic
Disorders: http://www-
rics.bwh.harvard.edu/sickle/ (Overview of sicklecell disease, thalassemia and iron kinetics)
The Sickle Cell Information Center, Emory
University:
http://www.emory.edu:80/PEDS/SICKLE/(Includes PowerPoint presentations on sickle
cell disease)
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