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Hemoglobinopathies (Qualitative)
Hereditary Disorders Abnormal Hgb Structure > 300 Types Abnormal Hgb (Hgb S Disorders - Most Prevalent 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
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
Unstable Hemoglobinopathies
Increased O2 Affinity: Stabilization of Oxyconformation = inc O2 affinity Confirmed by left shift O2 Saturation Curve Typically exhibit erythrocytosis
Decreased O2 Affinity: Stabilization of Deoxyconformation = dec O2 affinity Confirmed by right shift O2 Saturation Curve Typically somewhat anemic
HEMOGLOBINOPATHIES
Few
to many codocytes
Hb M
OR B- CHAIN MUTATION IN HIS TYR RESIDUE OF HEME POCKET Autooxidation of iron to Fe3+) methemoglobin (+) SCHUMMS TEST
A
6th valine for glutamic acid 73rd aspartic acid for asparagine (Korle Bu mutation) of beta & alpha chain variants that migrate in an alkaline pH at the same electrophoretic position as HgB S
Hgb D & G:
Group
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
Hemoglobin Barts
Hemoglobin M
g4
Absent
Normal
Normal
Normal
HEREDITARY PERSISTENCE OF Hb F
Hemoglobinopathy S
(Disease
Homozygous: sickling begins when O2 saturation < 85% Heterozygous: sickling begins when O2 saturation < 40%
Hemoglobin S Disorders
Discovered 1904 man from Grenada Point Mutation of B Globin Gene (146 aa of B globin chain) Incidence:
Complications
Sequestration crisis: Destruction of RBC in liver & spleen shock HSM Aplastic crisis: Aplasia of BM
Hand-Foot Syndrome: children < 3 y/o w/ sickle cell anemia exhibit painful swelling in the hands and feet
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
PBS: SICKLE, BRONZE ELLIPTOCYTES; Normocytic Normochromic Reticulocytic count BM exam: erythroid hyperplasia
Sickle Cell screening test Hgb <7g/dL Use of 10 x 75mm tube, instead of 12 x 75 Infants <6 months of age
(+) SICKLING PHENOMENON (Na METABISULFIDE TEST) Sickledex - In Vitro Sickling After Adding Reducing Agt
Normal RBCs Sickled RBCs
Treatment
During attacks:
Between attacks:
Transfusion Iron chelating agents Splenectomy Hydroxyurea Butyrate Increases proportion of HgB F in adults
Reactivate Fetal Hemoglobin Production using Hydroxyurea Chemical inhibition of Hb S polymerization Increase in intracellular hydration Altering RBC/Endothelial cell interactions BMT Gene therapy
HEMOGLOBINOPATHIES
NN anemia Marked increased in codocytes (target cells) Tetragonal crystals of HgB C on blood smear Marked increase in retics Very little to no HgB A HgB C (90%) HgB F (7%) HgB A2 (3%)
NN anemia HgB: 11 - 13 g/dL Retic: 3 - 5% PBS: Few sickle cells, codocytes, & intraerythrocytic crystalline structures
Moderate hemolytic anemia Moderate splenomegaly Sodium dithionite test (+)
Joint Center for Sickle Cell and Thalassemic Disorders: http://wwwrics.bwh.harvard.edu/sickle/ (Overview of sickle cell 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)