Hemoglobinopathies

Hemoglobinopathies
Abnormal Hgb Structure (Qualitative) Hereditary Disorders > 300 Types Abnormal Hgb Hgb S Disorders - Most Prevalent

Sickle

Cell Dse - Homozygous (SS) Sickle Cell Trait - Heterozygous

40% Hgb S, 60% Hgb A (Anemia Rare)

Possible Consequences of a Hemoglobinopathy

No detectable effect Instability of Hgb molecule An increase or a decrease in O2 affinity Inability to maintain heme iron in its active, reduced state (methemoglobinemia) Dec solubility of hgb molecule

Hemoglobin M Disease

Substitution at the locus of either proximal or distal histidine Typically, involves his - tyr substitution iron-phenolate complex Hgb in Fe+++ state is incapable of binding oxygen Methemoglobin has a brownish appearance Patients w/ Hgb M dse are typically cyanotic

Unstable Hemoglobinopathies

Most unstable hemoglobinopathies involve a mutation in region of heme pocket Mutations enable H2O to gain access to this hydrophobic region End result: heme instability, denaturation & release of heme from its binding site Heinz Bodies evidence of an unstable hgb mutant

Hemoglobinopathy Altering Oxygen Affinity

Increased Oxygen Affinity: Stabilization of Oxy- conformation = inc O2 affinity Such effect confirmed by left shift O2 Saturation Curve Individuals w/ inc O2 affinity typically exhibit erythrocytosis

Hemoglobinopathy Altering Oxygen Affinity

Decreased Oxygen Affinity: Stabilization of Deoxy- conformation = dec O2 affinity Such effect confirmed by right shift O2 Saturation Curve Individuals w/ dec in O2 affinity are typically somewhat anemic

Clinically Significant Variant Hemoglobins

Hemoglobinopathy Hemoglobin S Hemoglobin C Hemoglobin E Hemoglobin Constant Spring Hemoglobin H Hemoglobin Barts Hemoglobin M 2 2 2
S 2 C 2

Alpha Normal Normal Normal

Beta Defective Defective Defective Normal Normal Normal Normal

Comments Hemolytic anemia, splenomegaly, target cells are characteristic Benign, common in SE Asia Long alpha chain Paucity of alpha chains Screening test: Heat instability test Not compatible with life A group of abnormal hemoglobins in which a single amino acid substitution favors the formation of methemoglobin.

HCSpr Defective
4

Absent Absent Normal

Sickle cell anemia

AR; Chronic hemolytic anemia Pallor, Jaundice, Dark urine, HepatoSpleenoMegaly Types:

Homozygous

(Disease or Anemia) Heterozygous(Trait) SC, SD, S- THALASSEMIA

Hemoglobin S Disorders

Point Mutation of B Globin Gene

GLU

HgA HgS

6th
VAL

Hgb S Gene - 8% in American Blacks - 30% in Some African Populations - Confers Resistance to plasmodium falciparum Malaria

Sickle Cell Disease

Sickle cell
Deoxyge nation (or H 0 2 , H) p

O2

Ca K, O2

Polymerization of Hgb S

Complications

Hemolytic Crisis: Thrombotic crisis

Occlusion

of small BV: Heart infarction; CNS hemiplegia; mesentery abd. pain

Sequestration crisis: Destruction of RBC in liver & spleen shock HSM Aplastic crisis: Aplasia of BM Hyperhemolytic crisis: Acute hemolytic anemia

HEMOGLOBINOPATHY S

LAB DX: PBS: SICKLE, BRONZE ELLIPTOCYTES; Normocytic Normochromic Reticulocytic count (+) SICKLING PHENOMENON (Na METABISULFIDE TEST) SOLUBILITY TESTS (Na DITHIONATE T) BM exam: erythroid hyperplasia Hb S- INC/ Hb F- 1- 10% / Hb A2- N

Sickle Cell Anemia vs Sickle Cell Trait PBS

Target Cell

Sickled Cell

Sickle Cell Disorders

Diagnosis
Sickledex

- In Vitro Sickling After Adding Reducing Agt Electrophoresis - ID Hgb S Analysis - Prenatal Testing

Hgb DNA

Normal RBCs

Sickledex Screen

Sickled RBCs

Hemoglobin Electrophoresis

* Sickle Cell Trait Heterozygous

Treatment

During attacks:
Rest

in bed Hydration Sedation Antibiotics Transfusion

Between attacks:
Transfusion Iron

chelating agents Splenectomy

Prognosis: Improve with age

SICKLE CELL DISEASE Therapeutic Approaches

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
Hb C (GLULYSINE 6TH BETA) HGB C-C DISEASE:

Hb

F- FEW PBS: TARGET; BISCUIT CELL; TETRAGONAL C CRYSTALS SPLEENOMEGALY

HGB C-A TRAIT:

ASYMPTOMATIC

HEMOGLOBINOPATHIES

Hb E (GLULYSINE 26TH BETA)

AGAR

GEL E AT ACID Ph UNSTABLE IN OXIDANT EXPOSURE

Hb M
A

OR B- CHAIN MUTATION IN HIS TYR RESIDUE OF HEME POCKET (+) SCHUMMS TEST