Hemoglobinopathies
Diseases affecting the
structure, function or
production of Hb.
Types
1- Structural Hemoglobinopathies
A- Abnormal Hb polymerization --- Sickle
cell anemia
B- Altered O2 affinity --- High affinity –
polycythemia
--- Low affinity – Cyanosis, pseudo
anemia
C- Hb that oxidize readily
--- Unstable Hb (HA, jaundice)
--- MetHb (cyanosis)
2- Thalassemia
(defective biosynthesis of globin chains)
A- α-thalassemia
B- β-thalassemia
C- δβ, γδβ, αβ thalassemias
3- Thalassemic Hb variants
(structurally abnormal Hb associated with coinherited thalassemic phenotype)
A- Hb-E
B- Hb - Constant spring
C- Hb- Lepore
4- Hereditary persistence of fetal
Hb (HPHF)
(Hb F in adults)
5- Acquired Hemoglobinopathies
A- Met-Hb due to toxic exposure.
B- Sulf-Hb due to toxic exposure.
C- CarboxyHb due to CO.
D- Hb-H in erythroleukemia.
E- Elevated Hb-F in states of erythroid
stress & BM dysplasia.
Thalassemia
This is an inherited disorder of α or β globin chain
biosynthesis.
Causes reduced
production of Hb
tetramers causing hypochromia &microcytosis.
The latter is leading to ineffective erythropoiesis &
hemolytic anemia.
Normal Hb consists of 2α and 2β chains.
Two clusters of genes encode for globin synthesis
(β genes on chromosome 11 & α genes on
chromosome 16).
An unbalanced accumulation of α or β chains
results
α- Thalassemia
Decreased α-chain production relative to βchain production forming β4 (Hb-H inclusion
bodies).
RBCs bearing inclusion bodies are rapidly
removed from the circulation by RES cells
thus shortening RBC survival.
S&S
Deletion of 1 gene (-α/αα) & 2 genes (-/αα; -α/α) are virtually asymptomatic.
Deletion of 3 genes (--/-α) producing Hb H
disease (Hb Barts).
Moderate hypochromic microcytic anemia &
splenomegaly.
Hb= 8-10 g/dL, special stain shows Hb H inclusions.
Hb electrophoresis shows Hb H. Hb H tends to precipitate
during oxidative stress & under increased temperature as
in infections causing hemolysis.
Deletion of 4 genes (--/--) is the most severe
form that is incompatible with life leading to
intrauterine death of the fetus (hydrops
fetalis).
β- Thalassemia
Decrease in β-chain production relative to αchain production.
Common in Mediterranean, Asian & African
populations (areas endemic with malaria).
Trait --- asymptomatic.
Clinical anemia ---- is seen in homozygous or
compound heterozygous e.g. β
thalassemia/Hb E.
Reduced β globin chain synthesis leads to
accumulation of free α globin chains that
precipitate in early erythroblast
development since they are insoluble.
These lead to ineffective erythropoiesis in BM
& enhanced destruction in circulation.
Anemia, splenomegaly ± hypersplenism,
osteoporosis, skeletal & soft tissue changes
due to BM expansion, iron overload ( ↑GIT
absorption & blood transfusion) deposit in
liver, heart, pancreas, pituitary & other
endocrine organs.
Lab. Dx
Microcytic hypochromic anemia, MCV ↓.
Hb- electrophoresis --- Hb A2 ↑ > 4-6%, Hb F ↑
5-20%.
PCR, DNA probes.
Antenatal Dx --- Amniotic fluid analysis &
chorionic villous sampling.
℞
α-thalassemia ---- 1 gene or 2 genes
deletion may be asymptomatic and
require no
treatment.
Hb H disease- Folic acid 1mg/day
orally
Splenectomy for progressive anemia.
β thalassemia
Improved outcome recently due to the use of
aggressive blood transfusion support &
effective iron chelation therapy.
The only curative ttt by BM transplantation.
Blood transfusion
– non-transfused pt survives only 2 y in
homozygous state.
-- Aim to maintain Hb at 11-13g/dL
-- Pre-transfusion level>10g/dL
-- extend life to 2nd decade, minimize
bony abnormalities, and improve sexual
development.
-- Leukocyte-poor RBCs given to
minimize allosenstization & not to prejudice
future BMT.
-- HB vaccine given for pt with –ve Ab
test
Splenectomy
if transfusion requirement > 1.5 normal
(>200ml/kg/year)
-- preceded by polyvalent pneumococcal
vaccine (pediatric pt also given H influenza
& N meningitides vaccine)
Iron chelation
--- if not given pts will die of iron overload.
--- Subcutaneous desferrioxamine 1.5-2.5 g/d
--- Oral defroperone, deferasirox
--- S.C desferral 12-24 h infusion 5-6x/w --S/E visual disturbances, tinnitus, azotemia,
proteinuria.
Annual ophth & audiol exam needed.
--- Periodic estimation of iron burden (S Fe,
TIBC & S Ferritin)
--- Estimate of liver iron concentration
--- Annual cardiac evaluation to detect early
dis
--- GTT, thyroid function test, cortisol
determination
--- Hormone replacement therapy
Stem cell transplant
Allogeneic BMT for homozygous β
thalassemia
Manipulation of globin chain
gene expression with
5-azacytidine, hydroxyurea,
erythropoietin,
butyrate analogues to stimulate
Hb F synthesis by γ globin
chain augmentation
Experimental ttt
--- gene therapy
* For β globin alleles
* Still investigational