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Fifth stage
‫نزار‬.‫د‬
medicine
HEMOGLOBINOPATHIES
• Definition :
Hemoglobinopathies are inherited disorders in
which Mutation in or near the globin genes alter
the structure of amino acid sequences or the rate
of synthesis of a particular globin chain.
Hb-S  B6 glu val
Hb-C  B6 glu lys
Defective haemoglobin
Sickle cell anaemia
• It results from single base change in
the DNA coding for the amino acid in
the sixth position in the b-globin chain.
• This leads to an amino acid change
from glutamic acid to valine HbS will
be formed instead of the normal Hb.
• Sickle Cell Anemia is a
hereditary disease which is
cause by a disorder in the
blood, a mutation in the
Hemoglobin Beta Gene which
can be found in the
Lec2/11/2015
chromosome 11. This disease
causes the body to make
abnormally shapes red blood
cells. A normal red blood cell
is shaped as a round donut
while the abnormal red blood
cell has a “ C “ form.
• Hb S is insoluble and forms crystals when exposed to
low oxygen tension.
• Deoxygenated sickle Hb polymerizes into
long fibrils.
• The red cells sickle may block the different
areas of
the microcirculation or large vessels causing
infarcts
of various organs.
• It is widespread in Africa. Individuals with
sickle-cell trait are relatively resistant to the
lethal
effects of falciparum malaria in early
childhood.
INTRODUCTION CONT’
Hemoglobin Beta Gene (HB-B) also known as
Beta Globin is a protein that resides in the red
blood cells.
The HBB is 146 amino acids long and its
molecular weight is 15,867 Daltons.
The molecules of the hemoglobin are
responsible to carry oxygen through the body.
The HBB is found in part 15.5 of the
chromosome 11.
Pathophysiological effects of sickled cells
1.Extravascular hemolysis .
2. Loss of splenic function.
3.Anaemia.
4.Compromisation of the microcirculation.
CLINICAL MANIFESTATION
1.complication from moderate to severe
anaemia
2.slowed growth and development .
3.cardiac over load leads to CHF .
4.Bilirubin stones and cholecystitis .
5.Aplastic crisis.
Sickle cell crisis.
1.Splenic crisis (splenic sequestration syndrome,
auto splenectomy)
2.Infections.
3.CNS and ophthalmic events (CVA, proliferative
retinopathy).
4.Acute chest syndrome (chromic pulmonary
hypertension lead to cor-pulmonale).
5.GIT : diffuse abdominal Pain.
6.Genitourinary symptoms:
- Painless haematuria.
- hyposthenuia.
- priapism.
- hypogonadism.
Sickle cell crisis Cont.
7.skeletal complication
- hand-foot syndrome.
acute arthritis.
aseptic necrosis of the head of femur.
osteomyelitis .
8.Skin changes lead to chronic nonhealing ulcer
DIAGNOSIS
Peripheral blood smears :
sickled cells, target cells, Howell-Jolly bodies, normoblast,
red cell fragment, increase platelet and occasionally
leukocytosis.
screening test : sickling test
The presence of HbS can be demonstrated by exposing red
cells to a reducing agent such as sodium dithionite; HbA
gives a clear solution,whereas HbS polymerises to produce a
turbid solution.
Definitive diagnosis by
Hemoglobin electrophoresis (Hb-S =
87% , Hb-F = 9.7%, Hb-A2 = 3.3%)
Howell Jolly Body
Erythroblast
Diagnosis of sickle cell anaemia Cont.
Haemoglobin Electrophoresis:
Hb A 0 %
Hb S 87.0 %
Hb F 9.7 %
Hb A
2 3.3 %
Both parents of the affected individual will have
sickle-cell trait
TREATMENT
Painful vaso-occlusive crisis
1.hydration
2.precepitating factors
3.oxygen therapy
4.analgesic
5.exchange transfusion
*Antisickling agent (Hydroxyurea) increase Hb F
reduce sickling.
*Bone marrow transplantation(Allogeneic-BMT).
* Gene therapy.
maintenance therapy and prevention
1.folic acid 1 mg/d orally.
2.pneumococcal vaccine.
3.pregnancy (increase crisis, abortion, stillbirth)
folate,, exchange transfusion. Exchange
transfusion will increase Hb-A= 60%.
4.general anesthesia;Careful hydration and
oxygenation.
*Angiographic contrast media causing sickling should
be avoided
The thalassemia syndromes
are inherited disorders arising from globin
gene mutations that either reduce or totally
abolish the synthesis of one or more globin
chains.
These imbalance in chain synthesis lead to
formation of unstable Hb. or decrease Hb. lead to
hypochromic microcytic anaemia .
The thalassaemia named according to globin
chain involved.
THALASSEMIA
Pathophysiology of thalassemia
α- thalassemia, gene deletions are
responsible for the decrease or absence of
α- chains.
ß- thalassemia : usually due to an mRNA
abnormality.
This mutation reduces or eliminates the
production of ß-globin chains
Clinical manifestations of thalassemia
ß- thalassemia major (ßoßo): is the most severe Becomes apparent 3-6 months after birth when switch
from Hb-F to Hb-A takes place :
Hepatosplenomegaly (gall stones are also common )
Expansion of the bones (hair on end appearance on
skull X-ray examination).
Severe anaemia with growth retardation and delayed
sexual development
Damage to heart, pancreas, endocrines and liver due to
iron over load
Pathogenesis of anaemia of ß-thala.
Decreased B- globin production has two major •
consequences :
total Hb. synthesis is reduced leading to
microcytic anaemia, low level of Hb-A lead to
increase Hb-A2,Hb-F.
free α-chain accumulates in the RBC
α-chain accumulate and precipitate in
RBC lead to hemolysis, destruction of RBC in the BM.
Pathogenesis cont.
The extent to which ß-chain synthesis is
suppressed determine the degree of
anaemia(ineffective erythropoiesis)
Extramedullary hematopoiesis and
increased erythropoiesis in the BM lead to
over all RBC production is increased due to
accumalation of α chain.
DIAGNOSIS OF ß-THALASSAEMIA
Positive family history with:
a.non specific findings :
Blood smear reveals microcytic RBCs,
poikilocytosis, fragmented RBCs, MCV is low
(around 65fl).
Heinz bodies are evident by supravital stains.
b. specific findings :
Definitive diagnosis of ß-thala. Is based on the
following findings on Hb. Electrophoresis :
increased proportion of Hb-A2(> 3.5%).
increased proportion of Hb-F.
α –thalassaemia
Decrease synthesis of a-chains, lead to precipitation of
Hb-H (4-ß chains) or Hb- Bart’s (4 δ-chains)
Classification of α -thalassaemia :
1-Hydrops fetalis : severe, all 4 α -genes are
deleted lead to severely anaemic, edematous,
stillborn infant. Hb-barts (4 δ -chains had very
high oxygen affinity).
α-THALASSAEMIAS•
αThalassemia cont.
2- HbH disease : deletion of 3 α -genes
lead to unstable Hb. result in precipitation
and extra-vascular hemolysis.
3-α -thalassaemia Trait : deletion of 2 α
genes.
4-α-thalassaemia Carrier: deletion of 1 α
gene, asymptomatic.
DIAGNOSIS OF α-THALA
Positive family history with lab finding •
non specific findings :
Blood smear show microcytic,
hypochromic red cells, target cells, anisopoikilocytosis, and decrease
MCV.
Heinz bodies are evident.
Specific findings : definitive diagnosis is
finding of HbH by Hb electrophoresis.
34
Hb –H Diagnosis
Haemoglobin Electrophoresis:
Hb A 91.5 %
Fast moving band 8.5%
Hb A2 and Hb F decreased
Hb H Preparation
TREATMENT OF α- AND ß- THALASSEMIA
1.Regular red cell transfusions :
hypertransfusion program (keep the level of
Hb>110g/L)
2.Neocytes transfusion (increase RBC survival,
decrease frequency of transfusion, and
decrease iron over load).
2-3 units every 4-6 weeks .
3.Leukocyte filter will lowers rate of transfusion
reaction.
4.Folic acid supplementation (5 mg) to prevent
aplastic crisis.
5.Iron chelation:
*Desferioxamine (Desferal) either with each unit
of transfused blood (2 g) or by slow
subcutaneous daily infusions by pump
(1-4g over 8-12(
*(Exjade ) Deferasirox
*Deferiprone
6.Splenectomy ;indication:
mechanical difficulty,hypersplenism.
7.Bone Marrow Transplantation : prior to
development of hepatomegaly, portal fibrosis &
iron over load.
PRENATAL DIAGNOSIS OF THALASSAEMIA
Guide parents and physicians in deciding
whether to complete pregnancy.
Both parent carriers.
Fetal diagnosis:
fetoscope to sample fetal venous blood show α/ß
chain synthesis ratio.
Amniocentesis or trophoblast (chorionic villus)
biopsy for DAN analysis using DNA probes.
IMMUNE HEMOLYSIS
Definition :
red cell life span is shortened because
abnormalities in the components of the immune
system are specifically directed against the
patients own erythrocytes.
1.Auto-immune hemolytic anaemia.
2.Transfusion related hemolysis.
3.Drug-related immune hemolysis.
AUTO- IMMUNE HEMOLYTIC ANAEMIA
The auto antibodies can be activated by either
heat or cold.
Warm reactive auto immune hemolysis (37oC)
Causes :
1- idiopathic
2- secondary :
I. Drugs (Methyldopa)
II. Connective tissue disease (SLE)
III. Lymphoproliferative (CLL, HD, NHL)
CLINICAL MANIFESTATION
Onset rapid lead to anaemia, tiredness,
fatigue.
Elderly pts. With atherosclerosis lead to
chest pain.
Splenomegaly and Jaundice, may be absent
in acute phase.
Abdominal pain and fever may also occur.
Diagnosis
spherocytosis, reticulocytosis, increase
LDH, decrease serum haptoglolbin,
increase indirect bilirubin
positive direct coomb’s test; Patient’s
CELLS are tested for surface Ab’s
Treatment
1.Removal of the underlying cause
2.Corticosteroid : 1mg/kg prednisone (3-4
weeks / check-Hb. & retics.) then slow tapering
if pt. respond . in chronic cases, use low dose
therapy
3.Splenectomy : in case of steroid failure or
decrease Hb. following cessation / reduction of
steroid.
4.Blood transfusion.
*cold-reactive auto immune hemolysis
Auto Antibodies usually are IgM. Occasionally
IgG.
Low temp make the antigen(Ag) more prominent
on the membrane lead to antibodies reaction.
Warm temp hiding the Ag below the membrane
below the lipid component lead to prevention of
Ag-Antibodies(Ag-Ab.) reaction
CAUSES
1.Idiopathic.
2.Secondary:
*Infection(mycoplasma pneumonia,
infectious mononucleosis)
*Lymphoma
Pathogenesis and clinical effects
The Blood from warm body cavities come to the surface
low blood temp.this lead to activation of the autoAbs
and to agglutination resulting in impairing circulation
and producing cyanosis, pallor and ischemic pain
(Raynauds phenomenon).
IgM binds Ag temporarily, but it fixes complement. IgM
dis-engages from red cell to a attach to another cell.
The fixed complement remains and activate C5-C6
causing hemolysis . C3-sensitized RBC removed by
kuppfer cells in the liver and this why hemolysis not
respond to splenectomy.