Thalassemias

Ahmed K Yassin

MBChB,DM,CABM,
FIBMS(Clinical Hematology.)
FRCP(London)

(Mediterranean anemia, Cooley’s anemia)

5th year - hematology
Case 1

• M is 2 years old boy referred to you

because of pallor, jaundice,
hepatosplenomegaly

Note: A presentation like this should make

you think of thalassemia
Case 2

• S & I are 22 years old young

couple planning for marriage
• They asked your opinion as accidently the
laboratory evaluation is showing abnormal
indices.
Case 3

• Parents consulted you about their young

boy who have been diagnosed as TDT, what
are the complications and benefits if he is
not transfused , undertransfused ,
overtransfused.
Case 4

• What means the genetics diagnosis

compared with clinical behavior of
thalassemia
Definition of thalassemia

• A group of inherited disorders of Hemoglobin

synthesis, characterized by reduced or absent
synthesis of one or more of the globin chains of
Hemoglobin.
• They are labeled alpha-thalassemias, if it is the
alpha chain that is affected, or beta-thalassemias, if
it is the Beta.
 Types of normal Hemoglobins
• All Normal Hemoglobins consists of two pairs of
globin chains, at the centre of each is one heme group.
• Hb A ( Adult Hb) : 2 2 (~96%).
• Hb F (Fetal Hb) : 2 2 (<1.0%).
• Hb A2 (minor Adult Hb) : 2 2 (1.8-3.5%)
• These percentages are for those from age of 6 months through
adult life.
• At birth the major Hb is Hb F, and it decreases to adult level of
<1% by 6 months of age.

Normal Hb (Hb A2: α2δ2)

β Thalassaemia

• This is one of the most common inherited hematological disorders in

Iraq.
• It was estimated that around 4-5% of the population of the country
carry thalassemia genes.
• Recent studies documented it in ~7.5% of the population in Erbil
area.
• Note: Erbil has one of the highest rates of thalassemia
• Note: An issue here is that every transfusion-dependent patient is
given a thalassemia ID in the thalassemia centers here, and they may
have something other than thalassemia. This is important as
management differs and hence a careful clinical evaluation of the
patient and parents is needed, e.g., they both have to at least be
carriers for the child to have beta thalassemia.
 Genetics of  thalassemia
• There is one β globin gene on each chromosome 11 in human genome.
• This form of thalassemia is mostly caused by point mutations
involving various points in and around the beta globin gene.
• The inheritance of this disorder is autosomal recessive, so that
heterozygous are usually symptomless, while homozygotes are
severely or moderately affected.
Clinically β thalassemia could be classified
into:
• β Thalassemia Major: Severe clinical manifestations presenting
before the age of 2 years, usually transfusion dependent. Due usually
to homozygosity to β thalassemic gene defect.
• β Thalassemia minor (note: carriers): Mild or no clinical
manifestations, usually does not require specific management. Due
usually to heterozygosity to β thalassemia gene defect.
• β Thalassemia Intermedia: Moderate manifestations, intermediate
between major and minor.
  Defective  gene
Chr 11 Normal Normal  gene
 beta genes
Chr 11


Chr 11 Heterozygous to
 beta thalassaemia
Thalassamia
Chr 11 genetic defect Minor


Chr 11 Homozygous to Thalassamia
 beta thalassaemia
Major
Chr 11 genetic defect
β Thalassaemia Major
 Pathophysiology of β thalassemia major
  chains
Hb A tetramer (2 β2)
gene
(normal) β chains
β gene Hypochromic
(defect)
RBC
Excess  chains in RBC precurors
Compensatory mechanisms
Disturb RBC metabolism &  Chains
toxic to RBC membranes (Hb F,22) Erythoid hyperplasia*

Red cell damage Chains Extramedullary

Destroyed erythropoiesis
Leave marrow in marrow (HbA2, 22)
Hepato-
And destroyed in RES
splenomegaly
* note: causing skeletal abnormalities
Clinical features of β thalassaemia Major

• First diagnosis between age of 6 months and 2 years (note: beta

thalassemia does not cause neonatal jaundice; the pure beta
thalassemias do not manifest themselves in the newborn period[1])
• Presentation usually with Pallor, poor feeding, failure to thrive,
abdominal swelling (due to hepato-splenomegaly) and sometimes
Jaundice.
Later clinical picture depends on management, and falls into two
categories:
A. Clinical picture in Inadequately transfused patients.
B. Clinical picture in well transfused patients.
If thal. Major in infants is not adequately
transfused:
• Growth retardation.
• Progressive Splenomegaly (sometime hypersplenism).
• Deformities in the skull due to bone marrow expansion (Bossing, and
mongoloid facies; hair- on-end appearance on skull X-ray). There are
also dental problems and inadequate drainage of sinuses and middle
ear, leading to chronic sinusitis and deafness
• Increased frequency of infections.
• Note: untreated, death occurs within the first few years of life because
of progressive congestive heart failure.
• Note: the goal of transfusions is to correct anemia and suppress the
abnormal erythroid hyperplasia[1] (Dr. Ahmad: One goal of transfusion
is to prevent erythroid hyperplasia, so they’re over-transfused to
suppress the bone marrow’s production of the abnormal and useless
cells)
Clinical features – thal. major
Note: Under-transfused child.
 Bossing of the skull- thal. major

Facial Skeletal
Changes
Hair-on-end sign on skull X ray in thal. major

Widening of Diploic
space – Skull
Hepatosplenomegaly in thal major
If Thal. Major Child is well transfused:

• Early childhood development is normal

• Splenomegaly will be minimal or limited.
• Skeletal bone deformities are averted.
• However, with frequent transfusions, gradual Iron accumulation
starts to be symptomatic at ~ 10 years. Adolescent growth spurt fails
to occur (leading to short stature), and a variety of complications
related to iron deposition and damage in organs like liver, heart and
endocrine glands occur, including diabetes, hypoparathyroidism,
adrenal insufficiency, progressive liver failure, and heart failure.
• Secondary sexual development is delayed or fails.
Prognosis in thal major

• If no Transfusions, death usually occurs in the first few years of life

(note: due to anemia-induced heart failure)
• If iron overload is allowed to occur then death in 2nd or early third
decade, most commonly due to progressive cardiac damage due to
iron deposition, with heart failure or arrythmias (note: due to iron
deposition in the myocardium[1]), often precipitated by infections.
• However, if measures to prevent Iron overload by Iron Chelation are
instituted early on with the transfusion, Iron overload consequences
may be limited, although delayed puberty and stunted growth may
still be encountered, but otherwise patients may develop normally.
 Blood Picture in  Thalassemia major

• Hemoglobin is usually 3-7 g/dl.

• PCV is evidently reduced.
• MCV and MCH are both reduced.
• Leucocytes: May be normal or increased.
• Platelets: may be normal or increased.
• Reticulocytes: usually range 2-8%.
 Blood film in Thalassaemia major

Nucleated red cell

Hypochromic , aniso-cytosis, poikilocytosis, target cells

 Blood film in Thalassaemia major

Hypochromic , aniso-cytosis, poikilocytosis, target cells, tear

drop cell, microcytes
 Blood film in Thalassaemia major

Hypochromic, microcytic, target cells, and NRC

Hb electrophoresis in β thal major

• Depends on the molecular defect responsible for the thalassemia.

• Hb F is increased from 10-98%, Hb A may or may not be present, Hb
A2 variable.
• Remember that on birth Hb F is the major Hb, and it goes down to
<1% at the age of 6 months, therefore a definitive diagnosis is best
achieved > 6 months.
• Note: The child may need transfusion earlier than 6 months in which
case electrophoresis becomes unreliable and molecular analysis is
needed for diagnosis (?? Dr. Ahmad)
• Note: Unlike hemophilia, where the disease may be due to a
spontaneous mutation with no family history, a mutation must be
inherited and a positive family history or carrier parents must be
present [Dr. Ahmad]. The parents of a patient with thalassemia major
usually have thalassemia minor.
 Management of Thalassaemia major:

• Adequate Transfusion with Iron chelation.

-Maintain Hb 10-12 g/dl.
-Use of iron chelators .
• Folate supplements.
• (note: Allogenic) Bone marrow
transplantation (note: curative)
 IRON CHELATION

• Deferoxamine parentral
• Deferasirox chowable
• Deferiprone oral tab.
 Clinical Features of  thalassaemia minor:

• Usually, symptom free and discovered by chance.

• Some patients have tiredness, slight pallor.
• Mild Splenomegaly is sometimes encountered.
• In periods of stress, especially pregnancy, the patients may become
symptomatic because of aggravation of mild anemia.
  Thalassaemia Minor

• Due to heterozygosity to a  thal defect.


Heterozygous to Mildly
 beta thalassemia reduced
genetic defect
overall Beta
Chain
production
 Blood Picture of thal. minor

• Hemoglobin is usually reduced 1-2 g/dl less

than normal for age and sex.
• MCH and MCV are reduced.
• RBC count is > 5 x 1012/L in 85% of cases.
• Reticulocyte count is slightly increased or
normal.
• Blood film: slight hypochromia, anisocytosis,
poikilocytosis, microcytosis, tear drop cells
and target cells.
Blood Film in thal minor
Note: The cells are more uniform (In
the setting of microcytic anemia,
increased RDW suggests iron deficiency
anemia rather than thalassemia trait,
which typically has more uniform cell
sizes.)

Normal blood film

Thalassemia minor
Diagnostic tests in β thal minor:

• Increase in HbA2: Normal range of Hb A2 is 1.8-

3.5%; in Beta thalassemia minor, it is increased to
4-7% .
• Increased HbA2 is considered diagnostic of Beta
thalassemia minor.
• S. Transferrin saturation (S. Iron/TIBC) is usually
normal or upper normal.
Note: HBA2, beta thalassemia minor and iron
deficiency
• Iron deficiency modulates the synthesis of HbA2, resulting in reduced
HbA2 levels in patients with iron deficiency anemia.
• The diagnosis heterozygous beta-thalassemia is based on a raised
HbA2 level.
• Patients with beta-thalassemia and concomitant iron deficiency can
show normal HbA2 levels; the iron deficiency suppresses the level of
HbA2 to normal levels, thereby masking the underlying beta
thalassemia minor.
• Dr. Ahmad: a normal level of HbA2 in the face of iron deficiency
doesn't exclude beta thal minor. Iron status should be checked, and if
there is iron deficiency, it should be corrected before checking HbA2.
Management of β thal minor:

• No need for specific management (note: they can

live normally)
• Except in periods of stress like pregnancy, where
anemia becomes moderate, and transfusion may be
needed.
• Note: In pregnant women, you have to check the status
of the mother and the baby; even if the mother is
normal but the baby’s growth is restricted, you have to
correct the anemia (?? Dr. Ahmad)
β thalassemia Intermedia

• Intermediate clinical and Laboratory findings between Major and

minor.
• Usually diagnosed after the age of 2 years.
• May not require transfusion, or may require less frequent
transfusions than major (note: more frequently than minor)
• Note: liable to the complications like thalassemia major, including
gallstones, extramedullary hemopoiesis, leg ulcers, thromboembolic
events, and pulmonary hypertension, which is a major cause of heart
failure in these patients.
• Management depends on severity, but iron chelation therapy is
usually recommended.
Luspatercept

• Recombinant fusion protein

containing a modified
extracellular domain of ActRIIB
• Binds to GDF11 and other TGF-β
superfamily ligands, inhibits
Smad2/3 signaling, and promotes
RBC differentiation and
maturation
• Early data:
• Animal studies
• Phase I study of healthy human
volunteers
• Phase II trial in NTDT and TDT β-
thalassemia showed improved Hb
Levels and reduced transfusion
burden
SO HOW TO PREVENT THIS FATAL
DISEASE?

Premarital screening Program

Aim of premarital screening

• Aim is to detect thalassaemia

carrier state in the couple before
they get married, to identify
couples at risk and then counsel
them accordingly.
 Main outline of the Program

oWe screen using red cell indices both partners to

be married, before marriage.

oIf there is hypochromia or microcytosis, as

anticipated in thal minor

oWe do Hb A2 testing to determine if it is due to

thal minor

oIf both partners were thal minor then they are

at risk if the get married to have a thalassaemia
major child.
 IF BOTH PARTNERS ARE CARRIERS
(THAL MINOR)

• 25% (1/4) are Homozygous (Thal Major)

• 25% (1/4) are normal
• 50% are carriers (thal Minor)
 The use of Premarital screening
What are the couple’s Options?
** OPTION A :
- Either the couple will decide not to get married
and find another partner. (???)
-In Iran : 37 % did not proceed with the
wedding, but the majority proceeded with the
marriage.
- In Bahrain : ~ 50% separated.
-In Cyprus : only 2% decided to separate, 98%
proceeded with marriage.

- Dilemmas and complexities (Planned marriages!!!)

OPTION B

• Proceed to get married and then

decide to have no children
(unrealistic), or limit the number of
children to 2 only, and in this
situation 56% of such marriages will
not have an affected child.
OPTION C

• Proceed to get married and then do

prenatal DNA diagnosis early in
each pregnancy, and if the child is
affected then proceed to
therapeutic abortion.
 Opinion of Religion on abortion following
confirmatory prenatal diagnosis
• Fatwas in Pakistan have confirmed while selective
abortion for major defects in fetus could be
undertaken before 120 days (before
ensoulment), but not after that.
• Fatwas in Iran, confirmed that first trimester
abortion for serious disorders in fetus are
religiously acceptable.
• Most Christian religious sects approve of
selective abortion if the fetus is found to be
seriously defective (like in thalassaemia).
 The bottom line

• We have to do everything in our power to

prevent the misery of parents and children with
major hemoglobinopathy.

• A successful Preventive program will save

resources, will help direct such resources to
better care of already diagnosed cases and to
other health problems.
ERBIL Thal. Preventive Plan

Perform Hbpathy screening as premarital checkup

Identify couples at risk

Proceed with marriage

Separate
Prenatal Dx Have limited Family
 The Message

SHARE THE KNOWLEDGE

ABOUT PREVENTION OF
THALASSAEMIA
 Note: Alpha
thalassemia

Note: 4 gene deletion

 Hb Bart syndrome,
causes intrauterine
death or death just
after birth without
transfusion

(minor)