Thalassemia

(Cooley´s Anemia)

INSMC Alessandrescu Rusescu

Mirela Covacescu
Definition:

• Thalassemia syndrome is an inherited anemia

characterized by decrease of the normal hemoglobin
production. This decrease is determined by partial or
complete blockage of one of the polypeptide chains of
globins synthesis.

•  (alfa thalassemia)
•  (beta thalassemia= Cooley‘s anemia)

• AR transmission
• Globins: has
• 2  chains  their synthesis is codified by
4 genes located on the 16th chromosome

• 2 non- chains  chromosome 11

(2 genes)
• During intra-uterine life
• Hb G (before 3 months) 22
• Hb F (between 3 months – birth) 22

• At birth = HbF 1 year (~adult):

• HbA1 (22) 97%
• HbA2 (22) 3-3,5%
- thalassemia
↓↓
 Chains synthesis disorder  + thalassemia (partial blockage)
º thalassemia (complete blockage)
↓↓
Unaffected chains are normally synthesized
↓↓
Internal cellular precipitation of  chains, in excess, partially
compensated by  chains who is in insufficient quantity, and by non-
chains:
  HbF in their homozygote form
( HbA2 in their heterozygote form)
↓↓
↓↓
Hemolysis: Intra-medullar (inefficient erythropoiesis)
Extra-vascular (increased size of the spleen)
↓↓
Anemia  hypoxia  erythroid hyperplasia in bone marrow
 ectopic erythropoiesis in the bones
• Heterozygote form: (minor thalassemia)
•  ↑ HbA2 and/ or moderate of Hb F

 Beta thalassemia trait

– Patients have:
mild anemia
abnormal red cell indices, and
abnormal Hb electrophoresis with elevation of Hb A2,
Hb F, or both;
Menzer index < 13
- Peripheral blood examination usually reveals marked
hypochromia and microcytosis, target cells;
reduced clinical manifestations

 Silent carrier beta thalassemia

– Hb= N, without clinical manifestations;
- except for possible low RBC indices.
• Homozygote form

• Hb A1 ↓/ absent according to + or º
•  Thalassemia :
 Thalassemia intermedia:
– moderate anemia, clinically moderated
 Major thalassemia
– severe anemia, clinically sever

• More than one thousand inherited mutations that affect

either the structure or synthesis of the alpha and beta
globin chains are known to date.
• Beta thalassemia is much more common in
Mediterranean countries such as:
• Greece, Italy, and Spain, Many Mediterranean islands,
including Cyprus, Sardinia, and Malta

• Beta thalassemia is also common in North Africa, the

Middle East, India, and Eastern Europe
MAJOR THALASSEMIA
Clinical Manifestations:

Onset:
• before 6 months old:

• Progressive pallor of the mucous and skin (progressive

and continuous hemolysis)
• Anorexia
• Failure to thrive
• Conjunctive jaundice
• Increase of liver and spleen
Characteristic clinical picture – over 1 year old:

• General aspect:
• Grace, hypotrophy, thin limbs (muscular hypotrophy)
• Highly increased abdomen (increase of liver and
spleen)
• Brown skin (hemocromatosis)
 Special characteristics of the face:
(hyperplasic compensated bone marrow)

• Tall cranium (turiform)

• Frontal bossing, prominent
facial bones
• Hypertrophy of the superior
jaw
• Dental malocclusion
• Dentition bad implanted
• Enlarged nose base
• +/- Mongolian slit
• Permanent conjunctive
jaundice
• Ogival arch
• Look “like brothers”
• Growth is severe affected
• Hypotrophy, hypotonic muscles
• Puberty signs appeared very late
• Nervous and psychic development influenced (chronic
anemia hypoxia)
• Important hepatosplenomegaly (HSM)  “tumor” spleen
with or without manifestations of hematological
secondary hyperspleenism
• Cardiac disorders:
- tachycardia (according with the degree of
anemia)
- cardiomegaly
- cardiac failure (Hb<5g%)
Laboratory findings:

• Hypochromic microcitary hypersideremic anemia

• Regenerative (reticulocyte- only a little increase

because of intramedullar hemolysis)

• Hb  (severe progressive anemia ~ 5-8 g%)

• MCV  
• MCH  
• Characteristic blood
smear:
• marked hypochromia
with ”target RBC”
• Marked poikilocitosis
• Lots of erythroblasts
Lots of erythroblasts
• Iron deficiency anemia

• Major Thalassemia
Hemolysis:

• High levels of indirect bilirubin (unconjugated)

•  iron
• Reticulocytes ~ 2-8 % (inefficient erythropoiesis)
(normal value 1-2%)
• ferritin 
• Bone marrow exam: Erythroid hyperplasia
+/- megaloblasts; Granulocyte segmented - in
the periphery blood

• Diagnose is based on Hb electrophoresis

Hb F  (30-60%) homozygote form
(Major Thalassemia)
Hb A2  (>3,5 %) heterozygote form
Cranium radiography shows the big thickness of diploe
and radial spicules like “hairbrush cranium”
Long bones radiography shows the thinned
cortical and a widen medullar channel
 Chest XRay- cardiomegaly

Cardiac ultrasound and EKG show secondary cardiac myopathy with rhythm disorders.
Positive Diagnosis:

• Positive family history

• Clinically characteristic
• Chronic hyper-sideremic anemia
• Hb Electrophoresis
• +/- genetic test
 Complications: frequent, early complications

• Chronic hypoxic anemia is determining dwarfism and late

puberty

• Haemochromatosis (Iron overload)

• Hepatic  hepatic cirrhosis, hepatic failure
• Pancreatic  diabetes mellitus
• Cardiac  cardiomegaly, cardiac failure, arrhythmia
• Thyroid, suprarenal, hypophysis  insufficient endocrines
• Thalasemy miopathy

ferritin levels are used to evaluate iron status and

indicate the need to start chelation.
Complications (2)

• Megaloblastic secondary anemia

• gallstones ; trophy disorders (shank’s ulcers)
• Hyperspleenism or abdominal compression
phenomenon

• Izo-immunization (allo-antibodies)

• CMV (HIV, Hepatitis C, B)

Treatment:
• !!!! It is necessary to get a genetic advice and a prenatal
diagnosis
A.Commune Methods
• Blood Transfusions
• Chelation therapy
• Vitamins-therapy
• Spleen resection
B. Exceptional Methods – medullar transplant
C. Perspective Methods
• Genetic Engineering
• Pharmacological manipulation of Hb F sintesis
A. Commune Methods

I. Transfusions - Substitution treatment – repeated

transfusions iso-group Rh

• Hyper-transfusion regimen for Hb > 9,5-10 g/dl

• Clinical benefits (N growth,  HSM,

cardiomegaly decrease, bone changes diminish,
etc)

• Through the anemia improvement the intestinal

absorption of Fe is decreasing
• ~ We are administering 10-15 ml/Kg/ transfusion izo-
group izoRh

• Repeated every 4 to 6 weeks (according with the Hb)

• In case of cardiac failure or severe anemia - is given ~ 5

-10 ml/Kg for one administration and it is repeated

• Administration rhythm varies from case to case

• It is preferred to use dosage under 250 ml/Kg/year =

transfusion’s value (hemolytic index)

• Avoiding abuse of transfusions (iso-immunization,

CMV…..risk)
 II. Chelation therapy
• In thalassemia iron is raising because of:
• Raised intestinal absorption
• Resulted Fe from hemolysis
• Fe brought by blood components
(1 ml of Packed RBC brings ~ 1 mg Fe)

 Chelation treatment starts around the age of 5 years (some kids

get it before the age of 3 years old) usually in the same time with
transfusions

• Deferoxamine (desferal) 30- 40 mg/Kg sc, im;

It is preferred to administer using subcutaneous way; is infused

over 8-12 hours during the child's sleep for 5 days/week by a
mechanical pump, in such way that the ferritin to be less then
1000 ng/ml.

• Oral administration-new drug: EXJADE= deferasirox - daily;

20-30 mg/kg/day
III. Vitamins therapy

1. Ascorbic acid

• Dosage = 3- 5 mg/Kg/day (max 200 mg/day) in the

same days with Desferal administration – it is
mobilizing Ferrum from deposits and increase the
renal elimination

• Administration of vitamin C increases the urinary

excretion of iron. This is probably related to the fact
that vitamin C slows down the conversion of ferritin to
hemosiderin, leading to the availability of more
chelatable iron.
2. Folic acid
• = folic acid consume because of medullar hyper-
regeneration
• Dosage: 2-5 mg/day; 10- 15 days/ month
• This deficiency is a common complication in
patients with thalassemia

3. Vitamin E
• Dosage = 100-200 mg/day
• As an antioxidant, vitamin E is expected to
decrease cell toxicity (protects membrane’s lipids of
the free radicals formed in the presence of Fe excess
attack).
• + Vitamin B6, A, D
 IV. Splenectomy

• Indication:
• Huge compressive splenomegaly
• Hypersplenism
• Transfusion value > 250 ml/Kg/year
(hemolytic index)

• Determines the decreases of the need for

transfusion
• Postsplenectomy -risk of infections with encapsulated
organisms. The problem is minimal at the present time,
since presplenectomy immunizations or postsurgical
prophylactic antibiotics have decreased the rates of such
complications significantly.

• Aggressive treatment with antibiotics should always be

administered for any febrile illness while awaiting the results
of cultures.

• Traditionally, the splenectomy is delayed whenever possible

until the child is aged 4-5 years or older.
 B. Exceptional methods
Allogenic medullar transplant
• Hematopoietic stem cell transplantation

• Identical donator of HLA, unaffected; difficult to find

• We have better results (80%) if we perform it:

• During the first years of life- children without prior
transfusions / with a few prior transfusions
• Without cardiac lesions (haemochromatosis)

• Big % of unsuccessful interventions related to:

• Transplant preparation
• Graft rejection - The disease graft against host
appears
• Thalassemia has been cured using bone marrow
transplants.

• This form of treatment is possible only for a small

minority of patients who have a suitable bone marrow
donor, and the transplant procedure is still risky and
can result in death.
 C. Perspective methods
I. Genetic therapy
• Inside the sick genome - insert a normal gene
responsible of Hb synthesis. This therapy is a very
attractive therapeutic modality, the efficacy of which
remains to be demonstrated.

II. Pharmacological manipulation of Hb synthesis

Investigational agents known to increase Hb level
• Research – Agents combinations (EPO + hydroxy
ureea) can raise the Hb production with the
improvement of RBC production

Immediate prognostic is depending on complications

appearance.
Late prognostic is death during the 2nd to the 3rd decade
of life.- better prognosis with the latest chelating
treatment (EXJADE)
Hereditary spherocytosis
(Minkowski-Chauffard disease)
Definition:
• This is the most frequent hemolytic anemia occurred to a
babies.

• Hereditary family abnormality of RBC membrane

• Transmission is autosomal dominant (in 75% of cases) one of

the parents having the diseases (possible without symptoms)

• 25% cases – without family history - suggesting:

• Variable penetration
• Novo mutation
• Autosomal recessive
 Pathogenesis:

• Membrane RBC – is
formed of 2 layers:
• Lipid superficial (FL,
cholesterol)
• Protein – forming
cellular skeleton

• Joined together by proteins

• All of these ensure the cell
form, the elasticity and its
deformability.
 Membranes lesions:
1. Membrane’s protein
alteration

• Spectrin deficiency
defects that decrease
the elasticity of
membrane
and
• Ankyrin deficiency that
decrease the surface of
the membrane

• Lower cellular surface
2. Functional disorder accompanied
by increased permeability for sodium
and water

• Perturbation of membrane’s exchanges (alteration of

Na-ATP pump) determining high penetration of Na in
RBC (Na >> H2O)  small degree of cellular dehydration
accompanied by ↑ concentration of Hb (MCHC ↑)

• ions membrane’s pumps are overwork (with high

consume of ATP due to the burn of glucoses) 
microspherocyte are more dependable of glucoses from
the environment then the normal erythrocytes.
3. Membrane’s lipids
damage

↓ of the membrane’s
surface

 lipid microvesicles
are lost from the
membrane’s surface
with or without protein
molecules
 this contributes to
the bigger decrease of
the membrane’s
surface
• Coming out of the bone marrow→
RBC have normal form
↓
• They get into the blood stream
↓
• Then in the spleen  they become
microspherocyte
because of:
• Slow circulation
• Plasma is passing to fast
• Is created a high concentration of
RBC

• A severe metabolic impasse occurs
(microspherocyte are more
dependable of glucoses from the
environment )

• The spherical process of the RBC is
determined
• Spleen macrophages:

- Complet and destructive phagocytosis

or
- Limited phagocytosis with membrane lesions

• New passing through the spleen

• Destruction (↑↑metabolic impasse)
• Hyperplasic process of the monocyte-macrophages
system from the spleen
 determines
SPLEENOMEGALY (hemolytic site )
 Clinical manifestations (1):

Age of the onset– variable:

• Newborn – the first hemolytic crisis occurs

• Jaundice 
• Indirect bilirubin (BI) 
• Anemia
• Splenomegaly (SM)
 Clinical manifestations (2):
• Toddler, child:
• No-symptoms until adult
age

• Insidious onset with:

• Pallor
• Jaundice
• Asthenia
• SM (splenomegaly)

• Acute onset– frequent

acute hemolytic crisis:
• Fever
• Jaundice with BI
• Splenomegaly
• Abdominal pain
Evolution:
Commune form:
• Mild compensated hemolysis (20-30%)
• low jaundice
• Mild splenomegaly (SM)
• No anemia
diagnose is accidentally (using the blood smear aspect!)

• De-compensated hemolysis (mild  moderate)(60-70%)

• Mild anemia to moderate
• Jaundice
• SM moderate

Severe form (3-5%)- – evolution with severe anemia from

birth, transfusions dependant
Prognosis – aggravated by occurred complications:

1. Megaloblastic crisis

• Appear because of high levels of folic acid

consume (because of medullar hyper-
regeneration)

• Anemia is accentuated and is hyporegenerative

• In the peripheral blood there are macrocytes,

hypersegmented granulocyte
• In the bone marrow appears megaloblasts.
2. Acute hemolytic crisis

• Typically
• Usually installed after infections
• Brutal onset with high fever
• Jaundice, hyper-chromic urines
• SM (splenomegaly)
• Pallor (severe anemia)  cardiac
insufficiency
• Abdominal pain

•  Hb,  RBC, Retic.  , BI , Hb in urine;

• BM – eryithroid hiperplasy
3. Hypo or aplastic crisis (OWREN-GASSER)

• Frequently determined by parvovirus B19

• Sometimes follows after a severe hemolytic crisis
• Medullar transitory aplasia is produced
• Sudden intense pallor appears without jaundice
installation or SM

• Severe anemia  IC, hypoxia, collapse, vital risk

• Leucopenia, Thrombocytopenia, Reticulocytopenia
• MO- important erythroblastopenia
• Self limited evolution in ~ 10 days
4. Gallstones
• It is showed by the bilirubin precipitation inside the
biliary canal
• Risk is increasing with the age

5. Others
• Growth disorders
• Late puberty
• Transfusion’s complications
 Laboratory findings:
= Microcitary normochromic regenerative anemia
•  Hb (6-10 g%);  RBC; WBC and Plt are normal (excepting
a-plastic crisis)
•  Reticulocytes (higher value more than thalassemia)
• MCH; MCHC ; MCV

• !! The smear: is characteristic and makes the diagnosis in

over 60% of the cases (hematology doctor with experience)
• microspherocytes > 20-50%
• macrocytes polychromatophily= reticulocyte
• bone marrow aspirate (rarely is necessary ) shows erithroid
hyperplasia
• suggestive elements for hemolysis:
• BI 
• Iron 
•  urobilinogen in urine
Normal blood smear Spherocytosis
• Diagnosis: osmotic resistance determination is low
• Normally hemolysis begins at 4,5‰ and it is total at
3,5 ‰
• Spherocytosis – begins at 8 ‰ and it is total at 4 ‰

• Autohemolysis test – is determining the osmotic

resistance after incubation of 24h, 37º C simple or with
glucoses supplement.

• Scintigraphy with Cr 51, Fe 59 – for determining the

place of hemolysis (accessory spleen identification)
Treatment:
1. Folic acid for supporting erythropoiesis and
avoiding megaloblastic crises
Dosage: 2- 5 mg/day, 10-14 days/ month

2. Acute crisis treatment (hemolytic or aplastic)

Transfusions with packed RBC or izo-group
blood izo Rh for increasing Hb +/- low level of
Platelets, Neutropenia
3. Elective- Spleenectomy (Hemolysis site) +
accessory spleens

• After the age of 5 - 6 years

(contraindicated < 3 years)

• Indications for spleen resection are:

• Frequent hemolytic crisis
• Frequent aplastic crisis
• Un-satisfactory hematological
rehabilitation after transfusions
• After spleen resection:
• Clinical and biological manifestations are ameliorating
(decrease of RBC destruction)
• There is an infection risk, with severe evolution (greater with
the child being younger):

SREPTOCOCCUS PNEUMONIAE, NEISSERIA

MENINGITIS,
STAFILOCOCCUS, STREPTOCOCCUS,
HAEMOPHILUS INFLUENZAE etc,

• !! It is necessary to have an anti-pneumococcal vaccination, as

well as an anti-meningococcal and anti-haemophilus before
spleen resection or to create a prophylaxy using V Penicillin 1 tb
× 2 /day; Amoxicillin 20 mg / Kg /day; Cotrimoxazole 4 mg/
kg/day + powerful
• treatment for any febrile illness while awaiting the results of
cultures!!
 Partial splenectomy - may be useful in
children under 5 years

 Increase the Hb level while maintaining
splenic phagocytic function and immune
function
 Glucose-6-phosphate dehydrogenase (G6PD)
deficiency

• is an X-linked recessive
hereditary disease

• characterised by abnormally
low levels of glucose-6-
phosphate dehydrogenase
(G6PD), a metabolic enzyme
involved in the pentose
phosphate pathway,
especially important in red
blood cell metabolism.
 Glucose-6-phosphate dehydrogenase (G6PD)
deficiency

• symptomatic patients are almost exclusively male

(or girl homosigote)

• pacients with the disease may exhibit nonimmune

hemolytic anemia in response to a number of
causes, most commonly exposure to certain
medications or chemicals

• Some deseases (infections, diabetic acidosis,

hepatitis) can precipitate the hemolysis in those
with G6PD deficiency
 Agents precipitating hemolysis in G6PD
deficiency
• Antibacterials: • Others:
• Sulfonamides (including co- • Vitamin K analogs
trimoxazole) • Methylene blue
• Quinolone • Probenecid
• Chloramphenicol • Acetylsalicylic acid
• Nitrofurantoin

• Chemicals:
• Antimalarials: • Benzene
• Primaquine/ Pamaquine • Naphtalene
• Cloroquine/ Quinacrine
Clinical manifestations = acute hemolysis:
• Jaundice
• Pallor (anemia)
• Transient splenomegaly
• Hemoglobinuria
• Abdominal pain

Lab exam:

• The same like other hemolytic anemias

• enzyme activity of G6PD= is definitive test

 Management

• Avoidance of substances that may precipitate

haemolysis is essential.

• Management of acute haemolysis:

• Blood transfusions may be needed
• Dialysis may be required in acute renal failure
• Nelson Textbook of Pediatrics 21th edition
• Esentialul in Pediatrie- Carmen Ciofu, Prof Eugen Ciofu
• Nathan and Oski’s Hematology of infancy and childhood