THALASSEMIAS

Dr. Philip Peprah

 OUTLINE

• Definitions/Epidemiology
• Pathophysiology and Classification
• Clinical Presentation and Management
• Prognosis
• Summary
• Case Presentation
 CASE SCENARIO
• 8-year-old female with no significant medical history presented with a 5-day history of fever and
LUQ abdominal pain, cola-like urine and jaundice.
• Sickling positive- AS
HB (g/dL) 6.5 11.5- 15 Electrophoresis
RBC(x 106/uL) 4.23 3.85-5.20
HCT (%) 19 34.5-46.5 HbA-48% (>96%),
MCV (fL) 58.8 79-95 HbS-26.8% (0.0%),
MCH (pg) 22.2 26-32 Hb F-24.0% (<2%)
WBC (x 103/uL) 14.7 4- 11 HbA2–1.2% (<3.3%)
Retic (%) 7.5% 0.5-2.5
 Definitions

• Thalassemia is a spectrum of inherited hemoglobinopathies in

which impaired production of one type of globin chain causes an
imbalance in the ratio between alpha and beta chains, which is
normally tightly controlled. (Uptodate)
 Definitions
• Beta thalassemia —caused mutations in the beta globin gene that lead to
impaired production of beta globin chains and an excess of alpha or alpha-
type chains.

• Alpha thalassemia — caused by mutations in the hemoglobin alpha globin

gene that lead to impaired production of alpha globin chains and results
in a relative excess of beta and beta-like chains.
 Epidemiology

• There are >200 different mutations resulting in absent or

decreased globin production.

• The 20 most common abnormal alleles constitute 80% of the k

nown thalassemias worldwide

• 3% of the world's population carries alleles for β-thalassemia,

• Southeast Asia 5–10% of the population carry alleles for
α-thalassemia.
• Alpha thalassemia- Southern
China, Malaysia, and Thailand.

• Mild forms in individuals of

African origin.

•Beta thalassemia –present in

Africa; est. rate of heterozygosity
of approximately 1%
INHERITANCE

Beta Thalassemia
INHERITANCE

Alpha Thalassemia
Haemoglobin Genes and Structure
• Gower-1 (ζ2 ε2 )
• Gower-2 (α2 ε2 )
• Portland (ζ2 γ2 )
• HbF (α2 γ2 ) <2.5%
• HbA (α2 β2 ) ≥95%
• HbA2 (α2 δ2 ) ≤3.5

• α-globin synthesis- 5th to 6th week

• β-globin synthesis-35th to 38th week
abruptly increases after birth
 Haemoglobin Genes and Structure
• Hemoglobin is a tetramer consisting of 2 pairs of globin chains
• Two hemoglobin (Hb) gene clusters are located at the end of the short arms of
chromosomes 16 and 11

 Chromosome 16- 3 genes within the alpha gene cluster (zeta (ζ), alpha 1 (α1 ),
and alpha 2 (α2 ).

 Each Individual therefore has 2 pairs of alpha globin chains

 Chromosome 11- 5 genes within the beta gene cluster; epsilon (ε), gamma 1 (γ)
gamma 2 (γ2 ), delta (δ), and beta (β).
• HbBart (γ4)

• HbH (β4 )

• α-
globin(α4 )
 Classification
• β0 –thalassemia-absence of production of the β-globin.

• β+ -thalassemia-mutation that makes decreased amounts of normal β-globin(HbA).

• β-Thalassemia Major- β0/β0 (Transfusion-Dependent Thalassemia/Cooley’s Anemia)- r

efers to severe β- thalassemia that requires early transfusion therapy.

 Hemoglobin E(β+ )/β0 thalassemia, is by far the most common severe form of β thalassemia i
n Asia and, globally, comprises approximately 50% of the clinically severe β-thalassemia
 Classification

• β-Thalassemia Intermedia, β + /β+ ; β 0 /β+ -(Non–Transfusion Dependent / T

ransfusion-Dependent Thalassemia)- less severe clinical phenotype; does n
ot require regular transfusion therapy in childhood.

• β-thalassemia Minor, β/ β +, β /β0

Usually asymptomatic
Classification
 Classification
α0 –thalassemia no α-chains produced from that chromosome (− −/)
α+ -thalassemia produces a decreased amount of α-globin chain from that chromosome.
 Alpha + Beta

 Alpha and beta thalassemia – Individuals with coinheritance of

homozygous beta+ thalassemia (b+/b+) and alpha thalassemia (-a/-a,
--/aa, -a/aa, or --/aa) present with intermediate clinical severity.

 The concomitant reduction of both alpha and beta chains reduces the d
egree of imbalance relative to what would occur if only one or the ot
her type of chain was affected.
 Clinical Presentation

History
 Age-
• Alpha Thalassemia- in utero/ from birth
• Beta Thalassemia – from 6 months, intermedia-2-4yrs
 Anemia- easy fatigue, palpitations, dyspnea
 Poor appetite, Poor growth, Failure to thrive
 Hx of hemotransfusions
 Family Hx
 `

*Credit: McMaster Pathophysiology Review

 CLINICAL PRESENTATION

FEATURES
OF
HEMOLYSIS
 Pallor
 Jaundice
 Hyperuricaemia (Gout)
 Gallstones
 CLINICAL PRESENTATION
Excessive Erythropoeisis and Bone Marrow Expansion

Thalassemia Facies
• Frontal bossing
• Flat nasal bridge
• Maxilla hyperplasia, prominent malar
eminence
• Inadequate Lip Seal, Dental malocclusion

 ‘Chipmunk Facies’
 CLINICAL PRESENTATION
EXCESSIVE ERYTHROPOEISIS

BONE CHANGES EXTRAMEDULARY ERYTHROPOEISIS

 Medullary expansion – cortical thinning, risk of  Hepatomegaly

pathological fracture  Splenomegaly

 Bone pain, backache

 Vertebral expansion lead to spinal cord

compression – neurological manifestations
 CLINICAL PRESENTATION
IRON OVERLOAD

ENDOCRINE FAILURE HEPATIC INVOLVEMENT

 Short stature  Cirrhosis

 Delayed puberty  Hepatic fibrosis
 Estrogen / testosterone
deficiency
 Diabetes mellitus
 Hypoparathyroidism
 Hypothyroidism
 CLINICAL PRESENTATION
IRON OVERLOAD

Cardiac Involvement Hypercoaguable Disease

 Arrhythmia  Deep vein thrombosis

 Cardiomyopathy  Pulmonary embolism
 Pericarditis
 CCF

Dermatological

Leg Ulcers
 Clinical Outcomes of Alpha Thalassemia

Silent Carrier (αα/α-)

 Asymptomatic

Alpha-Thalassemia Minor (αα/- - ) or (α -/α-)

 No anemia
 Microcytosis

Alpha Intermedia- Hb H Disease (α -/- -)

 Anemia and microcytosis
 Bone deformities
 Splenomegaly
 Clinical Outcomes of Alpha Thalassemia

Hb Constant Spring (ααcs/- -)

 Similar to HbH but no microcytosis
 Anemia
 Growth delay

Alpha Thalassemia Major (- - /- -)

 Hemoglobin Bart’s
 Fatal hydrops fetalis
 Investigations
• Hemoglobin Analysis- High performance •Peripheral Film Comment
Liquid Chromatography/ HB Electrophoresis • Hypochromia
• HBH, Hb Barts- alpha thalassemia • Anisopoikilocytosis
• Relatively High HbF and HbA2 • Target cells, teardrop cells, schistocytes
• RBC inclusions
• HbA Variable

•DNA Analysis
• Full Blood Count-
• Microcytic, hypochromic anemia (Low MCV,
MCH)
• High RBC count, Inappropriately low Retic Count
• Mentzer Index <13 (MCV/RBC Count)
 HPLC
BETA THALASSEMIA
CLINICAL FEATURES LABORATORY FEATURES

 Anemia  Hb: < 7 g/dL

THALASSEMIA  Hepatosplenomegaly  HbF : > 90%
MAJOR  Growth failure  HbA2: normal or high
 HbA : usually absent
 Milder anemia  Hb: < 8-10 g/dL
THALASSEMIA  Thalassemia facies  HbF : > 10%
INTERMEDIA  Hepatosplenomegaly  HbA2: 4-9%, if > 10% suggests HbE
 HbA : 5-90%
 Hb : < 10 g/dL
 MCH : < 27 pg
THALASSEMIA  Normal to mild anemia  HbF : > 2.5-5%
TRAIT  No organomegaly  HbA2: 4-9%, if >20% suggests HbE trait

 HbA : > 90%

HbF<2.5% ; HbA≥95% HbA2 ≤3.5

Beta Thal Major
LABORATORY
LABORATORY FINDINGS
FINDINGS

Methylene Blue / Brilliant Cresyl blue Stain showing

Golf Ball Appearance- HbH Disease
 Investigations

Supportive
• Iron Studies-
• Serum Ferritin- low in Fe Def; High in Fe overload
• High Serum Fe; Low TIBC- Fe overload
• Liver Iron Concentration- MRI
• LFT- Hyperbilirubinemia,
• Infection screen

 Family Screening
Differentials
Differentials Characteristic Feature
Iron Deficiency Anemia Low RBC count, Low Retic Count,
High RDW Low Ferritin
Anemia Of Chronic Disease Normochromic Normocytic Anemia
Low Retic Count
Sideroblastic Anemia BMA smear reveals numerous ring
sideroblasts
Sickle Cell Disease Electrophoresis/ HPLC- HbS
Pyruvate Kinase Deficiency Low PK enzyme
G6PD Defeciency Low G6PD enzyme
 Management (TIF Guidelines 2021)

• Regular maintenance blood transfusion and iron chelation therapy is the

mainstay of treatment

• AIM: For normal physical activity and growth, abolishes chronic hypoxemia,
reduces compensatory marrow hyperplasia and minimizes transfusional iron
accumulation
 Management (TIF Guidelines)
Laboratory criteria:
- Haemoglobin level (Hb) <7 g/dL on 2 occasions, > 2 weeks apart
(excluding all other contributory causes such as infections) AND/OR

Clinical criteria irrespective of haemoglobin level:

 Significant symptoms of anaemia
 Poor growth / failure to thrive
 Complications from excessive intramedullary haematopoiesis such as pathological
fractures and facial changes
 Clinically significant extramedullary haematopoiesis
 Management
How Much, Of What?
 Volume: 10-15 mls/kg packed red cells (PRBC)

 (Desired – actual Hb (g/l)) x weight (kg) x 0.3 = ml to be transfused

(assuming the haematocrit of the unit is 0.58)

 Use compatible leucodepleted (leucocyte filters) PRBC

 Management (TIF Guidelines)

How Often?
 Maintain the pre-transfusion haemoglobin level 9.5-10.5 g/dL
 Usually 4 weekly interval (usual rate of Hb decline is at 1 g/dL/week)
 Interval varies from individual patients (range from 2 to 5 weekly)

 Target- Keep mean post-transfusion Hb at 13-15 g/dL

 Management

Luspatercept for Transfusion-dependent Beta Thalassemia

• Initiated in adults >18yrs
• Improves RBC maturation
• Reduces transfusions required

Stem Cell Transplant and Gene Therapy

 Management

Iron Chelation Therapy-

Desferrioxamine / Deferasirox/ Deferiprone
• Usually when the child is > 2-4 years old
• When serum ferritin reaches 1000 ug/L
• Usually after 10-20 blood transfusions
Management

Supportive
• Nutritional Assessment and Counselling
• Low Fe diet
• Micronutrient Supplementation
• Folic Acid
• Calcium, Zinc, Vitamin D
• Vitamin E
 Complications
• Hemotransfusion Reactions
• Transfusion Related Infections- Hep B, Hep C, HIV
• Iron Overload Related
• Endocrinopathies (thyroid, PTH, diabetes, hypogonadism)
• Cardiac Failure
• Liver Cirrhosis
 Prognosis
The prognosis in thalassemia is highly variable and survival continues to increase
with advances in therapy.
• Untreated beta thalassemia major is fatal by the age of five years for approximately 85% of
patients

• Hematopoietic cell transplantation (HCT), begun in the 1980s, is potentially curative, many
individuals will not have access to HCT due to comorbidities, lack of a suitable donor, and/or
cost.

• For individuals who receive optimal management of excess iron stores, survival into the
fourth, fifth, and sixth decades of life are increasingly seen
 Summary

• Alpha and beta thalassemia are distinct clinical phenotypes. Each has a variable prognosis
depending on the severity of anemia, need for transfusions, and use of iron chelation.

• Thalassemia minor is an asymptomatic carrier state that does not limit survival and may
never come to medical attention.

• Management involves regular transfusions and iron chelation therapy to maintain normal
physical activity and growth.
 CASE SCENARIO
• 8-year-old female with no significant medical history presented with a 5-day history of fever and
LUQ abdominal pain, cola-like urine and jaundice.
• Sickling positive- AS

HB (g/dL) 6.5 11.5- 15

HCT (%) 19 34.5-46.5 HbA-48% (>96%),

MCV (fL) 64.8 79-95 HbS-26.8% (0.0%),

MCH (pg) 22.2 26-32 Hb F-24.0% (<2%)

WBC (x 103/uL) 14.7 4- 11 HbA2–1.2% (<3.3%)

Retic (%) 7.5% 0.5-2.5

Mentzer Index- 9
 Summary
• CBC- DON’T LOOK AT HB AND WBC ONLY!!!!
• MCV
• MCH
• RBC Count
• RDW
• Absolute Neutrophil Count
• Platelet
THANK YOU
Supervisor: Dr. Osei Tutu
Haem-Oncology Team
 References
• Uptodate
• Nelson Textbook Of Pediatrics, 21st Edition
• Medscape. [Link]
• Borgna-Pignatti C. Modern treatment of thalassaemia intermedia. Br J Haematol 2007; 138:291.
• Olivieri NF. The beta-thalassemias. N Engl J Med 1999; 341:99.
• Fucharoen S, Weatherall DJ. The hemoglobin E thalassemias. Cold Spring Harb Perspect Med. 2012;2(8):a0
11734. Published 2012 Aug 1. doi:10.1101/cshperspect.a011734
• Guidelines for Management of Transfusion Dependent Thalassemia Fourth Edition, 2021; Thalassemia Inte
rnational Federation