Thalassemia

Dr Ng Ee Wei
 Objectives
• To define Thalassemia
• Know the indications for initiation of
transfusion and monitoring on chronic tx
• How to manage iron overload and monitoring
for SE of chelators
• Disease monitoring
• Indications for splenectomy
• Options for treatment
 Case
• 5 mo boy / BW 2.6 kg / SVD at 36 weeks / 1st
hospitalization / Development and immunizations upto
age

• Presented on 25/6/15
– poor feeding, inactive x 2 days
– pallor 1/12
– No fever / URTI, UTI, AGE sx
– No bleeding tendencies

– Prior – under KK Bingkor for FTT and anemia for investigation

– Diet : exclusive BF
– Family hx : both parents beta-thal carrier, non consanguineous
• Vital signs :
– T 37.2 degC / HR 113 bpm / SPO2 100% RA / BP
88/57 mmHg / RR 48

– General + systemic examination : lethargic,

pallor, otherwise unremarkable

• Investigations :
– FBC : Hb 7.6 / TWC 19.8 (L 78/N14) / Plt 576
/MCV 61.9 / MCH 21.6 / RBC 2.47
– Iron study : Ferritin 349 / Iron 24.3 / TIBC 72.1
– FBP : rejected
 Differentials?? For anemia in infancy /
toddler group…
 Iron deficiency
 Infections
 Blood loss
 Hb disorders
 Red cell membrane disorders
 Enzyme disorders
 Autoimmune hemolytic anemia
 Transient erythroblastopenia of childhood (TEC)
 Leukemia
• Admitted 3 days (25-28/6/15)
– Dx : symptomatic anemia for investigation
– Transfused 14 cc/kg
– Hb on discharge : 13.5 g/dL

• TCA clinic 13/7/15

– Hb 10.1 g/dL
• TCA clinic 10/8/15
– Hb 7.3 g/dL , asymptomatic

• Presented to A&E on 17/8/15

– Hb 7 g/dL
– Admitted 17-20/8/15
– Dx : symptomatic anemia likely due to Beta Thalassemia
– Transfused total 36 cc/kg
– Hb on discharge
15/9/15 – started DCU follow up
 Overview
• Types of Thalassemias
• Inheritance
• Diagnosis
• Complications
• Management
• Updates
 What is Thalassemia
• Greek
thalassa "sea"
-emia "blood“
“sea in blood” – Mediterranean anemia
• a group of inherited disorders characterized by
reduced or absent amounts of hemoglobin.
• Deficiency of one type of chain leads to excess
of the other
EPIDEMIOLOGY
• Worldwide,
– Between 300,000 – 500,000 children are born annually
with a severe hemoglobin disorder
– 80% of affected children are born in middle and low
income countries
– 70% are born with sickle cell and the rest with
thalassemia disorders
– 50 – 80% of children with sickle cell anaemia and 50,000
– 100,000 children with β-thalassaemia major die each
year in low and middle income countries

Source : World Bank 2006, report of a joint WHO-March of

Dimes meeting 2006)
 EPIDEMIOLOGY
mmigration Trends Impacting Thalassemia (Weatherall, 2012)

Source : Thalassemia International Federation

NTDT : non transfusion dependent Thalassemia
• In Malaysia
– Most common genetic disorder
in Malaysia
– ~4.5% of the Malays and
Chinese are β-thalassemia
carriers. Each ethnic group
possesses its own specific set of
mutations
– Alpha-thalassemia  Hb Bart’s
hydrops fetalis, mainly in
Chinese. Malays have single α-
globin gene deletion .
– Thalassemia has rarely been
observed in the Malaysian
Indians.
• Conclusion :
– Because of high prevalence in this group,
screening should be made as routine to
identify carriers
– Challenge : education. Genetic counseling and
prenatal diagnosis for carrier parents
– Routine care of β-thalassemia major
– Proposed programs for screening and care at
district level
HbA 97%, HbA2 2-3%, HbF < 1 %
Types of Thalassemias
Inheritance – autosomal recessive
 Diagnosis
• FBC – microcytic hypochromic anemia
• FBP
• Hb Analysis
– Hb electrophoresis / HPLC
• DNA analysis – for difficult cases, can detect
carrier states
• Antenatal diagnosis
 Normal
Hb electrophoresis

Thalassemia
 Hb electrophoresis
Beta Thal Beta Thal
Indices Normal
major minor

HbA 97% Almost none 90%

HbA2 1-3% variable 5-10%

HbF <1% 10-98% Variable

Complications ?
1.Anemia
2.Iron overload / chelator SE
3.Transfusion related

HOW TO MANAGE THALASSEMIA ?

Others :
1.Acute infections :
Yersinia
2. Chronic pain
 Management Goals
• Optimize transfusions
• Iron chelation + compliance
• Assessment and control of SE from chelators
• Monitoring of complications from disease
• Curative options
• Prevention of infections
• Nutrition
• Psychosocial support
 Blood transfusions
• Decision to transfuse
– Symptoms of chronic anemia, poor growth
– Extramedullary compensation
– Hb level < 7g/dL, 2x > 2/52 apart
– Rule out other causes of anemia (E.g. infections)
• Baseline testing
– RBC typing
– Infectious screening
– Liver profile
• Aims of transfusion :
– Normal growth and activity
– Prevention of marrow hyperplasia

• Blood product :
– Fresh leukodepleted packed cells
– Calculated volume
 Targets
• Pre transfusion Hb 9-10 g/dL
• Post tranfusion Hb 14 g/dL
• If cardiac compromise, may need higher pre-
transfusion Hb with smaller volume
transfusions at more freq intervals
• ± Frusemide
• Annual tranfusion vol < 200 cc/kg/yr 
exceeding : hypersplenism / alloantibodies
• Adverse transfusion reactions
– Alloimmunization & autoantibodies  needs
extended RBC typing
– Transfusion-transmitted infections
– allergic / febrile reactions
• Hypersplenism + splenectomy
– Effect : pancytopenia, increased tx
requirements, reduced effective chelation
– Splenectomy should be avoided unless
symptoms from above
– Post splenectomy : VTE prevention,
immunization (pneumococcal, Hib, N
meningitides), + lifelong penicillin prophylaxis
 Iron overload and chelation
• Transfusion independent complication
– But more rapid in transfused pts

• Free iron (toxic) leads to organ damage

– Liver ~ 6/12
– Heart ~ 8-10 years
Sites Of Iron Deposition
 How to remove excess iron ?
 Phlebotomy
 Iron chelators

 Initiation of chelation should be delayed til

significant iron loading
 Total blood transfused
 Serum Ferritin
 Liver iron concentration (Biopsy / MRI / SQUID)
Superconducting quantum interference
device (SQUID)
BASICALLY, IT MEASURES
A magnetic susceptometry technique which uses a very low-power
magnetic field with sensitive detectors to measure the interference of
MAGNETIC FIELDS FROM
iron in ferritin and hemosiderin.
The sensor requires a cryogenic environment, since it must be

LIVER IRON.
superconducting to operate. Linear correlations have been demonstrated
between SQUID measurements and liver biopsy liver iron concentration
(LIC) levels.
• Serum ferritin to guide chelation (LIC is
preferred)
Ferritin level Action

>1000 ng/mL (approx Initiate

20 transfusions)
1000 – 2500 ng/mL Aim and maintain dosing

>2500 intensive chelation

500 - 1000 lower dose

<500 stop chelation
 Iron Chelators
Drug Route Dose Side effects

Deferoxami Subcut / 30-60 mg/kg Auditory / ocular toxicity

ne IV Over 8-15 hours Local skin reactions
(Desferral) 5 days per week Growth reduction
(vertebral)
if cardiac iron T2* < 10
ms / LV dysfunction
IV 60 mg/kg/d x 3 days
via CVL
± deferasirox /
Deferiprone

But still need daily

chelation
Deferasirox PO daily Starting : 20 mg/kg/d Renal impairment (check
(Exjade) - Can be May go up to 40 mg/kg/d RP monthly)
added to (increment 5-10 Skin rash
fruit mg/kg/d) GI sx
juice
Deferiprone PO 75 – 100 mg/kg/d – Neutropenia /
 Disease monitoring
• Liver Disease / HBS
• Growth / endocrine
• Cardiac disease
• Pulmonary Hypertension
• Dental
 Growth and endocrine
• Endocrinopathies
– Mainly due to iron deposition in endocrine glands
– hypogonadotrophic hypogonadism,
hypothyroidism, hypoparathyroidism and
diabetes mellitus / IGT

• Growth failure, delayed puberty, reduction in

final height (multifactorial)
– Chronic anemia and hypoxia
– Chronic liver disease
– Iron overload
– Intensive chelation (DFO)
Issue Suggested evaluation / mx
GH deficiency Poor growth velocity , or fall of 5% growth curve
IGF level
Dietary assessment

hypogonadism pubertal age group, if failing to attain / delayed

Tanner staging 6 monthly
Check bone age, check FSH /LH levels, estradiol /
testerone level
Consider replacement
Hypothyroidism After 5 yo or 3 years of transfusion
Hypoparathyroidism Check yearly – PTH level and serum calcium
Rx : vitamin D and calcium
Adrenal insufficiency Check 2x yearly after 5yo – ACTH stimulation

Mx :
Is it adrenal crisis ?
If yes  ABCDE, Stress dose replacement
If no  replacement therapy
 Issue Suggested evaluation / mx
Diabetes mellitus / IGT OGTT
Optimize chelation
Referral as appropriate

Osteoporosis DEXA scan

Annual check Ca, PTH
Review nutrition and provide supplement s (Ca, Vitamin D)
Dietician review
Referral to endocrinologist , KIV bisphosphonates

e:
nd out if endocrine problem is primary / secondary / tertiary
all above, early diagnosis is important and consider endocrinologist consult
 TANNER
STAGING
 Liver
• Liver dysfunction due to :
– Liver iron
– Transfusion acquired viruses – Hep B/C
• ALT, AST, ALP
• Hep B and C screening
– HepBsAb, HepBsAg
– HepCAb. If positive Hep C PCR
– If positive Hep B/C, liver biopsy recommended
– AFP for HCC
– 6 monthly US HBS : for cirrhosis
– Decision to treat (IFN-α + ribavirin/other
antiviral) depending on biopsy findings, clinical
 Others :
• Heart
– Accumulation of cardiac iron
– Optimize Chelation – DFO, DFP (*)
– Baseline echo for PA pressure, Systolic /
diastolic function,
– Monthly review includes cardiac symptoms and
CVS exam
– MRI : cardiac T2* if available
• If heart failure established  cardiac iron
– Needs continuous chelation, consider adding DFP
– Cardiologist referral
– KIV ACEi, β-blockers, diuretics, digoxin
– Aim for higher pre-transfusion Hb ~ 12 g/dL

• Pulmonary HTN
– d/t HF
– Vasoactive fragments of platelets and RBCs (usually
removed by spleen) causing pulm vasoconstriction
– Mx : optimize transfusion, avoid hypoxia,
supplemental O2, coagulopathy screen, KIV
warfarin and keep INR ~1.5-2
– VTEs / Pulm embolism
 Acute infections
• Major COD in thalassemia patients
• Gram negative organisms
• Yersinia enterocolitica (iron avid)
– Sx : Fever, abdominal pain, diarrhea and vomiting
– antibiotics before stool & blood culture results
– Stop chelation (desferral) until yersinia treated
• Others :
– Strep epidermidis if CVC
 Vaccinations
 MUST BE CURRENT
 Pneumococcal
 At 2 mo : 7-valent conjugate
 At 2 yo : booster 23 valent
 Pneumovax booster q5-10 years
 Influenza vaccine yearly
 Hep A and B vaccine + boosters
 Splenectomy : Hib and pneumococcal vax,
meningococcal conjugate vax before splenectomy
 HIV / hep C : NO LIVE VACCINE
 Nutrition
• Increased nutritional requirements
• Annual dietary evaluation
• Dietary supplements
– Calcium, vit D, folate
– Trace elements
– Vitamins C, E
• Low iron diet if not on chelation
• Tea can increase iron elimination
• Avoidance of alcohol and smoking
 Hematopoietic Stem Cell Transplant

• Only possible cure to date

• Donor : preferably HLA matched sibling, or unrelated
matched donor, umbilical cord blood SCT
• Risk stratification :
– Age of patient
– Adequacy of chelation
– Presence of liver fibrosis
– Presence of hepatomegaly

• 80-95% survival post HSCT in low risk

• Immunosuppressive therapy improves the problems of
rejection
 Research and Updates
• HbF increasing agents :
– EPO (SE : marrow expansion)
– PO hydroxyurea – but may not preclude
eventual need for transfusion
– Histone deacetylase inhibitors (HDAC)
Gene therapy
• Challenges :
– minimize the adverse consequences that can result
from random integration of vectors into the genome 
oncogenes
 References
1. Illustrated text book of paediatrics 3e
2. Malaysian paediatric protocol 3e
3. Standards of Care Guidelines 2012, Children’s Hospital and Research Centre Oakland
4. Gupta, G., Kumar, S., Singh, R., & Shanmugasamy, K. (2010). Intussusception Caused
by Yersinia enterocolitica Enterocolitis in a Patient with Sickle Cell Anemia. Clinical Medicine
Insights. Pathology, 3, 7–11.
5. Andreas Kyriakou, MD and Nicos Skordis, MD. Thalassaemia and Aberrations of Growth and
Puberty. Mediterr J Hematol Infect Dis. 2009; 1(1): .
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033154/ (accessed 15 November 2015).