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WELCOME TO SEMINAR
Dr. Aysha SabihaDr. Maimuna Sayeed
Dr. Sharmin Akter LunaResidents (Phase-A)
Halima, a 11 years old girl of consanguineous parents presented with complaints of not growing well, gradual pallor & abdominal distension for 7 years.
On examination she was severely pale, facial dysmorphism & hepatosplenomegaly were present. She had history of repeated blood transfusion.
Case Scinerio
Hereditary hemolytic anemia
Diagnosis
SEMINAR ON
THALASSEMIA
Introduction
The term “Thalassemia” refers to a genetic disorder of hemoglobin synthesis characterized by a lack or decreased synthesis of one or more of the four Globin chains causing excessive breakdown of RBC.
"Thalassemia" is a Greek term derived from “Thalassa”, which means "the sea" and “Emia” means "related to blood."
World:• Beta thalassemia trait -
8% of population• More than - 100 million
carrier• Hb E - 53 millions
Bangladesh:• Beta thalassemia trait-
4.1%• Hb E trait - 6.1%• Hb E Beta thalassemia-
10.2%(Source: DSH Thalassemia center)
Incidence
Site of synthesis of globin
Normal hemoglobin component
Hb type Name ComponentsAdult A α2β2
A2 α2δ2Fetal F α2γ2Embryonic Portland ξ2γ2
Gower 1 ξ2ε2Gower 2 α2ε2
HbA98%
HbA2 <3.5%
HbF ~1%
Hemoglobin in normal adult
• α Thalassemia
• β Thalassemia
Types of thalassemia
Autosomal recessive
Inheritance
α-THALASSEMIA
Chromosome 16 defect
2 1 2 12
2 12 1
2 12 1
2 12 1
Normal Hb
One α gene deletionsilent carrier
Two α gene deletions- α-Thal. Minor
Four α gene deletionsHydrops fetalis or also
called: Erythroblastosis Fetalis.
Three α gene deletionsHb-H disease
CLINICAL PRESENTATION
Variants of alpha thalassemia Signs &Symptoms
Silent carrier AsymptomaticTrait Asymptomatic
Hb H diseaseModerate to severe hemolytic anemiaModest degree of ineffective erythropoiesisSplenomegalyVariable bone changes
Hb Bart's Born with massive generalized edema, usually fatal
Diagnosis of α-Thalassemia
CBC:• Silent Carrier: no microcytosis , no anaemia.• α-Thalassemia trait: microcytosis,
hypochromia, mild anaemia.• Hb H disease: variable severity of anaemia &
hemolysis.PBF: Hb H inclusion body (brilliant cresyl blue) in Hb H disease.
Hb electrophoresis – Hb H:
• (2-40%) Hb H• others Hb A• Hb F & Hb A2
Hb Bart's:• (80-90%) Bart's,• no Hb A, Hb F, Hb
A2
Diagnosis of α-thalassemia
Treatment of α-thalassemia
• Silent carrier & trait: do not require treatment.• Hb H disease: usually does not require regular
transfusions. But, with intercurrent illnesses, patient may require transfusion .
β-Thalassemia
With a mutation on one of the 2 beta globin genes , a carrier is formed with lower protein production but enough hemoglobin
Without a mutation enough hemoglobin
No carrier
With one mutation less hemoglobin
Beta thalassemia carrier but
less hemoglobin
Slight anemia
With two mutation No beta globin
Beta thalassemia major pt with
severe anemia
Gene from fatherGene from
mother
Chromosome 11 gene defects
Clinical syndrome Genotype Sign & symptom
Minor/ +
or/ °
Asymptomatic
Intermedia +/+ Variable degree of severity
Major+/°
or°/°
- Present within 1 year of age- Severe anemia- Growth retardation - Organomegaly- Skeletal deformities-Transfusion require within 2 year
Variants of β-thalassemia
An absence or deficiency of β-chain synthesis of adult HbAg
Pathophysiology of β-thalassemia
β Chain synthesis Hb-A
α , γ and δ chain
Hb A = α2β2
Pathophysiology of β-thalassemia
Physical Findings
An approach to thalassemia
History
Lab Investigations
• Severe Anemia• Thalassemic facies• Hepatosplenomegaly• Growth retardation,
etc
• Symptoms of anemia• +ve family history• H/0 blood transfusion• FTT
Thalassemia Major
Child with no transfusion or
inadequate transfusion
Child with regular blood transfusion but no chelation
Child with regular blood transfusion &
chelation
Leads natural course of disease,
may die within 5 yrs of age
Manifestation of iron overload at the
end of 1st decade
May enter into normal puberty & have normal life
expectancy
Clinical features
Natural course
General features
WeaknessGradual PallorFatigueDyspnoea on exertionPoor appetitePalpitationPoor growth
Features of marrow
expansion
Features of extramedullary hematopoiesis
Features of hemolysis
JaundiceHyperurecemia-Gout
Gallstone
Scoliosis,Kyphosis,vertebral collapse with cord compression
Features of iron overload
CirrhosisDiabetes Infertility
Pituitary failureHypothyroidism
ArrythmiaHeart failureDark skin
Liver Heart Endocrine organs
Hb E β-Thalassemia
• Most prevalent thalassemia variant in Southeast Asia & Bangladesh.
• Double heterozygous state.• Lysine substitutes glutamic acid in 26th position. • Divided into mild, moderate & severe form with
clinical features varying from thalassemia intermedia to thalassemia major
Types Sign & symptomMild Hb E β Thalassemia
Asymptomatic , Hb :9 -12 gm/ dl , require no treatment .
Moderately severe Hb E β Thalassemia
Majority of patient are in this group, Hb : 6 -7 gm/dl , resemble Thalassemia intermedia.
Severe Hb E β - Thalassemia
Clinical manifestation resemble Thalassemia major (severe anaemia, growth retardation, hepatosplenomegaly, skeletal deformities). Hb: 4-5 gm/dl , treated as thalassemia major.
Variants of Hb E β-thalassemia
Complications of thalassemia
A. Excessive erythropoiesisB. Iron overloadC. Chronic hemolysisD. Hypercoagulable diseaseE. InfectionF. Treatment of related complications
Facial changes:• Maxillary over growth• Malocclusion of teeth• Frontal bossing• Chronic sinusitis• Impaired hearing
A. Excess erythropoiesis
• Medullary expansion – cortical thinning, risk of fracture, osteopenia, osteoporosis, back ache.
• Vertebral expansion lead to spinal cord compression – neurological manifestations.
Bone Changes
• Hepatosplenomegaly• Lymphadenopathy
Endocrine failure:• Short stature• Delayed puberty• Estrogen/ testosterone
deficiency• Diabetes mellitus• Hypoparathyroidism
B. Iron Overload
B. Iron overload
Cardiac involvement:• Cardiomyopathy• Pericarditis• Arrhythmia• CCF
Hepatic involvement:CirrhosisHepatic fibrosis
B. Iron overload
C. Chronic hemolysis
• Gallstone 50-70% by around 15 years.
D. Hypercoagulable disease
Impaired platelet function Deep venous thrombosis
Elevated endothelial adhesion protein level Pulmonary embolism
Activation of coagulation cascade by damage RBC Cerebral ischemia
E. Infection
• Anemia• Iron overload – Yersinia, Klebsiella• Hypersplenism• Splenectomy – Pneumococci, Meningococci,
Hemophilus influenzae• Transfusion related – HBV, HCV, HIV etc.
F. Complications due to blood transfusion
• Acute hemolytic reactions• Delayed transfusion reaction• Autoimmune hemolytic anemia• Febrile transfusion reaction• Allergic reaction• Transfusion related acute lung injury (TRALI)• Graft versus host disease (GVHD)• Volume overload• Transfusion of disease – HAV, HBV, HIV
Causes of death in thalassemia
• Congestive heart failure• Arrhythmia• Sepsis due to increase susceptibility to infection• Multiple organ failure due to hemochromatosis
INVESTIGATIONS
Investigations
CBC:• Hb level - Depends on severity
– β-thalassemia minor: 10-13 gm/dl– β-thalassemia intermedia: 7-10 gm/dl– β-thalassemia major: 3-6 gm/dl
• TC/DC– normal / increased / decreased• Platelet- normal / decreased• RBC Indices- MCV, MCH, MCHC are low• RDW- Normal or raised• Reticulocyte count- Increased(5-10%)
PBF: Microcytic hypochromic cells with marked anisocytosis, poikilocytosis and other abnormal cells.
Abnormal RBCs in PBF
1. Target cell2. Tear drop cell3. Elliptocyte4. Hypochromic5. Microcyte
PBF: Normal
PBF: β-thalassemia major
PBF: β-thalassemia minor
Investigations
• Osmotic fragility: Decrease • Iron Profile:
S. Iron & ferritin- Increased TIBC- Decreased High % saturation of transferrin
• S. bilirubin (indirect): Increased
Hb electrophoresis
Hb NORMAL MAJOR MINOR INTERMEDIATE
Hb F <1% 90-98% 1-5 % Variable
Hb A 97% Absent 90-95% Variable
Hb A2 1-3% Variable 3.5-7% >3.5%
Normal Hb electrophoresis
Hb electrophoresis of homozygous β° thalassemia
• Widened diploic spaces
• Hair-on-end appearance
• Thinning of cortex
X-ray Skull
• Rectangular appearance• Medullary portion of bone
is widened• Bony cortex thinned out• Coarse trabecular pattern
in medulla
X-ray of hand
Investigations
• DNA analysis:Determine specific defect at molecular DNA level.
• HPLC (High Performance Liquid Chromatography):
Identify & quantify large number of abnormal Hb.
Normal10% (33)
β thalassemia trait44% (145)
homozygous β tha-lassemia5% (18)
Hb E β Thalassemia16% (52)
Hb E talassemia trait
21% (71)
Hb E disease2% (5)
β-Thalassemia major2% (7)
Unknown0% (1)
Patient diagnose as different variety of thalassemia by DNA analysis in BSMMU during the period of Sept 2007 to Aug 2016 (Total=332)
Diagnosing ThalassemiaFull medical and family history, CBC and RBC indices and PBF
Low MCV (< 80fl)± Low MCH (< 27pg)
Other cause of anemia?
Serum ferritin
≤12 ng/mlConsider iron
deficiency anemia
Adequate iron supplement for 3 months
Hb electrophoresis and HPLC
Improved
Not improved
Hb A2 variableHb F > 90-98%
Hb A2 ≥ 4%Hb F ≤ 0.1-5%
Hb A2 > 4%Hb F variable
Hb A2 < 4%Hb F < 1%
+ Other normal Hb variant
ß-Thalassemia major
ß-Thalassemiaminor
ß-Thalassemia intermedia 𝛼-Thalassemia Hb S, Hb E,
Hb C and others
DNA analysis for -globin ß-globin chain mutation
Serum ferritin>12 ng/ml
Microcytosis, Hypochromia, Target cells± inclusion bodies (Hb H)
To see complications
• Liver function test• Thyroid function test• FSH, LH, Testosterone, Estradiol• Blood Sugar• Bone profile• Ca, Phosphate, PTH• Liver Iron Concentration (LIC): T2 MRI, Liver
Biopsy• Cardiac Iron Measurement by: T2 MRI
• Bright areas represent high iron concentration.• Dark areas represent low iron concentration.
Monitoring iron overload by MRI
MANAGEMENT OF THALASSEMIA
Treatment modalities
A. SupportiveB. CurativeC. Preventive
A. Supportive management
• Multi-disciplinary approach• Focus on each patient’s clinical course
Transfusion
Iron Chelation
Fetal Hb Induction
Splenectomy
Objectives of supportive management
• Maintenance of growth and development• Correction of anemia• Prevention of iron overload• Treatment of complications• Counseling and Prevention
Blood Transfusion
Whom to transfuse?
Confirmed diagnosis of thalassemia major• Laboratory criteria:
• Hb < 7gm/dl on 2 occasions > 2 weeks apartor
• Hb > 7gm/dl with:• Facial changes• Poor growth• Fractures • Extramedullary hematopoiesis
Important issues before starting transfusion
• Blood grouping:– ABO and Rh(D) compatibility checked– Extended red cell antigen typing at least C, c,
E, e and Kell.• Screening of donor blood for HBV, HCV, HIV,
Syphilis, Malaria.• Avoidance of transfusion first-degree relative
donors.• Quality, adequacy and safety of blood
Transfusion protocol
To maintain pre transfusion Hb >9–9.5 gm/dl.• Typical programs:
• Transfusion of 10–15 cc/kg of packed Leuko-depleted red cells
• Lifelong regular blood transfusions, every 2–5 weeks
A higher pre-transfusion hemoglobin level of 11-12 gm/dl for patients with:
• Heart disease or other medical conditions • Patients who do not achieve adequate
suppression of bone marrow activity at lower Hb level.
Blood products for transfusion
• Packed red cell• Leukocyte reduced red cell• Washed red cell• Neocyte
Target in Hb Haematocrit of Donor Red Cells
50% 60% 75% 80%
1 gm/dl 4.2 ml/kg 3.5 ml/kg 2.8 ml/kg 2.6 ml/kg
2 gm/dl 8.4 ml/kg 7.0 ml/kg 5.6 ml/kg 5.2 ml/kg
3 gm/dl 12.6 ml/kg
10.5 ml/kg 8.4 ml/kg 7.8 ml/kg
4 gm/dl 16.8 ml/kg
14.0 ml/kg
11.2 ml/kg
10.4 ml/kg
Regularly Transfused
Irregularly Transfused
• Normal growth • Normal physical activities• Adequately suppresses
bone marrow activity• Minimizes iron
accumulation
Regular transfusion allows
Diet and supplementation
• High iron contained food should be avoided.• Diet which decreases iron absorption such as
milk & milk products should be taken adequately
• Folic acid• Zinc• Vit. D, Vit. E
Thalassemic diet
CHELATION THERAPY
Chelator MetalChelator
Toxic
Excretion
Metal
What is chelation therapy?
Evaluation of iron overload
Serum ferritin concentration
Liver iron concentration (LIC) Liver biopsy
– n=1.8 -7 mg/dry wt , >15-20 mg SQUID MRIOthers: NTBI and T2*MRI
Guideline- Thalassemia International Federation-2008
Guidelines for starting treatment of iron overload in patients with β-thalassemia major
Thalassemia International Federation guidelines for the clinical management of thalassemia (2008)1 recommend that chelation therapy is considered when patients:
Have received 10–20 transfusion episodesORHave a serum ferritin level of >1000 ng/mL
1Thalassemia International Federation. Guidelines for the clinical management of thalassemia, 2nd Edition revised 2008; 2Angelucci E et al. Haematologica 2008;93:741–752
Primary goals of chelation therapy
Completechelation
The primary goals of iron chelation therapy are to remove excess iron and provideprotection from the effects of toxic iron
Iron balance
Removal of ironat a rate equal to transfused
iron inputPrevents end-organ damage
due to iron
Normalization of stored tissue
iron
May take years in established iron overloadSafe levels of
tissue iron differs between
organs
Control of toxic iron over 24-hr
period
24-hr control of NTBI/LPI and
intracellular labile iron
Prevents end-organ damage
due to iron
Goals of chelation Therapy is achieved by:• Keeping serum ferritin <1000-2,000 ng/mL or• LIC <15 mg/g dry weight
Iron chelating agents
• Desferrioxamine (DFO)• Deferiprone• Deferasirox
Management: iron chelatorsAgent Route T1/2
hoursSchedule Clearance Toxicity
Deferoxamine IV/SQSlow
infusion
0.5 8-24 hours
5-7 days per week
Renal andhepatic
Infusion site reactions,allergic reactions,ocular and auditory
Deferiprone Oral 2-3 3 daily Renal Nausea/ vomiting, arthropathy,neutropenia, agranulocytosis
Desferrioxamine
Oral 12-16 1 daily Hepatic Bad taste, nausea,epigastric pain, rash
Desferrioxamine
Regular rotation of the site of infusion allows proper absorption of the medication and decreases the risk of skin breakdown and scar tissue formation.The most common sites are abdomen, thighs and upper arms.
Deferioxamine……contdIntensive chelation with Desferrioxamine – continuous 24-hourly infusions IV or SC.Indications:
a) Persistently high serum ferritin;b) LIC > 15 mg/g dry weight;c) Significant heart disease, and;d) Prior to pregnancy or bone marrow transplantation
Dose: 50 mg/kg/day (up to 60 mg/kg/day)In-dwelling catheters: danger of infection and thrombosis
Fetal Hb Induction
Induction of fetal hemoglobin
Hb F enhancement• Hydroxyurea• Myelaran• Butyrate derivatives• Erythropoietin • 5-Azacytadine
• Increasing the synthesis of fetal hemoglobin can help to alleviate anaemia and thereby improve the clinical status of patients with thalassemia intermedia.
• Agents including cytosine arabinoside and hydroxyurea may alter the pattern of erythropoiesis and increase the expression of alpha-chain genes.
• Erythropoietin has been shown to be effective, with a possible additive effect in combination with hydroxyurea.
• Butyrate are a further experimental category, still unlicensed and with difficult intake.
SPLENECTOMY
Deferred as long as possible. At least till 5-6 yrs age.
Indications:• Massive splenomegaly causing mechanical
discomfort• Blood requirements >200-220 ml/kg/year• Hypersplenism
The risk of splenectomy
Overwhelming infection
Age—(<2 years of age)
Time since splenectomy (1-4 years after surgery)Immune status of patient
Commonly associated pathogen
Streptococcus pneumoniae
Haemophilus influenzae
Neisseria meningitidis
Preventative measures
Immunoprophylaxis– At least 2 weeks before splenectomy Pneumococcus/meningococcus/Hemophilus
Chemoprophylaxis- Chemoprophylaxis with life-long oral
penicillin. Education
Only curative option available.Overall outcome depends on-
• Inadequate chelation therapy,
• hepatomegaly,• presence of portal
fibrosis.Treatment-related mortality is approximately 10%.
Bone marrow/stem cell transplantation
Guideline- Thalassemia International Federation-2008
Risk stratification for BMT
Hepatomegaly >3cms Liver fibrosis Inadequate chelation
Class I – no risk factors Class II- one to two risk factors Class III- all three risk factors
Outcome of BMT in thalassemia
Guideline- Thalassemia International Federation-2008
Class probabilities of survival (%)
disease-free survival (%)
risk of rejection (%)
risk of mortality (%
I 93 91 2 8
II 87 83 3 15
III 79 58 28 19
B. Curative treatment in thalassemia
• Stem cell transplantation• Gene therapy
Stem cell transplantation?
Stem cell transplantation
Whom to offer?
Stem cell transplantation
Cost Vs Risk benefit of patient
andAvailability of
DONOR
Stem cell transplantation
Gene therapy
Gene therapy
• Insertion of normal globin genes into marrow stem cell may ultimately cure Thalassemia .
• Globin gene transfer in autologous CD34+cells is beginning to be evaluated
• As per FDA recommendation, the current study is restricted to adults. Paediatric patients will be included at a later date after reviewing safety and efficacy data obtained in adults.
Guidelines for the Management of transfusion dependent Thalassemia,3rd
Role of surgery in thalassemia
• Cholelithiasis – Cholecystectomy• Choledocholithiasis – Choledocholithotomy• Cirrhosis (due to iron overload) – Liver biopsy
and liver transplantation• Leg ulcer – Surgical dressing• Pathological fracture – Surgical correction• Spinal cord compression - Laminectomy
Follow up
Follow up
Monthly:• Complete blood count• Complete blood chemistry (including liver
function tests, BUN, creatinine) if taking deferasirox
• Record transfusion volume.
Follow up
Every 3 months:• Measurement of height and weight• Measurement of ferritin (trends in ferritin used
to adjust chelation); • Complete blood chemistry, including liver
function tests
Follow up
Every 6 months:• Complete physical examination including Tanner
staging, • Monitor growth and development• Dental examination
Follow upEvery year:• Cardiac function – echocardiograph, ECG, Holter
monitor (as indicated)• Endocrine function (TFTs, PTH, FSH/LH, fasting
glucose, testosterone/estradiol, FSH, LH, IGF-1, Vitamin D levels)
• Ophthalmological examination and auditory acuity
• Viral serologies (HAV, HBV panel, HCV (or if HCV1, quantitative HCV RNA PCR), HIV)
• Bone densitometry• Ongoing psychosocial support.
Follow up
Every 2 years:• Evaluation of tissue iron burden• Liver iron measurement – R2 MRI, SQUID, or
biopsy• T2* MRI measurement of cardiac iron (age .10
years).
C. Prevention and control
Career detection/Screening Genetic counseling Prenatal diagnosis Health education
Screening
• RBC indices (MCV, MCH, MCHC)• NESTROFT• HbA2
Career detection/screening
Mass screening: NESTROFT (Necked Eye Single Tube Red Cell Osmotic Fragility Test)
• Very cheap and easy to perform require small amount of blood
• Based on principle that Thalassemic red cell resists hypotonic solution more than that of normal person
• Give positive result on NESTROFT• Sensitivity 90-98% and specificity 85-90%
NESTROFT
Career detection/screening
Automated CBC:• Thalassemic red cells are microcytic and
hypochromic• WHO recommends MCV <77fl and MCH <27 pg
as screening tools to pick up cases for confirmation by electrophoresis
DCIP (Di Chloro phenol indol phenol): Screening for Hb E
Genetic counseling
• Index case parents and relatives.• Antenatal visits of pregnant mothers.
Genetic counseling
• β/α ratio: <0.025 in fetal blood
• Chorionic villous biopsy (10-12 weeks)
• Cordocentesis• Amniocentesis (15-18th
week) Analysis of fetal DNA
• PCR to detect β globin gene
Prenatal diagnosis
Chorionic Villus Biopsy
Health education/awareness
• Knowledge of genetic nature of thalassemia• Transmission of the disease• Ways to avoid to have further child with the
disease• Aware about economic burden to the family and
govt.
Prognosis
Thalassemia major-life expectancy:
• Without regular transfusion - Less than 10 years• With regular transfusion and no or poor iron
chelation - Less than 25 years• With regular transfusion and good iron chelation
- 40 years, or longer?
The commonest cause of death is iron overload
Conclusion
• Management needs extensive hands • Prevention program is rudimentary• Awareness about thalassemia is though
increasing still very much lacking• Manpower is developing-good news• Thalassemia center dedicated to children to be
established
Thalassemia day
8th May is the international Thalassemia Day. This day is dedicated to Thalassemia, to raise public awareness for prevention of Thalassemia and to highlight the importance of clinical care for Thalassemia patients in all countries.
Thank You