thalassemia
TRANSCRIPT
![Page 1: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/1.jpg)
WELCOME TO SEMINAR
Dr. Aysha SabihaDr. Maimuna Sayeed
Dr. Sharmin Akter LunaResidents (Phase-A)
![Page 2: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/2.jpg)
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
![Page 3: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/3.jpg)
Hereditary hemolytic anemia
Diagnosis
![Page 4: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/4.jpg)
SEMINAR ON
THALASSEMIA
![Page 5: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/5.jpg)
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."
![Page 6: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/6.jpg)
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
![Page 7: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/7.jpg)
![Page 8: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/8.jpg)
Site of synthesis of globin
![Page 9: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/9.jpg)
Normal hemoglobin component
Hb type Name ComponentsAdult A α2β2
A2 α2δ2Fetal F α2γ2Embryonic Portland ξ2γ2
Gower 1 ξ2ε2Gower 2 α2ε2
![Page 10: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/10.jpg)
HbA98%
HbA2 <3.5%
HbF ~1%
Hemoglobin in normal adult
![Page 11: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/11.jpg)
• α Thalassemia
• β Thalassemia
Types of thalassemia
![Page 12: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/12.jpg)
Autosomal recessive
Inheritance
![Page 13: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/13.jpg)
α-THALASSEMIA
![Page 14: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/14.jpg)
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
![Page 15: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/15.jpg)
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
![Page 16: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/16.jpg)
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.
![Page 17: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/17.jpg)
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
![Page 18: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/18.jpg)
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 .
![Page 19: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/19.jpg)
β-Thalassemia
![Page 20: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/20.jpg)
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
![Page 21: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/21.jpg)
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
![Page 22: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/22.jpg)
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
![Page 23: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/23.jpg)
Pathophysiology of β-thalassemia
![Page 24: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/24.jpg)
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
![Page 25: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/25.jpg)
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
![Page 26: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/26.jpg)
Natural course
General features
WeaknessGradual PallorFatigueDyspnoea on exertionPoor appetitePalpitationPoor growth
Features of marrow
expansion
![Page 27: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/27.jpg)
Features of extramedullary hematopoiesis
Features of hemolysis
JaundiceHyperurecemia-Gout
Gallstone
Scoliosis,Kyphosis,vertebral collapse with cord compression
![Page 28: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/28.jpg)
Features of iron overload
CirrhosisDiabetes Infertility
Pituitary failureHypothyroidism
ArrythmiaHeart failureDark skin
Liver Heart Endocrine organs
![Page 29: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/29.jpg)
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
![Page 30: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/30.jpg)
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
![Page 31: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/31.jpg)
Complications of thalassemia
A. Excessive erythropoiesisB. Iron overloadC. Chronic hemolysisD. Hypercoagulable diseaseE. InfectionF. Treatment of related complications
![Page 32: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/32.jpg)
Facial changes:• Maxillary over growth• Malocclusion of teeth• Frontal bossing• Chronic sinusitis• Impaired hearing
A. Excess erythropoiesis
![Page 33: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/33.jpg)
• Medullary expansion – cortical thinning, risk of fracture, osteopenia, osteoporosis, back ache.
• Vertebral expansion lead to spinal cord compression – neurological manifestations.
Bone Changes
![Page 34: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/34.jpg)
• Hepatosplenomegaly• Lymphadenopathy
![Page 35: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/35.jpg)
Endocrine failure:• Short stature• Delayed puberty• Estrogen/ testosterone
deficiency• Diabetes mellitus• Hypoparathyroidism
B. Iron Overload
![Page 36: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/36.jpg)
B. Iron overload
Cardiac involvement:• Cardiomyopathy• Pericarditis• Arrhythmia• CCF
![Page 37: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/37.jpg)
Hepatic involvement:CirrhosisHepatic fibrosis
B. Iron overload
![Page 38: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/38.jpg)
C. Chronic hemolysis
• Gallstone 50-70% by around 15 years.
![Page 39: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/39.jpg)
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
![Page 40: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/40.jpg)
E. Infection
• Anemia• Iron overload – Yersinia, Klebsiella• Hypersplenism• Splenectomy – Pneumococci, Meningococci,
Hemophilus influenzae• Transfusion related – HBV, HCV, HIV etc.
![Page 41: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/41.jpg)
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
![Page 42: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/42.jpg)
Causes of death in thalassemia
• Congestive heart failure• Arrhythmia• Sepsis due to increase susceptibility to infection• Multiple organ failure due to hemochromatosis
![Page 43: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/43.jpg)
INVESTIGATIONS
![Page 44: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/44.jpg)
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.
![Page 45: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/45.jpg)
Abnormal RBCs in PBF
1. Target cell2. Tear drop cell3. Elliptocyte4. Hypochromic5. Microcyte
![Page 46: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/46.jpg)
PBF: Normal
![Page 47: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/47.jpg)
PBF: β-thalassemia major
![Page 48: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/48.jpg)
PBF: β-thalassemia minor
![Page 49: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/49.jpg)
Investigations
• Osmotic fragility: Decrease • Iron Profile:
S. Iron & ferritin- Increased TIBC- Decreased High % saturation of transferrin
• S. bilirubin (indirect): Increased
![Page 50: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/50.jpg)
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%
![Page 51: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/51.jpg)
Normal Hb electrophoresis
![Page 52: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/52.jpg)
Hb electrophoresis of homozygous β° thalassemia
![Page 53: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/53.jpg)
• Widened diploic spaces
• Hair-on-end appearance
• Thinning of cortex
X-ray Skull
![Page 54: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/54.jpg)
• Rectangular appearance• Medullary portion of bone
is widened• Bony cortex thinned out• Coarse trabecular pattern
in medulla
X-ray of hand
![Page 55: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/55.jpg)
Investigations
• DNA analysis:Determine specific defect at molecular DNA level.
• HPLC (High Performance Liquid Chromatography):
Identify & quantify large number of abnormal Hb.
![Page 56: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/56.jpg)
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)
![Page 57: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/57.jpg)
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)
![Page 58: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/58.jpg)
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
![Page 59: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/59.jpg)
• Bright areas represent high iron concentration.• Dark areas represent low iron concentration.
Monitoring iron overload by MRI
![Page 60: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/60.jpg)
MANAGEMENT OF THALASSEMIA
![Page 61: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/61.jpg)
Treatment modalities
A. SupportiveB. CurativeC. Preventive
![Page 62: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/62.jpg)
A. Supportive management
• Multi-disciplinary approach• Focus on each patient’s clinical course
Transfusion
Iron Chelation
Fetal Hb Induction
Splenectomy
![Page 63: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/63.jpg)
Objectives of supportive management
• Maintenance of growth and development• Correction of anemia• Prevention of iron overload• Treatment of complications• Counseling and Prevention
![Page 64: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/64.jpg)
Blood Transfusion
![Page 65: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/65.jpg)
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
![Page 66: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/66.jpg)
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
![Page 67: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/67.jpg)
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
![Page 68: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/68.jpg)
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.
![Page 69: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/69.jpg)
Blood products for transfusion
• Packed red cell• Leukocyte reduced red cell• Washed red cell• Neocyte
![Page 70: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/70.jpg)
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
![Page 71: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/71.jpg)
Regularly Transfused
Irregularly Transfused
![Page 72: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/72.jpg)
• Normal growth • Normal physical activities• Adequately suppresses
bone marrow activity• Minimizes iron
accumulation
Regular transfusion allows
![Page 73: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/73.jpg)
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
![Page 74: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/74.jpg)
Thalassemic diet
![Page 75: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/75.jpg)
CHELATION THERAPY
![Page 76: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/76.jpg)
Chelator MetalChelator
Toxic
Excretion
Metal
What is chelation therapy?
![Page 77: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/77.jpg)
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
![Page 78: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/78.jpg)
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
![Page 79: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/79.jpg)
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
![Page 80: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/80.jpg)
Goals of chelation Therapy is achieved by:• Keeping serum ferritin <1000-2,000 ng/mL or• LIC <15 mg/g dry weight
![Page 81: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/81.jpg)
Iron chelating agents
• Desferrioxamine (DFO)• Deferiprone• Deferasirox
![Page 82: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/82.jpg)
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
![Page 83: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/83.jpg)
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.
![Page 84: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/84.jpg)
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
![Page 85: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/85.jpg)
Fetal Hb Induction
![Page 86: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/86.jpg)
Induction of fetal hemoglobin
Hb F enhancement• Hydroxyurea• Myelaran• Butyrate derivatives• Erythropoietin • 5-Azacytadine
![Page 87: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/87.jpg)
• 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.
![Page 88: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/88.jpg)
• 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.
![Page 89: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/89.jpg)
SPLENECTOMY
![Page 90: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/90.jpg)
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
![Page 91: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/91.jpg)
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
![Page 92: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/92.jpg)
Preventative measures
Immunoprophylaxis– At least 2 weeks before splenectomy Pneumococcus/meningococcus/Hemophilus
Chemoprophylaxis- Chemoprophylaxis with life-long oral
penicillin. Education
![Page 93: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/93.jpg)
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
![Page 94: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/94.jpg)
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
![Page 95: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/95.jpg)
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
![Page 96: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/96.jpg)
B. Curative treatment in thalassemia
• Stem cell transplantation• Gene therapy
![Page 97: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/97.jpg)
Stem cell transplantation?
![Page 98: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/98.jpg)
Stem cell transplantation
![Page 99: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/99.jpg)
Whom to offer?
Stem cell transplantation
![Page 100: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/100.jpg)
Cost Vs Risk benefit of patient
andAvailability of
DONOR
Stem cell transplantation
![Page 101: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/101.jpg)
Gene therapy
![Page 102: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/102.jpg)
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
![Page 103: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/103.jpg)
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
![Page 104: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/104.jpg)
Follow up
![Page 105: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/105.jpg)
Follow up
Monthly:• Complete blood count• Complete blood chemistry (including liver
function tests, BUN, creatinine) if taking deferasirox
• Record transfusion volume.
![Page 106: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/106.jpg)
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
![Page 107: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/107.jpg)
Follow up
Every 6 months:• Complete physical examination including Tanner
staging, • Monitor growth and development• Dental examination
![Page 108: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/108.jpg)
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.
![Page 109: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/109.jpg)
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).
![Page 110: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/110.jpg)
C. Prevention and control
Career detection/Screening Genetic counseling Prenatal diagnosis Health education
![Page 111: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/111.jpg)
Screening
• RBC indices (MCV, MCH, MCHC)• NESTROFT• HbA2
![Page 112: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/112.jpg)
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%
![Page 113: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/113.jpg)
NESTROFT
![Page 114: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/114.jpg)
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
![Page 115: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/115.jpg)
Genetic counseling
• Index case parents and relatives.• Antenatal visits of pregnant mothers.
![Page 116: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/116.jpg)
Genetic counseling
![Page 117: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/117.jpg)
• 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
![Page 118: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/118.jpg)
Chorionic Villus Biopsy
![Page 119: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/119.jpg)
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.
![Page 120: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/120.jpg)
Prognosis
![Page 121: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/121.jpg)
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
![Page 122: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/122.jpg)
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
![Page 123: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/123.jpg)
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.
![Page 124: Thalassemia](https://reader036.vdocuments.site/reader036/viewer/2022062522/58a2fe781a28abea508b46a3/html5/thumbnails/124.jpg)
Thank You