Thalassemia

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The document discusses various types of hemoglobinopathies including thalassemias, their classification, clinical features, diagnosis and screening methods.

Hemoglobinopathies are classified into two major groups: 1) thalassemias which are quantitative deficiencies in the production of globin chains, and 2) hemoglobin disorders which are structural abnormalities of globin chains.

The common thalassemias are classified based on which globin chain is deficient. The document discusses various genotypes and their associated clinical features and hemoglobin electrophoresis patterns.

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THALASSEMIA


HEMATO-ONCOLOGY DIVISION
PEDIATRIC DEPARTEMENT
MEDICAL SCHOOL
UNIVERSITY OF NORTH SUMATERA


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3
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HEMOGLOBINOPATHIES

CLASSIFIED INTO TWO MAJOR GROUPS

1. THALASSEMIAS
Quantitative deficiencies in the
production of globin chains

2. HEMOGLOBINS DISORDER
Structural abnormalities of globin chains

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CLASSIFICATION OF THE COMMON
THALASSEMIAS AND RELATED DISORDERS
-Thalassemia

+

o
- Thalassemia

i
+
Hb Lepore thalassemia
(

)
o

(
A
)
o

- Thalassemia
()
o
- Thalassemia
-or- Thalassemia associated with -chain variants
Hb S -Thalassemia
Hb E -Thalassemia
many others
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CLASSIFICATION OF THE COMMON
THALASSEMIAS AND RELATED DISORDERS

-Thalassemia

+
(deletion)

+
(non-deletion)

o
Hereditary persistence of HbF
Deletion
Non-deletion
A

+ G

+

Unlike to -globin gene cluster


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- THALASSEMIA

DIAGNOSE :
African, Mediteranian, Middle Eastern,
Chinese, or Southeast Asian ancestry

Microcytic, hypochromic anemia of
variable severity

Hemoglobin Barts detected by neonatal
screening
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PATOPHYSIOLOGY
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USUAL
GENOTYP
ES
-
GENE
NUMBE
R
CLINICAL
FEATURE
S
HEMOGLOBIN
ELECTROPHORESIS
BIRTH > 6 MO
/ 4 NORMAL NORMAL NORMAL
- / 3
SILENT
CARRIER
0 3% Hb Barts NORMAL
-- / or
- / -
2
- THAL
TRAIT
2 10% Hb Barts NORMAL
-- / - 1
Hb H
DISEASE
15 30% Hb
Barts
Hb H
PRESENT
-- / -- 0
FETAL
HYDROP
S
> 75% Hb Bart,s -
Table 1. The - thalassemias
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Thalassemia _alpha
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TREATMENT
-thalassemia trait require no treatment

Hb H disease should receive folic acid
avoid the same oxidant drugs
Transfusions may be required
Splenectomy
Genetic counseling and prenatal diagnosis

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-THALASSEMIA

Essentials of diagnosis & typical features

-thalassemia minor
- mild hypochromic microcytic anemia
Haemoglobi 90-110g/l
Mean cell volume 50-70 fl
mean corpuscular haemoglobin 20-22 pq
- no clinical features, patient asymptomatic
- often diagnosed on routine blood count
- raised Hb A
2
level
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-Thalassemia major :
severe anemia
Blood film
- pronounced variation in red cell size and shape
- pale (hypochromic) red cells
- target cells
- basophillic stippling
- nucleated red cells
- moderately raised reticulocyte count
infants are well at birth but develop anemia in first
few months of life when switch occurs from to
globin chains
progressive splenomegaly; iron loading; proneness to
infection
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SCREENING
Peripheral blood stain
Mean corpuscular volume (MCV) value
and MCH value
Mentzer index
RDW index
Hb-electroforese


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PRENATAL DIAGNOSIS
If mother suffered thalassemia
DNA analysis by CVS (chorion vilus
sampling) at 9-12
th
week of gestation
PCR rapid detection of mutation
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Thalassemia_beta
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Thalassemia minor
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Thalassemia major
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22
thalassemia
Hb elektroforese
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TREATMENT
red cell transfusion : PRC, neocyte
infective complication
- viral hepatitis
- Yersinia infection
splenectomy
chelation theraphy : desferrioxamine
if serum ferritin 1500 g or got
transfusion 10-20 x
Dose of desferrioxamine :20-40 mg/kgBW
for children
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INFECTIONS IN THALASSAEMIA MAJOR
The second commonest cause of death in thalassaemia major
The reasons for infection are :
Transmission by blood transfusion
Altered host immunity due to :
Hypersplenisme
Iron overload and chelation therapy
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HEPATITIS C VIRUS
RNA virus was first characterized in 1989
Antibodies after infection are strain specific
Preventive : careful selection of voluntary donors and
blood donor screening

The severity of hep.C greater because of:
Concomitant iron overload
Other concurrent viral infections ( HBV, HIV )

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COMPLICATIONS OF INFECTION
Acute infection
Chronic infection
Cirrhosis
End-stage liver disease
Hepatocellular carcinoma (HCC)
Non hepatic manifestations : arthritis, keratoconjunctivitis
sicca, lichen planus, glomerulonephritis, and vasculitis.
Essential mixed cryoglobulinemia (EMC)
Porphyria cutanea tarda

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DIAGNOSIS AND MONITORING
Antibody Testing
HCV RNA
Detected by PCR
Moct reliable indicator of viral activity
Precedes sALT elevation in acute or recurrent cases by
2-10 weeks
Anti HCV
Detected by RIBA
Liver biopsy
Determined of the extend of liver disease
Assesment liver tissue iron load
Monitoring progression and response to antiviral virus
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TREATMENT
Selection of patients for therapy
Confirmed presence of HCV-RNA
Moderate to high sALT level
Abnormal liver histology
Presence of persistent HCV RNA sufficient to consider
treatment
Response to treatment
Biochemical (sALT)
Virological (HCV-RNA)
The timing of the above response
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Treatment regiment : Interferone
Dose: 3 MU sc or IM , 3 times daily
Duration : 12 24 months
Side effect : flu like symptoms, insomnia, cognitive
and mood changes, neutropenia, thrombocytopenia,
hypothyroidism, heart failure
Monitoring side effect : thyroid function, blood
counts

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RE-TREATMENT
if non response, relaps, partial response, and
breakthrough patient

Re-treatment options :
Recombinant interferon with Ribavirin for 6 months
The same drug with longer periode (12-24 months),
or higher dose for 6-12 months
A different interferon
Side effect : haemolysis in thalassaemia patients

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Management of liver disease is important for :
Children
Cirrhosis
Immunosuppresed patients
Pregnancy
Acute hepatitis C

PREVENTION
No vaccine or immunoglobulin
Safe sexual practices
Avoiding sharing toothbrushes, razors, eating utensils.
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HEPATITIS B VIRUS
In thalassaemia major : HBsAg positive varies from <1%
to >20%, and past infection rates range from <10-70%

HBV marker :
Acute : HBsAg (4-5 mo), HBeAg (1-3 mo)
Chronic : HBsAg, anti - HBc
Previous infection or vaccination : antibody for HBsAg,
with anti HBc (prev. inf), or without anti
HBc(vaccination)
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Natural history :
Acute hepatitis : incubation periode 4-20 weeks
Progression to chronic hepatitis B : 5-10% in healthy
adults, and 90% in neonates
Cirrhosis : 1-2,2 % per year
Hepatocellular carcinoma

PREVENTION
Hep B Vaccine: 3 times (at 0, 1 and 6 mo), and booster
Hep B vaccine and HBIg to neonates delivery by a carrier

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TREATMENT
Lamivudin (3 TC)
Recombinant -interferon

HUMAN IMMUNODEFICIENCY VIRUS (HIV)
Prevalence in thalassaemia : <1% - > 20%
Management :
Antiretroviral therapy
Erythropoetin
Caution for drug that can exacerbate neutropenia
Control of iron overload
splenectomy
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CYTOMEGALOVIRUS
Treatment : Bone Marrow Transplantation
Leucoreduction of blood product

PARVOVIRUS B 19
May cause transient aplastic crisis
Characterized by :
A fall in Hb 2 g/dl or more
Reticulocytes < 0,2%
Absence of red blood precursors in the bone marrow
B 19 DNA viraemia reach up to 10
14
virious/ml
Transient drop lymphocytes, neutrophils, platelet

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Treatment :
Blood transfusion : acute B19 crises
Immunoglobulin administrations : chronics illness

MALARIA AND CHAGAS DISEASE
Plasmodium sp and Trypanosoma cruzii remain viable
in refrigerator blood components at least 2 weeks
Prevent transmission through blood product.
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IRON ASSOCIATED INFECTION
Bacterial Infections : Yersinia anterocolica, Klebsiella sp,
E. colli, Strept. Pneumonia, Pseudomonas aeroginosa,
Listeria monocytogenes

YERSINIA ENTEROCOLITICA
Lives in an iron rich environment
Transmitted by : ingested of contaminated food, meat,
water.
Mortality rate among recipient > 50%

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Clinical manifestations :
Severe in thalassaemia
Fever, abvdominal pain, diarrhoea, or vomiting
Athralgia, skin rashes
Complications : abdominal abscess, nephritis, splenic
abscess

Laboratory diagnosis
Culture from stool, blood, samples of affected tissue (e.g.
gut, lymph node)
Serial IgG titres

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TREATMENT
Stop iron chelation therapy immediately
Obtain suitable laboratory samples
Antibiotic treatment
Ciprofloxacin
Gentamycin
Chloramphenicol
Trimethoprim-sulfomethoxazole
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Table 1. Clinical and laboratory evaluation checklist
Monthly
CBC

Every 3 months
serum feritin
clinical chemistry
glucose
urate
creatinine
iron
TIBC
alk. Phosphatase
- GT
ALT/GPT
AST/GOT
LDH
Every 6 months
cardiac evaluations
cardiac echo
EKG
heart chamber
dimensions
systolic function
diastolic function
Fractional shortening
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Table 1. Clinical and laboratory evaluation checklist
Yearly
Virology
Hep C panel ( anti-
HCV, anti-HCV RIBA )
Hep B panel (HBsAg,
anti HBs, anti HBc Ig)
anti HIV 1+ 2

liver biopsi

endocrine function
evaluation
free T
4
and TSH
parathyroid hormone
FSH
LH
testosterone
estradiol
DHEA-S
fasting a.m. cortisol
OGTT
bone age and density
zinc, cooper,
selenium,
Vit C, vit E

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Table 1. Clinical and laboratory evaluation checklist
Yearly
complete physical exam
opthalmology
examination
audiology examination

As Indicated
24 hour Holter monitor
Cardiac stress test ( EST)
anti HBc Ig M
anti HBe
HBeAg
anti HDV
HCV - RNA

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INSERTION OF
DESFEROXAMINE
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4
post splenectomy
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