Ma Thal Managment
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Thalassemia
Management
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Outline
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Case presentation
27 years old gentleman from Pakistan
Known case of:
Beta Thalassemia since birth on regular blood transfusions and Iron chelation therapy
Hepatitis C and liver cirrhosis, Hypoganadizm,
hypoadrenalism, and DM
Refered from GS team on 04/07/2011 for
splenectomy.
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Case presentation
Recently blood transfusion requirements increased so he
was referred to RH for splenectomy.
Medical problems on admission:
Anaemia
Low platelet count
Severely disturbed coagulation
? Cardiac status
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Case presentation
Past medical Hx:
Beta Thalassemia since birth on regular blood transfusions
and Iron chelating therapy.
Hepatitis C (2005) and liver cirrhosis (2008) complicated to: Grade I oesophageal varices (2010),
Hyperspleenism (2011)
2008: Hypoganadizm, hypoadrenalism, DM, arrhythmia.
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Case presentation
Family history: 7 siblings: 1 brother and 1 sister have TM
Mother and father are carriers
Social history:
not smoking or drinking alcohol.
Medication and allergic history:
Medication:
Propranolol 10mg BD
Magnesium 250mg BD
Lantus 4U HS
Vitamin D 50,000 IV once / 3W Vitamin C 100mg OD
Folic acid 5mg OD
Desferal 3gm 6d/1W
Alendronate 70mg once/week
Calcium carbonate 600mg OD
Not known for any allergy.
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Case presentation
Physical examination on admission:
Conscious, alert and oriented.
Signs of pallor (pale skin, mucosal lining and nails bed).
Vitally stable.
Chest: clear.
CVS: S1 + S2 no murmurs
Abdomen:
soft, lax, no tenderness
Hepatosplenomegaly : Liver: 7cm below costal margin
Spleen: 6cm below costal margin
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Case presentation
Laboratory values on admission:
CB
C
WBC 1.8
Hb 7.3
Plat 55
MCV 84.7
MCH 28.5
HTC 21.6
RDW 17.5
PT 16.8
INR 1.47
PTT 45.5
LFT
Albumin 2.9Alk. Phos 109
ALAT 66
T. Bilir. 2.7
TP 9.1
Globulin 6.2
LDH 252
GGT 27
ASAT 96
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Case presentation
Plan:
For splenectomy
Vitamin K 10mg PO 3/7
Echo
Coagulation follow up
PRBC 2U
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Follow up
05/07/2011:
Transfuse FFP 4U
Transfuse PRBC 2U
Lasix 20mg iv
Continue Vit. K
06/07/201109/07/2011:
Transfuse FFP 4U
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Follow up
10/07/2011:
Splenectomy planed on 13/07/2011
Transfuse FFP 4U daily
On operation day to give:
FFP 6U
Cryoprecipitate 10U
NOVO 7
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Follow up
12/07/2011:
Developed mild breathing difficulty.
No finding on examination.
Received Cryo 4U
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Follow up
13/07/2011:
Complain of diarrhia, abdominal pain.
SoB still there.
Plan:
Chest X-ray.
Postpone surgery to 17/07/2011
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Chest X-Ray
13/07/2011
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Follow up
14/07/201117/07/2011:
Vit. K 10mg OD
Cryo 4U
FFP 4U
Prednisolone 20mg BD
Ciprofloxacin 500mg BD
Transfuse Plat. 6U
PRBC 2U
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Follow up
17/07/2011:
For splenectomy today
Labs
Chest Xray
To give factor 7 Intra30mcg/kg when start
operating and to repeat it
after 30min.
FFP 4U and 6U postop
PRBC 2U stat andprepare 6U for surgery.
Cryo 4U
CBC
WBC 1.7
Hb 6.1
Plat 47
MCV 84.5
MCH 289
HTC 17.8
RDW 18
PT 21.7
INR 1.74
PTT 45.9
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Chest X-RayAM: 17/07/2011
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Splenectomy
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Splenectomy
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Splenectomy
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cholecystectomy
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Chest X-RayPM: 17/07/2011
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Chest X-Ray
AM: 19/07/2011
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Hemoglobin
Tetramer of 4 globin
chains (proteins)
Each with a heme group
containing iron Can be distinguished by
electrophoresis
Chain types
Alpha Beta
Gamma
Delta
Zeta and epsilon are
embryonic
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Fetal and Neonatal Hemoglobins
birth After 1 year
Fetal Hgb F
(alpha2 + gamma 2)
60 - 85 02
Adult (major)
95%
Hgb A
(alpha2 +beta 2)
15 - 40 9698
Adult (minor) Hgb A2
(alpha 2 + delta2)
1 1 - 3
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About Hemoglobin
Hemoglobin binds oxygen and carries it to tissues
Erythrocytes (red blood cells) consist mainly of
hemoglobin
Function of red blood cell dependent on:
Hemoglobin type and content
Membrane stability
Energy production
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RBC
Formed in bone marrow
Life span is 120 days (+/- 20 days)
Cleared in spleen
Reticulocytes are newly formed RBC in circulation
If no new production, Hgb drops 1 gm/week
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Anemia
Hgb > 2 standard deviations below the mean for age.
General mechanisms
hgb loss (usually bleeding)
hgb production
destruction of RBC
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Anemia Approach
History
Diet
Blood loss
Family history
Recent illness
Past history of anemia and cause
Physical Examination
Evaluate conjunctiva and mucous membranes for paleness
Cardiovascular system for murmur
Liver
Spleen
Lymph nodes
Look for jaundice or purpura
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Anemia Approach
Labs
Complete blood count with differential and platelets
Evaluation of smear with red cell indices
Reticulocyte count
Other tests Serum bilirubin, LDH, hgb electrophoresis, quantitative hgb
A2 and F
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Anemia Approach
smear
HypochromicMicrocytic
NormochromicNormocytic
Macrochromic
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Hypocromic Microcytic Anemia
Causes:
Childhood:
iron deficiency anemia,
thalassemia
Adulthood: iron deficiency anemia
sideroblastic anemia, congenital or acquired
anemia of chronic disease
lead poisoning (rare)
pyridoxine deficiency myeloma
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Thalassemia
group of inherited disorders (autosomal recessive) that
affect the synthesis of hemoglobin;
characterized by a reduced or absent output of one or
more of the globin chains of adult hemoglobin .
The name is derived from the Greek words Thalasso =
Sea" and "Hemia = Blood" in reference to anemia of the
sea.
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Thalassemiacont
Mutations in a givenglobin gene can cause a
decrease in production
of that globin, resulting in
deficiency
Depending on the
involved genes,
the defect is classified
as: -thalassaemia
-thalassaemia
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Alpha Thalassemia
mutation of 1 or more of the 4 alpha globin genes on
chromosome 16
severity of disease depends on number of genes
affected
results in an excess of beta globins Subtypes:
Silent Carriers
-thalassaemia trait
Hgb H disease
-thalassaemia major
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Silent Carriers (heterozygotes +/-)
3 functional alpha globingenes
No symptoms, but
thalassemia couldpotentially appear in
offspring
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Alpha Thalassemia Trait
2 functional globin genes
results in smaller blood
cells that are lighter in
color
no serious symptoms,
except slight anemia
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Hemoglobin H Disease
1 functional globin gene
results in very lightly
colored red blood cells
and possible severe
anemia
hemoglobin H is
susceptible to oxidation,
therefore oxidant drugs
and foods are avoided
treated with folate to aid
blood cell production
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Alpha Thalassemia Major
no functional globingenes
death before birth
(embryonic lethality)
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Beta Thalassemia
mutations on chromosome 11
hundreds of mutations possible in the beta globin gene,
therefore beta thalassemia is more diverse
Results in excess of alpha globins
Subtypes:
Minor
Intermedia
Major or Cooleys anemia
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-thalassaemia Minor
slight lack of beta globin
smaller red blood cells
that are lighter in colour
due to lack ofhemoglobin
no major symptoms
except slight anemia
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-thalassaemia Intermedia
lack of beta globin is moresignificant
bony deformities can be
seen.
causes late development,
exercise intolerance, andhigh levels of iron in blood
due to reabsorption in the
GI tract
if unable to maintain
hemoglobin levels between67 gm/dl, transfusion or
splenectomy is
recommended
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-thalassaemia Major
complete absence ofbeta globin
enlarged spleen, lightly
colored blood cells
severe anemia
chronic transfusions
required, in conjunction
with chelating therapy to
reduce iron
(desferoxamine)
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-thalassaemia Major Molecular basis:
Patients with -thalassaemia major have inherited two -
thalassaemia alleles
Located on each copy of chromosome 11
Hypochromic, abnormally shaped red blood cells
Contain significantly reduced amounts of haemoglobin than normalblood cells because of diminished HbA synthesis
Deposition of precipitated aggregates of free
-globin chains results in accumulation
Damages erythrocytes, precursor cells in bone marrow
Resulting anaemia so severe that patients usually require chronicblood transfusions
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.
Pathophysiologic Sequelae of Untreated Thalassaemia and
Corresponding Clinical Manifestations
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Epidemiology
Thalassemias are particularly associated with people of
Mediterranean origin, Arabs, and Asians.
The Maldives has the highest incidence of Thalassemia
in the world with a carrier rate of 18% of the population.
The estimated prevalence is 16% in people from Cyprus,
1% in Thailand, and 3-8% in populations from
Bangladesh, China, India, Malaysia and Pakistan.
UAE:
one in 12 persons in the UAE is a thalassemia carrier
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Due to the continual migration of populations from
one area to another, there is virtually no country of the
world now in which thalassaemia does not affect
some percentage of the inhabitants
ThalassaemiaGlobal Distribution
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-thalassaemia Major
Clinical features: Clinical manifestations of anaemia emerge at 6 months2 years
Infants protected by prenatal HbF production
If untreated Facial and skeletal changes result from bone marrow expansion
Average survival
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Clinical manifestations
General appearance
Slated-grey hyperpigmentation (Iron
overload)
Short stature (growth retardation)
Hands
Finger clubbing -> Chronic liver
disease
Pallor over palmar crease
Face:
Frontal bossing
Prominent cheeks Flat nasal bridge
Inter-dental widening
Jaw protuberance
Eyes
Jaundice
Pallor
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Clinical manifestations
Chest
Signs of heart failure
Abdomen:
Hepatomegaly (Extramedullary erythropoiesis, ironoverload, HCV, HBV infection)
Massive splenomegaly
Splenectomy scar
Insulin injection marks
Desferioxamine-infusion pump
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B Thal Iron deficiency Anemia
Serum Fe / ferritin N
TIBC N
Fe / TIBC N
Hgb A2 Hgb F N
MCV/RBC 13
RDW N
RBC morphology Basophilic stippling Slightly abnormal
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Basophilic stippling
H t t Diff ti t M j f I t di
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Hot to Differentiate Major from Intermedia
Thalassaemia Major Thalassaemia IntermediaMore Likely More Likely
ClinicalPresentation (years) 2Hb levels (g/dL) 67 810Liver/spleen enlargement Severe Moderate to severe
HaematologicHbF (%) >50 1050 (may be up to 100%)
HbA2 (%) 4GeneticParents Both carriers of high HbA2 1 or both atypical carriers:
-thalassaemia - High HbF -thalassaemia- Borderline HbA2
Molecular
Type of mutation Severe Mild/silent
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Laboratory diagnosis
Thalassemia minor:
Blood smear shows hypochromia and microcytosis
(similar to Iron Deficiency Anemia).
Blood indices:
MCV< 75 fl, Hb usually> 10,
Hematocrit> 30%,
RDW < 14%.
Hemoglobin A2 often elevated > 3%, sometimes reaching 7-
8%.
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Laboratory diagnosis- Cont
Thalassemia major:
-Blood smear shows profound microcytic anemia,
with extreme hypochromia, tear drop, target cells andnucleated RBCs.
-Hemoglobin may be very low at 3-4 g/dl.
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Complications Thalassaemia major complications mostly due to iron
overload and frequent blood transfusions Heart failure
Infection (blood transfusion, postsplenectomy)
Hypogonadism and infertility
Diabetes mellitus
Hypothyroidism
Thalassaemia intermedia complications include
Thrombosis
Pulmonary hypertension
Leg ulcers
Extramedullary haematopoiesis
Endocrine disorders (osteoporosis, hypogonadism)
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Iron Overload
Iron overload occurs when:
Transfusion of red blood cells (thalassaemia major)
Increased absorption of iron from the digestive tract
(thalassaemia intermedia)
Because there is no mechanism in humans to excretethe excess iron, this has to be removed by chelation
therapy
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Iron Overload
1 unit of blood contains approximately200250 mg of iron
Chronic transfusion-dependent patients have an iron excess of ~
0.320.64 mg/kg/d
With repeated infusions, iron accumulates Signs of iron overload can be seen after anywhere from 10 to 20
transfusions.
Normal intestinal iron absorption is about 11.5 mg/d
In thalassaemic patients who do not receive any transfusion,
iron absorption increases
This represents a supplementary 12 g of iron loading per year
Iron overload can lead to early mortality
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Evaluation of Iron Overload
Serum ferritin concentration Noninvasive
Accuracy in iron overload questionable
Liver iron concentration (LIC)
Liver biopsy Reference standard
MRI
Noninvasive, FDA-approved technique
SQUID: Superconducting QuantumInterference Device:
This imaging modality uses a very low-
power magnetic field with sensitive
detectors that measure the interference
of iron within the field
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Prognosis
Depends on the time of presentation
Related to degree of severity
Usually in first few years of life
Untreated severe thalassemia
--/--: Prenatal or perinatal death
--/- & --/cs: Normal life span with chronic hemolytic anemia
Untreated thalassemia
Major: Death in first or second decade of life
Intermedia: Usually normal life span
Minor/Minima: Normal life span
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Management of B Thal Major
Standards of Care Guidelines for Thalassemia2009(published by Childrens Hospital & Research center in
Oakland):
DNA Testing Prior to Treatment
Decide for regular transfusion:
initial hemoglob in level is well below 6 g/dL.
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Management B Thal Major
Splenectomy:
Indicated in the transfusion-dependent patient when
hypersplenism blood transfusion requirement and prevents
adequate control of body iron with chelation therapy.
An enlarged spleenwithout an associated increase intransfusion requirementis not necessarily an indication for
surgery.
Patients must receive adequate immunization prior to surgery
against Streptococcus pneumoniae,
Haemophilus influenzae type B, and
Neisseria meningitides.
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Management B Thal Major
Splenectomy:
After splenectomy, patients should receive oral penicillin
prophylaxis (250 mg twice daily) and be instructed to seek
urgent medical attention for a fever over 38C
Post-splenectomy thrombocytosis is common, and low-doseaspirin should be given during this time.
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Hep C:
Treatment consists of pegylated interferon alfa given as a
subcutaneous injection once a week and oral ribavirin twice
daily for patients 18 years and older.
Endocrine dysfunction:
due to iron deposition and toxicity to the endocrine tissue
significant morbidity:
Gonadal failure,
sterility, growth failure ,
osteopenia and osteoporosis.
Diabetes mellitus.
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Hematopoietic Cell Transplantation: First performed on thalassemia patient in 1981
Is the only treatment that offers a potential cure for thalassemia at
this time.
HCT relies on high-dose chemotherapy to eliminate thalassemia-
producing cells in the marrow and replaces them with healthy
donor cells from bone marrow or umbilical cord blood, usually
taken from a human-leukocyte antigen (HLA) match.
This therapy should be considered for all patients who have a
suitable donor. Early referral to a transplant center is
recommended, as HCT has a better outcome in younger patients.
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Conclusion
Thalassaemias heterogeneous group of disorders ofhaemoglobin production
-TM present in first year of life, requires transfusions
-TI later presentation, may not require transfusion therapy
Iron overload may be present in both conditions, caused
by transfusion therapy or excess GI iron absorption
Current treatment involves chelation therapy
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References
Standards of Care Guidelines for Thalassemia2009(published by Childrens Hospital & Research center in
Oakland):
http://www.thalassemia.com/documents/thalhandbook20
08.final.pdf
Olivieri, N. F. "The Beta Thalassemias." The New
England Journal of Medicine 341 (1999): 99-109.
Forget BG. In Hoffman: Hematology: Basic Principles
and Practice, 2005.
http://www.thalassemia.com/documents/thalhandbook2008.final.pdfhttp://www.thalassemia.com/documents/thalhandbook2008.final.pdfhttp://www.thalassemia.com/documents/thalhandbook2008.final.pdfhttp://www.thalassemia.com/documents/thalhandbook2008.final.pdf -
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