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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
http://3.bp.blogspot.com/_au5dJPQRwPc/SuW-DqyNqDI/AAAAAAAAAYs/UhZsxjhKzjw/s1600-h/B-T.JPG


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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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