Thalassemia &

Treatment

Hematology Oncology Sub Division

Padjadjaran University – Hasan Sadikin Hospital
Bandung
2011
 What is thalassemia?

Genetic blood disorder resulting in a

mutation or deletion of the genes that
control globin production.

 damage the cell membrane, leading

either to hemolysis, ineffective
erythropoiesis, or both.

result in mild, moderate to severe anemia

 Molekul Hemoglobin

- 2 rantai globin-
- 4 molekul heme
- 2 rantai globin-
 GEN PENYANDI SINTESIS RANTAI GLOBIN  DAN 

2 2 1
Gen globin  Kromosom 16
& sejenis
 G A  
Gen globin  Kromosom 11
& sejenis
Hb Gower 1
(2 2)
Hemoglobins Hb Gower 2 HbF HbA2 HbA
(22) (22) (2  2) (2  2)
Hb Portland
(22)

Masa Embrio Janin Dewasa

Perkembangan
Hemoglobin Types

Hemoglobin Type Globin Chains

Komposisi Hb dewasa:
• Hgb A1—92%--------- 22
• Hgb A2—2.5%-------- 22
• HbA (>98%) – 22
• Hgb F — <1%---------22
• HbA2 (2,5-3,5%) - 22
• Hgb H ------------------ 4
• HbF (<1%) - 22
• Bart’s Hgb--------------4
• Hgb S--------------------226 gluval

• Hgb C------------------- 226 glulys

Jenis hemoglobin selama perkembangan

HbGower1 HbF HbA & HbA2

HbGower2 <<HbF
HbPortland
 Two Basic Groups of
Thalassemia Disorder
• Alpha Thalassemia

• Beta Thalassemia:
• Thalassemia Minor
• Thalassemia Intermediate.
• Thalassemia Major or Cooley's Anemia
Alpha Thalassemia

Result from gene deletions on chromosome 16

1 deletion—Silent carrier; no clinical significance

2 deletions— Thal trait; mild hypochromic
microcytic anemia
3 deletions—Hgb H; variable severity, but less severe
than Beta Thal Major
4 deletions—Bart’s Hgb; Hydrops Fetalis; In Utero or
early neonatal death
Alpha Thalassemias
• Usually no treatment indicated
• 4 deletions incompatible with life
• 3 or fewer deletions have only mild
anemia
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

• Erythropoiesis increases, sometimes
becomes extramedullary
-Thal—Clinical Presentation
 -Thalassemia Minor
• Minor point mutation
• Minimal anemia; no treatment indicated
 -Thalassemia Intermedia
• Homozygous minor point mutation or more severe
heterozygote
• Can be a spectrum; most often do not require chronic
transfusions
 -Thalassemia Major-Cooley’s Anemia
• Severe gene mutations
• Need careful observation and intensive treatment
 Beta Thalassemia Major
• Reduced or nonexistent production of -globin
• Poor oxygen-carrying capacity of RBCs
• Failure to thrive, poor brain development
• Increased alpha globin production and precipitation
• RBC precursors are destroyed within the marrow

• Increased splenic destruction of dysfunctional RBCs

• Anemia, jaundice, splenomegaly

• Hyperplastic Bone Marrow

• Ineffective erythropoiesis—RBC precursors destroyed
• Poor bone growth, frontal bossing, bone pain
• Increase in extramedullary erythropoiesis

• Iron overload—increased absorption and transfusions

• Endocrine disorders, Cardiomyopathy, Liver failure
b-Thalassemia Major—Lab findings

• Hypochromic, microcytic anemia

• Target Cells, nucleated RBCs, anisocytosis
• Reticulocytosis
• Hemoglobin electrophoresis shows
• Increased Hgb A2—delta globin production
• Increased Hgb F—gamma globin production
• Hyperbilirubinemia
• LFT abnormalities (late finding)
• TFT abnormalities, hyperglycemia (late endocrine
findings)
Normal Defisiensi Fe Thalassemia
-Thalassemia Major--Treatment
• Chronic Transfusion Therapy
• Maximizes growth and development
• Suppresses the patient’s own ineffective erythropoiesis and excessive
dietary iron absorption
• PRBC transfusions often monthly to maintain Hgb 10-12

• Chelation Therapy
• Binds free iron and reduces hemosiderin deposits
• 8-hour subcutaneous infusion of deferoxamine, 5 nights/week
• Start after 1year of chronic transfusions or ferritin>1000 ng/dl

• Splenectomy--indications
• Trasfusion requirements increase 50% in 6mo
• PRBCs per year >250cc/kg
• Severe leukopenia or thrombocytopenia
-Thalassemia Major Complications and
Emergencies
• Sepsis—Encapsulated organisms
• Strep Pneumo
• Cardiomyopathy—presentation in CHF
• Use diuretics, digoxin, and
deferoxamine
• Endocrinopathies—presentation in
DKA
• Take care during hydration so as not
to precipitate CHF from fluid
overload
Anticipatory Guidance and Follow Up

• Immunizations—Hepatitis B, Pneumovax
• Follow for signs of diabetes, hypothyroid,
gonadotropin deficiency
• Follow for signs of cardiomyopathy or CHF
• Follow for signs of hepatic dysfunction
• Osteoporosis prevention
• Diet, exercise
• Hormone supplementation
• Osteoclast-inhibiting medications
• Follow ferritin levels
 On The Horizon

• Pharmacologically upregulating gamma

globin synthesis, increasing Hgb F
• Carries O2 better than Hgb A2
• Will help bind  globins and decrease
precipitate
• Bone Marrow transplant
• Gene Therapy
• Inserting healthy  genes into stem
cells and transplanting
 Permanent Treatment Options
 Bone Marrow Transplants
 Replacing patient’s marrow with donor marrow
 First performed on thalassemia patient in 1981
 Difficult, because donor must be exact match for
recipient
 Even a sibling would only have a 1 in 4 chance of
being a donor

 Cord Blood Transplants

 Rich in stem cells
 Also needs to be an exact match
 Iron Loading From Blood
Transfusions
• 1 unit of blood contains approximately
200 mg of irona
• Normally, total body iron is approximately
3 to 4 g
• Chronic transfusion-dependent patients
have an iron excess of 0.3 to 0.7
mg/kg/day, equivalent to 4 to 10 g of iron
per yearb
• Iron accumulates with repeated blood
transfusion

a Porter JB. Br J Haematol. 2001;115:239-252.

b Andrews NC. N Engl J Med. 1999;341:1986-1995.
 Organ Systems Affected by
Iron Overload
Pituitary gland
Heart
• Iron overload results in non–
Liver transferrin-bound
Pancreas iron in the plasma
• Increased iron uptake into
selective organs
Gonadal • Generation of free hydroxyl
radicals

Tissue damage
Complications of Iron Overload

• Cardiomyopathy and cardiac failure

• Hepatic cirrhosis

• Diabetes mellitus

• Impaired growth

• Hypogonadism and infertility

Andrews NC. N Engl J Med. 1999;341:1986–1995

 Iron Chelation Agents

T½,
Agent Route hours Schedule Clearance Toxicity
Deferoxamine Slow 0.5 8 - 24 hours Renal Infusion site rxns,
(Desferal®) infusion 5 - 7 days and allergic rxns,
per week hepatic ocular, auditory
Deferiprone Oral 2-3 3 daily Renal Nausea/vomiting,
(Ferriprox®) arthropathy,
neutropenia,
agranulocytosis,
 liver fibrosis (?)
Deferasirox Oral 12 - 16 1 daily Hepato- Transient nausea,
(Exjade®) biliary diarrhea, rash

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Terima Kasih