Thalassemia.pptx l3v6p

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- - 2 rantai globin-

- 4 molekul heme

GEN PENYANDI SINTESIS RANTAI GLOBIN  DAN 

2

2 1

Gen globin  & sejenis Gen globin  & sejenis

Hemoglobins

Masa Perkembangan

Kromosom 16 

G A

 

Kromosom 11

Hb Gower 1 (2 2) Hb Gower 2 (22) Hb Portland (22)

HbF (22)

HbA2 HbA (2  2) (2  2)

Embrio

Janin

Dewasa

Hemoglobin Types Hemoglobin Type • • • • • • •

Globin Chains

Hgb A1—92%--------- 22 Hgb A2—2.5%-------- 22 Hgb F — <1%---------22 Hgb H ------------------ 4 Bart’s Hgb--------------4 gluval 226 Hgb S-------------------glulys 226 Hgb C-------------------

Komposisi Hb dewasa: • HbA (>98%) – 22 • HbA2 (2,5-3,5%) - 22 • HbF (<1%) - 22

Jenis hemoglobin selama perkembangan

HbGower1 HbF HbGower2 HbPortland

HbA & HbA2 <

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 b

Porter JB. Br J Haematol. 2001;115:239-252. Andrews NC. N Engl J Med. 1999;341:1986-1995.

Organ Systems Affected by Iron Overload Pituitary gland Heart • Liver Pancreas Gonadal

Iron overload results in non– transferrin-bound iron in the plasma

•

Increased iron uptake into selective organs

•

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

Deferoxamine (Desferal®)

Slow infusion

0.5

Deferiprone (Ferriprox®)

Oral

2-3

3 daily

Renal

Nausea/vomiting, arthropathy, neutropenia, agranulocytosis,  liver fibrosis (?)

Deferasirox (Exjade®)

Oral

12 - 16

1 daily

Hepatobiliary

Transient nausea, diarrhea, rash

8 - 24 hours Renal 5 - 7 days and per week hepatic

23

Toxicity Infusion site rxns, allergic rxns, ocular, auditory

Terima Kasih