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Anemia Hemolitik Pada Anak: Gambaran Klinis Thalassemia

BLOK XIII HEMATOLOGI DAN LIMFATIK FK UMP 2012


RINI PF

Basic Features
Thalassemia syndromes are characterized by varying degrees of ineffective hematopoiesis and increased hemolysis. Clinical syndromes are divided into and -thalassemias, each with varying numbers of their respective globin genes mutated

b-Thalassemia 1. b0-Thalassemia: No detectable chain synthesis due to absent -chain messenger RNA (mRNA) 2. b+-Thalassemia: Reduced -chain synthesis due to reduced or nonfunctional -chain mRNA 3. db-Thalassemia: - and -chain genes deleted

4. Eb-Thalassemia: Hemoglobin E (lysine glutamic acid at 26) and chain genes deletion 5. Hb Lepore: A fusion globin due to unequal crossover of the - and globin genes (the globin is produced at a low level because it is under globin regulation).

-Thalassemia 1. Silent carrier a-thalassemia: Deletion of one -globin gene 2. a-Thalassemia trait: Deletion of two -globin genes 3. Hb Constant Spring: Abnormal -chain variant produced in very small amounts, thereby mimicking deficiency of the gene 4. HbH disease: Deletion of 3 -globin genes, resulting in significant reduction of -chain synthesis 5. Hydrops fetalis: Deletion of all 4 -globin genes; no normal adult or fetal hemoglobin

-Thalassemia
Pathogenesis 1. Variable reduction of -chain synthesis (0, +, and variants) 2. Relative -globin chain excess resulting in intracellular precipitation of insoluble -chains 3. Increased but ineffective erythropoiesis with many red cell precursors prematurely destroyed; related to -chain excess

Sequelae

1. Hyperplastic marrow (bone marrow expansion with cortical thinning and bony abnormalities) 2. Increased iron absorption and iron overload (especially with repeated blood transfusion), resulting in a. Fibrosis/cirrhosis of the liver b. Endocrine disturbances (e.g., diabetes mellitus, hypothyroidism, hypogonadism, hypoparathyroidism, hypopituitarism) c. Skin hyperpigmentation d. Cardiac hemochromatosis manifesting as pericarditis, arrhythmias, cardiomegaly, pericarditis, and ultimately, cardiac failure

3. Hypersplenism a. Plasma volume expansion b. Shortened red cell life (of autologous and donor cells) c. Leukopenia d. Thrombocytopenia.

Hematology 1. Anemia: Hypochromic, microcytic 2. Reticulocytosis 3. Leukopenia and thrombocytopenia (may develop with hypersplenism) 4. Blood smear: Target cells and nucleated red cells, extreme anisocytosis, contracted red cells, polychromasia, punctate basophilia, circulating normoblasts

5. 51Cr-labeled red cell life span reduced (but the ineffective erythropoiesis is more important in the production of anemia) 6. Hemoglobin F raised; hemoglobin A2 increased 7. Bone marrow: May be megaloblastic (due to folate depletion); erythroid hyperplasia 8. Osmotic fragility: Decreased 9. Serum ferritin: Raised.

Biochemistry 1. Raised bilirubin (chiefly indirect) 2. Evidence of liver dysfunction (late, as cirrhosis develops) 3. Evidence of endocrine abnormalities, for example, diabetes (typically late), hypogonadism (low estrogen and testosterone).

Clinical Features Because of the variability in the severity of the fundamental defect, there is a spectrum of clinical severity (major to intermedia) that considerably influences management. -Thalassemia intermedia is defined as homozygous or doubly heterogeneous thalassemia, which is generally not transfusion dependent

1. Failure to thrive in early childhood 2. Anemia 3. Jaundice, usually slight; gallstones 4. Hepatosplenomegaly, which may be massive; hypersplenism 5. Abnormal facies, prominence of malar eminences, frontal bossing, depression of bridge of the nose, and exposure of upper central teeth

a. Skull radiographs showing hair-on-end appearance due to widening of diploic spaces b. Fractures due to marrow expansion and abnormal bone structure c. Generalized skeletal osteoporosis 6. Growth retardation, delayed puberty, primary amenorrhea in females, and other endocrine disturbances secondary to chronic anemia and iron overload 7. Leg ulcers 8. Skin bronzing

Complications Complications develop as a result of: Chronic anemia in patients who are undertransfused or in untransfused thalassemia intermedia patients Chronic transfusion with resultant hemosiderosis and hemochromatosis Poor compliance with chelation therapy (generally).

Complications: Endocrine disturbances (e.g., growth retardation, pituitary failure with impaired gonadotropins, hypogonadism, insulindependent diabetes mellitus, adrenal insufficiency, hypothyroidism, hypoparathyroidism) Cirrhosis of the liver and liver failure Cardiac failure due to myocardial iron overload (often associated with arrhythmias and pericarditis)

Extramedullary hematopoiesis, resulting in bony deformities. The causes of this include medullary expansion, deficiency of estrogen and testosterone, nutritional deficiency, and desferrioxamine toxicity. Manifestations include rickets, scoliosis, spinal deformities, nerve compression, fractures, and severe osteoporosis. Osteoporosis can be delayed by the early institution of chelation in childhood and sex hormone replacement early in adolescence.

Causes of Death 1. Congestive heart failure 2. Arrhythmia 3. Sepsis secondary to increased susceptibility to infection postsplenectomy 4. Multiple organ failure due to hemochromatosis.

Supportive Care 1. Folic acid is not necessary in hypertransfused patients; 1 mg daily orally is given to patients on low transfusion regimens. 2. Hepatitis B vaccination should be given to all patients. 3. Appropriate inotropic, antihypertensive, and antiarrhythmic drugs should be administered when indicated for cardiac dysfunction. 4. Endocrine intervention (i.e., thyroxine, growth hormone, estrogen, testosterone) should be implemented when indicated.

5. Cholecystectomy should be performed if gallstones are present. 6. Patients with high viral loads of hepatitis C that are not spontaneously decreasing should be treated with PEG-interferon and ribavirin. 7. HIV-positive patients should be treated with the appropriate antiviral medications

8. Genetic counseling and antenatal diagnosis (when indicated) should be carried out using chorionic villus sampling or amniocentesis. 9. Management of osteoporosis guidelines thalassemia

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