You are on page 1of 40


Damanik Sam Raj Rayan Day/Date : Tuesday, 22nd of June 2010 Supervisor : dr. Lily Irsa, Sp.A(K)

INTRODUCTION Thalassemias are genetic disorders in globin chain production, inherited autosomal recessive blood disease. In thalassemia, the genetic defect results in reduced rate of synthesis of one of the globin chains that make up hemoglobin. Reduced synthesis of one of the globin chains causes the formation of abnormal hemoglobin molecules, and this in turn causes the anemia which is the characteristic presenting symptom of the thalassemias.1,2 Thalassemia was first defined in 1925 when Dr. Thomas B. Cooley described five young children with severe anemia, splenomegaly, and unusual bone abnormalities and called the disorder erythroblastic or Mediterranean anemia because of circulating nucleated red blood cells and because all of his patients were of Italian or Greek ethnicity. In 1932 Whipple and Bradford coined the term thalassemia from the Greek word thalassa, which means the sea (Mediterranean) to describe this entity. Somewhat later, a mild microcytic anemia was described in families of Cooley anemia patients, and it was soon realized that this disorder was caused by heterozygous inheritance of abnormal genes that, when homozygous, produced severe Cooley anemia.2,3 In Europe, Riette described Italian children with unexplained mild hypochromic and microcytic anemia in the same year Cooley reported the severe form of anemia later named after him. In addition, Wintrobe and coworkers in the United States reported a mild anemia in both parents of a child with Cooley anemia. This anemia was similar to the one that Riette described in Italy. Only then was Cooley's severe anemia recognized as the homozygous form of the mild

hypochromic and microcytic anemia that Riette and Wintrobe described. This severe form was then labeled as thalassemia major and the mild form as thalassemia minor. These initial patients are now recognized to have been afflicted with β thalassemia. In the following few years, different types of thalassemia that involved polypeptide chains other than β chains were recognized and described in detail. In recent years, the molecular biology and genetics of the thalassemia syndromes have been described in detail, revealing the wide range of mutations encountered in each type of thalassemia.2,4 EPIDEMIOLOGY Certain types of thalassemia are more common in specific parts of the world. β thalassemia is much more common in Mediterranean countries such as Greece, Italy, and Spain. Many Mediterranean islands, including Cyprus, Sardinia, and Malta, have a significantly high incidence of severe β thalassemia, constituting a major public health problem. For instance, in Cyprus, 1 in 7 individuals carries the gene, which translates into 1 in 49 marriages between carriers and 1 in 158 newborns expected to have b thalassemia major. As a result, preventive measures established and enforced by public health authorities have been very effective in decreasing the incidence among their populations. b thalassemia is also common in North Africa, the Middle East, India, and Eastern Europe. Conversely, α thalassemia is more common in Southeast Asia, India, the Middle East, and Africa. Worldwide, 15 million people have clinically apparent thalassemic disorders. Reportedly, disorders worldwide, and people who carry thalassemia in India alone number approximately 30 million. These facts confirm that thalassemias are among the most common genetic disorders in humans; they are encountered among all ethnic groups and in almost every country around the world.2,4,5 Although β-thalassemia has >200 mutations, most are rare. Approximately 20 common alleles constitute 80% of the known thalassemias worldwide; 3% of the world's population carries genes for β-thalassemia, and in Southeast Asia, 5– 10% of the population carries genes for α-thalassemia. In a particular area there


are fewer common alleles. In the U.S., an estimated 2,000 individuals have βthalassemia.1 ETIOLOGY Thalassemia syndromes are characterized by varying degrees of ineffective hematopoiesis and increased hemolysis. Clinical syndromes are divided into αand β-thalassemias, each with varying numbers of their respective globin genes mutated. There is a wide array of genetic defects and a corresponding diversity of clinical syndromes. Most β-thalassemias are due to point mutations in one or both of the two β-globin genes (chromosome 11), which can affect every step in the pathway of β-globin expression from initiation of transcription to messenger RNA synthesis to translation and post translation modification. Picture below shows the organization of the genes (i.e., ε and γ, which are active in embryonic and fetal life, respectively) and activation of the genes in the locus control region (LCR), which promote transcription of the β-globin gene. There are four genes for αglobin synthesis (two on each chromosome 16). Most α-thalassemia syndromes are due to deletion of one or more of the α-globin genes rather than to point mutations. Mutations of β-globin genes occur predominantly in children of Mediterranean, Southern, and Southeast Asian ancestry. Those of α-globin are most common in those of Southeast Asian and African ancestry.6

(source: Manual of Pediatric Hematology and Oncology) Major deletions in β thalassemia are unusual (in contrast to α thalassemia), and most of the encountered mutations are single base changes, small deletions, or insertions of 1-2 bases at a critical site along the gene, as in the image below.


(source: Thalassemia, Emedicine Multimedia) CLASSIFICATION The thalassemias can be defined as a heterogeneous group of genetic disorders of hemoglobin synthesis, all of which result from a reduced rate of production of one or more of the globin chains of hemoglobin. This basic defect results in imbalanced globin chain synthesis, which is the hallmark of all forms of thalassemia. The thalassemias can be classified at different levels. Clinically, it is useful to divide them into three groups: the severe transfusion-dependent (major) varieties; the symptomless carrier states (minor) varieties; and a group of conditions of intermediate severity that fall under the loose heading thalassemia intermedia”. This classification is retained because it has implications for both diagnosis and management.4


β-THALASSEMIA2,8 The β-thalassemia syndromes are caused by abnormalities of the b-gene complex on chromosome 11. More than 150 different mutations have been described, and most of these are small nucleotide substitutions within the b gene complex. Deletions and mutations that result in abnormal cleavage or splicing of β-globin RNA may also result in thalassemia characterized by absent (β0) or reduced (β+) production of β-globin chains.2,7 THALASSEMIA MINOR (THALASSEMIA TRAIT) Heterozygosity for a b-thalassemia gene results in a mild reduction of bchain synthesis and, therefore, a reduction in HbA and mild anemia. Hemoglobin levels are 10 to 20 g/L lower than that of normal persons of the same age and gender, but the anemia may worsen during pregnancy. This mild anemia usually produces no symptoms, and longevity is normal. Thalassemia trait is almost always accompanied by familial microcytosis and hypochromia of the red blood cells. Target cells, elliptocytes, and basophilic stippling are seen on the peripheral blood smear. Almost all individuals with b-thalassemia trait have MCVs less than 75 fL, and mean MCV is 68 fL. In thalassemia trait the MCV is disproportionately low for the degree of anemia because of a red blood cell count that is normal or increased. The RDW is normal in thalassemia trait. The ratio of MCV/RBC (Mentzer index) is <11 in thalassemia trait but >12 in iron deficiency. Iron studies are normal. In an individual with microcytic red blood cells, a diagnosis of bthalassemia trait is confirmed by an elevated HbA2 (α2δ2) level. The normal level of HbA2 is 1.5 to 3.4%, and HbA2 >3.5% is diagnostic of the most common form of β-thalassemia trait. Levels of HbF (α2γ2) are normal (<2.0%) in about half of individuals with classical thalassemia trait and moderately elevated (2.0 to 7%) in the rest. Less common forms of β-thalassemia trait include βδ-thalassemia trait, characterized by familial microcytosis, normal levels of HbA2, and elevated levels of HbF (5-15%), and Lepore hemoglobin trait, characterized by the presence of 5 to 10% HbLepore, a hemoglobin that migrates electrophoretically in the position of HbS. Lepore hemoglobin is a fusion product resulting from an unequal crossover between b and d genes and associated with decreased b-chain synthesis.


Occasionally a silent carrier is identified on the basis of being a parent of a child with severe thalassemia but slight or no microcytosis or elevations of HbA 2 or HbF. The importance of establishing a diagnosis of β-thalassemia trait is to avoid unnecessary treatment with medicinal iron and to provide genetic counseling. Two individuals with b-thalassemia trait face a 25% risk with each pregnancy of having a child with homozygous β-thalassemia. Populations with a high prevalence of thalassemia trait can be screened to provide genetic counseling. In at-risk pregnancies, prenatal diagnosis can be performed as early as 10 to 12 weeks of gestation using fetal DNA obtained by chorionic villus biopsy. HOMOZYGOUS COOLEY ANEMIA) Homozygosity for β-thalassemia genes is usually associated with severe anemia because of a marked reduction of synthesis of the b-globin chains of HbA. However, reduction of HbA synthesis does not explain the hemolysis and ineffective erythropoiesis that are a consequence of unbalanced globin chain synthesis. In homozygous β-thalassemia, α-globin chains are produced in normal amounts and accumulate, denature, and precipitate in the RBC precursors in the bone marrow and circulating RBC. These precipitated α-globin chains damage the RBC membrane, resulting in destruction within the bone marrow (ineffective erythropoiesis) and in the peripheral blood. The fetus and the newborn infant with homozygous β-thalassemia are clinically and hematologically normal. In vitro measurements demonstrate reduced or absent β-chain synthesis. Increasingly, homozygous β-thalassemia is being diagnosed in the United States by neonatal electrophoretic hemoglobin screening that shows only HbF and no HbA Symptoms of β-thalassemia major develop gradually in the first 6 to 12 months after birth, when the normal postnatal switchover from γ-chains to β-chains results in a decreased level of HbF). By the age of 6 to 12 months, most affected infants show pallor, irritability, growth retardation, jaundice, and hepatosplenomegaly as a result of extramedullary hematopoiesis. By 2 years of age, 90% of infants are symptomatic, β-THALASSEMIA (THALASSEMIA MAJOR,


and progressive changes in the facial and cranial bones develop. The hemoglobin level may be as low as 30 to 50 g/L at the time of diagnosis. Other varian of β-thalassemia are:6 • Silent carrier β thalassemia: Similar to patients who silently carry α thalassemia, these patients have no symptoms, except for possible low RBC indices. The mutation that causes the thalassemia is very mild and represents a β+ thalassemia. • Thalassemia intermedia: This condition is usually due to a compound heterozygous state, resulting in anemia of intermediate severity, which typically does not require regular blood transfusions. • β thalassemia associated with β chain structural variants: The most significant condition in this group of thalassemic syndromes is the Hb E/β thalassemia, which may vary in its clinical severity from as mild as thalassemia intermedia to as severe as β thalassemia major. α-THALASSEMIA2,9 The a-thalassemia syndromes are prevalent in people from Southeast Asia and usually result from deletion of one or more of the four α-globin genes on chromosome 16. In general, the severity is proportional to the number of α-globin genes deleted which can be quantitated by DNA analysis.1,6 SILENT CARRIER (α2-THALASSEMIA TRAIT, - α/αα) Individuals with a single α-globin gene deletion are clinically and hematologically normal, but they may be identified at birth by the presence of small amounts (1-3%) of the fast-migrating Barts hemoglobin (γ4) by neonatal hemoglobin electrophoresis. In later life, the diagnosis can be established only by determining the number of aglobin genes by DNA analysis. α1-THALASSEMIA TRAIT (-α/-α OR --/αα) Individuals in whom two of four α-globin genes are deleted have mild microcytic anemia. At birth, relative microcytosis with 5 to 8% of HbBarts is present. Barts hemoglobin disappears by 3 to 6 months of age, and the hemoglobin electrophoresis becomes normal. After the newborn period, a definitive diagnosis may be impractical in this mild


disorder, and the diagnosis is usually suspected when other causes of microcytic anemia, such as β-thalassemia trait or iron deficiency, are ruled out. α1-Thalassemia trait can occur in two ways: a cis-deletion in which the two deleted a genes are on the same chromosome 16, and a trans-deletion in which one a-gene is deleted from each of the 16 chromosomes. The cis-deletion is usual in Southeast Asian populations, whereas the trans-deletions are usual in people of African ethnicity. Thus, although α-thalassemia commonly occurs in African people, a maximum of only two genes can be deleted in any individual because of the trans-configuration. Consequently, the more severe α-thalassemia syndromes associated with three and four α-deletions are not seen. HEMOGLOBIN H DISEASE (--/-α) Three α-globin gene deletions result in hemoglobin H disease, which is associated with a marked imbalance between a- and β-globin chain synthesis. Excess free β chains accumulate and combine to form an abnormal hemoglobin, a tetramer of β chains (β4) called HbH. HbH is unstable and precipitates within red blood cells, leading to chronic microcytic, hemolytic anemia. Laboratory findings include a moderately severe microcytosic anemia (Hb 60-100 g/L with evidence of hemolysis). Precipitated HbH can be demonstrated in the red blood cells with supravital stains. On hemoglobin electrophoresis, HbH has a fast mobility and accounts for 10 to 15% of the total hemoglobin. FETAL HYDROPS SYNDROME (--/--) Deletion of all four a-globin genes results in a syndrome of hydrops fetalis with stillbirth or immediate postnatal death. In the absence of α-chain synthesis, such fetuses are incapable of synthesizing embryonic hemoglobins. At birth, hemoglobin electrophoresis shows predominantly Barts hemoglobin (γ4) and small amounts hemoglobin H (β4) as well as embryonic hemoglobins. The high oxygen affinity of Barts hemoglobin makes it oxygen transport ineffective, leading to the intrauterine manifestations of severe hypoxia, out of proportion to the degree of anemia. A number of infants with this syndrome who have been identified prenatally and treated with intrauterine and postnatal transfusions have survived. These infants are transfusion dependent, but some are developing normally. As in thalassemia major, the only curative therapy is bone marrow transplantation. Termination of


the pregnancy is often recommended because of a high frequency of severe maternal toxemia associated with a hydropic fetus. Thalassemias can also be classified at the genetic level into the α, β, δβ or εγδβ thalassemias, according to which globin chain is produced in reduced amounts. In some thalassemias, no globin chain is synthesized at all, and hence they are called α0 or β0 thalassemias, whereas in others some globin chain is produced but at a reduced rate; these are designated α+ or β+ thalassemias. The δβ thalassemias, in which there is defective δ and β chain synthesis, can be subdivided in the same way, i.e., into (δβ)+ and (δβ)0 varieties.4

(source: Pediatric Hematology) PATHOPHYSIOLOGY2,4,6,9 The basic defect in all types of thalassemia is imbalanced globin chain synthesis. However, the consequences of accumulation of the excessive globin


chains in the various types of thalassemia are different. In β thalassemia, excessive α chains, unable to form Hb tetramers, precipitate in the RBC precursors and, in one way or another, produce most of the manifestations encountered in all of the β thalassemia syndromes; this is not the situation in α thalassemia. The excessive chains in α thalassemia are γ chains earlier in life and β chains later in life. Because such chains are relatively soluble, they are able to form homotetramers that, although relatively unstable, nevertheless remain viable and able to produce soluble Hb molecules such as Hb Bart (4 γ chains) and Hb H (4 β chains). These basic differences in the 2 main types of thalassemia are responsible for the major differences in their clinical manifestations and severity. α chains that accumulate in the RBC precursors are insoluble, precipitate in the cell, interact with the membrane (causing significant damage), and interfere with cell division. This leads to excessive intramedullary destruction of the RBC precursors. In addition, the surviving cells that arrive in the peripheral blood with intracellular inclusion bodies (excess chains) are subject to hemolysis; this means that both hemolysis and ineffective erythropoiesis cause anemia in the person with β thalassemia. The ability of some RBCs to maintain the production of γ chains, which are capable of pairing with some of the excessive α chains to produce Hb F, is advantageous. Binding some of the excess a chains undoubtedly reduces the symptoms of the disease and provides additional Hb with oxygen-carrying ability. Furthermore, increased production of Hb F, in response to severe anemia, adds another mechanism to protect the RBCs in persons with β thalassemia. The elevated Hb F level increases oxygen affinity, leading to hypoxia, which, together with the profound anemia, stimulates the production of erythropoietin. As a result, severe expansion of the ineffective erythroid mass leads to severe bone expansion and deformities. Both iron absorption and metabolic rate increase, adding more symptoms to the clinical and laboratory manifestations of the disease. The large numbers of abnormal RBCs processed by the spleen, together with its hematopoietic response to the anemia if untreated, results in massive splenomegaly, leading to manifestations of hypersplenism.


If the chronic anemia in these patients is corrected with regular blood transfusions, the severe expansion of the ineffective marrow is reversed. Adding a second source of iron would theoretically result in more harm to the patient. However, this is not the case because iron absorption is regulated by 2 major factors: ineffective erythropoiesis and iron status in the patient. Ineffective erythropoiesis results in increased absorption of iron because of downregulation of the HAMP gene, which produces a liver hormone called hepcidin. Hepcidin regulates dietary iron absorption, plasma iron concentration, and tissue iron distribution and is the major regulator of iron. It acts by causing degradation of its receptor, the cellular iron exporter ferroportin. When ferroportin is degraded, it decreases iron flow into the plasma from the gut, from macrophages, and from hepatocytes, leading to a low plasma iron concentration. In severe hepcidin deficiency, iron absorption is increased and macrophages are usually iron depleted, such as is observed in patients with thalassemia intermedia. Malfunctions of the hepcidin-ferroportin axis contribute to the etiology of different anemias, such as is seen in thalassemia, anemia of inflammation, and chronic renal diseases. Improvement and availability of hepcidin assays facilitates diagnosis of such conditions. The development of hepcidin agonists and antagonists may enhance the treatment of such anemias. By administering blood transfusions, the ineffective erythropoiesis is reversed, and the hepcidin level is increased; thus, iron absorption is decreased and macrophages retain iron. Iron status is another important factor that influences iron absorption. In patients with iron overload (eg, hemochromatosis), the iron absorption decreases because of an increased hepcidin level. However, this is not the case in patients with severe β thalassemia because a putative plasma factor overrides such mechanisms and prevents the production of hepcidin. Thus, iron absorption continues despite the iron overload status. As mentioned above, the effect of hepcidin on iron recycling is carried through its receptor "ferroportin," which exports iron from enterocytes and macrophages to the plasma and exports iron from the placenta to the fetus. Ferroportin is upregulated by iron stores and downregulated by hepcidin. This


relationship may also explain why patients with β thalassemia who have similar iron loads have different ferritin levels based on whether or not they receive regular blood transfusions. For example, patients with β thalassemia intermedia who are not receiving blood transfusions have lower ferritin levels than those with β thalassemia major who are receiving regular transfusion regimens, despite a similar iron overload. In the latter group, hepcidin allows recycling of the iron from the macrophages, releasing high amounts of ferritin. In patients with β thalassemia intermedia, in whom the macrophages are depleted despite iron overload, lower amounts of ferritin are released, resulting in a lower ferritin level. Most nonheme iron in healthy individuals is bound tightly to its carrier protein, transferrin. In iron overload conditions, such as severe thalassemia, the transferrin becomes saturated, and free iron is found in the plasma. This iron is harmful since it provides the material for the production of hydroxyl radicals and additionally accumulates in various organs, such as the heart, endocrine glands, and liver, resulting in significant damage to these organs. CLINICAL MANIFESTATIONS History Thalassemia minor usually presents as an asymptomatic mild microcytic anemia and is detected through routine blood tests. Thalassemia major is a severe anemia that presents during the first few months after birth. Thalassemia minor (beta thalassemia trait) usually is asymptomatic, and it typically is identified during routine blood count evaluation. Thalassemia major (homozygous beta thalassemia) is detected during the first few months of life, when the patient's level of fetal Hb decreases. Physical Examination Patients with the beta thalassemia trait generally have no unusual physical findings. The physical findings are related to severe anemia, ineffective erythropoiesis, extramedullary hematopoiesis, and iron overload resulting from transfusion and increased iron absorption. Skin may show pallor from anemia and


jaundice from hyperbilirubinemia. The skull and other bones may be deformed secondary to erythroid hyperplasia with intramedullary expansion and cortical bone thinning. Heart examination may reveal findings of cardiac failure and arrhythmia, related to either severe anemia or iron overload. Abdominal examination may reveal changes in the liver, gall bladder, and spleen.1,2,5 Hepatomegaly related to significant extramedullary hematopoiesis typically is observed. Patients who have received blood transfusions may have hepatomegaly or chronic hepatitis due to iron overload; transfusion-associated viral hepatitis resulting in cirrhosis or portal hypertension also may be seen. The gall bladder may contain bilirubin stones formed as a result of the patient's lifelong hemolytic state. Splenomegaly typically is observed as part of the extramedullary hematopoiesis or as a hypertrophic response related to the extravascular hemolysis. Extremities may demonstrate skin ulceration. Iron overload also may cause endocrine dysfunction, especially affecting the pancreas, testes, and thyroid.11 Laboratory Findings2,10,12 The CBC count and peripheral blood film examination results are usually sufficient to suspect the diagnosis. Hemoglobin (Hb) evaluation confirms the diagnosis in β thalassemia, Hb H disease, and Hb E/b thalassemia. In the severe forms of thalassemia, the Hb level ranges from 2-8 g/dL. Mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) are significantly low, but, unlike thalassemia trait, thalassemia major is associated with a markedly elevated RDW, reflecting the extreme anisocytosis. The WBC count is usually elevated in β thalassemia major; this is due, in part, to miscounting the many nucleated RBCs as leukocytes. Leukocytosis is usually present, even after excluding the nucleated RBCs. A shift to the left is also encountered, reflecting the hemolytic process. Platelet count is usually normal, unless the spleen is markedly enlarged. Peripheral blood film examination reveals marked hypochromasia and microcytosis, hypochromic macrocytes that represent the polychromatophilic


cells, nucleated RBCs, basophilic stippling, and occasional immature leukocytes, as shown below.

(source: Color Atlas of Hematology) The diagnosis of beta thalassemia minor usually is suggested by the presence of an isolated, mild microcytic anemia, target cells on the peripheral

blood smear, and a normal red blood cell count. Hb electrophoresis usually reveals an elevated Hb F fraction, which is distributed heterogeneously in the RBCs of patients with β thalassemia, Hb H in patients with Hb H disease, and Hb Bart in newborns with a thalassemia trait. In β0 thalassemia, no Hb A is usually present; only Hb A2 and Hb F are found. An elevation of Hb A2 (2 alpha-globin chains complexed with 2 delta-globin chains) demonstrated by electrophoresis or column chromatography confirms the diagnosis of beta thalassemia trait. The Hb A2 level in these patients usually is approximately 4-6%. In rare cases of concurrent severe iron deficiency, the increased Hb A2 level may not be observed, although it becomes evident with iron repletion. The increased Hb A2 level also is not observed in patients with the rare delta-beta thalassemia trait.2,5 Iron studies (iron, transferrin, ferritin) are useful in excluding iron deficiency and the anemia of chronic disorders as the cause of the patient's anemia. (talasemia beta) Serum iron level is elevated, with saturation reaching as high as 80%. The serum ferritin level, which is frequently used to monitor the status of iron overload, is also elevated. However, an assessment using serum ferritin levels may underestimate the iron concentration in the liver of a transfusion-independent patient with thalassemia.2,13 Complete RBC phenotype, hepatitis screen, folic acid level, and human leukocyte antigen (HLA) typing are recommended before initiation of blood transfusion therapy.2 Patients may require a bone marrow examination to exclude certain other causes of microcytic anemia. Physicians must perform an iron stain (Prussian blue stain) to diagnose sideroblastic anemia (ringed sideroblasts). Radiologic Examinations The skeletal abnormalities observed in patients with thalassemia major include an expanded bone marrow space, resulting in the thinning of the bone cortex. These changes are particularly dramatic in the skull, which may show the characteristic hair-on-end appearance. Bone changes also can be observed in the long bones, vertebrae, and pelvis.2,5,8


Skeletal survey and other imaging studies reveal classic changes of the bones that are usually encountered in patients who are not regularly transfused. The striking expansion of the erythroid marrow widens the marrow spaces, thinning the cortex and causing osteoporosis. These changes, which result from the expanding marrow spaces, usually disappear when marrow activity is halted by regular transfusions. Osteoporosis and osteopenia may cause fractures, even in patients whose conditions are well-controlled. In addition to the classic "hair on end" appearance of the skull, shown below, which results from widening of the diploic spaces and observed on plain radiographs, the maxilla may overgrow, which results in maxillary overbite, prominence of the upper incisors, and separation of the orbit. These changes contribute to the classic "chipmunk facies observed in patients with thalassemia major. Other bony structures, such as ribs, long bones, and flat bones, may also be sites of major deformities. Plain radiographs of the long bones may reveal a lacy trabecular pattern. Changes in the pelvis, skull, and spine become more evident during the second decade of life, when the marrow in the peripheral bones becomes inactive while more activity occurs in the central bones. Compression fractures and paravertebral expansion of extramedullary masses, which could behave clinically like tumors, more frequently occur during the second decade of life.2 The liver and biliary tract of patients with thalassemia major may show evidence of extramedullary hematopoiesis and damage secondary to iron overload resulting from multiple transfusion therapy. Transfusion also may result in infection with the hepatitis virus, which leads to cirrhosis and portal hypertension. Gallbladder images may show the presence of bilirubin stones. The heart is a major organ that is affected by iron overload and anemia. Cardiac dysfunction in patients with thalassemia major includes conduction system defects, decreased myocardial function, and fibrosis. Some patients also develop pericarditis.


DIFFERENTIAL DIAGNOSIS The differential diagnosis of the thalassemia syndromes are other microcytic anemias.6

(source: Manual of Pediatric Hematology and Oncology) MANAGEMENT 6,13 Hypertransfusion Protocol The hypertransfusion protocol is used to maintain a pretransfusion hemoglobin between 10.5 and 11.0 g/dL at all times using 15 cc/kg leukocyte-depleted crossmatched packed red cells. Post-transfusion hemoglobin falls roughly 1 gram per week, necessitating transfusions every 3–4 weeks. Transfusion therapy should be started when a diagnosis is made and the hemoglobin level falls below 7 g/dL. Hypertransfusion results in: 1. Maximizing growth and development


2. Minimizing extramedullary hematopoiesis and decreasing facial and skeletal abnormalities 3. Reducing excessive iron absorption from gut 4. Retarding the development of splenomegaly and hypersplenism by reducing the number of red cells containing 〈-chain precipitates that reach the spleen 5. Reducing and/or delaying the onset of complications (e.g., cardiac) Chelation Therapy The objectives of chelation therapy are: 1. To bind free extracellular iron 2. To remove excess intracellular iron 3. To attain a negative iron balance (i.e., iron excretion > iron input). Iron overload results from: 1. Ongoing transfusion therapy 2. Increased gut absorption of iron 3. Chronic hemolysis. Chelation using desferrioxamine (Desferal) is recommended as follows:
1. Chelation should be instituted when the ferritin level is greater than 1000

ng/mL and adequate iron is excreted into the urine with the desferrioxamine challenge. 2. •
• • • •

The desferrioxamine challenge is performed as follows: A 24-hour urine collection is started. Desferrioxamine 40 mg/kg is infused IV over 8 hours, starting at the beginning of the collection. The urine collection continues for 16 more hours, and the urine is assayed for total iron content. If the 24-hour urinary iron excretion is greater than or equal to 50% of the daily iron overload, the patient is ready for chelation. Daily iron load is calculated using roughly 1 mg iron/1 mL packed red blood cells (PRBCs). For example, if a patient receives 210 cc PRBCs


every 21 days, the daily iron load is 10 mg. If the patient excretes 5 mg iron with the 24-hour challenge, chelation should be started.
3. Desferrioxamine, 40–60 mg/kg/day, is infused subcutaneously over 8–10

hours nightly via a portable electronic pump 4–6 nights per week, depending on iron overload.
4. In selected cases, with severe iron overload, desferrioxamine is

administered IV in a high dose, maximum 10 g/day. This may be done immediately posttransfusion to bind transiently increased free serum iron.
5. The aim is to maintain the serum ferritin level close to 1000 ng/mL. The

ferritin level should be monitored every 3–6 months. The complications of desferrioxamine administration include: •

Swelling at infusion site Local reactions: pruritus, rash, and hyperemia (add hydrocortisone 2 mg/mL to the desferrioxamine solution) Anaphylactoid reactions (treat by desensitization) Toxic effects on the eye; cataracts, reduction of visual fields and visual acuity, and night blindness; occurs with prolonged or high-dose therapy or if desferrioxamine is used without sufficient iron overload

Hearing impairment with prolonged or high-dose therapy, typically without sufficient iron overload Metaphyseal dysplasias Desferrioxamine toxicity exacerbated when there is insufficient excretable iron relative to the amount of desferrioxamine given.

1. Splenectomy

reduces the transfusion requirements in

patients with hypersplenism. It is usually performed in adolescents when transfusion requirements have increased secondary to hypersplenism.
2. Two







pneumococcal and meningococcal vaccine should be given.


If the patient has not received a Haemophilus influenzae vaccine, this should also be given. Following splenectomy, prophylactic penicillin 250 mg bid is given to reduce the risk of overwhelming postsplenectomy infection. 3. Indications for splenectomy include:

Persistent increase in blood transfusion requirements by 50% or more over initial needs for more than 6 months Annual packed cell transfusion requirements in excess of 250 mL/kg/year in the face of uncontrolled iron overload (ferritin greater than 1500 ng/mL or increased hepatic iron concentration)

Evidence of severe leukopenia and/or thrombocytopenia.

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.

Patients with high viral loads of hepatitis C that are not spontaneously decreasing should be treated with PEGinterferon and ribavirin. Ribavirin increases hemolysis and transfusion requirements typically increase during therapy.

7. HIV-positive







appropriate antiviral medications.

8. Genetic






indicated) should be carried out using chorionic villus sampling or amniocentesis. 9. Management of osteoporosis includes:

Periodic screening and prevention through early hormonal replacement. Yearly screening of adolescents with bone densitometry and gonadal hormone evaluation. Early in adolescence, patients should receive

estrogen/progesterone or testosterone replacement to prevent gonadal insufficiency–induced bone loss, which may result in a decreased adult height due to fusion of the epiphyses. The possible increased risk of breast cancer with hormonal replacement therapy should be explained to female patients.

Two new agents are available to treat osteoporosis: (1) Calcitonin prevents trabecular bone loss by inhibiting osteoclastic activity. Parenteral and intranasal preparations are available. Miacalcin is the intranasal preparation. The dose is 1 spray into alternating nostrils daily. Miacalcin should be taken with calcium carbonate 1500 mg daily and vitamin D 400 units daily. (2) Bisphosphonates (alendronate sodium) also inhibit osteoclast-mediated bone resorption. The usual dose of Fosamax is 10 mg orally taken daily with a full glass of water 30 minutes before breakfast.

Hematopoietic Stem Cell Transplantation 6,13
1. Stem cell transplantation from an HLA-identical sibling is a curative mode

of therapy.
2. The greater the degree of hepatomegaly, hemosiderosis, and portal fibrosis

of the liver prior to transplant, the worse the outcome.


3. Stem cell transplantation is a controversial mode of therapy because its

risks must be weighed against the fact that patients who are least symptomatic have the best transplant results. The following information is available about transplantation:
• • •

Results are better among patients less than 3 years of age who have received few transfusions and are without significant complications. GVHD occurs less frequently in younger patients. The refinement of methods of preparation for transplantation has brought about a drastic reduction in morbidity and mortality.

Gene Therapy 14,15 Research is under way on methods of inserting a normal β-globin gene into mammalian cells. Ultimately, the aim is to insert the gene into stem cells and utilize these for stem cell transplant.

FOLLOW-UP 2,6 Follow-up of patients with thalassemia includes:
• • • •

Monthly: Measure the pretransfusion hemoglobin. Every 3 months: Measure height and weight; measure ferritin; perform complete blood chemistry, including liver function tests. Every 6 months: Complete physical examination and dental examination. Every year: Evaluate growth and development; evaluate iron balance; complete evaluation of cardiac function (echocardiograph, ECG, Holter monitor as indicated); endocrine function (TFTs, PTH, FSH/LH, testosterone/estradiol, IGF-1, fasting cortisol); visual and auditory acuity; viral serologies (HAV, HBV panel, HCV [or if HCV+, quantitative HCV RNA PCR], HIV); bone densitometry; ongoing psychosocial support.

Every 1–2 years: Evaluation of tissue iron burden: SQUID (superconducting quantum interference device) measurement of liver iron; T2-star measurement of cardiac iron (in select patients with cardiac disease); liver biopsy for iron concentration and histology.


PREVENTIONS Screening and prevention includes the following:

In persons with β thalassemia trait, confirming the diagnosis is usually easy. In such situations, genetic counseling is necessary, and, if both parents are carriers, a detailed discussion with the couple should include all possible outcomes. These include the 1 in 4 chance of having a severely affected or completely healthy child and a 1 in 2 chance of having a child with heterozygous thalassemia.8

For α thalassemia carriers, confirmation is not that simple. Hemoglobin (Hb) electrophoresis is usually not informative. For this reason, more sophisticated studies are warranted if confirmation is critical. Genetic counseling should be provided for patients with b thalassemia if a sibling or a family member is known to be affected.9 Prenatal DNA testing has been available for several years. The decision to

perform prenatal diagnosis in parents known to be at risk for having a child with thalassemia is complex and is usually influenced by several factors, such as religion, culture, education, and the number of children in the family. Genetic counseling by professionals that addresses the details of both the genetic risks and the testing risks involved is expected to help the parents make an informed and intelligent decision concerning the procedure. 2,6 Screening of children, pregnant women, and individuals visiting public health facilities is effective in identifying individuals at risk who require further testing. A simple CBC count, with emphasis on the RBC counts and indices, including the mean corpuscular volume (MCV), mean corpuscular Hb (MCH), and RBC distribution width (RDW), is the main component of such screening processes. Persons suspected to be positive for thalassemia are checked for elevated levels of Hb A2, Hb F, or both for confirmation. In some situations, this simple method is not adequate, and further testing, including analyses of globin chain synthesis, must be performed to reach a final diagnosis.6,11,13 Prenatal diagnosis includes the following:


Globin chain synthesis, which was once used in postnatal diagnosis, was also used on fetal cells obtained by fetoscopy to screen the fetus. This test reveals imbalanced production of certain globin chains that are diagnostic of thalassemia.

Since polymerase chain reaction (PCR) techniques have become available, several new methods are now in use to identify affected babies or carrier individuals accurately and quickly. The DNA material is obtained by chorionic villus sampling (CVS), and mutations that change restriction enzyme cutting sites can be identified.

COMPLICATIONS 5,6 Complications include the following: Iron overload Traditionally, ferritin level assessment has been the most commonly used test for indirect evaluation of body iron stores, even though it reflects only 1% of the total iron storage pool. The test is not perfect or accurate, as various conditions complicate the interpretation of its values. For this reason, reliance on serum ferritin assessment alone can lead to an inaccurate assessment of body iron stores in patients with iron overload who have been transfused heavily and who have levels in excess of the upper limit for the physiologic ferritin synthesis (400 mcg/L). At high levels, the test loses its clinical relevance since ferritin can be released from damaged cells in certain pathologic conditions. Furthermore, certain drugs and clinical conditions such as ascorbate deficiency, fever, acute and chronic infections, and hemolysis may influence the ferritin level, producing misleading values. Despite its deficiencies, and for lack of a better practical, noninvasive test, ferritin assessment continues to be the most commonly used tool to diagnose and to monitor iron overload. MRI or CT scanning is used to assess liver iron levels as a measure of total body iron load. Liver biopsy may be performed to assess liver iron concentration, which is considered the most sensitive method to assess body iron burden. Again, this procedure is an invasive one and not without complications. Furthermore, because iron distribution in the thalassemic liver is uneven and could be affected by


fibrosis, one can expect conflicting and inaccurate results in some patients. Grading of stainable iron or measuring parenchymal iron by atomic absorption spectroscopy has been helpful in measuring tissue iron levels, with good correlation to calculated body iron burden. Cardiac complications Most deaths in patients with thalassemia are due to cardiac involvement. These complications range from constrictive pericarditis to heart failure and arrhythmias. Transfusional hemosiderosis has been classified into 3 stages based on the number of blood units given. The higher the number of packed red blood cell (PRBC) units given, the more advanced the stage. Advanced stage is associated with more severe clinical symptoms and more abnormal findings on cardiac function studies. Cardiac hemosiderosis does not occur without significant accumulation of iron in other tissues. Chelation therapy has shown promising results in patients with cardiac symptoms due to iron overload. Ventricular myocardium is the first site of cardiac iron deposition, while the conduction system is usually the last to be affected. The value of endomyocardial biopsy, which has been used to evaluate iron deposits in the heart, has been questioned. Iron has been reported as absent from the right ventricular subendocardium in some patients with cardiac iron overload. Echocardiography, radionuclide cineangiography, and 24-hour ECG are to be used to monitor these patients. Hepatic complications Patients who have received regular blood transfusions for some time develop liver enlargement due to swelling of the phagocytic and parenchymal cells from the deposition of hemosiderin.Liver enzyme levels are not typically elevated unless hemosiderin deposition is associated with hepatitis. Chelation therapy may prevent or delay progressive liver disease, which may end in cirrhosis. Long-term therapy complications


Because of improved medical care, patients with thalassemia are surviving their disease longer and reaching old age. With this longer survival comes new issues related to complications that need to be addressed. Hepatitis C virus (HCV) has emerged as the paramount risk in patients who have been receiving blood transfusions all their lives. Unfortunately, a high incidence rate of HCV continues in developing countries, leading to an increased incidence of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), especially in the presence of a second risk factor such as iron overload. For this reason, many centers advocate screening patients with HCV every 6 months by obtaining a fetoprotein (AFP) and an ultrasound of the liver. Two-thirds of patients with β thalassemia major have multiple calcified bilirubin stones by age 15 years. Hematologic complications Thrombosis was encountered in relatively significant numbers of patients with thalassemia. Short-term antithrombotic therapy, both perioperatively and in the presence of thrombotic risk factors, is recommended. Patients who have undergone splenectomy and have a platelet count in excess of 600,000/µL receive low-dose daily aspirin Pulmonary hypertension as a result of small pulmonary thrombi represents a significant indication of the increased risk for clotting in such patients. This complication is emerging as major cause of morbidity and mortality in patients with chronic hemolytic anemia. The incidence in such population was estimated at 10%. According to one study, endothelial dysfunction due to lack of bioavailability of NO is one of the main reasons for developing such complications. Free plasma Hb resulting from hemolysis directly consumes NO, and the presence of arginase in the hemolysate depletes arginine, which is the substrate for NO synthetase, thus preventing generation of such product. The presence of excessive oxygen radicals in patients with chronic hemolytic anemia who are on regular packed RBC (PRBC) transfusions adds to the problem by causing rapid consumption of NO. Studies have showed that treatment with hydroxyurea may improve or prevent this complication.


Silent cerebral infarction (SCI) was diagnosed by MRI in 24% of patients with β -thalassemia/Hb E disease in a study conducted in Thailand. A Cambodian child who also has β -thalassemia/Hb E disease has also been described. Increasing reports addressing the issue of thrombotic tendency in patients with thalassemia have revealed that such tendency is indeed seen in all types of chronic hemolytic anemia and is not limited to thalassemia intermedia as suggested earlier. Numerous factors for the thrombotic complications in this patients population were reported by many authors. A study conducted on patients with thalassemia has shown that the patients platelets, as well as their RBCs when mixed individually with normal RBCs or normal platelets, have resulted in increased platelets adhesions; this was not noticed when control cells were used in both instances. This finding may suggest that both platelets and RBCs in thalassemia could induce increased platelets adhesion which may predispose to thrombotic events. Based on these reports and several others which confirm the presence of hypercoagulable state in patients with chronic hemolysis such as thalassemia and sickle cell disease, one should seriously reconsider the role of splenectomy in such conditions to avoid further risk for thrombotic events in this population of patients. Endocrine complications People with thalassemia major frequently exhibit features of diabetes mellitus; 50% or more exhibit clinical or subclinical diabetes. This is believed to be due to defective pancreatic production of insulin, but insulin resistance also has been implicated. Glucose intolerance encountered in these patients usually correlates with the numbers of transfusions received and the patient's age and genetic background. Thus, the underlying disease may modulate iron-related endocrine injury. Growth retardation Growth retardation is frequently severe in patients with thalassemia (30%). This retardation is caused, in part, by the diversion of caloric resources for


erythropoiesis, as well as by the chronic anemia because hypertransfusion usually restores normal growth. Unless chelation therapy is initiated early in life, patients rarely grow normally. Excessive chelation with DFO may also cause growth retardation. The direct cause of growth retardation in these patients is thought to be an impaired growth hormone production or deficiency in production of somatomedin by the hemosiderotic liver. This has been questioned by a report that suggested GHD does not correlate with the efficacy of transfusional or chelation therapy. Other factors are thought to be involved. Involvement of the adrenal glands or the thyroid gland may also contribute to growth failure. Fertility and pregnancy complications The survival of patients with thalassemia major has improved significantly. Since the introduction of effective transfusion and chelation regimens. Patients are now reaching their adulthood, and the questions regarding fertility becomes relevant. Adult patients with thalassemia major have low fertility; this was thought to be related to endocrine toxicity as a consequence to iron overload. Patients with abnormal semen parameters were noticed to have low ferritin level, whereas those with high ferritin had normal sperms parameters. This is an interesting observation that is not fully understood; however, it raises the question whether the abnormal sperm parameters are related to a negative effect of intensive chelation therapy. Females are frequently oligomenorrheic or amenorrheic. Pregnancy complications are also seen frequently and are likely due to endocrinologic and cardiac complications. Case reports demonstrated, however, that successful pregnancy and delivery of healthy babies is possible in women with thalassemia major. Gonadal dysfunction that results in arrested or delayed puberty is reported in females with thalassemia major receiving transfusion and chelation therapy.36 A small uterus was noted in all women with delayed or arrested puberty. The size may improve with hormonal replacement therapy (HRT).


Adequate transfusion to keep Hb at normal or near normal level at all times, effective chelation and early intervention with hormonal therapy may prevent permanent damage and help to preserve fertility. PROGNOSIS 1,2,16 The prognosis depends on the type and severity of thalassemia. As stated above, the clinical course of thalassemia varies greatly from mild or even asymptomatic to severe and life threatening. CASE REPORT AH, 10 year-old boy, body weight 25 kg, body length 123 cm was admitted to H. Adam Malik General Hospital on 3rd June 2010. • • • • Main complaint is paleness for the last a week. History of nausea, vomiting, icteric were not found. Defecation and urination were positive and normal. History of immunization was complete (BCG scar in right deltoid was positive.

Os was diagnosed with Thalassemia

Major from the result of Hb

electrophoresis that was done when the patient was 1 year old.

History of any family members having the same type of problem or having Thalassemia was negative.

Os was the former patient of Non-Infection Unit/ Hemato-Oncology Unit HAM General Hospital and given PRC transfusion regularly.

PHYSICAL EXAMINATION Consciousness was alert, body weight 25 kg, body temperature 37,4oC. There were anemi. Ichteric eyes, cyanosis, edema and dyspnoe were not confirmed.


Head : Eye : light reflexes (+/+), isochoric pupil, pale inferior palpebra conjunctiva (+/+) E/N/M : normal Neck : Lymph node enlargement (-) Chest : Symmetrical fusiform, no retraction HR : 96 bpm, regular, no murmur RR : 28 tpm, regular, no rales Abdominal : Soepel, peristaltic was normal Hepar Lien : Palpable 5 cm below right costal arc : Palpable Schuffner II

Extremities : Pulse 96 tpm, regular, pressure/ volume normal

LABORATORY FINDINGS Hematology Complete Blood Count (CBC) •
• •

Hemoglobine (HGB) : 5.70 gr% Erythrocyte Leucocyte Hematocrite Thrombocyte MCV MCH MCHC RDW Neutrophil Lymphocyte Monocyte : 2.50 x 106/ mm3 : 6.41 x 103 / mm3 : 18.20 % : 114 x 103 /mm3 : 72.80 fL : 22.80 pg : 31.30 gr% : 18.80 % : 41.10 % : 49.60 % : 6.10 %

• • • • Diftel • • •


• • • • •

Eosinophil Basophil Erythrocyte Leucocyte Thrombocyte

: 3.00 % : 0.20 % : anisocytosis, hypochromic microcyter : normal : normal


Conclusion : anemia hypochromic microcyter + thrombocytopenia Liver Function Test • • • • • Total Bilirubin Direct Bilirubin : 0.83 mg/dl : 0.28 mg/dl

Alkaline phosphatase : 140 U/L AST/SGOT ALT/SGPT : 154 U/L : 146 U/L

Renal Function Test • • • Ureum Creatinine Uric Acid : 16.70 mg/dl : 0.49 mg/dl : 4.7 mg/dl

Working diagnosis is Thalassemia β Major. Treatments were given : • PRC transfusion as needed Transfusion requirement : Δ Hb x 4 x BB : (10-5,7) x 4 x 23 : 395,6 cc : ≈ 2 ½ bags Transfusion ability • •

: 5cc/kgBW : 5 x 23 : 115 cc : ¾ bag

Folic Acid 1 x 1 mg Vitamine E 1 X 100 UI Diet MB 1500 kcal with 50 grams protein

Nutritional Status was normal (normoweight) with 108%.


FOLLOW UP 3RD OF JUNE 2010 (15.00 WIB) Consciousness was alert, body weight 25 kg, BB/TB : 103%, body temperature 36oC. There was paleness. Ichteric eyes, cyanosis, edema and dyspnoe were not confirmed. Head : Eye : light reflexes (+/+), isochoric pupil, pale inferior palpebra conjunctiva (+/+) E/N/M : normal Neck : Lymph node enlargement (-) Chest : Symmetrical fusiform, no retraction HR : 92 bpm, regular, no murmur RR : 32 tpm, regular, no rales Abdominal : Soepel, peristaltic was normal Hepar Lien : Palpable 5 cm below right costal arc : Palpable Schuffner II

Extremities : Pulse 92 tpm, regular, pressure/ volume normal Working diagnosis is Thalassemia β Major Treatments: •

PRC transfusion as needed IVFD D5% NaCl 0,45% 10 gtt/i micro Folic Acid 1 x 1 mg Vitamine E 1 X 100 UI Diet MB 1500 kcal with 50 grams protein Transfusion requirement : Δ Hb x 4 x BB : (10-5,7) x 4 x 23 : 395,6 cc : ≈ 2 ½ bags Transfusion ability : 5cc/kgBW : 5 x 23 : 115 cc : ¾ bag

• • • •

FOLLOW UP 4TH OF JUNE 2010 (06.00 WIB) Consciousness was alert, body weight 25 kg, BB/TB : 103%, body temperature 36,8oC. There was paleness. Ichteric eyes, cyanosis, edema and dyspnoe were not confirmed.


Head : Eye : light reflexes (+/+), isochoric pupil, pale inferior palpebra conjunctiva (+/+) E/N/M : normal Neck : Lymph node enlargement (-) Chest : Symmetrical fusiform, no retraction HR : 106 bpm, regular, no murmur RR : 32 tpm, regular, no rales Abdominal : Soepel, peristaltic was normal Hepar Lien : Palpable 5 cm below right costal arc : Palpable Schuffner II

Extremities : Pulse 96 tpm, regular, pressure/ volume normal BP : 105/75 mmHg Working diagnosis is Thalassemia β Major Treatments:

IVFD D5% NaCl 0,45% 10 gtt/i micro Folic Acid 1 x 1 mg Vitamine E 1 X 100 UI Diet MB 1500 kcal with 50 grams protein Disferal (20-50 mg/kgBW/day) = 20-50 (25) = 500-1250 mg/day ≈ 1000 mg/day ( 3 days ) PRC transfusion (day 2)

• • • • •

Further Prescription :

FOLLOW UP 4TH OF JUNE 2010 (16.00 WIB) Consciousness was alert, body weight 25 kg, BB/TB : 103%, body temperature 36,3oC. There was paleness. Ichteric eyes, cyanosis, edema and dyspnoe were not confirmed. Head : Eye : light reflexes (+/+), isochoric pupil, pale inferior palpebra conjunctiva (+/+) E/N/M : normal Neck : Lymph node enlargement (-) Chest : Symmetrical fusiform, no retraction


HR : 92 bpm, regular, no murmur RR : 30 tpm, regular, no rales Abdominal : Soepel, peristaltic was normal Hepar Lien : Palpable 5 cm below right costal arc : Palpable Schuffner II

Extremities : Pulse 92 tpm, regular, pressure/ volume normal Working diagnosis is Thalassemia β Major Treatments:

IVFD D5% NaCl 0,45% 10 gtt/i micro Folic Acid 1 x 1 mg Vitamine E 1 X 100 UI PRC transfusion (day 3, last transfusion) Diet MB 1500 kcal with 50 grams protein Infusion Desferal 1000 mg in 250 cc NaCl 0.9 % for 6 hours (13.10-19.10 WIB)

• • •

Modul Hemato-Oncology Futher Prescription : • • • Desferal 1000 mg ( day 2 ) Routine Blood Analysis Ferriprox 1 x 1 tablet

FOLLOW UP 5TH OF JUNE 2010 (06.00 WIB) Consciousness was alert, body weight 25 kg, BB/TB : 103%, body temperature 37oC. There was not anemi. Ichteric eyes, cyanosis, edema and dyspnoe were not confirmed. Head : Eye : light reflexes (+/+), isochoric pupil, pale inferior palpebra conjunctiva (-/-) E/N/M : normal Neck : Lymph node enlargement (-) Chest : Symmetrical fusiform, no retraction HR : 96 bpm, regular, no murmur RR : 28 tpm, regular, no rales

Abdominal : Soepel, peristaltic was normal Hepar Lien : Palpable 5 cm below right costal arc : Palpable Schuffner II

Extremities : Pulse 92 tpm, regular, pressure/ volume normal Working diagnosis is Thalassemia β Major Treatments:

IVFD D5% NaCl 0,45% 10 gtt/i micro Folic Acid 1 x 1 mg Vitamine E 1 X 100 UI Diet MB 1500 kcal with 50 grams protein Infusion Desferal 1000 mg in 250 cc NaCl 0.9 % for 6 hours ( day 2 )

• • •

Modul Hemato-Oncology Futher Prescription : Routine Blood Analysis post transfusion The patient was discharged in 5th of June 2010, with Hb > 10 gr/dl, no paleness, and the PRC transfusion had been finished. DISCUSSION There is family history of Thalassemia of patient with Thalassemia. Symptoms of β-thalassemia major develop gradually in the first 6 to 12 months after birth. By the age of 6 to 12 months, most affected infants show pallor, irritability, growth retardation, jaundice, and hepatosplenomegaly as a result of extramedullary hematopoiesis.17,18 Patient did not have family history of Thalassemia. This patient was diagnosed Thalassemia β Major in 1 year of life. This patient had pallor before diagnosed with Thalasemia and did not have growth retardation (nutritional status of patient patient was normoweight). There was hepatosplenomegali on physical diagnostic. In the severe forms of thalassemia, the Hb level ranges from 2-8 g/dL. Mean corpuscular volume (MCV) and mean corpuscular Hb (MCH) are significantly low, reflecting anemia hypochromic microcyter. Thalassemia major is associated with a markedly elevated RDW, reflecting the extreme anisocytosis. Platelet count is usually normal, unless the spleen is markedly enlarged.1,6 Patient had 5.70 gr%

of Hb value, so that he had severe anemia, that indicated patient had to get RBC transfusion. In hematology laboratory findings, there was declining of MCV, MCH, and MCHC value, but not significantly, that described the type of anemia hypochromic microcyter. There was inclining of RDW value significantly that reflects the morphology of RBC is anisocytosis. There was thrombocytopenia, unless there was enlarging of spleen. Liver involvement is common in those who undergo long-term transfusions. Early cirrhotic changes can be observed as early as age 7 years in some people with thalassemia. Upregulation of the transport of NTBI is observed in cultured hepatocytes and is likely to occur in vivo. Once cirrhosis develops, the risk of hepatocellular carcinoma (HCC) is increased. There was augmentation of SGOT and SGPT that indicated there was damage process of hepatocyte, as the initial sign of cirrhocis due to iron overload. Transfusion therapy should be started when a diagnosis is made and the hemoglobin level falls below 7 g/dL. The hypertransfusion protocol is used to maintain a pretransfusion hemoglobin between 10.5 and 11.0 g/dL at all times using 15 cc/kg leukocyte-depleted cross matched packed red cells. The primary treatment for iron overload in thalassemia is chelation.

The transfusion had

started. The formula for finding amount of transfusion requirement was not 15 cc/kgBW. It was used formula : Transfusion requirement : Δ Hb x 4 x BB. Desferal IV was administered to patient after transfusion. Nutritional deficiencies are common in thalassemia, due to hemolytic anemia, increased nutritional requirements. Patients should be evaluated annually by a registered dietitian regarding adequate dietary intake of calcium, vitamin D, folate, trace minerals (copper, zinc, and selenium) and antioxidant vitamins (E and C). Energy and protein intake for 10 years old boy: Energy à 75 kcal/kgBW/day and Protein à 1.2 gr/kgBW/day. Dietary intake for this patien is MB (makanan biasa “usual meal”) with energy amount 1500kcal and protein 50 grams.20 SUMMARY


It has been reported a case of a boy, 10 years old with Thalassemia β Major. The diagnosis was established based on anamnesis, clinical sign, symptoms, and physical examination. The prognostic of this patient was not good, due to continuous transfusion. This patient should remain controlled as an outpatient to prevent complication of continuous transfusion. This patient also needed chelation to reduce the accumulation of iron, along with other nutrient (calcium, vitamin D, folate, trace minerals (copper, zinc, and selenium) and antioxidant vitamins (E and C)).


1. Kliegman









Hemoglobinopathies: Thalassemia Syndrome. In: Kliegman MR, Behrman RE, Jenson HB, Stanton BF, Eds. Nelson Text Book of Pediatric. 18th ed. Philadelphia, Saunders; 2008.


2. Yaish HM. Thalassemia. eMedicine Specialties, Pediatrics: General








from: Accessed June 5, 2010.
3. Pearson HA. Thalassemia. In: Rudolph CD, Rudolph AM, Hostetter MK,

Lister G, Eds. Rudolph’s Pediatric. 21st ed. United States of America, McGraw-Hill; 2002.
4. Oliveri NF and Weatherall DJ. Thalassemia. In: Arceci RJ, Hann IM, and

Smith IP. Pediatric Hematology, 3rd ed. Victoria, Blackwell; 2006.
5. Rund D and Rachmillewitz E. β-Thalassemia. NEJM [cited March 20, 2007]. Available from: Accesed

June 9, 2010.
6. Atlas M. Hemolytic Anemia: Thalassemia. In: Lanzkowsky P. Manual of

Pediatric Hematology and Oncology. 4th ed. California, Elsevier; 2005.
7. Provan D, Singer CR, Baglin T, and Lilleyman J. Red Cell Disorders:

Thalassemia. In: Provan D, Singer CR, Baglin T, and Lilleyman J. Oxford Handbook of Clinical Hematology. 2nd ed. United States, Oxford University Press; 2004.
8. Takeshita K. Thalassemia, Beta. eMedicine Specialties, Hematology: Red

Blood Cells and Disorders [cited Augustus 24, 2009]. Available from: Accessed June 5, 2010.
9. Bleibel SA, Leonard RJ, Jones-Crawford JL, Kutlar A, and Hendricks LK.

Thalassemia, Alpha. eMedicine Specialties, Hematology: Red Blood Cells and Disorders [cited Augustus 26, 2009]. Available from: Accessed June 5, 2010.



Theml A, Heinz D, and Haferlach T. Hypochromic Anemias:

Hypochromic Anemias with Hemolysis: Thalassemias. In: Theml A, Heinz D, and Haferlach T. Color Atlas of Hematology: Practical Microscopic and Clinical Diagnosis. 2nd revised ed. Stutgart, New York, Thieme; 2004.

Lo L, and Singer ST. Thalassemia: Current Approach to An Old

Disease . The Pediatric Clinics of North America [cited 2002]. Available from: Accessed Juni 6, 2010.

Weatherall DJ. The Hereditary Anemia: The Thalassemias. In:

Provan D. ABC of Clinical Haematology. 2nd ed. London, BMJ books; 2003.

Vichinsky E, Levine L, Bhatia S, Bojanowski J, Coates T, Foote D, Research Center Oakland; Hematology/Oncology

et al. Standard of Care Guidelines for Thalassemia. Children’s Hospital & Department; Thalassemia Outreach, Oakland CA; 2008.

Malik P and Arumugam PI. Gene Therapy for β- Thalassemia. Society of Hematology [citedn 2005]. Available from:

American Accessed Juni 3, 2010.

Perrine SP. Fetal Globin Induction- Can It Cure β- Thalassemia?.

Boston, American Society of Hematology; 2005.

Cohen AR. Hematologic Emergencies: Disorders of Hemoglobin

Function and Structure: Thalassemia Major (Cooley’s Anemia). In: Fleisher GR, Ludwig S, Silverman, and Henretig FM. Textbook of Pediatric Emergency Medicine. 4th ed. Lippincott, Wiliams & Wilkins, Philadelphia; 2000.

Hays T. Hematologic Disorders: Congenital Hemolytic Anemias:

Hemoglobinopathies . In: Hay WW, Levin MJ, Sondheimer JM, and Deterding RR. Current Diagnosis and Treatment: Pediatric. 19th ed. McGraw-Hill, United Stated of America; 2007.



Lissauer T and Clayden G. Haematological Disorders: Anaemia:

Increased Red Cell Destruction (Haemolytic Anaemia): β- Thalassemia. In: Lissauer T and Clayden G. Illustrated Textbook of Paediatrics. 3rd ed. Mosby Elsevier, USA; 2007.

Butler C. Transfusion Issues in Thalassemia. The Cooley’s Anemia

Foundation, New York; 2010.

Lissauer T and Clayden G. Nutrition: The Nutritional Vulnerability

of Infants and Children. In: Lissauer T and Clayden G. Illustrated Textbook of Paediatrics. 3rd ed. Mosby Elsevier, USA; 2007.