Thalassemia Case Report

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CASE REPORT THALASSEMIA β MAJOR Presenter : Gracelia R. E. Damanik Sam Raj Rayan Day/Date : Tuesday, 22 nd 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 2

Transcript of Thalassemia Case Report

Page 1: Thalassemia Case Report

CASE REPORT

THALASSEMIA β MAJOR

Presenter : Gracelia R. E. 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

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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

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are fewer common alleles. In the U.S., an estimated 2,000 individuals have β-

thalassemia.1

ETIOLOGY

Thalassemia syndromes are characterized by varying degrees of ineffective

hematopoiesis and increased hemolysis. Clinical syndromes are divided into α-

and 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 α-

globin 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.

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(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

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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 b-

chain 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 b-

thalassemia 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

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with severe thalassemia but slight or no microcytosis or elevations of HbA2 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 β-THALASSEMIA (THALASSEMIA MAJOR,

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,

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.

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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 a-

globin 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.

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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.

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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

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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

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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

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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

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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 life-

long 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.

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(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

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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.

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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

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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

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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.

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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.

Splenectomy

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 weeks prior to splenectomy, a polyvalent

pneumococcal and meningococcal vaccine should be given.

If the patient has not received a Haemophilus influenzae

vaccine, this should also be given. Following splenectomy,

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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.

6. Patients with high viral loads of hepatitis C that are not

spontaneously decreasing should be treated with PEG-

interferon and ribavirin. Ribavirin increases hemolysis and

transfusion requirements typically increase during therapy.

7. HIV-positive patients should be treated with the

appropriate antiviral medications.

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8. Genetic counseling and antenatal diagnosis (when

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.

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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.

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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:

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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

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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

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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.

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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

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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).

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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 (-)

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Chest : Symmetrical fusiform, no retraction

HR : 96 bpm, regular, no murmur

RR : 28 tpm, regular, no rales

Abdominal : Soepel, peristaltic was normal

Hepar : Palpable 5 cm below right costal arc

Lien : Palpable Schuffner II

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

LABORATORY FINDINGS

Hematology

Complete Blood Count (CBC)

Hemoglobine (HGB) : 5.70 gr%

Erythrocyte : 2.50 x 106/ mm3

Leucocyte : 6.41 x 103 / mm3

Hematocrite : 18.20 %

Thrombocyte : 114 x 103 /mm3

MCV : 72.80 fL

MCH : 22.80 pg

MCHC : 31.30 gr%

RDW : 18.80 %

Diftel

Neutrophil : 41.10 %

Lymphocyte : 49.60 %

Monocyte : 6.10 %

Eosinophil : 3.00 %

Basophil : 0.20 %

Morphology

Erythrocyte : anisocytosis, hypochromic microcyter

Leucocyte : normal

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Thrombocyte : normal

Conclusion : anemia hypochromic microcyter + thrombocytopenia

Liver Function Test

Total Bilirubin : 0.83 mg/dl

Direct Bilirubin : 0.28 mg/dl

Alkaline phosphatase : 140 U/L

AST/SGOT : 154 U/L

ALT/SGPT : 146 U/L

Renal Function Test

Ureum : 16.70 mg/dl

Creatinine : 0.49 mg/dl

Uric Acid : 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.

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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 : Palpable 5 cm below right costal arc

Lien : 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

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HR : 106 bpm, regular, no murmur

RR : 32 tpm, regular, no rales

Abdominal : Soepel, peristaltic was normal

Hepar : Palpable 5 cm below right costal arc

Lien : 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

Further Prescription :

Disferal (20-50 mg/kgBW/day) = 20-50 (25) = 500-1250 mg/day

≈ 1000 mg/day ( 3 days )

PRC transfusion (day 2)

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 : Palpable 5 cm below right costal arc

Lien : Palpable Schuffner II

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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 : Palpable 5 cm below right costal arc

Lien : Palpable Schuffner II

Extremities : Pulse 92 tpm, regular, pressure/ volume normal

Working diagnosis is Thalassemia β Major

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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

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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. 6,13,19 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

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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)).

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