ALPHA THALASSEMIA Background The alpha thalassemia (-thalassemia) syndromes are a group of hereditary anemias of varying clinical severity.

They are characterized by reduced or absent production of 1 or more of the globin chains of which human hemoglobin is composed. The oxygen carrying capability of the red blood cells (RBCs) relies on hemoglobin, a tetramer protein that comprises 4 globin chains bound to the heme molecule. There are 4 major types of globins: alpha (), beta (), gamma (), and delta (). The dominant hemoglobin in adults (hemoglobin A) is composed of 2 alpha and 2 beta chains. Two minor forms of hemoglobin constitute a small percentage of normal blood: hemoglobin F (fetal), composed of 2 alpha chains and 2 gamma chains, and hemoglobin A2, composed of 2 alpha chains and 2 delta chains. A very tightly controlled globin chain production process keeps the ratio of alpha chains to non-alpha chains at 1.00 ( 0.05). Thalassemia, by altering this process, disrupts this ratio. Decreased production of alpha2 -globin or alpha1 -globin gene products yields a relative excess of beta chains, which results in less stable chains; this leads to the clinical disease known as alpha thalassemia.[1] Similarly, impaired production of beta globin gene products manifests with a more severe disease known as beta thalassemia.[2, 3] Thalassemia is one of the worlds most common single-gene disorders. Individuals with thalassemia syndrome are most often of African, Asian, Mediterranean, or Middle Eastern descent. Mutations and gene deletions causing the thalassemia genotype have arisen independently in different populations but have subsequently propagated by means of natural selection. Thalassemia is more prevalent in regions in which malaria is endemic because the RBC phenotype confers some protection against malaria.[4] Individuals with beta thalassemia syndromes have somewhat better protection against malaria than individuals with alpha thalassemia syndromes. Pathophysiology Genes that regulate both the synthesis and the structure of different globins are organized into 2 separate clusters. The alpha-globin genes are encoded on chromosome 16, and the gamma-, delta-, and beta-globin genes are encoded on chromosome 11. Healthy individuals have 4 alpha-globin genes, 2 on each chromosome 16 (/; see the image below). Alpha thalassemia syndromes are caused by deficient expression of 1 or more of the 4 alpha-globin genes on chromosome 16 and are characterized by absent or reduced synthesis of alpha-globin chains.

Alpha-chain genes in duplication on chromosome 16 pairing with non-alpha chains to produce various normal hemoglobins. Abnormal production of alpha-globin chains results in a relative excess of gammaglobin chains in fetuses and newborns and of beta-globin chains in children and adults. Furthermore, the beta-globin chains are capable of forming soluble tetramers (4, or hemoglobin H [HbH]); yet this form of hemoglobin is unstable and tends to precipitate within the cell, forming insoluble inclusions (Heinz bodies) that damage the red cell membrane. In addition, diminished hemoglobinization of individual red blood cells results in damage to erythrocyte precursors and ineffective erythropoiesis in the bone marrow, as well as hypochromia and microcytosis of circulating red blood cells. From a genetic standpoint, alpha thalassemias are extremely heterogeneous; however, their phenotypic expression may be described in simplified clinical terms related to the number of inherited alpha-globin genes. Alpha thalassemias may be broadly classified according to whether the loss of alpha-globin genes is complete or partial that is, alpha(0) thalassemia or alpha(+) thalassemia. Within the latter category, they may be subcategorized according to the number of genes affected. In all, there are 4 general forms of alpha thalassemia. Alpha(0) thalassemia More than 20 different genetic mutations resulting in the functional deletion of both pairs of alpha-globin genes (--/--) have been identified. The resulting disorder is referred to as hydrops fetalis, alpha thalassemia major, or hemoglobin Barts. Individuals with this disorder cannot produce any functional alpha globin and thus are unable to make any functional hemoglobin A, F, or A2. Hydrops fetalis is incompatible with extrauterine life. Fetuses with this condition die either in utero or shortly after birth because of severe anemia. Alpha(+) thalassemia There are more than 15 different genetic mutations that result in decreased production of alpha globin, usually through functional deletion of 1 or more of the 4 alpha-globin genes. Alpha(+) thalassemia is subclassified into the following 3 general forms on the basis of the number of inherited alpha genes. Silent carrier Persons who inherit 3 normal alpha-globin genes (-/) are referred to clinically as silent carriers. Other names for this condition are alpha thalassemia minima, alpha thalassemia-2 trait, and heterozygosity for alpha(+) thalassemia minor. The affected individuals exhibit no clinical abnormalities and may be hematologically normal or

have mild reductions in RBC mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Alpha thalassemia trait Inheritance of 2 normal alpha-globin genes through either heterozygosity for alpha(0) thalassemia (/--) or homozygosity for alpha(+) thalassemia (-/-) results in the development of alpha thalassemia trait, also referred to as alpha thalassemia minor or alpha thalassemia-1 trait. If both alpha2 -globin and alpha1 -globin genes are deleted on the same chromosome (--/), the genotype is said to have the cis form; if the 2 alpha2 -globin genes of both alleles of chromosome 16 are deleted but the alpha1 globin genes are intact (-/-), it is said to have the trans form. The affected individuals are clinically normal but frequently have minimal anemia and reduced MCV and MCH. The RBC count is usually increased, typically exceeding 5.5 1012/L. Hemoglobin H disease Inheritance of 1 normal alpha-globin gene (-/--) leads to a condition known as HbH disease. The loss of 3 alpha-globin genes results in abundant formation of HbH, which is characterized by a high ratio of beta globin to alpha globin and a 2-fold to 5fold excess in beta-globin production. The excess beta chains aggregate into tetramers, which account for 5-30% of the hemoglobin level in patients with HbH disease.[5] HbH has a high affinity for oxygen and has no Bohr effect or heme-heme interaction; therefore, it is an ineffective supplier of oxygen to the tissues under physiologic conditions. Patients with significant amounts of HbH have a defect in oxygencarrying capacity that is more severe than would be expected on the basis of the hemoglobin concentration alone. RBCs that contain HbH are sensitive to oxidative stress; thus, they may be more susceptible to hemolysis when oxidants such as sulfonamides are administered. Aging erythrocytes contain more precipitated HbH than younger erythrocytes; consequently, they are removed from the circulation prematurely. Thus, HbH disease is primarily a hemolytic disorder. When bone marrow cells are examined, HbH inclusions are rare, and erythropoiesis is apparently effective. Erythroid hyperplasia can result in typical structural bone abnormalities with marrow hyperplasia, bone thinning, maxillary hyperplasia, and pathologic fractures. Etiology Normal hemoglobin biosynthesis requires an intact gene, silencers, enhancers, promoters, and locus control region (LCR) sequences. Several hundred mutations causing thalassemia have been described. These may affect any step in globin gene expression, transcription, pre-mRNA splicing, mRNA translation and stability, and posttranslational assembly and stability of globin polypeptides. The most common mechanism of aberrant alpha-globin production involves deletion of either portions of the alpha-globin genes themselves or the genetic regulatory

elements that control their expression. Regulatory elements may be located on the same chromosome (cis -acting elements) or on separate chromosomes (trans -acting elements). The (--SEA) type of alpha thalassemia deletion removes both alpha-globin genes in cis, is common in Southeast Asia, and is the most common cause of HbH disease and hydrops fetalis in that part of the world. Nondeletional forms of alpha thalassemia in which the alpha-globin genes are intact are caused by mutations similar to those causing beta thalassemia and are relatively uncommon.[6, 7] Production of functional hemoglobin is also impaired in alpha thalassemia when point mutations, frame shift mutations, nonsense mutations, and chain termination mutations occur within or around the coding sequences of the alpha-globin gene cluster. These gene-level mutations may in turn affect RNA splicing, hinder initiation of mRNA translation, or result in the generation of unstable alpha-globin chain variants. Mutations affecting transcription, pre-mRNA splicing, or canonical splice signals are rare causes of alpha thalassemia. Other forms of alpha thalassemia are caused by either premature or failed translation termination. More rare mutations have been found to cause thalassemia by interfering with the normal folding of otherwise normal globin peptide. Epidemiology United States statistics The frequency of alpha thalassemia is low among whites. It is estimated that about 15% of American blacks are silent carriers for alpha thalassemia and about 3% have alpha thalassemia trait; HbH disease is rare in this population. In North America, many multicultural communities are growing, and these populations have increased frequencies of thalassemia syndromes. In some ethnic groups, such as the Southeast Asian population (in particular) and Mediterranean populations, HbH disease and hemoglobin Barts (4) are common because of the frequent coinheritance of an allele lacking both alpha-globin genes and another allele lacking 1 alpha-globin gene. The high frequency of hemoglobin Constant Spring (CS) in the Southeast Asian population can lead to the HbH (--/-CS) phenotype, which involves an elongated form of alpha globin.[8, 1] The results of one study suggested that HbH Constant Spring (HCS) should be identified as a distinct thalassemia syndrome with a high-risk of life-threatening anemia.[9] The study also found that HbH disease was managed without blood transfusions and was not associated with an increased rate of severe anemia. Because many patients with these disorders encompassed mixed ethnic backgrounds, the study emphasizes the need for extended newborn screening in populations that are customarily considered to be at low risk for HbH.[9] According to the National Institutes of Health (NIH)-sponsored North American Thalassemia Clinical Research Network (TCRN) study of the epidemiology of thalassemia in North America, 59% of patients with alpha thalassemia have a single

alpha-globin gene (-/--), 8% have no alpha-globin genes (--/--), and 33% have gene deletions with structural mutations. International statistics Alpha thalassemia is perhaps the most common single-gene disorder in the world. It is estimated that there are 270 million carriers of mutant globin genes that can potentially cause severe forms of thalassemia. In addition, 300,000-400,000 severely affected infants are born every year, more than 95% of whom are in Asia, India, or the Middle East. Before the introduction of DNA analysis, population surveys for alpha thalassemia were based entirely on the measurement of hemoglobin Barts levels in cord blood. However, single-gene-deletion heterozygotes do not always have detectable hemoglobin Barts in the neonatal period. As a result, reliable data on population frequencies for various types of alpha thalassemia are not always available. Alpha thalassemia is common throughout parts of the world where malaria is endemic. Multiple studies have suggested that the presence of both single and double alpha-globin gene deletions has a protective effect against malaria. The frequency of alpha thalassemia alleles is 5-10% in the Mediterranean basin, 2030% in portions of West Africa, and as high as 60-80% in parts of Saudi Arabia, India, Thailand, Papua New Guinea, and Melanesia. In Thailand, which has a population of 62 million people, approximately 7000 infants are born each year with HbH disease. The frequency of heterozygote carrier status among the Chinese population has been reported to range from 5% to 15%. The frequency of alpha thalassemia is lower than 0.01% in Great Britain, Iceland, and Japan.[10, 11, 12, 13] Age-related demographics Abnormalities of alpha-globin chains are genetic, and individuals are born with the disorder. The exception to this rule is patients with alpha thalassemia myelodysplastic syndrome (ATMDS), who are usually elderly, with a mean age of 68 years at diagnosis. Sex-related demographics In general, males and females are equally affected. However, there is a type of alpha thalassemia that is associated with mental retardation and affects only males. This condition is referred to as alpha thalassemia mental retardation-X syndrome (ATR-X). However, a report by Haas et al identified 2 females in a single center with ATMDS and mutations in the ATR-X gene (ATRX).[14] The investigators observed that although it was possible that females may be less likely to develop ATMDS if the inactivated copy of ATRX is reactivated throughout life, this hypothesis was ruled out in their study by the use of a cross-sectional analysis of healthy females ranging in age from neonate to 90 years to examine the pattern of ATRX inactivation. Race-related demographics Alpha thalassemia occurs in individuals of all ethnic backgrounds but particularly those of African, Asian, Central American, Mediterranean, and Middle Eastern descent. Emigration from regions in which carrier frequency is high increases the

presence of thalassemia syndromes in other parts of the world. The North American TCRN study showed that 85% of patients with alpha thalassemia are Asian, 4% are white, and 11% are of other ethnicities, including African, black, mixed ethnicity, and unknown. Prognosis For silent carriers and individuals with alpha thalassemia trait, the prognosis is excellent. For individuals with HbH disease, the overall survival rate varies but is generally good, with most patients surviving into adulthood. However, some patients have a more complicated course and may not do as well. Patients with HbH disease are at risk for severe anemia and have a lifelong requirement for transfusions. One study suggests that the subtype of hemoglobin H Constant Spring (HCS) is associated with a high risk of life-threatening anemia.[9] Patients identified with this subtype of HbH disease require close follow-up. If anemia is well managed and iron overload is prevented with chelation therapy, individuals with HbH disease can live long and healthy lives. Hydrops fetalis (alpha thalassemia major) is incompatible with life and requires identification in utero and in utero transfusions if the fetus is to survive and be born. To identify fetuses with this condition, family genetic studies must be done, high-risk couples identified, and the fetus tested in utero for the absence of alpha-globin chains. Those rare fetuses that survive to be born, with the help of intrauterine transfusions, continue to require lifelong transfusions and medical care. They may be considered for hematopoietic stem cell transplantation, which is curative of their alpha thalassemia major syndrome. History and Physical Examination The history and physical findings in patients with alpha thalassemia vary according to the number of alpha-globin chains deleted. Additional beta-chain and other hemoglobin abnormalities may also contribute to the clinical presentation and course. Silent carrier Silent carriers (-/) are essentially asymptomatic, and complete blood count (CBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), peripheral smear, and hemoglobin electrophoresis are all typically normal. Slight hypochromia and microcytosis may be evident by microscopic evaluation. Silent carriers may be detected by alpha gene analysis. They may be identified when related carriers of the allele mate and have children with hemoglobin H (HbH) disease. Alpha thalassemia trait Individuals with alpha thalassemia trait (-/- or --/) are asymptomatic, with a normal CBC. The peripheral blood smear typically shows hypochromia, microcytosis, and target cells. The MCV is frequently less than 80 fL, and the MCH is always below 27 pg. RBC counts are usually higher than normal. Hemoglobin electrophoresis is normal. Although elevation of hemoglobin A2 does not occur, elevations of

hemoglobin F have been reported. Individuals of African origin usually carry a homozygous state of the alpha2 allele (the trans deletion, -/-), and deletion usually involves the less active of 2 normal alleles. Alpha thalassemia trait tends to be milder in this population. In Asia, the cis deletion ( --/) is common, and subpopulations exhibit more dramatic features of thalassemia trait. If patients have the hemoglobin Constant Spring (CS) mutation, a slowly migrating abnormal hemoglobin band is present on hemoglobin electrophoresis. The condition is generally diagnosed as a result of incidental laboratory abnormalities and family studies to characterize a relative. Alpha-globin gene analysis can confirm the absence of 2 alpha-globin genes. Persons with this condition may be identified when a child is born with HbH disease. Hemoglobin H disease Symptoms of HbH disease (--/-) are consistent with a chronic hemolytic anemia and include episodes of severe pallor and anemia. Patients are often symptomatic at birth; many others present with neonatal jaundice or anemia. Indirect hyperbilirubinemia, elevated lactate dehydrogenase levels, and reduced haptoglobin are all consistently seen with hemolytic anemia. Exacerbations of hemolysis may occur when patients are exposed to stressors such as infections, fever, ingestion of oxidative compounds, or drug use, and patients may require transfusions. Generally, HbH disease is thought to be a mild disorder. However, because of the marked variability in degree of anemia, patients may range from asymptomatic to needing periodic transfusions to having severe anemia with hepatomegaly and splenomegaly. Some patients may also suffer hydrops fetalis syndrome in utero. Pregnancy may also be a special circumstance, in which patients may develop severe anemia and require transfusions.[8] The subset of patients with HbH Constant Spring (CS) may have a high risk of life-threatening anemia and require close follow-up.[9] Complications occur in varying degrees and include the following: Hepatosplenomegaly Leg ulcers Gallstones Aplastic or hypoplastic crises Skeletal, developmental, and metabolic changes due to ineffective erythropoiesis (these resemble the changes characteristic of beta thalassemia intermedia or beta thalassemia major) Prominent frontal bossing (due to bone marrow expansion) Delayed pneumatization of sinuses Marked overgrowth of the maxillae Ribs and long bones becoming boxlike and convex Premature closure of epiphyses resulting in shortened limbs Compression fracture of the spine (which may result in cord compression or other neurologic deficits) Osteopenia and fractures Splenectomy or transfusional support is often necessary in the second or third decade of life. Iron overload may also occur as a result of increased iron absorption and

frequent transfusions. Acquired cases are observed in myeloproliferative diseases (eg, acute myelogenous leukemia, erythroleukemia, refractory sideroblastic anemia, acute lymphocytic leukemia). Hydrops fetalis (alpha thalassemia major) Individuals with hydrops fetalis (--/--) have no functional alpha-globin chains and thus are unable to make functional hemoglobin. Usually, they die in utero or shortly after birth. Infants who survive to be born have massive total body edema with highoutput congestive heart failure due to the severe anemia. They also have massive hepatomegaly due to heart failure and extramedullary hematopoiesis. An excess of hemoglobin Barts, which is unable to carry oxygen effectively, is indicated. There have been several case reports of individuals with hemoglobin Barts who have survived for variable amounts of time, but many have developmental abnormalities, and all have undergone intrauterine transfusions and required regular blood transfusion and chelation therapy. Alpha thalassemia mental retardation syndromes There are 2 clinical entities described in which patients are noted to have mild forms of alpha thalassemia in conjunction with mental retardation: the ATR-16 syndrome and the ATR-X syndrome. In the ATR-16 syndrome, affected children have large chromosomal rearrangements involving the short arm of the chromosome 16 telomere, which includes the alphaglobin complex. This results in monosomy for the 16p telomere and the alphathalassemia phenotype. If an affected child also inherits a single alpha-globin gene deletion from the other parent, HbH disease results. These children may also have mental retardation and other congenital anomalies that are thought to be due to deletions of dose-sensitive genes on chromosome 16p. The ATR-X syndrome is an X-linked disorder caused by mutations of the ATRX gene located on chromosome Xq13.3.[14] This gene acts as a regulator of alpha-globin gene expression. Patients who are affected have normal alpha-globin genes, but the expression of these genes is downregulated. The ATR-X syndrome is more common than the ATR-16 syndrome. Males who are affected usually have severe intellectual and physical handicaps and other congenital anomalies. Skeletal deformities are present in as many as 90% of patients. The alphathalassemia phenotype varies, with HbH inclusion bodies found in 0-32% of circulating erythrocytes. Alpha thalassemia myelodysplastic syndrome A particularly severe acquired form of HbH disease may occur in elderly men with clonal myeloproliferative diseases, in whom HbH levels may be as high as 60%. This disease, commonly referred to as alpha thalassemia myelodysplastic syndrome (ATMDS), is characterized by marked hypochromic microcytic anemia and the presence of HbH as demonstrated by hemoglobin electrophoresis and supravital staining.

ATMDS patients are also found to have a very low ratio of alpha-globin chains to beta-globin chains (/ ratio), often less than 0.2. This ratio is lower than would be expected for patients with a single functioning alpha-globin gene (--/-), which suggests downregulation of all 4 alpha-globin genes by a trans -acting mutation. Low alpha-globin messenger RNA levels are found in bone marrow cells. When archival blood and bone marrow from patients with ATMDS are studied, acquired ATR-X mutations are found in most patients. Hemolytic disease caused by HbH disease may wax and wane over the course of the myeloproliferative disease. Complications The morbidity and mortality of alpha thalassemia are related to the degree of imbalanced globin production and therefore correlate well with the number of affected alpha-globin genes. Individuals who are silent carriers (-/) or have alpha thalassemia trait (--/ or -/) are phenotypically normal or have mild anemia as the only major morbidity associated with their disease.[15] In patients with HbH disease (--/-), the degree of anemia varies, and morbidity and mortality are largely related to the degree. As a result of multiple blood transfusions, consequences of iron overload on the heart, liver, and other organs may be present; these can contribute to morbidity and mortality. Patients with HbH disease may develop hypersplenism, gallstones, leg ulcers, frequent infections, and various forms of venous thrombosis. The most severe form of alpha thalassemia, hemoglobin Barts, is characteristic of individuals with no functional alpha-globin genes (--/--). After a gestation of about 33 weeks, these infants develop hydrops fetalis syndrome and usually die in utero, during delivery, or shortly after birth. Diagnostic Considerations During pregnancy, iron and folic acid deficiencies can alter the mean corpuscular volume (MCV). As a result, thalassemia may be difficult to diagnose or exclude during pregnancy. If a strong suspicion exists and if a definitive answer is required, polymerase chain reaction (PCR) evaluation should be performed for globin-chain analysis. Pregnant women with hemoglobin H (HbH) disease require special care because women with severe anemia may have serious health problems during their pregnancy, and these problems may adversely affect the health of their fetuses. The incidence of low birth weight is also high in women with HbH disease and severe anemia.[16, 17] Other problems to be considered include the following: Autoimmune hemolytic anemia Hemoglobin S thalassemia syndrome Hemoglobin E thalassemia syndrome Hemoglobinopathies

 Hereditary persistence of hemoglobin F (fetal hemoglobin) High hemoglobin F syndromes Nonimmune hemolytic anemia Sideroblastic anemia Differential Diagnoses Anemia, Acute Anemia, Chronic Beta Thalassemia Hemoglobin C Disease Hemolytic Anemia Iron Deficiency Anemia Thalassemia Thalassemia Intermedia Approach Considerations Alpha thalassemia is frequently mistaken for iron deficiency anemia because both disorders have microcytic red blood cells. Iron therapy is not required for alpha thalassemia, and the procedures used to find a source of bleeding in patients with iron deficiency anemia have no value in patients with thalassemia. Measurements of serum iron and ferritin can provide laboratory evidence to exclude iron deficiency as the etiology for microcytosis. Failure to exclude iron deficiency anemia in a patient with an alpha thalassemia syndrome may lead to continuation of supplemental iron therapy for an extended period, and the resulting iron overload may lead to secondary hemochromatosis. If iron overload continues longer than 1-2 years, it can lead to damage in multiple organs, including cardiac, hepatic, and endocrine dysfunction. Workup relies primarily on laboratory evaluation, hemoglobin electrophoresis, and genetic testing. Bone marrow aspiration and biopsy are generally not helpful in diagnosing these conditions; they may be indicated if other confounding problems are noted. Laboratory Studies Silent carrier The following findings are noted in silent carriers (-/): Hemoglobin level - Within the reference range Reticulocyte count - Normal Mean corpuscular volume (MCV) 75-85 fL Mean corpuscular hemoglobin (MCH) - Around 26 pg Alpha thalassemia trait The following findings are noted in individuals with alpha thalassemia trait (-/- or -/): Hemoglobin level - Within the reference range Reticulocyte count - Normal MCV - 65-75 fL

 MCH - Around 22 pg Hemoglobin H disease Individuals with hemoglobin H (HbH) disease (-/--) have moderate-to-severe anemia. The following findings are noted: Hemoglobin level - 7-10 g/dL Reticulocyte count - 5-10% (the higher the reticulocyte count, the more severe the hemolysis) MCV - 55-65 fL MCH - 20 pg Peripheral blood smear - Small misshapen red cells, hypochromia, microcytosis, and targeting Brilliant cresyl blue stain - HbH inclusion bodies Hydrops fetalis (alpha thalassemia major) Individuals with hydrops fetalis (--/--) have severe anemia. The following findings are noted: Hemoglobin - 4-10 g/dL MCV - 110-120 fL Peripheral blood smear - Severe anisopoikilocytosis, severe hypochromia, and nucleated red blood cells (RBCs) Alpha thalassemia with sickle-cell anemia Alpha thalassemia combined with sickle-cell anemia results in a higher hemoglobin concentration and improved RBC survival. The alpha-globin gene deletion is associated with improved RBC deformability, but the improved rheologic benefits often are overcome by the greater viscosity of a higher hematocrit. Clinically, this scenario is evidenced by a greater number of painful vaso-occlusive crises. It is noteworthy, however, that the incidence of stroke is lower than that seen in sickle-cell disease alone. Hemoglobin Electrophoresis Although hemoglobin electrophoresis is not sensitive enough to diagnose alpha thalassemia syndromes, it can be very useful in quantitating and identifying different hemoglobin types. Hemoglobin Barts is elevated at birth in patients with alpha thalassemia. In persons with HbH disease, 20-40% of total hemoglobin is hemoglobin Barts, along with typical findings of adult hemoglobin A, hemoglobin A2, and hemoglobin F. In silent carriers, however, the percentage is only 1-2%, with low or normal amounts of hemoglobin A2.[18] In persons with alpha thalassemia trait, hemoglobin Barts accounts for about 5-15% of total hemoglobin. The thalassemias were initially defined in terms of the ratio between the quantities of alpha-globin and beta-globin chains (/ ratio). Altered / synthetic ratios occur in both alpha and beta thalassemias. The / ratios progressively decrease from silent carrier state to alpha thalassemia trait to HbH disease. Tests are performed by incubating red blood cells with radiolabeled amino acid and subsequently separating alpha- and beta-globin chains with urea carboxymethyl cellulose (CMC)

chromatography. Imaging Studies In general, imaging studies are not useful in alpha thalassemia. However, because hepatosplenomegaly and gallstones are common in HbH disease, some imaging of these organs can be useful. Ultrasonography of the liver, gallbladder, and spleen frequently reveals gallstones, which consist of pigment resulting from hemolysis. Hepatomegaly was seen in 70% of 502 patients in Thailand, 60% of 153 patients in Sardinia, and 14% of 88 patients in Taiwan. Splenomegaly is also common in HbH disease and was found in 79% of patients in Thailand, 60% in Sardinia, and 47% in Taiwan. Genetic Testing Genetic testing is currently available to establish the diagnosis and clarify the genetic abnormalities in patients with a family history or laboratory results suggestive of an alpha thalassemia syndrome.[19] Polymerase chain reaction (PCR) and restriction endonuclease testing may be used. Recombinant DNA technology can be diagnostic, but is still considered research. Other genetic tests include gene mapping and anti-L globin monoclonal antibodies. Genetic techniques can be helpful in some cases in which both the patients and the parents alpha-chain configurations are elucidated exactly, which can be useful in predicting the risk that a couples future offspring will be affected. Histologic Findings Peripheral blood smear may reveal target cells, microcytosis, hypochromia, and anisopoikilocytosis. Most silent carriers have only mild microcytosis, which can be differentiated from other common causes of microcytosis on the basis of serum iron and ferritin concentrations within the reference range.

Peripheral smear from patient with hemoglobin H disease showing target cells, microcytosis, hypochromia, and anisopoikilocytosis. Morphologic abnormalities are similar to those observed in beta thalassemia. In silent carriers, only mild microcytosis is observed. Approach Considerations Individuals with mild forms of alpha thalassemia may not require specific treatment except as needed for management of low hemoglobin levels. In some patients, supplementation of iron or folic acid may be useful. Patients with more severe anemia may require lifelong transfusion therapy. Surgical therapy is considered only in selected cases. Iron and Folic Acid Supplementation Iron deficiency must be documented carefully with laboratory testing before supplemental iron is given. Iron supplementation does not improve hematologic values in alpha thalassemia. Many patients with apparent iron deficiency actually have iron overload (hemochromatosis), the effects of which can contribute to morbidity and mortality. Iron overload is a particular concern in patients with hemoglobin H (HbH) disease or those rare surviving patients with alpha thalassemia major. In patients with elevated ferritin levels, the diet should be low in iron. Folic acid supplementation may be beneficial in patients with elevated reticulocyte counts, indicating increased utilization resulting from the hemolytic process and the high bone marrow turnover rate. General Supportive Care General supportive care in HbH disease, including transfusions, may be needed periodically or in periods of severe anemia, such as during parvovirus infections. Guidelines for transfusion in neonates and older children have been established.[20] Blood transfusions should be administered only if necessary. Usually, patients with HbH disease live fairly normal lives and require few transfusions. Hemoglobin levels usually range from 7-10 g/dL. Transfusion therapy is reserved for patients with severe anemia (usually < 7 g/dL) and symptomatic anemia. If chronic transfusion therapy is needed, iron chelation therapy should be considered to prevent iron overload. Even patients who have not received a large number of transfusions may have elevated total body iron loads and may require chelation therapy. Hemolytic episodes may be triggered either by drug use or by infection. The use of special red blood cell units (eg, washed, irradiated, or leukocyte-depleted) is usually unnecessary. Other Medical Measures Be aware of the risk of infections, particularly in children who have undergone splenectomy. Administer appropriate vaccines to these individuals.

In very severe cases, allogeneic hematopoietic stem cell transplantation may be considered. This measure is curative because the hematopoietic system of the patient is replaced by that of the donor. A sibling who is fully matched for human leukocyte antigen (HLA) and who is, at most, a carrier for alpha thalassemia (deletion of 2 alpha-globin genes) is the most suitable donor. However, because of the toxicity of the procedure, bone marrow transplantation should be limited to the most severely affected patients. Splenectomy and Orthopedic Surgery Surgical care is not needed for silent carriers or persons with alpha thalassemia trait. However, splenectomy may be beneficial for some patients with HbH disease. Usually, splenectomy is reserved for patients with symptoms of hypersplenism (as reflected by leukopenia, thrombocytopenia, and worsening anemia) or for patients who were previously stable and have developed a transfusion requirement. Orthopedic or orthodontic surgery may be necessary to correct skeletal abnormalities due to erythroid hyperplasia. Prevention Prenatal testing is available for families at risk (eg, families in which the parents are members of ethnic groups with the highest carrier rates). Globin-chain analysis can be performed by means of polymerase chain reaction (PCR) testing.[21] Although neonatal screening is not sufficient in the diagnosis of HbH disease, patients who have the disease at birth have large amounts of hemoglobin Barts, which is detectable by neonatal screening. Consultations Patients usually undergo evaluation by a hematologist for initial diagnosis. Patients who are silent carriers or have the alpha thalassemia trait generally need no further hematology follow-up. Patients with HbH disease usually undergo close follow-up monitoring by a hematologist who can coordinate care and treat the patient during acute hemolytic and anemic episodes. Medication Summary No medications are needed for silent carriers or individuals with alpha thalassemia trait. In general, no medications are needed for patients with hemoglobin H (HbH) disease; however, if the reticulocyte count is elevated, the diet should be supplemented with folic acid. If a patient has an elevated ferritin level, chelation therapy with deferoxamine or deferasirox should be considered. Deferasirox is preferred because it is orally administered, whereas deferoxamine is administered intravenously (IV) or subcutaneously (SC). Vitamins

Class Summary This agent is a supplement with folic acid, a vitamin necessary for red blood cell (RBC) production. View full drug information Folic acid (Folacin-800) Folic acid is a necessary coenzyme for nucleoprotein synthesis and maintenance in patients with erythropoiesis. Chelation agents Class Summary Iron overload (usually from multiple transfusions) may require chelation therapy, which usually begins when the ferritin level is greater than 1000 ng/mL. View full drug information Deferoxamine mesylate (Desferal) Deferoxamine is freely soluble in water. Approximately 8 mg of iron is bound by 100 mg of deferoxamine. Deferoxamine is excreted in urine and bile and discolors the urine red. It readily chelates iron from ferritin and hemosiderin but not from transferrin. It is most effective when provided to the circulation continuously by means of infusion. Deferoxamine may be administered by intramuscular (IM) injection, slow infusion, SC bolus, or continuous infusion. It does not effectively chelate other trace metals of nutritional importance. View full drug information Deferasirox (Exjade) Deferasirox is available as a tablet for oral suspension. It is an oral iron-chelating agent that reduces liver iron concentration and serum ferritin levels. Deferasirox binds iron with high affinity in a 2:1 ratio. It is approved for treatment of treat chronic iron overload due to multiple blood transfusions and nontransfusion-dependent thalassemia.

BETA THALASSEMIA Background Beta thalassemia syndromes are a group of hereditary disorders characterized by a genetic deficiency in the synthesis of beta-globin chains. In the homozygous state, beta thalassemia (ie, thalassemia major) causes severe, transfusion-dependent anemia. In the heterozygous state, the beta thalassemia trait (ie, thalassemia minor) causes mild to moderate microcytic anemia. (See Etiology.) Hemoglobin (Hb) E, a common Hb variant found in Southeast Asia, is associated with a beta thalassemia phenotype, and this variant is included in the beta thalassemia category of diseases. Complications associated with beta thalassemia Complications associated with beta thalassemia, aside from the aforementioned anemia, are as follows (see Prognosis, Clinical, Workup, Treatment, and Medications): Extramedullary hematopoiesis Asplenia secondary to splenectomy Medical complications from long-term transfusional therapy - Iron overload and transfusion-associated infections (eg, hepatitis) Increased risk for infections resulting from asplenia (eg, encapsulated organisms such as pneumococcus) or from iron overload (eg, Yersinia species) Cholelithiasis (eg, bilirubin stones) Etiology Beta-globin gene mutations Mutations in globin genes cause thalassemias. Beta thalassemia affects 1 or both of the beta-globin genes. (Alpha thalassemia affects the alpha-globin gene[s].) These mutations, by causing impaired synthesis of the beta-globin protein component of Hb, result in anemia.[1, 2] The defect can be a complete absence of the beta-globin protein (ie, beta-zero thalassemia) or a severely reduced synthesis of the beta-globin protein (ie, beta-plus thalassemia). (See the image below.)

Peripheral smear in beta-zero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes. The genetic defect usually is a missense or nonsense mutation in the beta-globin gene,

although occasional defects due to gene deletions of the beta-globin gene and surrounding regions also have been reported. In beta thalassemia minor (ie, beta thalassemia trait or heterozygous carrier-type), one of the beta-globin genes is defective, resulting in an approximately 50% decrease in the synthesis of the beta-globin protein. In beta thalassemia major (ie, homozygous beta thalassemia), the production of the beta-globin chains is severely impaired because both beta-globin genes are mutated. The severe imbalance of globin chain synthesis (alpha >> beta) results in ineffective erythropoiesis and severe microcytic hypochromic anemia. (See the image below.)

Peripheral smear from a patient with beta-zero thalassemia major showing more marked microcytosis (M) and anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent. The excess unpaired alpha-globin chains aggregate to form precipitates that damage red cell membranes, resulting in intravascular hemolysis. Premature destruction of erythroid precursors results in intramedullary death and ineffective erythropoiesis. The profound anemia typically is associated with erythroid hyperplasia and extramedullary hematopoiesis. Although beta thalassemia is caused by a genetic mutation in the beta-globin gene (which is located on chromosome 11), many additional factors influence the clinical manifestations of the disease. That is, the same mutations may have different clinical manifestations in different patients. The factors below are known to influence the clinical phenotype. Intracellular fetal Hb concentrations The level of expression of fetal Hb (ie, the expression level of the gamma-globin gene) in red blood cells determines, in part, the severity of the disease. Patients with high fetal Hb have milder disease. Coinheritance of alpha thalassemia Patients with coinheritance of alpha thalassemia have a milder clinical course because they have a less severe alpha-beta chain imbalance. Coexistence of sickle cell trait The coexistence of sickle cell trait and beta thalassemia is a major and symptomatic hemoglobinopathy with most of the symptoms and complications of sickle cell

disease. Unlike sickle cell trait, in which most Hb-on-Hb electrophoresis is Hb A (AS), S is the dominant Hb (SA) and usually constitutes about 60% or more of the circulating Hb, depending on the transfusion status of the patient and the nature of the coexisting beta-thalassemia mutation (ie, beta-zero vs beta-plus). Pathophysiology Occurrence in the United States The frequency of beta thalassemia varies widely, depending on the ethnic population. The disease is reported most commonly in Mediterranean, African, and Southeast Asian populations. International occurrence The disease is found most commonly in the Mediterranean region, Africa, and Southeast Asia, presumably as an adaptive association to endemic malaria. The incidence may be as high as 10% in these areas. Race-related demographics Beta thalassemia genes are reported throughout the world, although more frequently in Mediterranean, African, and Southeast Asian populations. Patients of Mediterranean extraction are more likely to be anemic with thalassemia trait than Africans because they tend to have beta-zero thalassemia rather than beta-plus thalassemia. The genetic defect in Mediterranean populations is caused most commonly by (1) a mutation creating an abnormal splicing site or (2) a mutation creating a premature translation termination codon. Southeast Asian populations also have a significant prevalence of Hb E and alpha thalassemia. African populations more commonly have genetic defects leading to alpha thalassemia. Age-related demographics The manifestations of the disease may not be apparent until a complete switch from fetal to adult Hb synthesis occurs. This switch typically is completed by the sixth month after birth. Prognosis Individuals with thalassemia minor (thalassemia trait) usually have mild, asymptomatic microcytic anemia. This state does not result in mortality or significant morbidity. The prognosis of patients with thalassemia major is highly dependent on the patient's adherence to long-term treatment programs, namely the hypertransfusion program and lifelong iron chelation. Allogeneic bone marrow transplantation may be curative. Morbidity and mortality The major causes of morbidity and mortality in beta thalassemia are anemia and iron overload. The severe anemia resulting from this disease, if untreated, can result in high-output cardiac failure; the intramedullary erythroid expansion may result in

associated skeletal changes such as cortical bone thinning. The long-term increase in red-cell turnover causes hyperbilirubinemia and bilirubin-containing gallstones. Increased iron deposition resulting from lifelong transfusions and enhanced iron absorption results in secondary iron overload. This overload causes clinical problems similar to those observed with primary hemochromatosis (eg, endocrine dysfunction, liver dysfunction, cardiac dysfunction). History and Physical Examination Patients with the beta thalassemia trait generally have no unusual physical findings. In patients with beta thalassemia major, the physical findings are related to severe anemia, ineffective erythropoiesis, extramedullary hematopoiesis, and iron overload resulting from transfusion and increased iron absorption. The skin may show pallor from anemia and jaundice from hyperbilirubinemia, and the skull and other bones may be deformed secondary to erythroid hyperplasia with intramedullary expansion and cortical bone thinning. The extremities may demonstrate skin ulceration. 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, gallbladder, and spleen. 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. The gallbladder 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. In addition to cardiac dysfunction, hepatomegaly, and hepatitis, iron overload can also cause endocrine dysfunction, especially affecting the pancreas, testes, and thyroid. Transfusion-associated viral hepatitis resulting in cirrhosis or portal hypertension also may be seen. Diagnostic Considerations A major diagnostic consideration is to distinguish mild microcytic anemia due to beta-thalassemia carrier state versus other causes of microcytic anemia. 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. The Mentzer index is defined as mean corpuscular volume per red cell count. An index of less than 13 suggests that the patient has the thalassemia trait, and an index of more than 13 suggests that the patient has iron deficiency. Alpha thalassemia is another known cause of mild microcytic anemia. Alpha thalassemia is characterized by genetic defects in the alpha-globin gene, and this variant has features similar to those of beta thalassemia. In contrast to betathalassemia minor (carrier) patients who have elevated levels of Hb A2 (2 alpha-

globin chains complexed with 2 delta-globin chains), patients with alpha-thalassemia have normal levels of Hb. Establishing the diagnosis of the alpha-thalassemia trait is often a diagnosis of exclusion; definitive diagnosis requires measuring either the alpha-beta chain synthesis ratio or performing genetic tests of the alpha-globin cluster (using Southern blot or polymerase chain reaction [PCR] assay tests). Unstable Hb levels and some types of red cell membrane disorders are other conditions to consider in the differential diagnosis of beta-thalassemia. Differential Diagnoses Anemia of Chronic Disease and Renal Failure Lead Nephropathy Lead poisoning Sideroblastic Anemias Approach Considerations Thalassemia major is a severe anemia that presents during the first few months after birth, when the patients level of fetal Hb decreases. The diagnosis is usually obvious in the right clinical setting of age and ethnic background. In some cases, the brisk erythropoiesis with increased erythroblasts may be mistaken for clonal proliferative disorders such as leukemia or myelodysplasia. In patients with longstanding beta-thalassemia major, 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. 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. Thalassemia minor usually presents as a mild, asymptomatic microcytic anemia and is detected through routine blood tests in adults as well as in older children. These laboratory findings should be evaluated as indicated. Laboratory Studies The diagnosis of beta thalassemia minor usually is suggested by the presence of a mild, isolated microcytic anemia; target cells on the peripheral blood smear; and a normal red blood cell count. (See the images below.)

Peripheral smear in beta-zero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes.

Peripheral smear from a patient with beta-zero thalassemia major showing more marked microcytosis (M) and anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent. An elevation of Hb A2, 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. An elevated Hb F level is not specific to patients with the beta thalassemia trait. Free erythrocyte porphyrin (FEP) tests may be useful in situations in which the diagnosis of beta thalassemia minor is unclear. The FEP level is normal in patients with the beta thalassemia trait, but it is elevated in patients with iron deficiency or lead poisoning. Alpha thalassemia is characterized by genetic defects in the alpha-globin gene, and this variant has features similar to beta thalassemia. As previously discussed, patients with this disorder have normal Hb A2 levels. Establishing the diagnosis of the alpha thalassemia trait requires measuring either the alpha-beta chain synthesis ratio or performing genetic tests of the alpha-globin cluster (using Southern blot or PCR assay tests). 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. 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).

The Mentzer index is defined as mean corpuscular volume per red cell count. An index of less than 13 suggests that the patient has the thalassemia trait, and an index of more than 13 suggests that the patient has iron deficiency. Prenatal Diagnosis Prenatal diagnosis is possible through analysis of deoxyribonucleic acid (DNA) obtained via chorionic villi sampling at 8-10 weeks fetal gestation or by amniocentesis at 14-20 weeks gestation. In most laboratories, the DNA is amplified using the PCR assay test and then is analyzed for the presence of the thalassemia mutation using a panel of oligonucleotide probes corresponding to known thalassemia mutations. Since the genetic defects are quite variable, family genotyping usually must be completed for diagnostic linkage (segregation) analysis. With the anticipated availability of large-scale mutation screening by DNA chip technology, extensive pedigree analyses may be obviated. Physicians can perform fetal blood sampling for Hb chain synthesis at 18-22 weeks gestation, but this procedure is not as reliable as DNA analysis sampling methods. Genetic therapy strategies are currently in the early stages of development. Approach Considerations Thalassemia is an iron-overloading disorder. Therapy with iron is contraindicated in this disease. Thalassemia minor Patients with thalassemia minor usually do not require any specific treatment. Inform patients that their condition is hereditary and that physicians sometimes mistake the disorder for iron deficiency. Some pregnant patients with the beta thalassemia trait may develop concurrent iron deficiency and severe anemia; they may require transfusional support if they are not responsive to iron repletion modalities. Thalassemia major Treatment for patients with thalassemia major includes chronic transfusion therapy, iron chelation, splenectomy, and allogeneic hematopoietic transplantation. The goal of long-term hypertransfusional support is to maintain the patient's Hb at 9-10 g/dL, thus improving his or her sense of well-being while simultaneously suppressing enhanced erythropoiesis. This strategy not only treats the anemia but also suppresses endogenous erythropoiesis so that extramedullary hematopoiesis and skeletal changes are suppressed. Patients receiving transfusion therapy also require iron chelation with desferrioxamine. Blood banking considerations for these patients include completely typing their erythrocytes prior to the first transfusion. This procedure helps future crossmatching processes. Allogeneic hematopoietic transplantation may be curative in some patients with thalassemia major. An Italian group led by Lucarelli has the most experience with this procedure.[3] This group's research documented a 90% long-term survival rate in

patients with favorable characteristics (young age, HLA match, no organ dysfunction). Diet and activity Drinking tea may help to reduce iron absorption through the intestinal tract. Vitamin C may improve iron excretion in patients receiving iron chelation. However, anecdotal reports suggest that large doses of vitamin C can cause fatal arrhythmias when administered without concomitant infusion of deferoxamine. Patient activity may be limited secondary to severe anemia. Surgical Treatment Splenectomy Physicians often use splenectomy to decrease transfusion requirements. (Patients with thalassemia minor only rarely require splenectomy.) Because postsplenectomy sepsis is possible, defer this procedure until the patient is older than 6-7 years. In addition, to minimize the risk of postsplenectomy sepsis, vaccinate the patient against Pneumococcus species, Meningococcus species, and Haemophilus influenzae. Administer penicillin prophylaxis to children after splenectomy. Cholecystectomy Patients with thalassemia minor may have bilirubin stones in their gallbladder and, if symptomatic, may require treatment. Perform a cholecystectomy using a laparoscope or carry out the procedure at the same time as the splenectomy. Medication Summary Medical therapy for beta thalassemia primarily involves iron chelation. The objective of iron chelation is to avoid the complications of iron overload such as cardiac and hepatic dysfunction. Chelation therapy significantly improves myocardial T2* and improves left ventricular function.[4, 5] Deferoxamine is an intravenously administered chelation agent currently approved for use in the United States. Deferiprone, an oral chelation agent, has been approved for use in Europe and received approval in the United States in October 2011 for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. Deferasirox (Exjade), another orally administered chelation agent, was approved for use in the United States by the US Food and Drug Administration (FDA) in 2005. Guidelines on chelation treatment in thalassemia major have been published.[6, 7] In January 2013, the FDA approved deferasirox for treatment of chronic iron overload caused by nontransfusion-dependent thalassemia. Deferasirox is a selective trivalent iron chelator that reduces liver iron concentration (LIC) and serum ferritin levels. Approval was based on two clinical trials that measured the number of patients whose LIC was reduced to < 5 mg/g dry weight after 52 weeks of treatment. In the first trial, 166 patients received 5 mg/kg or 10 mg/kg of deferasirox, or a placebo daily. Results showed 15% and 27% of deferasirox-treated patients, respectively, achieved the target LIC compared with 4% of placebo-treated patients.[11] The second trial included 133 patients from the first study who received an additional year of deferasirox treatment

or switched from placebo. Of the evaluable patients in this group, 35% achieved the target LIC.[12] Because fetal globin gene expression is associated with a milder phenotype, approaches to enhance intracellular Hb F levels (through drugs that activate gammaglobin gene expression) are under investigation. The 2 most widely studied drugs in this area are butyrates and hydroxyurea.[8] More recently, new therapeutic targets have been reported, such as BCL11A.[9] Gene therapy for beta thalassemia is being pursued by several research groups. Obstacles to gene therapy include an inability to express high levels of the beta-globin gene in erythroid cells and an inability to transduce hematopoietic pluripotent stem cells at high efficiency. In one study, an adult patient with severe, transfusiondependent beta thalassemia became transfusion independent for 21 months, 33 months after lentiviral beta-globin gene transfer, with peripheral blood hemoglobin being maintained at 9-10g/dL.[10] Chelating Agents Class Summary These agents bind iron and promote excretion. View full drug information Deferoxamine (Desferal) Deferoxamine is usually administered as a slow, subcutaneous infusion through a portable pump. It is freely soluble in water. Approximately 8 mg of iron is bound by 100 mg of deferoxamine. This agent is excreted in bile and urine, resulting in red discoloration. It readily chelates iron from ferritin and hemosiderin, but not from transferrin. Deferoxamine is most effective when it is administered as a continuous infusion. View full drug information Deferasirox (Exjade) Deferasirox is available as a tablet for oral suspension. It is an oral iron-chelating agent that reduces liver iron concentration and serum ferritin levels. Deferasirox binds iron with high affinity in a 2:1 ratio. It is approved for treatment of treat chronic iron overload due to multiple blood transfusions and nontransfusion-dependent thalassemia. View full drug information Deferiprone (Ferriprox) Deferiprone is an iron chelator indicated for patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. Approval is based on a reduction in serum ferritin levels. No controlled trials have demonstrated a direct treatment benefit, such as improvement in disease-related symptoms, functioning, or increased survival. It is available as 500-mg, film-coated tablets.