Complications Associated With Beta Thalassemia

8/21/2018 https://emedicine.medscape.
com/article/206490-print

emedicine.medscape.com
Beta Thalassemia
Updated: Nov 28, 2017
Author: Pooja Advani, MD; Chief Editor: Emmanuel C Besa, MD
Overview
Practice Essentials
Beta thalassemia syndromes are a group of hereditary disorders characterized by a genetic deficiency in the synthesis of
betaglobin 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.)
Patients in whom the clinical severity of the disease lies between that of thalassemia major and thalassemia minor are
categorized as having thalassemia intermedia. Several different genotypes are associated with thalassemia intermedia.
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.
Patients with thalassemia minor usually do not require any specific treatment. Treatment for patients with thalassemia major
includes longterm transfusion therapy, iron chelation, splenectomy, allogeneic hematopoietic transplantation, and supportive
measures. See Treatment.
Complications associated with beta thalassemia
Complications associated with beta thalassemia, aside from the aforementioned anemia, are as follows (see Prognosis,
Presentation, Workup, Treatment, and Medication):
Extramedullary hematopoiesis
Asplenia secondary to splenectomy
Medical complications from longterm transfusional therapy Iron overload and transfusionassociated 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
Betaglobin gene mutations
Mutations in globin genes cause thalassemias. Beta thalassemia affects 1 or both of the betaglobin genes. (Alpha
thalassemia affects the alphaglobin gene[s].) These mutations, by causing impaired synthesis of the betaglobin protein
component of Hb, result in anemia.[1, 2]
Beta thalassemia is inherited as an autosomal recessive disorder. The defect can be a complete absence of the betaglobin
protein (ie, betazero thalassemia) or a severely reduced synthesis of the betaglobin protein (ie, betaplus thalassemia).
(See the image below.)
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8/21/2018 https://emedicine.medscape.com/article/206490-print
Peripheral smear in betazero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes.
Peripheral smear in betazero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes.The genetic
defect usually is a missense or nonsense mutation in the betaglobin gene, although occasional defects due to gene
deletions of the betaglobin gene and surrounding regions also have been reported.
In beta thalassemia minor (ie, beta thalassemia trait or heterozygous carriertype), one of the betaglobin genes is defective,
resulting in an approximately 50% decrease in the synthesis of the betaglobin protein.
In beta thalassemia major (ie, homozygous beta thalassemia), the production of the betaglobin chains is severely impaired
because both betaglobin 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 betazero thalassemia major showing more marked microcytosis (M) and
anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent.
anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent. The excess unpaired
alphaglobin 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 betaglobin 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 gammaglobin 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 alphabeta
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 HbonHb 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 betathalassemia mutation (ie, betazero vs betaplus).
Epidemiology
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 prevalence may be as high as 10% in these areas.
Racerelated 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 than Africans to be anemic with
thalassemia trait, because they tend to have betazero thalassemia rather than betaplus thalassemia.
The genetic defect in Mediterranean populations is caused most commonly by either (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.
Agerelated 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 longterm 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 highoutput cardiac failure; the intramedullary erythroid expansion may result in
associated skeletal changes such as cortical bone thinning. The longterm increase in redcell turnover causes
hyperbilirubinemia and bilirubincontaining 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).
A broad spectrum of neurological complications has also been reported in beta thalassemia complications, although most
were subclinical. These have included the following[3] :
Cognitive impairment
Abnormal findings on evoked potentials
Cerebrovascular disease
Peripheral neuropathy
Patient Education
Educate patients with thalassemia minor about the genetic (hereditary) nature of their disease, and inform them that their
immediate family members (ie, parents, siblings, children) may be affected. The presence of betathalassemia minor in both
parents implies that there is about a one fourth chance that a child will have thalassemia major. Careful genetic counseling is
also appropriate for patients in whom one parent has betathalassemia minor and the other parent has some form of beta
globin–related disease, such as sickle cell carriage.
Inform patients with thalassemia minor that they do not have iron deficiency and that iron supplementation will not improve
their anemia.

Presentation
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. Skin ulceration may
be present on the extremities.
Thalassemia can result in maxillary enlargement, leading to an appearance known as chipmunk face, along with increased
spaces between teeth, overbite, and malocclusion. Painful swelling of salivary glands and a dry mouth may occur, which
leads to reduced salivary protection and an increased rate of tooth decay.[4]
Cardiac examination may reveal heart 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 is typically found. 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. Transfusionassociated viral hepatitis resulting in cirrhosis or portal
hypertension also may occur.

DDx
Diagnostic Considerations
A major diagnostic consideration is to distinguish mild microcytic anemia due to betathalassemia carrier state from
microcytic anemia due to other causes. 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.
Calculation of the Mentzer index (mean corpuscular volume per red cell count) may be helpful. A Mentzer 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.[5]
Alpha thalassemia, which is characterized by genetic defects in the alphaglobin gene, is another known cause of mild
microcytic anemia and has features similar to those of beta thalassemia. However, in contrast to betathalassemia minor
(carrier) patients who have elevated levels of Hb A2 (2 alphaglobin chains complexed with 2 deltaglobin chains), patients
with alphathalassemia have normal levels of Hb.
Establishing the diagnosis of the alphathalassemia trait is often a diagnosis of exclusion. Definitive diagnosis requires
measuring either the alphabeta chain synthesis ratio or performing genetic tests of the alphaglobin 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 betathalassemia.
Differential Diagnoses
Alpha Thalassemia
Anemia of Chronic Disease and Renal Failure
Iron Deficiency Anemia
Lead Nephropathy
Sideroblastic Anemias
Workup

Workup
Approach Considerations
Thalassemia major is a severe anemia that presents during the first few months after birth, when the patient’s level of fetal
hemoglobin decreases. The diagnosis is usually obvious in the clinical setting of appropriate 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.
Skeletal abnormalities in patients with longstanding beta thalassemia major include an expanded bone marrow space,
resulting in thinning of the bone cortex. These changes are particularly dramatic in the skull, which may show the
characteristic “haironend” appearance.[6] Bone changes can also 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 from multiple transfusion therapy. Transfusion also may result in infection with the
hepatitis virus, which leads to cirrhosis and portal hypertension. Gallbladder imaging may show the presence of bilirubin
stones.
The heart is a major organ 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.
Cardiac magnetic resonance imaging (MRI) is considered the criterion standard for measuring cardiac indices, as well as for
evaluating cardiac overload by measurement of T2* (relaxation parameter), with a cardiac T2* of less than 10 ms being the
most important predictor of development of heart failure.[7]
Thalassemia minor usually presents as a mild, asymptomatic microcytic anemia and is detected through routine blood tests
in adults and 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 the following:
Mild, isolated microcytic anemia
Target cells on the peripheral blood smear (see the images below)
A normal red blood cell (RBC) count
Peripheral smear in betazero thalassemia minor showing microcytes (M), target cells (T), and poikilocytes.
anisopoikilocytosis (P) than in thalassemia minor. Target cells (T) and hypochromia are prominent.
Heinz bodies, which represent inclusions within RBCs consisting of denatured hemoglobin (Hb), may also be seen in the
peripheral blood.[8]
Elevation of the Hb A2 level, demonstrated by electrophoresis or column chromatography, confirms the diagnosis of beta
thalassemia trait. The Hb A2 level in these patients usually is approximately 46%. In rare cases of concurrent severe iron
deficiency, an 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 deltabeta 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 alphaglobin gene, and this variant has features similar to beta
thalassemia (see Diagnostic Considerations). Patients with this disorder have normal Hb A2 levels. Establishing the
diagnosis of the alpha thalassemia trait requires measuring either the alphabeta chain synthesis ratio or performing genetic
tests of the alphaglobin cluster (using Southern blot or polymerase chain reaction [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.
Evidence of hemolysis in the form of indirect hyperbilirubinemia, low haptoglobin, and elevated lactate dehydrogenase may
be seen as a result of ineffective erythropoiesis and consequent destruction of these RBCs.
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 blood 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.[5]
Prenatal Diagnosis
Prenatal diagnosis is possible through analysis of DNA obtained via chorionic villi sampling at 810 weeks’ fetal gestation or
by amniocentesis at 1420 weeks’ gestation. In most laboratories, the DNA is amplified using PCR 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 largescale mutation screening by DNA chip technology, extensive
pedigree analyses may be obviated.
Physicians can perform fetal blood sampling for Hb chain synthesis at 1822 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.

Treatment
Approach Considerations
The therapeutic approach to thalassemia varies between thalassemia minor and thalassemia major.
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 the following:
Longterm transfusion therapy
Iron chelation
Splenectomy
Allogeneic hematopoietic transplantation
Supportive measures
Supportive measures include folic acid replacement and monitoring for the development of complications such as pulmonary
hypertension, osteoporosis, and bone fractures, poor dentition, heart failure, and aplastic crisis with parvovirus B19
infection.
Longterm transfusion therapy
The goal of longterm hypertransfusional support is to maintain the patient's hemoglobin level at 910 g/dL, thus improving
his or her sense of well being while simultaneously suppressing enhanced erythropoiesis. This strategy treats the anemia
and suppresses endogenous erythropoiesis so that extramedullary hematopoiesis and skeletal changes are suppressed.
Patients receiving longterm transfusion therapy also require iron chelation. (See Medication.)
Blood banking considerations for these patients include completely typing their erythrocytes for Rh and ABO antigens prior
to the first transfusion. This procedure helps future crossmatching processes and minimizes the chances of
alloimmunization. Transfusion of washed, leukocytepoor red blood cells (RBCs) at approximately 815 mL RBCs per
kilogram (kg) of body weight over 12 hours is recommended.[9]
Hapgood et al suggest that current recommendations lead to undertransfusion in males. As a result, males may be more
likely to have extramedullary hematopoiesis and thus more likely to require splenectomy or to develop spinal cord
compression, an uncommon but serious complication of paraspinal extramedullary hematopoiesis.[10]
In their study of 116 patients (51 males and 65 females) with thalassemia major, males were receiving more units of RBCs
per transfusion and had a higher annual transfusion volume, but with correction for weight, females were receiving a higher
transfused volume per kg: 225 versus 202 mL/kg in males (P=0.028). Erythropoietin (EPO) levels were higher in males: 72
versus 52 mIU/mL (P=0.006). The incidence of splenectomy was higher in males (61%, vs 40% in females; P=0.031).[10]
Hematopoietic stem cell transplantation
Allogeneic hematopoietic transplantation may be curative in some patients with thalassemia major.[11] The first successful
allogeneic stem cell transplant from an HLAidentical sibling donor was reported in 1982.[12] An Italian group led by Lucarelli
has the most experience with this procedure.[13] This group's research documented a 90% longterm survival rate in
patients with favorable characteristics (young age, HLA match, no organ dysfunction).
Transplantationrelated issues such as graft versus host disease, graft failure, chronic immunosuppressive therapy, and
transplantationrelated mortality should be carefully considered prior to proceeding with this approach.
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, especially with deferoxamine.[14] 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.
Gene therapy
Since the first successful gene therapy for thalassemia major, in 2007, researchers have worked to improve the efficacy and
safety of the procedure.[11, 15] In this process, autologous hematopoietic stem cells (HSCs) are harvested from the patient
and then genetically modified with a lentiviral vector expressing a normal globin gene. After the patient has undergone
appropriate conditioning therapy to destroy existing HSCs, the modified HSCTs are reinfused into the patient. Clinical trials of
gene therapy for thalassemia are currently recruiting participants.[16, 17]
A newer approach employs genome editing techniques, such as zinc finger nucleases (ZFN), transcription activator–like
effectors with Fokl nuclease (TALEN), or the clustered regularly interspaced short palindromic repeats (CRISPR) with Cas9
nuclease system. These can specifically target singlemutation sites and replace them with the normal sequence, restoring
the wildtype functional configuration of the gene. Producing a sufficiently large number of corrected genes is the major
challenge with this approach.[11]
Surgical Treatment
Splenectomy
Physicians often use splenectomy to decrease transfusion requirements in patients with thalassemia major. (Patients with
thalassemia minor only rarely require splenectomy.) Splenectomy is recommended when the calculated annual transfusion
requirement is greater than 200220 mL RBCs/kg/y with a hematocrit value of 70%.[9] In addition to reducing transfusion
requirements and the resultant iron overload, splenectomy also prevents extramedullary hematopoiesis.
Because postsplenectomy sepsis is possible, defer this procedure until the patient is older than 67 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. Postsplenectomy
thrombocytosis can increase the risk of thrombotic events. The risktobenefit ratio for this procedure should be cautiously
evaluated.
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.
Investigational Therapy
Emerging therapies include pharmacologic agents that induce fetal hemoglobin, Jak2 inhibitors to reverse splenomegaly,
hepcidinrelated compounds to improve iron metabolism, and gene therapy aimed at delivering the beta globin gene into
cells by a viral vector.[18]
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 two most widely studied
drugs in this area are butyrates and hydroxyurea.[19] More recently, new therapeutic targets have been reported, such as
BCL11A, which regulates fetal hemoglobin expression.[20, 21]
Other therapeutic approaches currently being investigated include the following[22, 23] :
Demethylating agents (eg, decitabine, 5azacytidine)
Histone deacetylase (HDAC) inhibitors (eg, vorinostat, panobinostat)
Immunomodulating agents (eg, pomalidomide)
Shortchain fatty acid derivatives (eg, arginine butyrate, sodium phenylbutyrate)
Sotatercept (ACE011) is a promising activin type IIA receptor fusion protein that has been recently reported to improve
anemia in patients with non–transfusiondependent thalassemia intermedia.[24]
Improvement in anemia has been reported with administration of erythropoietin in several studies; however, wellcontrolled
clinical trials have not been performed. The postulated mechanism of action of erythropoietin is that increasing the erythroid
mass (pathologic and less pathologic RBCs) and, thus hemoglobin, stimulates fetal hemoglobin, increases iron use, and
reduces oxidative stress.[25]
Gene therapy
Gene therapy for beta thalassemia is being pursued by several research groups. In one case report, an adult patient with
severe, transfusiondependent beta thalassemia became transfusion independent for 21 months, 33 months after lentiviral
betaglobin gene transfer, with peripheral blood hemoglobin being maintained at 910 g/dL.[26]
Obstacles to gene therapy include an inability to express high levels of the betaglobin gene in erythroid cells and an inability
to transduce hematopoietic pluripotent stem cells at high efficiency. Additionally, the quest for a safe and specific target
gene–delivering vector has been challenging.
A phase I clinical trial using autologous CD34+ hematopoietic progenitor cells transduced with a lentiviral vector encoding
the normal human betaglobin gene for treatment of beta thalassemia major is currently under way (NCT01639690).

Medication
Medication Summary
Medical therapy for beta thalassemia primarily involves iron chelation. Each unit of transfused red blood cells (RBCs)
contains approximately 200 mg of elemental iron. Additionally, anemia and ineffective erythropoiesis downregulates the
synthesis of hepcidin.[27, 28]
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* (a magnetic resonance technique for assessing tissue iron
concentration) and left ventricular function.[29, 30]
The following chelation agents are approved for use in the United States:
Deferoxamine – Intravenously administered
Deferiprone – Orally administered; indicated for patients with transfusional iron overload due to thalassemia
syndromes when current chelation therapy is inadequate.
Deferasirox [31] – Orally administered; approved for treatment of chronic iron overload due to multiple blood
transfusions and non–transfusiondependent thalassemia
A study in 197 beta thalassemia major patients who had evidence of myocardial siderosis (T2* 620 ms) but no sign of
cardiac dysfunction reported that deferasirox was noninferior to subcutaneous deferoxamine for myocardial iron removal
(assessed by improvement in myocardial T2*).[32]
Deferiprone is particularly effective for cardiac iron removal and is therefore recommended for use in patients with significant
cardiac iron loading or ironrelated cardiac disease. The adverse effects of most concern are agranulocytosis and milder
forms of neutropenia.[33] In clinical trials, agranulocytosis has occurred in 1.5% of patients taking deferiprone, most often
during the first year of therapy. Weekly monitoring of the absolute neutrophil count allows early detection of granulocytosis,
so that therapy can be interrupted.[34]
A comparison study by Poggi et al in 165 adults with beta thalassemia major found benefits of deferasirox compared with
other iron chelation regimens (deferoxamine, deferiprone, alone or in combination). After 5 consecutive years of therapy,
patients on deferasirox had the highest decrease in the prevalence of any endocrinopathy (diabetes mellitus,
hypothyroidism, or hypogonadism) A significant increase in mean bone mineral density Tscore (P < 0.001) and a
considerable decrease in osteoporosis prevalence were observed in patients receiving deferasirox but not other chelators.
[35]
Combinations of deferasirox with other chelating agents have also been evaluated. The combination of deferasirox and
deferiprone produced a higher reduction in serum ferritin, greater improvement in cardiac T2* and quality of life indices, and
better compliance compared with the combination of deferoxamine and deferiprone.[36]
Guidelines on chelation treatment in thalassemia major have been published.[37, 38] In general, iron chelation is started at
age 24 years after 2025 RBC units have been transfused, in patients with a serum ferritin level of greater than 1000 μg/dL
and a liver iron concentration (LIC) of greater than 3 mg iron/g dry weight as measured by liver biopsy or by hepatic T2* on
magnetic resonance imaging.[9]
Starting iron chelation therapy earlier had been avoided because of concerns over toxicity from deferoxamine; however, this
may increase the risk of toxicity from iron accumulation. However, Elalfy et al reported that chelation with deferiprone, which
has a lower affinity for iron than deferoxamine, could postpone transfusional iron overload while maintaining a good safety
profile.[39]
In their study, 61 patients with transfusiondependent thalassemia, aged 10 to 18 (median 12) months, with serum ferritin
levels between 400 and 1000 ng/mL, were randomized to early chelation with lowdose (50 mg/kg/day) of deferiprone or to
delayed chelation. By approximately 6 months after randomization, none of the patients in the earlychelation arm, but all of
those in the delayedchelation arm, had serum ferritin levels >1000 ng/mL and transferrin saturation levels >70%. None of
the patients in the earlychelation arm experienced unexpected, serious, or severe adverse events.[39]
Chelating Agents
Class Summary
These agents bind iron and promote excretion.
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.
Deferasirox (Exjade)
Deferasirox is available as a tablet for oral suspension. It is an oral ironchelating 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 chronic iron
overload due to multiple blood transfusions and non–transfusiondependent thalassemia.
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 diseaserelated symptoms, functioning, or increased
survival. It is available as 500mg, filmcoated tablets.

Contributor Information and Disclosures
Author
Pooja Advani, MD Clinical Fellow, Department of Hematology/Oncology, Mayo Clinic

Pooja Advani, MD is a member of the following medical societies: American Society of Hematology, American Society of
Clinical Oncology, Florida Society of Clinical Oncology

Disclosure: Nothing to disclose.
Specialty Editor Board
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of
Pharmacy; EditorinChief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.
Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the
Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of
Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology,
Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society
for Experimental Biology and Medicine, SWOG

Disclosure: Partner received none from No financial interests for none.
Chief Editor
Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and
Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education,
American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical
Research, American Society of Hematology, New York Academy of Sciences

Acknowledgements
Kenichi Takeshita, MD Adjunct Associate Professor, Department of Medicine, Division of Hematology, New York University
School of Medicine; Medical Director, Clinical Research and Development, Celgene
Kenichi Takeshita, MD is a member of the following medical societies: American Society of Hematology
References
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