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issues of optimal care for the disease complications and the magnitude of the
problem in developing countries, where conventional treatment with safe blood
and iron chelation therapy is often unavailable [10], as are effective programs for
prenatal screening.
This article discusses the approach for recognition, diagnosis, and management
of the thalassemias, and reviews new prospects of therapy, focusing mostly on the
b-thalassemias, which are the more severe and clinically important type.
Definitions
Thalassemias are classified according to the particular globin chain that is
ineffectively produced, a or b thalassemia being the more common and most
L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191 1167
important types. Less common types, not discussed in this article, include db
thalassemia and gdb thalassemia (Tables 1 and 2). Other hemoglobinopathies
frequently found in the same population as the thalassemias involve genes for
structural hemoglobin variants, such as hemoglobins S, C, and E. Frequently a
gene for thalassemia is inherited from one parent together with one of these
structural variants from another parent. The important diseases of this type are
hemoglobin E-b thalassemia and sickle-cell thalassemia; the latter is discussed
elsewhere as its clinical manifestations are those of sickle-cell disease.
Molecular aspects
b Thalassemia
The mutations can be classified as resulting in complete absence of b-globin
production: b zero thalassemia (b-0), or a reduction in synthesis, b plus
thalassemia (b+). More than 200 different mutations have been described and
the majority are nucleotide substitutions [13]. They generally involve one of
four mechanisms:
Beyond the underlying b mutation that affects the level of b globin chain
synthesis, other globin chain factors are involved in altering the phenotype.
Several mechanisms reduce the degree of globin chain imbalance, a key factor in
the determination of b thalassemia severity. These mechanisms include: (1) the
ability to synthesize larger amounts of g chains, which combine with the excess a
chains to form Hb F (a2g2). Generally a higher Hb F level results in a milder
phenotype. The mechanisms involved in persistent Hb F synthesis are not
fully understood; some include the g globin genes, whereas others are outside
the b globin gene cluster [14]; (2) the coexistence of one or two a thalassemia
genes results in more balanced globin chain synthesis. In addition, interactions
with structural hemoglobin variants affect disease manifestations. The most
common examples include hemoglobin S and hemoglobin E, the first resulting
in a different severity of sickle-cell disease, the second in a serious and
common type of thalassemia discussed later in this article. The diversity of the
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L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191
Table 1
a thalassemia
Definition Genotype Hb electrophoresis Hematologic expression Clinical expression
1 gene deletion - silent carrier – ,a/aa Newborn: Bart’s 1% – 2% Normal Normal
2 gene deletion - a thalassemia trait – ,a/ – ,a or – , – /a,a Newborn: Bart’s 3% – 10% Microcytosis, hypochromia Normal to mild anemia
3 gene deletion - Hb H – , – / – ,a Newborn: Bart’s 20 – 30% Marked microcytosis, Moderate anemia, splenomegaly,
Older child: Hb H 10% – 15% hypochromia occasional transfusions
Hb F 10%
Hb H + Constant Spring – , – /a,a cs 2% – 3% CS Hb H 20% – 40% Hypochromia and Moderate-severe anemia,
2 gene deletion and moderate microcytosis splenomegaly, occasional transfusions
Constant Spring mutation
4 gene deletion - Hydrops Fetalis –,–/–,– Newborn: Bart’s 80% – 100% Abnormal morphology, Severe anemia, edema,
hypochromia, anisopoikilocytosis hepatosplenomegaly
variant
Nondeletional mutation a,a/a,a 2% variant Hb Variable microcytosis Normal or variable anemia;
depending on the a chain stability
Table 2
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a Thalassemia
Normal individuals inherit a total of four a globin genes, two from each parent,
resulting in a a,a/a,a genotype. Most mutations are gene deletions; one or both a
genes may be affected per haploid genome [17,18]. Phenotypic expression of a
thalassemia therefore depends on the number of available a genes. Four clinical
syndromes emerge:
a thalassemia trait and silent carrier are mild variants. a thalassemia trait
expresses two a gene deletions (trans deletion, a– /a– ) or cis deletion
(a,a/ ), causing mild microcytic chromic anemia. Silent carriers have
one gene deletion and three intact a globin genes (a,a/a– ) and are
clinically and hematologically undetectable (Table 1).
phoresis and quantitative HbA2 should be performed (Fig. 1) [20,21]. Severe iron
deficiency can mask a diagnosis of thalassemia and therefore must be excluded
before a hemoglobin electrophoresis. If b thalassemia is unlikely (low indices with
a normal Hb A2) and a thalassemia is suspected, referral to centers that can
identify the different forms by DNA testing is recommended [22]. Screening of the
partner may not be necessary if the results are normal [23,24].
Once a couple has been identified as being at risk for having a child with
thalassemia, genetic counseling and education regarding prenatal testing should be
pursued [25,26]. First trimester testing is a more acceptable choice to those groups
Fig. 1. Assessment of MCV is accompanied by other complete blood count measurements: Increased
RDW suggests iron deficiency anemia; high reticulocyte may suggest hemolytic anemia and not iron
deficiency. RBC count is usually elevated in thalassemia syndromes, low or normal RBC count is
atypical for thalassemia. Normal ranges of MCV by age: See Nathan DG, Orkin SH. Hematology of
infancy and childhood. 5th edition. Philadelphia; Saunders: 1998; appendix 11.
1172 L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191
Postnatal diagnosis
A large percentage of patients who are not detected in prenatal screening are
detected during newborn screening in those countries and in areas of the United
States where newborn screening is implemented. Hb Barts (tetramer of g globin
chains) in a thalassemia patients or an elevated Hb A2 or Hb F in b thalas-
semia patients suggests these diagnoses. DNA-PCR analysis and parental
testing can specify further the type and severity of disease. b hemoglobin
variants, such as Hb E or an a hemoglobin variant named Hb Constant Spring,
also may be detected by newborn screening, the latter frequently requiring DNA
diagnosis [32].
In older children, suspicion of thalassemia arises with a microcytic, hypochro-
mic anemia and an abnormal hemoglobin electrophoresis. Other causes for
microcytic anemia need to be looked at also (Table 3).
a Thalassemia
The most important clinical form is hemoglobin H disease, a three-a gene
deletion, common in people from Asian descent and causing a chronic moderately
severe hemolytic anemia. Patients may develop splenomegaly, cholelithiasis, and
may require transfusions during episodes of oxidative stress induced by infections,
fever, or certain medications [33]. A more severe clinical form named hemoglobin
H-Constant Spring results from coinheritance of a nondeletional a gene variant,
hemoglobin Constant Spring, with two a gene deletions. Patients with this
disorder have more severe hemolytic anemia and hypersplenism requiring more
frequent transfusions. Conversely, concomitant hemoglobin H disease and
b thalassemia trait reduces severity of the a thalassemia. Monitoring of spleen
size and hemoglobin level, especially during febrile episodes, and supplementa-
tion with daily folic acid, are the main treatment measures. In addition, avoiding
L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191
Table 3
Diagnosis and intervention for a thalassemia trait and b thalassemia trait after the newborn period
Serum
Diagnosis Hb RBC MCV Hb A2 Hb F RDW FEP Fe/TIBC Intervention
b thalassemia trait Normal or Normal or <75 fL Elevated Slightly Normal Normal Normal
Screen partner, siblings
slightly low slightly elevated 3.5% – 7% increased No need for iron supplementation
Educate about the risk of an affected
child with thalassemia major
a thalassemia trait Normal Normal <75 fL <3% Normal Normal Normal Normal Screen partner, siblings
No need for iron supplementation
Educate about the risk of an affected
child with thalassemia major (if Asian)
Iron deficiency Low Low <83 fL <3% Normal Elevated Elevated Reduced/ Iron therapy
anemia elevated May look again for thalassemia after therapy,
as can be masked by low iron
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b Thalassemia
The important forms of b thalassemia result from homozygosity or compound
heterozygosity and are classified based solely on their clinical severity into
thalassemia major and thalassemia intermedia. Even within these categories,
however, there is a remarkable variability from a mild anemia to complete
transfusion dependency for survival.
Patients with thalassemia major usually develop anemia within the first 6 months
of life, because the decreasing levels of fetal hemoglobin cannot be replaced by
normal adult hemoglobin. Hemoglobin in the range of 3 – 4 g/dL is not uncommon.
If regular transfusion therapy is not initiated, a clinical picture of severe untreated
b thalassemia develops, characterized by profound anemia, splenomegaly, and
progressive bone changes caused by marrow expansion of blood-forming skeleton
areas. Typical bone changes result in characteristic thalassemic face: prominent
maxillary bones, flat nose bridge, and frontal bossing, and in thinning of long bones
and joint deformities. Occasionally masses of extramedullary hematopoiesis,
mostly in the paraspinal area, develop, occasionally resulting in spinal cord
compression and neurologic symptoms. These manifestations are uncommon in
developed countries where transfusion therapy is initiated early in life, ‘‘turning
off’’ the marrow and evading the continuous marrow expansion.
Patients are categorized as having b thalassemia intermedia when presenting
later in life, usually during the second year, and when they do not require early
intervention with blood transfusions. These children with a moderate but well
compensated anemia usually grow and develop well. Not infrequently, however,
symptoms of progressive anemia, heart failure, pulmonary hypertension, hyper-
splenism, and bone expansion evolve during the second and third decades of life.
These clinical developments essentially categorize the patient as having thalasse-
mia major, frequently necessitating initiation of regular transfusion therapy.
b thalassemia trait, the heterozygote or carrier state, is generally asymptomatic
and carries mainly a screening and diagnostic significance for genetic counseling.
In clinical practice, however, occasionally it needs to be distinguished from iron
deficiency anemia (Table 3).
Transfusions
Once a child is diagnosed with b thalassemia major, the decision to start regular
transfusions is usually a life-long commitment and entails its own risks for infec-
tions and iron overload [36]. These serious side effects together with the emotional
L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191 1175
impact make the decision a difficult one. Initiation of transfusions is based mostly
on clinical assessment and on the level of hemoglobin. Monitoring for signs of
anemia, heart failure, poor growth, splenomegaly, and marrow expansion deter-
mines the need to start transfusions. Occasionally the need for a single transfusion
may represent a nutritional deficiency, such as folic acid or iron, or an infectious
complication. Therefore, patients should be reevaluated once these issues are
corrected to avoid unnecessary premature initiation of transfusion therapy.
Chronic transfusions eliminate the primary complications of severe thalassemia
by ameliorating anemia and suppressing erythropoiesis. Current goals of chronic
transfusion also include lessening iron intake as opposed to the earlier ‘‘hyper-
transfusions’’ approach in which an attempt was made to completely turn off the
marrow by maintaining a higher post-transfusion hemoglobin. A practical regimen
is to transfuse every 3– 4 weeks and maintain baseline pretransfusion hemoglobin
of 9.5 – 10.5 g/dL and post-transfusion hemoglobin of 13 – 13.5 g/dL. This
adequately eradicates the consequences of anemia and erythropoiesis, yet mini-
mizes iron contribution. The patient’s red cell phenotype for ABO, Rh, C, E, and
Kell is determined before initiation of transfusion, and, ideally, blood matched for
these antigens should be given. Infection prevention mandates hepatitis B (HBV)
vaccination, ideally before starting transfusions, and the use of current methods of
leukocyte-depleted RBCs.
Splenectomy
Extramedullary hematopoiesis leads to splenomegaly and hypersplenism. It was
generally believed that splenectomy may decrease the transfusion requirements by
increasing red cell survival and it has been recommended when the total yearly
RBC use exceeds 200 cc/Kg [37]. Splenectomy has short- and long-term down-
sides, however. Spleen removal does not always result in a sustained reduced blood
consumption or a substantial decrease of iron burden. In addition, pilot studies
suggest that pulmonary vascular disease and thrombosis may be a long-term
problem. It is possible that with current effective transfusion regimens, spleno-
megaly and hypersplenism occur less often. In young children, a known risk for
overwhelming sepsis exists. These factors must be weighed against the increased
iron accumulation inherent in augmented transfusion requirements from hyper-
splenism. In nontransfused and intermittently transfused patients, splenomegaly
and hypersplenism develop at a younger age and can be ameliorated by removal of
the spleen. The plan for splenectomy must be accompanied by thorough family
education concerning fever and the risk for life-threatening infection. Vaccination
with 23-valent or 7-valent pneumococcal, Haemophilus influenzae, and meningo-
coccal vaccines, ideally 3– 6 weeks before splenectomy, is required. Lifelong
penicillin prophylaxis against pneumococcus is initiated postsplenectomy. Con-
siderations for a low-dose antiplatelet agent should be made in older splenectom-
ized patients, especially those with high platelet counts. An alternative approach of
partial splenectomy has been explored only in a limited number of thalassemia
patients and needs further evaluation [38].
1176 L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191
Iron overload
Iron overload is a major complication of b thalassemia and is the cause of organ
damage, morbidity, and mortality, unless adequately removed from parenchymal
tissues [41,42]. Moreover, the magnitude of the body iron load is the main
determinant of patients’ clinical outcomes [43]. A packed red blood cell unit of
250 cc delivers approximately 175 mg of iron. Because iron is highly conserved
and sparingly excreted by humans, iron introduced by transfusions accumulates
and exceeds 70 g by the beginning of the second decade in transfused patients
[44]. Methods for removal of the tissue iron with chelation therapy are a major
aspect of thalassemia management [45,46].
After approximately a year of regular transfusions, iron starts accumulating in
parenchymal tissues, where it can cause progressive toxic damage. As iron loading
persists, serum transferrin, the main iron-transporting protein, becomes saturated
so that nontransferrin-bound iron (NTBI) is present in plasma. This iron fraction is
able to catalyze reactions that generate free hydroxyl-radicals, which cause further
cell damage [47]. Most clinical manifestations of iron overload, which include
progressive dysfunction of the heart, liver, and endocrine organs, appear during
the second decade of life. There is evidence, however, that the harmful effects of
iron start earlier, as demonstrated by hepatic fibrosis seen in liver biopsies after
2 years of transfusion therapy [48,49].
The heart
Mortality from cardiac disease (heart failure or fatal arrhythmia) remains the
main cause of death in transfusion-induced iron-overload patients [51,52].
Myocardial iron deposition causes cardiac hypertrophy and dilatation and degen-
eration of myocardial fibers. The unbound iron generates toxic oxygen metabolites
resulting in further injury to the myocytes. Patients therefore develop conductive
disturbances and progressive heart failure [53]. In addition, a higher susceptibility
for myocarditis and the occasional development of pulmonary hypertension can
further accelerate the cardiac disease [54].
Currently, patients who started chelation therapy with desefrioxamine in early
childhood lived long enough to show that early and effective chelation can prevent
death from cardiac disease [45]. Quantitation of cardiac iron is difficult as cardiac
muscle biopsy is not regularly feasible and none of the imaging studies has been
shown to be optimal. Magnetic resonance imaging (MRI) can estimate cardiac
iron, but no good correlation with cardiac iron obtained by biopsy has been shown.
Recently a T2* MRI technique showed good correlation with cardiac iron stores
[55]. Methods for detecting early iron-induced cardiac dysfunction in asympto-
matic patients include low-dose dobutamine stimulation, exercise cardiac radio-
nucleotide angiography, and stress echocardiogram [54]. Their prognostic
significance for the development of symptomatic cardiac disease is debatable.
Regular monitoring for cardiac function and arrhythmias with annual echocardio-
gram, EKG, and 24-hour Holter monitoring is extremely important, though not
sufficiently sensitive for early detection of disease. In clinical practice, measure-
ments of liver iron has been shown to best correlate with the total body iron
burden and to predict the threshold for risk for cardiac disease and early death
(levels of 15 mg/g dry weight or greater) [42]. Persistent ferritin levels greater than
2500 mg/L and assessment of annual blood requirement can assist in predicting
development of cardiac disease.
Once diagnosed, every effort for aggressive chelation should be made, as
cardiac dysfunction still can be reversed and improved [36,56]. Treatment with
angiotensin-converting enzyme (ACE) inhibitors may prevent or delay congestive
heart failure in asymptomatic patients with left ventricular dysfunction. Digitalis
therapy, diuretics, and low sodium diet benefit those patients with established
congestive heart failure, in addition to intensive chelation therapy [54]. Those
patients refractory to pharmacologic therapy are candidates for cardiac transplant
assessment [57].
1178 L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191
Endocrine glands
As the life expectancy of well chelated thalassemia patients has improved,
endocrinopathies have emerged as important complications. Iron deposition in the
anterior pituitary gland, thyroid and parathyroid glands, pancreatic cells, and
adrenal cells, results in significant morbidity [66]. Delayed puberty, short stature,
and hypogonadism are major problems from childhood to adulthood, found in
more than half of the patients [67,68]. Yet again, appropriate iron chelation can
prevent or improve many of these complications.
Growth delay, short stature, and particularly a disproportional short trunk are
common findings; the causes are multifactorial and vary in different age groups
[69]. Chronic anemia and marrow expansion result in growth delay in non-
L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191 1179
usefulness around the world. Several agents reached clinical trials; the most
extensively evaluated is deferiprone; L1 [82]. Data have shown its short-term
efficacy, but controversy over its toxicity and effectiveness, together with a lack
of controlled studies, has limited its widespread use. Recent studies have
suggested synergistic and additive effect of using desferioxamine with defer-
iprone, a ‘‘shuttle’’ mechanism in which the oral agent mobilizes tissue iron,
then exchanges with the parenteral agent, has been proposed. Although a
promising approach, more studies are needed for assessment of the effectiveness
and toxicity [83].
Bone disease
Bone complications affect most adult patients and seem to occur despite ade-
quate transfusion or chelation status. Osteopenia and osteoporosis are the most
prevalent complications, occurring in more than 90% of patients with thalassemia
major [84]. Common clinical presentations include persistent backache, scoliosis,
fractures, cord compression, and spinal deformities. Those patients with diabetes,
pubertal delay, or male gender seem to be most frequently and severely affected by
osteoporosis. Testosterone stimulates osteoblastic activity, whereas estrogen and
progesterone can limit bone resorption. Therefore, gonadal failure, prevalent in
thalassemia major, largely contributes to bone disease. Bony abnormalities also
are associated with inadequate calcium and vitamin D levels, lack of physical
activity, iron deposition in the bone matrix, and long-term desferioxamine
chelation [85,86]. Other factors outside the thalassemia setting also can affect
bone mass; however, the significance for these patients has not been clearly
defined. These include genetic factors controlling the vitamin D receptor, estrogen
receptor, and type I collagen genes. Low bone mass is also common among
nontransfused adult thalassemia intermedia patients, likely caused by a different
mechanism of marrow expansion.
Early diagnosis and treatment intervention are extremely important. Dual x-
ray absorptiometry (DEXA), a low-irradiation, safe technique, is the preferred
method for bone density assessment. It can measure total body bone density, or
more commonly, only lumbar spine and the femoral neck. Based on the World
Health Organization (WHO) definitions, a T score of bone mineral density
value of less than – 2.5 defines osteoporosis. A value of – 1 to –2.5 signifies
osteopenia. Yearly screening for osteoporosis starting in the second decade is
recommended, as inadequate bone density may be detected in children as
young as 10 –12 years of age. Evaluation with plain radiographs is inadequate.
Easy preventative measures include calcium supplementation (1200 mg/day in
adolescents), maintenance of normal levels of vitamin D, and nutritional
counseling. Early initiation of hormone replacement therapy for hypogonadism
is critical for achieving a normal peak bone mass and preventing accelerated
bone resorption [87]. Biphosphonates, inhibitors of osteoclasts and bone
resorption, may improve established disease, as demonstrated in elderly
1182 L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191
osteoporotic women. Several studies reported improved T scores with the use
of a biphosphonate administered intravenously, or less commonly, orally. A
study looking at the causative factors and treatment intervention is under
way [88].
Hypercoagulable state
A less well recognized complication in b thalassemia major and thalassemia
intermedia is the hypercoagulable state. Pulmonary embolism, mostly asympto-
matic, cerebral ischemia, and deep vein thrombosis all have been described. A
multifactorial mechanism that involves abnormal platelet function, elevated
endothelial adhesion protein levels, and activation of the coagulation cascade
by the damaged RBC has been described [91].
Psychologic impact
The chronic nature of thalassemia and its intensive and demanding treatment
result in a significant psychologic burden on the patients and their families.
Social isolation, reduced self-esteem, lower academic achievements, and stig-
L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191 1183
matization all have been described. In addition, depression and fear of early
death are common findings. As increasing numbers of patients now reach
adulthood, marry, and work, the psychologic burden is changing. Rising
concerns include accomplishing future expectations, physical appearance, sexual
development, education, establishing relationships, and the ability to have a
family. In adolescents and young adults, low compliance with chelation treat-
ment, denial, anxiety, and a ‘‘living for today’’ approach are observed. Psycho-
logic support is therefore particularly important and is a vital part of the
comprehensive medical treatment. Support strategies need to be developed in
ways appropriate to each culture. Medical providers need to inform patients on
therapeutic developments and future directions and encourage psychologic
support [94,95].
Thalassemia intermedia
Thalassemia intermedia, a clinical definition, applies to those patients who
are more mildly affected than thalassemia major patients and therefore do not
have severe anemia, growth failure, or evidence of marrow expansion in the
first years of life and may not require chronic transfusion therapy. Thalas-
semia intermedia patients frequently do not get the careful clinical care they
deserve, and can develop complications that may be prevented, as they do not
represent a well defined group of patients who receive regular treatment and
followup [96].
It is an extremely heterogeneous disorder on a molecular and clinical level. The
molecular basis of b thalassemia intermedia arises from a multitude of factors.
Mild or silent b thalassemia mutations, coinheritance of a thalassemia, and
enhanced gamma chain production all improve clinical outcome. Double hetero-
zygosity for b thalassemia and triplicated a genes also may lead to thalassemia
intermedia. Coinheritance of unstable hemoglobin variants, such as Hb Knossos,
Hb Lepore, or Hb E, may alter clinical severity of b-thalassemia. Although
identifying the molecular defect allows a retrospective analysis of a patient’s
disease, the b-genotype alone cannot fully predict the phenotype [97]. Among the
a-thalassemias, patients with hemoglobin H disease (a 3 a gene deletion) have a
mild thalassemia intermedia phenotype; however, the coinheritance of hemo-
globin H disease with the Constant Spring termination codon mutation is a more
severe form of thalassemia intermedia, occasionally requiring intermittent trans-
fusion therapy [98].
Although thalassemia intermedia patients avoid the complications associated
with chronic transfusion therapy, they have progressive clinical manifestations of
chronic hemolytic anemia and ineffective erythropoiesis. They may experience
cardiac complications, pulmonary hypertension, skeletal deformities with chronic
bone and joint pain, and bone deformities and fractures [99]. Significant extra-
medullary marrow expansion may develop, with occasional paraspinal hemato-
poietic pseudotumors causing neurologic symptoms. Leg ulcers, hypersplenism,
and gallstones are other common complications. The endocrine system is
1184 L. Lo, S.T. Singer / Pediatr Clin N Am 49 (2002) 1165–1191
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