Management and Prognosis of The Thalassemias

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Management and prognosis of the thalassemias

Authors: Edward J Benz, Jr, MD, Emanuele Angelucci, MD
Section Editor: Stanley L Schrier, MD
Deputy Editor: Jennifer S Tirnauer, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2019. | This topic last updated: Apr 02, 2019.
INTRODUCTION
Management of the thalassemia syndromes can be challenging due to the numerous potential
disease complications and the lack of available therapies other than transfusion and hematopoietic
cell transplantation, both of which have associated morbidities and costs. This topic review
discusses the approach to managing alpha and beta thalassemias, including transfusion-
dependent and transfusion-independent (mild or intermediate severity) disease.
Separate topic reviews discuss other issues in the thalassemias:
● Scope of the disease – (see "Public health issues in the thalassemic syndromes")
● Pathophysiology – (see "Pathophysiology of beta thalassemia" and "Molecular genetics of

the thalassemia syndromes" and "Introduction to hemoglobin mutations")
● Prenatal screening – (see "Prenatal screening and testing for hemoglobinopathy")
● Diagnosis – (see "Clinical manifestations and diagnosis of the thalassemias" and "Methods
for hemoglobin analysis and hemoglobinopathy testing")
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● Iron chelation therapy – (see "Iron chelators: Choice of agent, dosing, and adverse effects")
● Hematopoietic cell transplantation – (see "Hematopoietic cell transplantation for

transfusion-dependent thalassemia" and "Thalassemia: Management after hematopoietic cell
transplantation")
TERMINOLOGY AND DISEASE CLASSIFICATION
Thalassemia refers to a group of inherited hemoglobinopathies where there is a quantitative defect

in the production of alpha globin or beta globin chains. The resulting imbalance in the ratio of alpha
to beta globin chains leads to precipitation of the unpaired chains, which in turn causes destruction
of developing red blood cell precursors in the bone marrow that can lead to ineffective
erythropoiesis, anemia, and iron overload. The classical thalassemia phenotypes (table 1), genetic
defects, and pathophysiology are discussed in detail separately. (See "Clinical manifestations and
diagnosis of the thalassemias" and "Molecular genetics of the thalassemia syndromes" and
"Pathophysiology of beta thalassemia".)
OVERVIEW OF APPROACH
Major issues in the management of thalassemia involve treatment of anemia (if severe enough to
cause symptoms); reduction of ineffective erythropoiesis, which can lead to various morbidities
such as impaired growth and development, bone expansion, hypersplenism, or cosmetic concerns;
prevention of excess iron stores; and treatment of the complications of iron overload if they occur.
In children with clinically significant disease, the chronic anemia and/or iron overload can lead to
comorbidities such as delayed puberty, other endocrine dysfunction, abnormal bone metabolism,
and/or delayed growth. These findings can occur even with the best feasible transfusion support,
although they can often be mitigated with therapy, usually requiring subspecialty consultation.
● Beta thalassemia major – Individuals with thalassemia major typically require chronic
transfusions with a prespecified pretransfusion hemoglobin level to treat severe, symptomatic
anemia. Iron overload is inevitable; monitoring iron stores and use of iron chelation are
integral components of therapy (see 'Management of anemia' below). Consideration of
allogeneic hematopoietic cell transplantation (HCT) or enrollment in a clinical trial testing other
disease-modifying therapies may be appropriate for selected individuals with severe disease.
(See 'Decision to pursue allogeneic HCT' below and 'Investigational disease-modifying
approaches' below.)
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● Beta thalassemia intermedia phenotypes – Individuals with thalassemia intermedia

phenotypes may be transfusion-independent; they may require intermittent transfusions during
periods of erythropoietic stress such as infection or pregnancy; or they may become
transfusion-dependent, similar to individuals with thalassemia major. (See 'Management of
anemia' below and 'Pregnancy' below.)
● Beta thalassemia minor (or trait) – Individuals with thalassemia minor, thalassemia trait, or
thalassemia minima typically do not require any interventions for anemia or other deviations
from routine medical care. However, it is important for these individuals to be aware of their
diagnosis so that they do not undergo unnecessary testing or empiric treatment with iron for
an incorrect diagnosis of iron deficiency, as well as for prenatal planning for potential
pregnancies.
● Severe forms of alpha thalassemia – Severe forms of alpha thalassemia such as hydrops
fetalis and hemoglobin Barts are defined separately. (See "Clinical manifestations and
diagnosis of the thalassemias", section on 'Alpha thalassemias'.)
Survival beyond the perinatal period for hydrops fetalis with hemoglobin Barts is rare. Those
infants are absolutely transfusion-dependent throughout life. The considerations described for
transfusion-dependent thalassemia below apply.
Patients with hemoglobin H (HbH) disease exhibit variable clinical severity, most often a
thalassemia intermedia phenotype, but occasional patients are chronically transfusion
dependent especially if they inherit a non-deletion variant such as hemoglobin Constant
Spring. (See "Clinical manifestations and diagnosis of the thalassemias", section on 'Alpha
thalassemias'.)
In addition to the management issue noted for the beta thalassemia intermedia phenotype, it
must be noted that HbH is an unstable variant, susceptible to forming Heinz body-like
inclusions in the presence of oxidant stresses such as infection or oxidant drugs, causing
transient exacerbation of the anemia. (See "Unstable hemoglobin variants".)
Alpha thalassemia one and alpha thalassemia two trait are generally not symptomatic.
Other aspects of care that apply to all individuals, regardless of disease severity, include the
following:
● Anemia – We suggest folic acid supplementation if there is evidence of ongoing hemolysis

(eg, 1 to 2 mg daily), and we avoid iron supplementation unless there is concomitant iron
deficiency. (See 'Management of anemia' below.)
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● Disease morbidity – We monitor for disease complications as appropriate to disease

severity. (See 'Monitoring and management of disease complications' below.)
● Coordination of care – We make the diagnosis and treatment plan available to the patient
and all providers to ensure continuity of care, including clinicians in other specialties such as
obstetrics and surgery. (See 'Special circumstances' below.)
● Genetic testing and counseling – We offer preconception genetic counseling and testing as
appropriate to individuals (female and male) of childbearing potential. (See 'Prenatal testing
and genetic counseling' below.)
Our approach is largely consistent with guidelines from the Thalassemia International Foundation
and the Italian Society of Hematology on the treatment of thalassemia [1,2]. Links to other
guidelines are provided in a separate document (see 'Society guideline links' below). Additional
resources that outline therapy are presented separately on the website for the UCSF Northern
California Comprehensive Thalassemia Center [3].
MANAGEMENT OF ANEMIA
General aspects of anemia management — The goals of treating anemia in individuals with
thalassemia include reducing symptoms and morbidities associated with anemia (such as impaired
growth and development in childhood); reducing or preventing extramedullary hematopoiesis,
which can lead to a number of morbidities associated with impaired growth and development, bone
expansion, and hypersplenism; and reducing excess iron stores associated with increased
intestinal iron absorption and/or transfusion [4-11].
In thalassemia, chronic transfusions are used to maintain the hemoglobin at a level that both
reduces symptoms of anemia and at least somewhat suppresses extramedullary hematopoiesis.
Thus, higher pretransfusion hemoglobin values are sought (typical range, 9 to 10 or 9.5 to 10.5
g/dL) [12]. This approach is referred to by different names ("hypertransfusion" in the United States;
"moderate transfusion" in Europe). These thresholds differ from those used in other anemias,
where the goal is only to raise the hemoglobin level above a certain threshold, typically with the
smallest number of transfusions as possible. (See 'Typical chronic transfusion regimen' below.)
Our approach according to disease severity and age of presentation is as follows (algorithm 1):
● For cases of alpha thalassemia major with severe fetal anemia, intrauterine transfusion may
be possible, followed by chronic transfusions after birth. (See "Intrauterine fetal transfusion of
red cells".)
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● For children with beta thalassemia major, we recommend chronic transfusion, initiated in early
childhood as soon as the disease manifestations (eg, severe anemia) become present. (See
'Typical chronic transfusion regimen' below.)
● For individuals with thalassemia intermedia who have anemia that is severe enough to require
transfusion, decisions must be made regarding whether to initiate a chronic transfusion
regimen in order to suppress ineffective erythropoiesis or to provide periodic transfusions for
symptomatic relief and/or during periods of increased stress. (See 'Decision to initiate regular
transfusions' below.)
● For individuals with thalassemia minor or minima, transfusions are not required; anemia is
very mild or absent. Development of anemia should prompt evaluation for a cause other than
thalassemia. (See "Approach to the child with anemia" and "Approach to the adult with
anemia".)
Individuals with thalassemia can develop anemia due to other causes that should be addressed
and treated in order to reduce the transfusional iron burden. Examples include hemolysis related to
glucose-6-phosphate dehydrogenase (G6PD) deficiency, which has a similar geographic
distribution as thalassemia; folate deficiency due to increased requirement caused by chronic
hemolysis; aplastic crisis due to parvovirus B19 infection; hemolytic crisis; or hypersplenism due to
extramedullary hematopoiesis. Evaluation for these other causes of anemia depends on the
patient history and presenting findings, as discussed below and in separate topic reviews. (See
"Approach to the child with anemia" and "Approach to the adult with anemia".)
In some cases of severe disease, it may be appropriate to pursue other interventions for anemia
such as splenectomy, hematopoietic cell transplantation (HCT), or other therapies discussed
below. (See 'Role of splenectomy' below and 'Decision to pursue allogeneic HCT' below and
'Investigational disease-modifying approaches' below.)
The role of activin ligand traps such as luspatercept is evolving rapidly, as discussed below. (See
'Drug therapies under investigation' below.)
Dietary restrictions and supplements — We suggest folic acid supplementation for all
individuals with thalassemia major and for any individual with thalassemia intermedia who has
evidence of chronic hemolysis. The typical dose is 1 to 2 mg per day. The purpose is to
compensate for increased folate requirements associated with increased red blood cell (RBC)
turnover. It may be reasonable to omit folic acid supplements if this is especially burdensome to
the patient or family and/or if there is no clinical evidence of folate deficiency.
It is prudent for individuals with thalassemia to avoid taking iron-containing supplements (eg,
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vitamins plus iron) unless they have documented iron deficiency given that thalassemia can be
associated with increased iron absorption [13]. We do not tell patients to avoid red meat entirely,
but we do advise them to be judicious about overall intake of iron-rich foods. We also do not advise
consumption of tea as a way to decrease iron absorption, but when appropriate we do share the
information that tea may reduce iron absorption [14]. Despite the general recommendations to
avoid excess iron, iron replacement therapy should not be withheld from those with true iron
deficiency anemia. (See "Iron deficiency in infants and children <12 years: Treatment" and
"Treatment of iron deficiency anemia in adults".)
We generally do not use zinc supplements unless the individual has documented zinc deficiency or
has symptoms suggestive of zinc deficiency such as impaired taste or smell. (See "Zinc deficiency
and supplementation in children and adolescents", section on 'Clinical manifestations'.)
Regular transfusions
Decision to initiate regular transfusions
● Thalassemia major – Individuals with thalassemia major are transfusion-dependent. For

these individuals, we suggest chronic transfusions administered on a regular basis to prevent
the hemoglobin from dropping below a prespecified level, rather than a more restrictive
strategy. In the context of thalassemia, chronic transfusion may be referred to as
"hypertransfusion" (in the United States) or "moderate transfusion" (in Europe). For most of
these individuals, we suggest a pretransfusion hemoglobin level of approximately 9.5 to 10
g/dL. The number of units transfused depends on the individual's body size and baseline
hemoglobin level. In adults, it is usually not practical to give more than two units of packed
RBCs at a time, so the interval between transfusions is adjusted to maintain the hemoglobin
level in the appropriate range. The timing of initiation is typically when the individual becomes
symptomatic transfusion-dependent in early infancy; the indication to initiate therapy in these
children is invariably straightforward.
Most individuals with alpha thalassemia major have hydrops fetalis and do not survive in
utero, although cases have been described in which exchange transfusion or hematopoietic
cell transplantation was performed in utero and followed, after birth, by hematopoietic cell
transplantation [15-19].
● Thalassemia intermedia – Thalassemia intermedia phenotypes encompass a range of

clinical phenotypes. Transfusions are given as needed; often, this is during periods of
erythropoietic stress such as acute infectious illnesses, periods of rapid growth, surgery, or
pregnancy.
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Many individuals with beta thalassemia intermedia will eventually become transfusion-
dependent and require chronic transfusion therapy, but this may not be needed until adulthood
(eg, third to fourth decade of life) and does not always occur [20]. Deciding to initiate regular
transfusions in such cases is significantly more challenging, and we individualize this decision
based on the patient's age and specific disease complications, balanced with the burdens of a
regular transfusion program including increased iron stores. The decision takes into account
the patient's activity limitations, growth, development, and the early appearance of skeletal
changes or other disease-related complications [9]. We generally initiate transfusions if the
patient has signs of cardiopulmonary compromise, functional deterioration, or signs and
symptoms of significant extramedullary hematopoiesis such as expanding bony masses,
pathologic fractures, or hypersplenism. Symptoms usually develop when the hemoglobin level
falls below 7 g/dL, although there is no specific hemoglobin level that can be used to guide the
decision. Assessment by a clinician with expertise in treating hemoglobinopathies is prudent.
Once the decision to initiate regular transfusions is made, the patient is treated similar to
those with beta thalassemia major.
Many individuals with alpha thalassemia intermedia phenotypes who have hemoglobin levels
above 8 to 9 g/dL will be able to avoid chronic transfusions, and these individuals may do well
with only intermittent transfusions when needed, such as in the setting of infection or
pregnancy. Individuals with hemoglobin H disease are at increased risk of oxidative stress to
RBCs and may require closer monitoring and possibly transfusion during infections or upon
exposure to oxidant drugs.
Typical chronic transfusion regimen — The typical chronic transfusion regimen (referred to
as hypertransfusion in the United States or moderate transfusion in Europe) is designed to
maintain a relatively stable hemoglobin level that is adequate to maintain good cardiovascular
status and exercise tolerance and to at least partially suppress ineffective erythropoiesis thus
limiting increased gastrointestinal adsorption.
For most individuals treated with chronic transfusion to reduce complications of ineffective or
extramedullary hematopoiesis, we suggest using a regimen that results in a pretransfusion
hemoglobin level in the range of 9 to 10 or 9.5 to 10.5 g/dL rather than higher or lower levels [12].
This approach is directed at achieving the optimal balance between suppressing hematopoiesis
and minimizing iron overload. A higher level may be used for individuals with heart disease,
clinically significant extramedullary hematopoiesis, inadequately suppressed bone marrow, or back
pain prior to transfusion [6]. A lower level (such as 8.5 g/dL) may be used if the primary goal of
transfusion is to treat anemia rather than to suppress ineffective erythropoiesis [6].
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We generally avoid giving more than 10 mL per kg of packed RBCs in a single day; this is a dose
that should yield a post-transfusion hemoglobin increase of about 3 to 3.5 g/dL. If there is
uncertainty about the appropriate number of units to give, administration of the equivalent of two
units of packed RBCs every two to four weeks or one to three units of packed RBCs every three to
five weeks is a good starting point. Occasional reports of bizarre reactions occurring within the first
24 to 48 hours after transfusion have led to the recommendation that no more than 10 to 15 mL of
RBCs per kg of body weight be administered during any 24-hour period, and we tend to favor the
more conservative end of this range (ie, no more than 10 mL of RBCs per kg) except in cases of
profound emergency.
Transfusions can be repeated daily or every two to three days until the pretransfusion hemoglobin
is in the range of 9.5 to 10.5 g/dL. The post-transfusion hemoglobin should be approximately 12 to
13 and no higher than 15 g/dL. The timing and dose of RBC transfusions can then be titrated for
the individual patient. Typically, a dose of 8 to 10 mL of RBCs per kg every two to three weeks will
maintain the desired hemoglobin levels if great care is taken to use thoroughly washed and
crossmatched RBC products.
For children undergoing chronic transfusions, we try to avoid central venous catheter placement;
however, an evaluation of the need for a central venous access catheter may be appropriate,
especially if lifelong transfusional support is anticipated. Ideally, we try to defer this until after the
rapid growth of infancy and toddlerhood has occurred in order to avoid the need for frequent
revision of intravenous access devices.
As noted below, extended crossmatching to prevent alloimmunization, leukocyte depletion to

reduce febrile nonhemolytic reactions, and other measures to reduce transfusion reactions are
used. (See 'Reduction of alloimmunization and other complications of transfusion' below.)
Supporting evidence — Evidence to support the benefits of chronic transfusion and the
appropriate nadir hemoglobin level comes from observational studies in which individuals with beta
thalassemia have been transfused using various hemoglobin or hematocrit values. No data are
available from randomized trials comparing clinical outcomes with different hemoglobin levels.
The following studies illustrate the association between transfusion using a higher baseline
hemoglobin level and reduced complications of extramedullary hematopoiesis or iron turnover:
● A 1964 cross-sectional survey compared outcomes in 35 children under 12 years of age with
beta thalassemia who were chronically transfused to low, intermediate, or high hemoglobin
levels (pretransfusion hemoglobin levels of 4 to 5.9, 6 to 7.9, or 8 to 9.9 g/dL, respectively)
[21]. Despite having relatively similar baseline ages and hematologic characteristics, these
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children demonstrated strong correlations between higher hemoglobin levels and improved
clinical outcomes, including greater height, smaller liver and spleen size (for those who had
not undergone splenectomy), less frontal skull thickening and maxillary overgrowth, less
periodontal and dental disease, and fewer bone fractures, all potential indicators of reduced
extramedullary hematopoiesis.
● A 1980 study evaluated the effect of using transfusion to maintain two different target
hematocrits, 27 versus 35 percent (approximate hemoglobin of 9 versus 12 g/dL, respectively)
in 10 individuals with beta thalassemia who were postsplenectomy and served as their own
controls [22]. Compared with the lower target, the higher target was associated with a slower
plasma iron clearance (mean half-life of transferrin-bound iron measured using radiolabeled
iron, from 24 to 108 minutes) and a slower plasma iron turnover (from approximately 10 to 2
mg/dL/day). Another report from 1980 selected a target hemoglobin of 11.5 g/dL based on
expert consensus [23].
● A 1997 study involving a cohort of 32 individuals with beta thalassemia receiving regular
transfusions found that lowering pretransfusion hemoglobin levels from approximately 11.5
g/dL to approximately 9.5 g/dL reduced iron overload without adverse effects; the proportion
entering normal puberty improved [12].
These initial studies were followed by attempts to further define the ideal target hemoglobin level.
As an example, a retrospective review evaluated 32 children with beta thalassemia who were
transfused to maintain a pretransfusion hemoglobin level of 10 to 12 g/dL (mean, 11.3 g/dL) and
then were subsequently switched to a lower pretransfusion hemoglobin level of 9 to 10 g/dL
(mean, 9.4 g/dL) [24]. The switch correlated with a decreased number of transfusions (from
approximately 137 to 104 mL/kg/year) and a decreased ferritin level (from 2280 to 1004 mcg/L);
the lower threshold did not appear to be associated with laboratory changes of increased erythroid
activity or adverse effects on growth or endocrine function.
The initial number of units (or volume of blood) to transfuse depends on the starting hemoglobin
level, the desired increase, the hematocrit of the packed RBCs, and the size of the patient (table
2). Adjustments require some empirical dose-finding for each individual. Regardless of the dose
and schedule, the post-transfusion hemoglobin level should not exceed 14 to 15 g/dL due to risks
of hyperviscosity [1].
Assessment of iron stores and initiation of chelation therapy — Individuals with thalassemia
major, as well as a subset of those with thalassemia intermedia phenotypes, will eventually
develop iron overload, which in turn can cause organ toxicity and even death [25]. Iron stores are
monitored on a regular basis in these individuals. We typically use the serum ferritin level for serial
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testing. We obtain baseline magnetic resonance imaging (MRI) and use MRI-based estimates of
liver or cardiac iron concentration for individuals with signs of organ injury if there is a significant
increase in serum ferritin or if ferritin values are discordant with clinical expectations. Liver biopsy
may be used, but this is less common with the availability of MRI. There are no reliable criteria for
pancreatic iron overload; liver iron overload is used as a surrogate.
Iron chelation is generally initiated in one or more of the following settings [1,2]:
● At the same time that a chronic transfusion program is started

● After the serum ferritin exceeds 1000 ng/mL (1000 mcg/L)
● After the liver iron concentration exceeds 3 mg iron per g of dry weight
● After transfusion of approximately 20 to 25 units of RBCs
For most children with beta thalassemia major, iron chelation is instituted before six years of age
(often as early as two to four years). For those with alpha or beta thalassemia intermedia, the need
for chelation depends on whether (or when) chronic transfusion is used and the parameters listed
above; often, this is in the second or third decade of life.
MRI appears to be superior to measurement of serum ferritin for estimating total body iron burden
in these patients, especially in individuals with beta thalassemia intermedia. This was illustrated in
a 2008 study in which 74 individuals with beta thalassemia intermedia had both serum ferritin
testing and liver MRI [26]. Serum iron levels increased with age according to both modalities.
However, serum ferritin correlated with liver iron only in those with thalassemia major and not in
those with thalassemia intermedia. A proposed hypothesis for this difference was that individuals
with thalassemia major were receiving more transfusions, leading to increased distribution to the
reticuloendothelial system and increased ferritin, whereas for those with thalassemia intermedia,
the main source of iron overload was increased intestinal absorption with deposition in the liver
and less of an increase in serum ferritin. Smaller studies of individuals with beta thalassemia
intermedia have appeared to corroborate this finding [27,28].
Once initiated, the chelation program requires close monitoring and attention. The details of
chelation therapy, including choice of chelating agent, administration, monitoring, and adverse
events, are discussed in detail separately. (See "Iron chelators: Choice of agent, dosing, and
adverse effects".)
Reduction of alloimmunization and other complications of transfusion — Individuals

receiving regular transfusions are at increased risk for alloimmunization, in which exposure to
foreign antigens on donor RBCs leads to formation of alloantibodies that react with donor RBCs
and typically cause delayed hemolytic transfusion reactions. (See "Hemolytic transfusion
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reactions".)
The prevalence of alloimmunization in thalassemia has been estimated to be in the range of 10 to

50 percent. Lower rates in some populations may reflect a more homogenous genetic background
(eg, 8 percent in Egypt, 6 percent in Eastern India) or the use of more extensive crossmatching
protocols [29-31].
When blood is requested, the blood bank or transfusion medicine service should be made aware
that the patient has thalassemia so that extra care can be taken to avoid possible
alloimmunization. This may include matching for Rh antigens other than Rh(D), such as C and E,
and Kell [32-35]. Some reports have suggested that starting the transfusion program at a younger
age may be associated with a lower rate of alloimmunization [34,36,37]. Other strategies to reduce
the risk of alloimmunization such as extended antigen matching or molecular matching are similar
to those used in patients with sickle cell disease. (See "Red blood cell transfusion in sickle cell
disease", section on 'Transfusion techniques'.)
Transfusions also carry other risks such as allergic reactions, febrile nonhemolytic reactions
(FNHTR), transfusion-related acute lung injury (TRALI), and transfusion-associated circulatory
overload (TACO). These reactions and approaches to reduce their risk are presented separately.
(See "Pretransfusion testing for red blood cell transfusion" and "Leukoreduction to prevent
complications of blood transfusion" and "Immunologic transfusion reactions".)
ROLE OF SPLENECTOMY
Splenectomy may be appropriate for individuals with thalassemia (typically beta thalassemia) who
have one or more of the following findings [9]:
● Severe anemia due to thalassemia (eg, persistent symptomatic anemia not due to iron
deficiency or other non-thalassemia conditions)
● A dramatic increase in transfusion requirement (eg, doubling of transfusion requirement over
the course of one year)
● Growth retardation
● Hypersplenism leading to other cytopenias (leukopenia [eg, absolute neutrophil count below
1000/microL], thrombocytopenia with a platelet count <10,000/microL)
● Symptomatic splenomegaly (eg, abdominal discomfort, early satiety)
● Splenic infarction or splenic vein thrombosis
Splenectomy may improve anemia and reduce transfusion requirements in some individuals,
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which in turn may reduce excess iron accumulation, although the benefit of splenectomy in
reducing iron accumulation is becoming less relevant with the institution of regular iron chelation
therapy [4,38,39]. Splenectomy may also improve cytopenias due to hypersplenism or symptoms
related to splenomegaly, although these findings are also becoming less common in the setting of
regular transfusions and chelation therapy.
These potential benefits must be balanced with the risks of surgery, the possibility that a benefit
may be transient, and the potential for postsplenectomy complications including an increased risk
of thromboembolism and life-threatening infection. The risk of thromboembolic disease appears to
be higher in individuals with thalassemia (especially beta thalassemia intermedia) following
splenectomy (over an increased baseline risk due to thalassemia). In a retrospective cohort of 83
individuals with beta thalassemia intermedia followed for a decade, 24 (29 percent) had an
episode of venous thromboembolism; all except one had undergone splenectomy for their disease
[40]. Case reports have described portal vein thrombosis after laparoscopic splenectomy in
thalassemia [41,42]. The relative contributions of splenectomy and thalassemia to these
complications is hard to disentangle. The underlying hypercoagulable state in thalassemia and
differences between different thalassemia phenotypes are discussed below. (See 'Venous
thromboembolism' below.)
The decision to pursue splenectomy is therefore a difficult one and should be made on a case-by-
case basis that balances risks and benefits for the individual patient. When pursued, splenectomy
is generally deferred until at least the age of four years, often much later [13]. Appropriate use of
pre-splenectomy vaccines and prophylactic antibiotics is important for reducing the risk of sepsis.
Additional considerations related to splenectomy such as the choice of surgical approach, pre-
splenectomy vaccinations, prophylactic antibiotics, and other potential short- and long-term
complications are discussed separately. (See "Prevention of infection in patients with impaired
splenic function" and "Clinical features, evaluation, and management of fever in patients with
impaired splenic function".)
DECISION TO PURSUE ALLOGENEIC HCT
Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for

thalassemia that may be appropriate for those with severe disease (eg, transfusion-dependent
beta thalassemia). However, transplant toxicities and transplant-related mortality are serious
concerns, even for the best candidates (ie, young children with no comorbidities and a human
leukocyte antigen [HLA]-identical sibling donor). Lack of a suitable donor or the lack of available
resources to perform HCT are both major barriers that eliminate the HCT option for many
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individuals. A role for HCT in alpha thalassemia (eg, hemoglobin H disease) has not been
established.
Despite these barriers, HCT may be appropriate for some individuals, such as children with beta
thalassemia major who have been treated with chronic transfusion and chelation and have a
suitable donor (algorithm 1). The decision whether, and when, to pursue HCT for a patient with
thalassemia is highly complex and should be made only in consultation with a thalassemia
specialist in conjunction with an experienced high-volume transplant center. The challenge is that
the mortality and significant morbidities associated with HCT are lowest if the HCT is administered
during the mid-first decade of life, prior to the development of significant iron overload and/or other
comorbidities such as liver fibrosis or hypersplenism; however, this is also the time when the long-
term clinical prognosis with conventional therapy is often not yet clear. Usually individuals with
hypersplenism undergo splenectomy before HCT. The decision will also be influenced by the
availability of a well-matched donor. As a general guide, a child who is transfusion-dependent,
requires iron chelation, and has a matched donor should be evaluated with an initial consultation
for HCT.
As investigational methods for performing HCT such as the use of partially matched donors and
reduced-intensity or nonmyeloablative conditioning regimens evolve, the indications may broaden,
especially for adolescents and young adults. Thus, any transfusion-dependent individual or
individual with significant comorbidities such as growth retardation or bony deformities may be
referred for a transplant evaluation.
Detailed information on best practices for HCT in thalassemia, as well as potential complications
and post-HCT care, is presented separately. (See "Hematopoietic cell transplantation for
transfusion-dependent thalassemia" and "Thalassemia: Management after hematopoietic cell
transplantation".)
MONITORING AND MANAGEMENT OF DISEASE COMPLICATIONS
Many of the complications of thalassemia are caused by iron overload. This occurs because
ineffective erythropoiesis promotes excessive iron absorption, which can be further exacerbated by
chronic transfusions. Thus, assessment of iron stores and reduction of excess iron stores is an
integral component of prevention and therapy for these complications. (See 'Assessment of iron
stores and initiation of chelation therapy' above.)
The pace of developing complications related to iron overload depends on the severity of
thalassemia and the frequency of transfusions. As an example, an individual with beta thalassemia
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major who receives chronic transfusions without chelation therapy may develop severe iron
overload in childhood, whereas one with beta thalassemia intermedia who receives intermittent
transfusions may not develop severe iron overload in childhood. Even though patients with the
thalassemia intermedia phenotype can live with only occasional or even no transfusions, they can
also develop later iron overload because their anemia and brisk ineffective erythropoiesis drive
excessive enteric iron uptake. The severity of anemia, frequency of transfusions, and especially
the intensity of ineffective erythropoiesis all modulate the onset and severity of iron overload.
These patients also require monitoring of iron burden.
Routine evaluations and monitoring — Individuals with thalassemia major are typically cared for
by a specialist and are seen at least two to four times a year to monitor progression of any of the
major morbidities. Once the pace of any complication is established to be stable, follow-up for
general care and monitoring can be done by either a specialist or the patient's primary clinician.
Frequent contact with the patient is feasible because of the regular transfusion schedule. Patients
can be evaluated when onsite for transfusion.
At follow-up visits for transfusion-dependent thalassemia, once the transfusion schedule is

established, and for thalassemia intermedia, we monitor a number of organ systems as well as
overall health. The use of a checklist can ensure that evaluations have been performed at
appropriate intervals [43]. An example with the frequency of monitoring for children and adults is
provided in the table (table 3); we generally monitor for complications as follows:
● Anemia – Complete blood count (CBC) and reticulocyte count at each visit. (See
'Management of anemia' above.)
● Iron stores – Serum ferritin and liver iron as described above. (See 'Assessment of iron
stores and initiation of chelation therapy' above.)
● Cardiac status – Cardiac magnetic resonance imaging (MRI) at initial evaluation and when
there are significant changes in ferritin. (See 'Cardiopulmonary complications' below.)
● Liver – Liver function tests and hepatitis serologies as described below. (See 'Liver disease'
below.)
● Kidney – Renal function, on a regular basis (eg, with each CBC).
● Bone health – Assessed if there is any evidence of growth retardation or bony abnormalities
(eg, facial deformities). Bone density testing is done annually starting at the age of two years,
with bone age films until age six years followed by annual dual-energy x-ray absorptiometry
(DXA) scans after age six. (See 'Bone health' below.)
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● Endocrine status – Thyroid function annually (more frequently if there are signs consistent
with thyroid dysfunction). Additional testing may be appropriate for children and adolescents
with delayed puberty. (See 'Endocrine complications' below.)
Individuals with thalassemia minor or thalassemia trait do not require evaluations or monitoring
other than those indicated for their non-thalassemia medical care, and these individuals typically
do not require specific follow-up or care by a hematologist. As noted below, it is important to offer
them preconception genetic counseling and testing when considering childbearing (see 'Prenatal
testing and genetic counseling' below). Individuals with thalassemia trait can be followed by
primary care providers with a hematologist or geneticist as backup for counseling or changes in
blood counts. It is important to educate these patients about the tendency of providers to confuse
thalassemia trait with iron deficiency and prescribe iron supplements, while at the same time
noting that they are susceptible to all of the usual causes of iron deficiency. Any change in their
blood counts or recommendation for iron therapy should prompt a visit to a hematologist for
counseling.
Pain management — Individuals with thalassemia can have pain related to osteoporosis or
splenomegaly. Joint pain is also common, although the mechanism is unclear. The pain is different
from the pain associated with sickle cell disease, which is mostly due to vaso-occlusion. By
contrast, the pain in thalassemia may be related to expansion of the bone marrow space due to
ineffective erythropoiesis-induced erythroid expansion. (See "Clinical manifestations and diagnosis
of the thalassemias", section on 'Clinical manifestations'.)
Management is directed at the underlying cause. Referral to a pain management consultant is

appropriate. (See "Evaluation and management of pain in children" and "Overview of the treatment
of chronic non-cancer pain".)
Cardiopulmonary complications — Individuals with thalassemia major or thalassemia intermedia

are at risk for a number of cardiopulmonary complications, including heart failure, pericarditis,
arrhythmias, and pulmonary hypertension. (See "Clinical manifestations and diagnosis of the
thalassemias", section on 'Heart failure and arrhythmias'.)
These may be due to combinations of hypoxemia, anemia, diabetic vascular disease, and iron
overload. Additional information on cardiovascular complications is provided in a 2008 guideline
from the Italian Federation of Cardiology and a 2013 consensus statement from the American
Heart Association [44,45].
There is no consensus on the best approach to cardiac monitoring, and data are limited. As noted
above, we perform a baseline cardiac MRI that is repeated if there are significant changes in
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ferritin (see 'Routine evaluations and monitoring' above). Other evaluations are individualized
according to the individual's symptoms, findings on physical examination, and availability of
resources such as MRI.
Cardiac MRI is considered the gold standard for measurement of all left and right ventricular
indices, while myocardial iron deposition can be quantified reproducibly with myocardial T2*, a
relaxation parameter that is increased with iron deposition [44]. Low T2* (eg, below 10 ms)
indicates iron deposition. The importance of using T2* MRI was illustrated in an international
survey involving 3095 patients with beta thalassemia major [46]. Of these, approximately half had
evidence of cardiac iron deposition on first MRI, and future development of heart failure correlated
strongly with reduced T2* on MRI. (See "Clinical utility of cardiovascular magnetic resonance
imaging", section on 'Iron overload' and 'Assessment of iron stores and initiation of chelation
therapy' above.)
The principal interventions for cardiac disease are transfusions for severe, symptomatic anemia
(see 'Management of anemia' above) and iron chelation to prevent or treat cardiac iron overload.
We routinely start chelation in all individuals treated with a chronic transfusion program and/or any
of the parameters of excess iron stores listed above. (See 'Assessment of iron stores and initiation
of chelation therapy' above.)
Additional management of chronic cardiopulmonary complications is discussed in separate topic

reviews. (See "Determining the etiology and severity of heart failure or cardiomyopathy" and
"Overview of the therapy of heart failure with reduced ejection fraction" and "Treatment and
prognosis of heart failure with preserved ejection fraction" and "Treatment of pulmonary
hypertension in adults".)
Acute decompensated heart failure in thalassemia is a medical emergency that requires close
electrocardiographic and hemodynamic monitoring; correction of electrolyte abnormalities,
maintenance of meticulous glucose control, and optimization of renal, hepatic, and thyroid function;
searching for other precipitating factors such as infection; and initiation of chelation therapy (if
indicated) [44]. Early involvement of specialist consultants is advised. (See "Treatment of acute
decompensated heart failure: Components of therapy" and "Iron chelators: Choice of agent,
dosing, and adverse effects".)
Treatment of pulmonary hypertension with phosphodiesterase type 5 inhibitors (eg, sildenafil) and
the endothelin receptor antagonist bosentan have been reported [47-51]. (See "Treatment of
pulmonary hypertension in adults", section on 'Pulmonary hypertension-specific therapy'.)
Liver disease — Iron overload can lead to impaired liver function and eventually cirrhosis if not
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treated. Monitoring of liver iron and initiation of chelation are discussed above. (See 'Assessment
of iron stores and initiation of chelation therapy' above.)
We typically perform a baseline ultrasound at the time of diagnosis and repeat testing at least twice
a year in individuals with thalassemia who are regularly transfused and/or have evidence of iron
overload, severe liver disease, or cirrhosis. Patients with cirrhosis should be monitored for
hepatocellular carcinoma (HCC). (See "Cirrhosis in adults: Overview of complications, general
management, and prognosis", section on 'Hepatocellular carcinoma'.)
Treatment of HCC is similar to individuals without thalassemia, with the exception that some
individuals with severe iron overload may not be candidates for liver transplantation. (See
"Overview of treatment approaches for hepatocellular carcinoma".)
Endocrine complications — Thalassemia major and thalassemia intermedia confer an increased

risk for a number of endocrine complications including diabetes, gonadal dysfunction with delayed
puberty and infertility, and thyroid dysfunction. (See "Clinical manifestations and diagnosis of the
thalassemias", section on 'Endocrine and metabolic abnormalities'.)
It is advisable to make baseline measurements of thyroid function and glucose at the time of
diagnosis. If there are any indications that puberty is delayed or that growth is lagging behind the
normal pace, referral to an endocrinologist is advisable. As with other complications of iron
overload, reduction of excess iron stores is one of the mainstays of treatment. Additional
information about specific types of endocrine dysfunction is presented separately. (See "Treatment
of hypopituitarism" and "Approach to the patient with delayed puberty" and "Acquired
hypothyroidism in childhood and adolescence" and "Initial management of blood glucose in adults
with type 2 diabetes mellitus".)
Bone health — The major bone complications of thalassemia intermedia and thalassemia major
are related to extramedullary hematopoiesis and expansion of the erythroid bone marrow. This can
lead to osteopenia/osteoporosis, premature limb shortening, delayed skeletal maturation, and
changes in the structure of facial and other bones, leading to cosmetic and dental abnormalities
and pathologic fractures. The severity of these complications tends to correlate with overall
disease severity; it has been suggested that individuals with thalassemia major have a much
higher rate of bone turnover than those with thalassemia intermedia [52]. (See "Clinical
manifestations and diagnosis of the thalassemias", section on 'Skeletal changes'.)
We typically assess bone mineral density starting in adolescence and monitor individuals with
evidence of osteopenia approximately twice per year.
Strategies to reduce the risk of osteoporosis include the following:
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● Encouragement of moderate to high-impact physical activity

● Avoidance of smoking
● Intake of adequate calcium, zinc, and vitamin D (may include measurement of serum levels)
● Early diagnosis and treatment of diabetes mellitus
● Prevention and/or correction of hypogonadism
● Adequate iron chelation when appropriate
● Blood transfusions to inhibit excessive bone marrow expansion
Bisphosphonates are used based on indications established for individuals without thalassemia.
Studies in which bisphosphonates have been administered to individuals with thalassemia and
osteopenia or osteoporosis have generally demonstrated improvements in surrogate endpoints
such as bone mineral density or markers of bone turnover [52-55]. As noted in a 2016 Cochrane
review of this subject, the few randomized trials that have been performed were mostly small, had
various risks of bias, and did not report on a reduction in fractures [56].
Rarely, surgical correction (eg, correction of maxillary expansion) may be needed.
Leg ulcers — Chronic leg ulcers are present at increased frequency in individuals with beta
thalassemia intermedia and are less likely, but may also be seen, in thalassemia major.
There is a lack of high-quality evidence to guide treatment of leg ulcers. Various approaches have
been tried, including blood transfusion, hydroxyurea, iron chelation, hyperbaric oxygen,
anticoagulation, topical antibiotics, plastic surgery, and granulocyte-macrophage colony-stimulating
factor (GM-CSF) [57-61].
Chronic transfusion is usually effective therapy for leg ulcers but is best reserved as a last resort
for the rare patients in whom more conservative measures are ineffective.
Gallstone disease — Thalassemia major confers an increased risk of pigment gallstones, similar
to other chronic hemolytic anemias. We do not alter management due to this increased risk (eg,
we do not perform additional screening or prophylactic cholecystectomy), but we do evaluate the
possibility of gallstone disease if an individual with thalassemia develops suspicious symptoms.
Additional issues related to surgery in thalassemia are discussed below. Removal of the
gallbladder at the time of splenectomy may be appropriate to reduce the risk of bilirubin stones;
this should be reviewed with the surgical team. (See 'Surgery/anesthesia concerns' below.)
Venous thromboembolism — The risk of venous thromboembolism (VTE) is increased in

individuals with thalassemia major and thalassemia intermedia, and this risk can be further
increased by splenectomy, as noted above. (See "Clinical manifestations and diagnosis of the
thalassemias" and 'Role of splenectomy' above.)
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Despite this increased risk, there are no randomized trials evaluating the benefit of prophylactic
anticoagulation or antiplatelet therapy in these individuals, and we do not routinely alter our
approach to VTE prophylaxis due to the presence of thalassemia (ie, we use the same indications
for prophylaxis as in individuals without thalassemia), other than having a heightened level of
vigilance and a higher index of suspicion if suspicious symptoms develop and making sure to
counsel individuals with thalassemia regarding avoiding prolonged immobility (eg, during travel).
Quality of life — Quality of life is an important consideration in individuals with thalassemia, as it

is in any chronic disorder. Quality of life studies have reported lower scores in individuals with
thalassemia compared with the general population, especially in individuals with transfusion-
dependent thalassemia [62-65]. Some of the issues that impact quality of life have been described
in a personal account of an individual with thalassemia born in the early 1970s [66].
INVESTIGATIONAL DISEASE-MODIFYING APPROACHES
The therapies discussed above are effective in treating complications of thalassemia but do not
modify the underlying defect in erythropoiesis, with the exception of HCT and/or gene therapy.
Approaches that restore or improve production of healthy red blood cells (RBCs) in the bone
marrow continue to be sought.
Drug therapies under investigation — Several approaches are under investigation to improve
erythropoiesis in beta thalassemia.
Luspatercept and sotatercept (ActRIIA ligand traps) — Luspatercept (previously called

ACE-536) is a subcutaneous agent that sequesters activin A as well as related members of the
transforming growth factor (TGF)-beta family, which appear to have an important role in RBC
maturation [67,68]. Luspatercept and other activin A traps (referred to as activin receptor IIA
[ActRIIA] ligand traps) appear to promote erythropoiesis and bone formation through a poorly
understood, erythropoietin- and hepcidin-independent mechanism [68,69].
● In an open-label dose-finding study, 64 patients with beta thalassemia (approximately half

were transfusion-dependent) were treated with luspatercept for 24 weeks, followed by an
extension stage for up to five years [70]. The drug was given subcutaneously once every 21
days. Many patients treated at the highest dose levels (0.6 to 1.25 mg/kg/dose) had a
significant improvement in hemoglobin level.
• 81 percent of transfusion-dependent participants were able to reduce transfusions by 20

percent or more.
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• 58 percent of non-transfusion-dependent participants had an increase in hemoglobin of

≥1.5 g/dL for at least two weeks.
Therapy was generally well tolerated, with mild bone pain, headache, and myalgia, which
tended to decrease over the course of the study.
The potential benefit of this therapy includes reduction in anemia, fewer transfusions, and less
iron overload [71]. Relevant questions that remain to be addressed include more detail
regarding efficacy and safety and the impact of this therapy on iron burden and need for
chelation.
● A randomized, placebo-controlled trial in transfusion-dependent thalassemia (BELIEVE) has

been completed, but results have not been published [72].
● Preclinical models of thalassemia are also consistent with improved erythropoiesis [73].
Luspatercept is not available outside of a clinical trial. Additional approaches to altering TGF-beta
signaling are discussed below. (See 'Drug therapies under investigation' above.)
Sotatercept (ActRIIA-Fc; previously called ACE-011) is another activin A sequestering compound

that reduces TGF-beta signaling; it was developed prior to luspatercept [67,68]. In a series of 46
individuals with thalassemia (16 transfusion-dependent and 30 non-transfusion-dependent) who
were treated with sotatercept, most had improvements in hemoglobin levels [74]. The authors
noted that a decision had been made not to advance further trials of sotatercept in beta
thalassemia because luspatercept is more specific.
While these agents appear to be effective and generally well-tolerated for an extended period in
these studies, further observation will be needed to establish the very long term efficacy and safety
in patients with lifelong anemias.
Other drug therapy approaches — Some agents such as histone deacetylase (HDAC)
inhibitors and hypomethylating agents may improve erythropoiesis via epigenetic mechanisms
(see "Genetics: Glossary of terms", section on 'Epigenetic change' and "Principles of epigenetics"):
● Hypomethylating agents such as decitabine (5-aza-2'-deoxycytidine) may alter erythropoiesis

in the bone marrow. A pilot study suggested decitabine could potentially activate gamma
globin gene expression, increase fetal hemoglobin (HbF) levels, and improve the hemoglobin
level in beta thalassemia [75,76].
● HDAC inhibitors such as butyrates (eg, arginine butyrate, sodium phenylbutyrate) activate
gamma globin gene expression and could potentially raise HbF levels and reduce anemia
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[76-80]. Most of these agents are administered intravenously, making routine use less
attractive. HQK-1001 (sodium 2,2 dimethylbutyrate) is an orally available short-chain fatty acid
derivative that modestly increased HbF levels (by approximately 5 to 10 percent) in a small
randomized trial and two pilot studies involving patients with beta thalassemia intermedia
and/or beta thalassemia major [81-83]. The use of HDAC inhibitors in combination with
hydroxyurea has also been explored.
Other agents may act by stimulating erythropoiesis:
● The inadequate tissue oxygenation in thalassemia produces a compensatory increase in

erythropoietin, which accelerates erythropoiesis and may contribute to ineffective
erythropoiesis (see "Pathophysiology of beta thalassemia", section on 'Ineffective
erythropoiesis'). Upregulation of the kinase JAK2 may contribute. In a single-arm study in
which 27 patients with transfusion-dependent thalassemia were treated with the JAK2 inhibitor
ruxolitinib, 12 (44 percent) had a decrease in transfusion requirements; there was also a
nonsignificant trend towards improvement in pretransfusion hemoglobin level with ruxolitinib
[84]. Ruxolitinib reduced median spleen size by approximately 25 percent. While these results
are interesting and merit further study, further trials with larger numbers of patients with longer
follow-up are needed before adopting this approach.
● Agents that act on hematopoietic stem cells such as kit ligand may also have potential
therapeutic use in these diseases. In an in vitro study, addition of kit ligand to cells from
patients with thalassemia resulted in increased proliferation, decreased apoptosis, and
increased HbF levels [85].
The ultimate benefit of these therapies may result from a combination of effects, including
increased production of HbF and decreased apoptosis. Other potential regulators of HbF are
discussed separately. (See "Fetal hemoglobin (hemoglobin F) in health and disease".)
In some cases, these agents have been studied or are in clinical use for other disorders, and
additional information about their dosing and adverse events may be available from these other
settings. (See "Investigational therapies for sickle cell disease".)
Of note, the therapies that increase gamma globin production (and HbF levels) have no role in
treating alpha thalassemia because gamma globin is a beta-like chain; therapies for alpha
thalassemia would have to induce production of more alpha chains.
Gene therapy and other modifications of HCT — Allogeneic hematopoietic cell transplantation
(HCT) is used in some children with beta thalassemia major who have an available sibling donor,
as discussed in detail separately. Modifications such as the use of haploidentical transplant,
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matched unrelated donor transplant, and nonmyeloablative conditioning regimens are also
discussed. (See "Hematopoietic cell transplantation for transfusion-dependent thalassemia".)
Gene therapy is also under investigation, using virally transduced transfer of a normally functioning
beta globin gene into autologous hematopoietic stem cells (HSCs) and/or exploring genome
editing techniques to repair pathogenic beta globin gene variants [86]. Gene therapy would
necessarily involve autologous HCT because the replacement gene (or corrected gene) must be
incorporated into a long-term repopulating hematopoietic stem cell. Injection of the HSCs directly
into bone has also been explored, as described in the clinical studies below [87].
Gene therapy for thalassemia is especially challenging because it requires tightly regulated long-
term expression of the replacement gene at quantitatively very high levels. The targeting vector is
critical, as there must be tight regulation of beta globin expression levels to match (but not exceed)
expression levels of alpha globin.
● A pair of studies from 2018 described the use of gene therapy in 22 patients with transfusion-
dependent beta thalassemia [88]. These individuals underwent HCT using autologous HSCs
transduced with the LentiGlobin BB305 vector, which encodes an antisickling variant of beta
globin (T87Q); the variant allows quantification of the expression level from the transgene.
Clinical benefits were impressive, especially in patients with some production of hemoglobin A
at baseline. In the most severe patients, the results were positive but not curative, indicating
the high quantitative bar that must be cleared in order to achieve cure:
• At a median of 26 months, 12 of 13 individuals with non-beta0/beta0 genotypes became

transfusion-independent, with hemoglobin levels between 9.2 and 13.7 g/dL. This
included nine individuals with compound heterozygosity for hemoglobin E and a beta0
mutation.
• In the nine individuals with a beta0/beta0 genotype or two copies of the IVS1-110
mutation, the median annualized number of transfusions was decreased by 74 percent,
and three of the nine (33 percent) became transfusion-independent.
• The toxicities of the therapy were significant in the sense that they involved autologous
transplantation; adverse effects were as expected related to myeloablative busulfan
conditioning. However, there were no added toxicities due to the gene transfer per se.
● A study from 2019 described the use of gene therapy in nine individuals with transfusion-
dependent beta thalassemia (six children and three adults) [87]. HCT was performed using
myeloablative chemotherapy with direct intra-bone injection of HSCs transduced with the
GLOBE lentiviral vector, which encodes a mini beta globin gene with a modified enhancer
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region [89]. The rationale for intra-bone injection was to overcome the lower number of HSCs
in umbilical cord blood; direct injection into bone favors homing of HSCs to bone marrow
spaces avoids the trapping HSCs in filter organs. With a median follow up of 18 months, all
participants had reduced transfusion requirements, and three of four evaluated children were
transfusion-free at 14, 15, and 19 months. Therapy was well-tolerated with expected mild
chemotherapy-related toxicities and no vector-related adverse events.
These observations highlight the promise, limitations, and quantitative challenges of gene therapy.
Longer follow-up to monitor the durability of transfected gene activity will be extremely important.
Safety concerns related to this and other gene therapy approaches are paramount. The use of
lentiviral rather than retroviral vectors appears to be a promising advance. The modified
autologous stem cells must be nonimmunogenic (immunogenicity can result from "leaky"
expression of vector proteins) and must sustain long-term expression of the replacement gene.
Research that addresses these concerns is ongoing [86,89-105].
Gene editing (eg, to disrupt aberrant splice sites and restore normal beta globin expression) is
under investigation [106]. Use of gene editing to disrupt the transcriptional repressor BCL11A as a
means of reactivating fetal hemoglobin (HbF) expression is also being studied [107-109]. Gene
editing might be more amenable to nonmyeloablative approaches involving direct injection of the
vector. (See "Fetal hemoglobin (hemoglobin F) in health and disease", section on 'BCL11A'.)
No effective means of gene therapy are in advanced stages of development for alpha thalassemia.
Combinations with hydroxyurea — Hydroxyurea alone is not particularly effective in modifying

the course of thalassemia despite its significant benefits for patients with sickle cell disease (SCD)
(see "Hydroxyurea use in sickle cell disease"). Hydroxyurea promotes the production of fetal
hemoglobin (HbF), which can ameliorate the severity of beta thalassemia, and efforts persist to
determine if hydroxyurea might be of benefit as part of a multidrug regimen.
The efficacy of hydroxyurea in reducing transfusion requirements in thalassemia was evaluated in

a 2017 systematic review and meta-analysis of studies (17 studies, mostly observational) involving
709 individuals with non-transfusion-dependent beta thalassemia who nevertheless required
transfusions periodically [110]. For the individuals who required four or more transfusions per year,
hydroxyurea use was associated with a 42 percent reduction in transfusion requirements (95% CI
29-56 percent) and a decrease in the transfusion requirement by half or more in 79 percent (95%
CI 71-86 percent). Therapy was well tolerated, but there was no control arm, and follow-up was
short (one to two years in most studies). A 2016 Cochrane review addressing the role of
hydroxyurea in thalassemia identified one randomized trial comparing two doses of hydroxyurea
(10 versus 20 mg/kg daily), which found higher hemoglobin levels with the lower dose of
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hydroxyurea (mean difference, 2.4 mg/dL; 95% CI 2.0-2.8); the trial did not report the effects on
transfusion requirements, and the authors of the systematic review concluded that high-quality
data were lacking to show any benefit of hydroxyurea in these individuals [111].
The explanation for the reduced efficacy in thalassemia compared with SCD may be related to the
differences in erythropoietic activity between the two disorders. In SCD, sickling and hemolysis
occur predominantly in the peripheral circulation, where decreases in oxygen tension lead to
hemoglobin polymerization. By contrast, thalassemias are characterized by ineffective
erythropoiesis in the bone marrow, with failure of normal red blood cell (RBC) maturation and
premature death of RBC precursors. This process is also called intramedullary hemolysis to
distinguish it from hemolysis within the peripheral circulation. Hydroxyurea appears to improve
production of HbF-containing RBCs but does not ameliorate intramedullary hemolysis and
apoptosis. In addition, hydroxyurea is myelosuppressive, which may exacerbate the anemia in
thalassemia to a greater degree than in SCD. It is also possible that the benefit of hydroxyurea in
SCD is more greatly mediated by effects on the vasculature and vaso-occlusion, possibly because
of the lowered neutrophil counts (untreated individuals with SCD usually exhibit some level of
neutrophilia), which are not major considerations in thalassemia. Hydroxyurea would not be
expected to lead to improvements in alpha thalassemia because its major mechanism of action is
increasing production of the beta-like gamma globin chains used to make HbF. (See
"Pathophysiology of beta thalassemia".)
PRENATAL TESTING AND GENETIC COUNSELING
Genetic testing and counseling are offered as a part of routine care and family planning for all
individuals with thalassemia of any severity, including beta thalassemia trait. Concerns about alpha
thalassemia trait are less relevant. It is important for patients and clinicians to be aware that two
parents with thalassemia trait can conceive a child with thalassemia major [13]. This subject,
including the content of counseling and appropriate types of testing, is described in more detail
separately. (See "Prenatal screening and testing for hemoglobinopathy" and "Methods for
hemoglobin analysis and hemoglobinopathy testing", section on 'Molecular (DNA-based)
methods'.)
SPECIAL CIRCUMSTANCES
Pregnancy — Pregnancy is possible in individuals with thalassemia minor and thalassemia

intermedia, and favorable pregnancy outcomes have been reported in beta thalassemia major
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[112-115]. As an example, a report of 129 pregnancies in 72 women with thalassemia (including

beta thalassemia major, hemoglobin H disease, beta thalassemia intermedia, and others) found
that over 70 percent of pregnancies resulted in live births and 88 percent of live births occurred at
full term [115]. Many of the women received regular or intermittent transfusions and approximately
40 percent had received chelation.
A 2007 practice bulletin from the American College of Obstetricians and Gynecologists (ACOG)
states that women with beta thalassemia major should only pursue pregnancy if they have normal
cardiac function and have undergone chronic transfusion therapy with iron chelation [116].
Physiologic (dilutional anemia) anemia of pregnancy may further worsen anemia due to
thalassemia, and the need for transfusions may be increased. The hemoglobin level should be
maintained at or near 10 g/dL with transfusions, and chelation is usually discontinued during
pregnancy because the safety of this agent during pregnancy has not been established [116]. Fetal
growth should be monitored by ultrasound. The mode of delivery is determined by obstetric
indications.
Surgery/anesthesia concerns — Surgical considerations in individuals with thalassemia include

the following:
● Preoperative hemoglobin level – We generally prefer to have a preoperative hemoglobin

level of 10 to 11 g/dL, which may require preoperative transfusion in some individuals. It is
worth noting that patients requiring surgery for an inflammatory condition such as cholecystitis
may have a temporary decline in hemoglobin level due to reduced bone marrow function that
often accompanies inflammatory conditions.
● Cardiac and hepatic function – The surgeon and anesthesiologist should be aware of the
possibility of underlying cardiac and/or hepatic dysfunction due to excess iron stores. Some
individuals may have pulmonary hypertension (see "Clinical manifestations and diagnosis of
the thalassemias", section on 'Heart failure and arrhythmias'). The preoperative evaluation
may include additional testing depending on the patient's age, clinical condition, and findings
on history and physical examination. Cardiovascular status is monitored closely during
surgery.
● Skeletal abnormalities – The deformities of the skull, facial bones, and spine that may
accompany thalassemia may increase difficulty with airway management. Skeletal
abnormalities may also make regional anesthesia (ie, neuraxial anesthesia and/or peripheral
nerve blocks) difficult or impossible. (See "Clinical manifestations and diagnosis of the
thalassemias", section on 'Skeletal changes'.)
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● Venous thromboembolism prophylaxis – As noted above, we use the same guidelines for
venous thromboembolism prophylaxis as we use in individuals without thalassemia (see
'Venous thromboembolism' above). Information about VTE prophylaxis following surgery is
provided separately. (See "Prevention of venous thromboembolic disease in adult
nonorthopedic surgical patients" and "Prevention of venous thromboembolism in adult
orthopedic surgical patients".)
Transition from pediatric to adult care — Transitions in care require special attention to ensure
consistent use of appropriate monitoring and interventions as well as to establish trust between the
individual, family, and provider.
● It is also important in thalassemia to attend to endocrine status and puberty, with close
gynecologic follow up for women. (See "Normal puberty" and "Approach to the patient with
delayed puberty".)
● Genetic counseling is appropriate, especially in those of childbearing potential who may have
children affected with thalassemia. (See "Prenatal screening and testing for
hemoglobinopathy".)
Some of this information may have been given to the parents when the individual was under the
care of a pediatrician, but it warrants discussion and education as the individual gets older and
begins to take on more responsibility for health and prenatal concerns.
PROGNOSIS
The prognosis in thalassemia is highly variable and survival continues to increase with advances in
therapy.
● Untreated severe alpha thalassemia with no production of alpha globin chains (--/--) causes
intrauterine death due to hydrops fetalis.
● Untreated beta thalassemia major is fatal by the age of five years for approximately 85
percent of patients [4].
● Alpha and beta thalassemia intermedia are distinct clinical phenotypes. Each has a variable
prognosis depending on the severity of anemia, need for transfusions, and use of iron
chelation.
● Thalassemia minor is an asymptomatic carrier state that does not limit survival and may never
come to medical attention.
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For those with thalassemia major, cardiovascular complications are the major cause of death,
either from heart failure due to severe anemia or iron overload-induced cardiomyopathy [45,117].
Introduction of chronic transfusion regimens in the 1960s addressed the former and exacerbated
the latter. Subsequently, the use of iron chelation, introduced in the 1970s, has transformed
thalassemia major into a chronic disease in which long-term survival is possible. Hematopoietic
cell transplantation (HCT), begun in the 1980s, is potentially curative, although many individuals
will not have access to HCT due to comorbidities, lack of a suitable donor, and/or cost.
For individuals who receive optimal management of excess iron stores, survival into the fourth,
fifth, and sixth decades of life are increasingly seen [118].
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Hemoglobinopathies".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Beta thalassemia (The Basics)")
SUMMARY AND RECOMMENDATIONS
● For all individuals with thalassemia major or intermedia, we suggest folic acid supplementation
(Grade 2C). It is reasonable to omit folic acid supplements if this is especially burdensome to
the patient or family and/or if there is no clinical evidence of folate deficiency. (See 'Dietary
27 of 45 6/6/2019, 12:35 AM
restrictions and supplements' above.)
● Transfusion therapy is used in individuals with thalassemia to reduce symptoms and

morbidities associated with both anemia and ineffective erythropoiesis; ineffective
erythropoiesis can lead to impaired growth and development in childhood, skeletal
abnormalities, splenomegaly, and increased intestinal iron absorption with iron overload.
Our approach to the use of transfusion therapy is as follows (algorithm 1) (see 'Overview of
approach' above and 'Management of anemia' above):
• Thalassemia major – Individuals with thalassemia major are transfusion-dependent due

to anemia and various degrees of ineffective erythropoiesis. For these individuals, we
suggest chronic transfusion to reduce symptoms of anemia and suppress extramedullary
hematopoiesis rather than a more restrictive approach (Grade 2C). For most individuals
with thalassemia major, we suggest a pretransfusion hemoglobin level of 9.5 to 10.5 g/dL
rather than a higher or lower nadir hemoglobin level (Grade 2C). This value is based on
clinical experience and observational studies demonstrating that increasing hemoglobin
with transfusion leads to reduced extramedullary hematopoiesis, and, for most
individuals, a hemoglobin level in this range is sufficient. Different levels may be
appropriate in individuals with certain comorbidities or in those without clinically significant
ineffective erythropoiesis. (See 'Decision to initiate regular transfusions' above and
'Typical chronic transfusion regimen' above.)
• Thalassemia intermedia phenotype – Decisions regarding transfusion in patients with

thalassemia intermedia are individualized based on the patient's age and specific disease
complications (eg, activity limitations, impairment of growth and development, early
appearance of skeletal changes). Most patients need only periodic transfusions for
symptomatic relief or during periods of increased stress (eg, during periods of rapid
growth, infection-associated bone marrow suppression, surgery, or pregnancy). Some
patients may become dependent on regular transfusions; if this occurs, management is
the same as for patients with thalassemia major. (See 'Decision to initiate regular
transfusions' above.)
• Thalassemia minor – Chronic transfusion therapy is not required in patients with

thalassemia minor since anemia is very mild or absent. Indications for transfusion are
similar to the general population.
● Patients receiving chronic transfusion therapy or periodic transfusions require regular

assessment and treatment of excess iron stores. (See 'Assessment of iron stores and
28 of 45 6/6/2019, 12:35 AM
initiation of chelation therapy' above and "Iron chelators: Choice of agent, dosing, and adverse
effects".)
● Splenectomy is an option for some patients with severe anemia, hypersplenism, or other
splenic complications; however, we generally try to avoid splenectomy if possible.
Splenectomy may reduce transfusion requirements; however, the benefit may only be
transient and must be weighed against the risks of thromboembolism and life-threatening
infection. When pursued, splenectomy is generally deferred until the age of four years.
Appropriate use of pre-splenectomy vaccines and prophylactic antibiotics is important for
reducing the risk of sepsis. (See 'Role of splenectomy' above.)
● Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for

thalassemia that may be appropriate for those with severe disease (ie, transfusion-dependent
thalassemia) (algorithm 1). The decision whether, and when, to pursue HCT for a patient with
thalassemia is highly complex and should be made only in consultation with a thalassemia
specialist and an experienced high-volume transplant center. (See 'Decision to pursue
allogeneic HCT' above.)
● Individuals with thalassemia major are typically cared for by a specialist and seen at least two
to four times a year to monitor progression of any of the major morbidities (table 3). Our
approach to monitoring and managing disease complications includes close attention to iron
stores as well as attention to the issues noted above. (See 'Monitoring and management of
disease complications' above.)
● Several drug therapies and gene therapy approaches for thalassemia are under investigation.
Agents such as luspatercept that reduce TGF-beta signaling and alter erythropoietic programs
appear promising but are not available outside of a clinical trial. (See 'Investigational disease-
modifying approaches' above.)
● Genetic testing and counseling is offered as a part of routine care and family planning for all
individuals with thalassemia of any severity. (See 'Prenatal testing and genetic counseling'
above.)
● Additional aspects of management during pregnancy, surgery, and the transition from pediatric
to adult care are noted above. (See 'Special circumstances' above.)
● The prognosis in thalassemia is highly variable and survival continues to increase with
advances in therapy. Cardiovascular complications are the major cause of death in
thalassemia major. With optimal management of excess iron stores, survival into the fourth,
fifth, and sixth decades of life is increasingly seen. (See 'Prognosis' above.)
29 of 45 6/6/2019, 12:35 AM
REFERENCES
1. http://www.thalassaemia.org.cy/uploads/1466152679tifguidelinesformanagementfinalmerged.
pdf (Accessed on May 12, 2017).
2. Angelucci E, Barosi G, Camaschella C, et al. Italian Society of Hematology practice

guidelines for the management of iron overload in thalassemia major and related disorders.
Haematologica 2008; 93:741.
3. http://thalassemia.com/#gsc.tab=0 (Accessed on May 12, 2017).
4. Rachmilewitz EA, Giardina PJ. How I treat thalassemia. Blood 2011; 118:3479.
5. Higgs DR, Engel JD, Stamatoyannopoulos G. Thalassaemia. Lancet 2012; 379:373.
6. Liu C, Grossman BJ. Red blood cell transfusion for hematologic disorders. Hematology Am
Soc Hematol Educ Program 2015; 2015:454.
7. Musallam KM, Rivella S, Vichinsky E, Rachmilewitz EA. Non-transfusion-dependent

thalassemias. Haematologica 2013; 98:833.
8. Rund D, Rachmilewitz E. Beta-thalassemia. N Engl J Med 2005; 353:1135.
9. Taher AT, Musallam KM, Cappellini MD, Weatherall DJ. Optimal management of β
thalassaemia intermedia. Br J Haematol 2011; 152:512.
10. Borgna-Pignatti C. Modern treatment of thalassaemia intermedia. Br J Haematol 2007;

138:291.
11. Olivieri NF. The beta-thalassemias. N Engl J Med 1999; 341:99.
12. Cazzola M, Borgna-Pignatti C, Locatelli F, et al. A moderate transfusion regimen may reduce
iron loading in beta-thalassemia major without producing excessive expansion of
erythropoiesis. Transfusion 1997; 37:135.
13. Muncie HL Jr, Campbell J. Alpha and beta thalassemia. Am Fam Physician 2009; 80:339.
14. de Alarcon PA, Donovan ME, Forbes GB, et al. Iron absorption in the thalassemia syndromes
and its inhibition by tea. N Engl J Med 1979; 300:5.
15. Carr S, Rubin L, Dixon D, et al. Intrauterine therapy for homozygous alpha-thalassemia.
30 of 45 6/6/2019, 12:35 AM
Obstet Gynecol 1995; 85:876.
16. Singer ST, Styles L, Bojanowski J, et al. Changing outcome of homozygous alpha-
thalassemia: cautious optimism. J Pediatr Hematol Oncol 2000; 22:539.
17. Yi JS, Moertel CL, Baker KS. Homozygous alpha-thalassemia treated with intrauterine
transfusions and unrelated donor hematopoietic cell transplantation. J Pediatr 2009; 154:766.
18. Lee SY, Chow CB, Li CK, Chiu MC. Outcome of intensive care of homozygous alpha-
thalassaemia without prior intra-uterine therapy. J Paediatr Child Health 2007; 43:546.
19. Lücke T, Pfister S, Dürken M. Neurodevelopmental outcome and haematological course of a

long-time survivor with homozygous alpha-thalassaemia: case report and review of the
literature. Acta Paediatr 2005; 94:1330.
20. Aessopos A, Kati M, Meletis J. Thalassemia intermedia today: should patients regularly
receive transfusions? Transfusion 2007; 47:792.
21. WOLMAN IJ. TRANSFUSION THERAPY IN COOLEY'S ANEMIA: GROWTH AND HEALTH
AS RELATED TO LONG-RANGE HEMOGLOBIN LEVELS. A PROGRESS REPORT. Ann N
Y Acad Sci 1964; 119:736.
22. Propper RD, Button LN, Nathan DG. New approaches to the transfusion management of
thalassemia. Blood 1980; 55:55.
23. Piomelli S, Hart D, Graziano J, et al. Current strategies in the management of Cooley's
anemia. Ann N Y Acad Sci 1985; 445:256.
24. Cazzola M, De Stefano P, Ponchio L, et al. Relationship between transfusion regimen and
suppression of erythropoiesis in beta-thalassaemia major. Br J Haematol 1995; 89:473.
25. Musallam KM, Cappellini MD, Wood JC, et al. Elevated liver iron concentration is a marker of
increased morbidity in patients with β thalassemia intermedia. Haematologica 2011; 96:1605.
26. Taher A, El Rassi F, Isma'eel H, et al. Correlation of liver iron concentration determined by R2
magnetic resonance imaging with serum ferritin in patients with thalassemia intermedia.
27. Tony S, Daar S, Elshinawy M, et al. T2* MRI in regularly transfused children with thalassemia
intermedia: serum ferritin does not reflect liver iron stores. Pediatr Hematol Oncol 2012;
31 of 45 6/6/2019, 12:35 AM
29:579.
28. Musallam KM, Cappellini MD, Taher AT. Iron overload in β-thalassemia intermedia: an
emerging concern. Curr Opin Hematol 2013; 20:187.
29. Abdelrazik AM, Elshafie SM, El Said MN, et al. Study of red blood cell alloimmunization risk
factors in multiply transfused thalassemia patients: role in improving thalassemia transfusion
practice in Fayoum, Egypt. Transfusion 2016; 56:2303.
30. Datta SS, Mukherjee S, Talukder B, et al. Frequency of Red Cell Alloimmunization and
Autoimmunization in Thalassemia Patients: A Report from Eastern India. Adv Hematol 2015;
2015:610931.
31. Dhawan HK, Kumawat V, Marwaha N, et al. Alloimmunization and autoimmunization in

transfusion dependent thalassemia major patients: Study on 319 patients. Asian J Transfus
Sci 2014; 8:84.
32. Chou ST, Liem RI, Thompson AA. Challenges of alloimmunization in patients with
haemoglobinopathies. Br J Haematol 2012; 159:394.
33. Azarkeivan A, Ansari S, Ahmadi MH, et al. Blood transfusion and alloimmunization in patients
with thalassemia: multicenter study. Pediatr Hematol Oncol 2011; 28:479.
34. Vichinsky E, Neumayr L, Trimble S, et al. Transfusion complications in thalassemia patients:

a report from the Centers for Disease Control and Prevention (CME). Transfusion 2014;
54:972.
35. Singer ST, Wu V, Mignacca R, et al. Alloimmunization and erythrocyte autoimmunization in

transfusion-dependent thalassemia patients of predominantly asian descent. Blood 2000;
96:3369.
36. Spanos T, Karageorga M, Ladis V, et al. Red cell alloantibodies in patients with thalassemia.
Vox Sang 1990; 58:50.
37. Michail-Merianou V, Pamphili-Panousopoulou L, Piperi-Lowes L, et al. Alloimmunization to

red cell antigens in thalassemia: comparative study of usual versus better-match transfusion
programmes. Vox Sang 1987; 52:95.
38. Graziano JH, Piomelli S, Hilgartner M, et al. Chelation therapy in beta-thalassemia major. III.
The role of splenectomy in achieving iron balance. J Pediatr 1981; 99:695.
32 of 45 6/6/2019, 12:35 AM
39. Cohen AR, Glimm E, Porter JB. Effect of transfusional iron intake on response to chelation
therapy in beta-thalassemia major. Blood 2008; 111:583.
40. Cappellini MD, Robbiolo L, Bottasso BM, et al. Venous thromboembolism and
hypercoagulability in splenectomized patients with thalassaemia intermedia. Br J Haematol
2000; 111:467.
41. Ikeda M, Sekimoto M, Takiguchi S, et al. High incidence of thrombosis of the portal venous
system after laparoscopic splenectomy: a prospective study with contrast-enhanced CT
scan. Ann Surg 2005; 241:208.
42. Sok J, Su W, Hopkins MA. Portal vein thrombosis following laparoscopic splenectomy for
beta-thalassemia: a case study. Surg Endosc 2001; 15:1489.
43. http://thalassemia.com/treatment-checklist.aspx#gsc.tab=0 (Accessed on July 21, 2017).
44. Pennell DJ, Udelson JE, Arai AE, et al. Cardiovascular function and treatment in
β-thalassemia major: a consensus statement from the American Heart Association.
Circulation 2013; 128:281.
45. Cogliandro T, Derchi G, Mancuso L, et al. Guideline recommendations for heart

complications in thalassemia major. J Cardiovasc Med (Hagerstown) 2008; 9:515.
46. Carpenter JP, Roughton M, Pennell DJ, Myocardial Iron in Thalassemia (MINT) Investigators.
International survey of T2* cardiovascular magnetic resonance in β-thalassemia major.
47. Littera R, La Nasa G, Derchi G, et al. Long-term treatment with sildenafil in a thalassemic
patient with pulmonary hypertension. Blood 2002; 100:1516.
48. Derchi G, Forni GL, Formisano F, et al. Efficacy and safety of sildenafil in the treatment of
severe pulmonary hypertension in patients with hemoglobinopathies. Haematologica 2005;
90:452.
49. Anthi A, Tsangaris I, Hamodraka ES, et al. Treatment with bosentan in a patient with
thalassemia intermedia and pulmonary arterial hypertension. Blood 2012; 120:1531.
50. Morris CR, Kim HY, Wood J, et al. Sildenafil therapy in thalassemia patients with Doppler-
defined risk of pulmonary hypertension. Haematologica 2013; 98:1359.
51. Derchi G, Balocco M, Bina P, et al. Efficacy and safety of sildenafil for the treatment of severe
33 of 45 6/6/2019, 12:35 AM
pulmonary hypertension in patients with hemoglobinopathies: results from a long-term follow

up. Haematologica 2014; 99:e17.
52. Chatterjee R, Shah FT, Davis BA, et al. Prospective study of histomorphometry, biochemical
bone markers and bone densitometric response to pamidronate in β-thalassaemia presenting
with osteopenia-osteoporosis syndrome. Br J Haematol 2012; 159:462.
53. Voskaridou E, Terpos E, Spina G, et al. Pamidronate is an effective treatment for

osteoporosis in patients with beta-thalassaemia. Br J Haematol 2003; 123:730.
54. Otrock ZK, Azar ST, Shamseddeen WA, et al. Intravenous zoledronic acid treatment in
thalassemia-induced osteoporosis: results of a phase II clinical trial. Ann Hematol 2006;
85:605.
55. Mamtani M, Kulkarni H. Bone recovery after zoledronate therapy in thalassemia-induced

osteoporosis: a meta-analysis and systematic review. Osteoporos Int 2010; 21:183.
56. Bhardwaj A, Swe KM, Sinha NK, Osunkwo I. Treatment for osteoporosis in people with
ß-thalassaemia. Cochrane Database Syst Rev 2016; 3:CD010429.
57. Taher AT, Musallam KM, Karimi M, et al. Overview on practices in thalassemia intermedia
management aiming for lowering complication rates across a region of endemicity: the
OPTIMAL CARE study. Blood 2010; 115:1886.
58. Matta BN, Abbas O, Maakaron JE, et al. Leg ulcers in patients with β-thalassaemia
intermedia: a single centre's experience. J Eur Acad Dermatol Venereol 2014; 28:1245.
59. Musallam KM, Taher AT, Rachmilewitz EA. β-thalassemia intermedia: a clinical perspective.
Cold Spring Harb Perspect Med 2012; 2:a013482.
60. Aessopos A, Kati M, Tsironi M, et al. Exchange blood transfusions for the treatment of leg
ulcerations in thalassemia intermedia. Haematologica 2006; 91:ECR11.
61. Gamberini MR, Fortini M, De Sanctis V. Healing of leg ulcers with hydroxyurea in
thalassaemia intermedia patients with associated endocrine complications. Pediatr
Endocrinol Rev 2004; 2 Suppl 2:319.
62. Adam S, Afifi H, Thomas M, et al. Quality of Life Outcomes in a Pediatric Thalassemia
Population in Egypt. Hemoglobin 2017; 41:16.
63. Tuysuz G, Tayfun F. Health-related Quality of Life and its Predictors Among Transfusion-
34 of 45 6/6/2019, 12:35 AM
dependent Thalassemia Patients. J Pediatr Hematol Oncol 2017; 39:332.
64. Seyedifar M, Dorkoosh FA, Hamidieh AA, et al. Health-Related Quality of Life and Health
Utility Values in Beta Thalassemia Major Patients Receiving Different Types of Iron Chelators
in Iran. Int J Hematol Oncol Stem Cell Res 2016; 10:224.
65. Sharma S, Seth B, Jawade P, et al. Quality of Life in Children with Thalassemia and their
Caregivers in India. Indian J Pediatr 2017; 84:188.
66. Hadjidemetriou M. Thalassemia: Yesterday, Today, Tomorrow. Am J Hematol 2017; 92:490.
67. Walpurgis K, Thomas A, Vogel M, et al. Testing for the erythropoiesis-stimulating agent
Sotatercept/ACE-011 (ActRIIA-Fc) in serum by means of Western blotting and LC-HRMS.
Drug Test Anal 2016; 8:1152.
68. Langdon JM, Barkataki S, Berger AE, et al. RAP-011, an activin receptor ligand trap,
increases hemoglobin concentration in hepcidin transgenic mice. Am J Hematol 2015; 90:8.
69. Ear J, Huang H, Wilson T, et al. RAP-011 improves erythropoiesis in zebrafish model of
Diamond-Blackfan anemia through antagonizing lefty1. Blood 2015; 126:880.
70. Piga A, Perrotta S, Gamberini MR, et al. Luspatercept improves hemoglobin levels and blood
transfusion requirements in a study of patients with β-thalassemia. Blood 2019; 133:1279.
71. Angelucci E. A new medical therapy for anemia in thalassemia. Blood 2019; 133:1267.
72. https://clinicaltrials.gov/ct2/show/NCT02604433 (Accessed on January 11, 2019).
73. Suragani RN, Cawley SM, Li R, et al. Modified activin receptor IIB ligand trap mitigates
ineffective erythropoiesis and disease complications in murine β-thalassemia. Blood 2014;
123:3864.
74. Cappellini MD, Porter J, Origa R, et al. Sotatercept, a novel transforming growth factor β
ligand trap, improves anemia in β-thalassemia: a phase II, open-label, dose-finding study.
75. Olivieri NF, Saunthararajah Y, Thayalasuthan V, et al. A pilot study of subcutaneous

decitabine in β-thalassemia intermedia. Blood 2011; 118:2708.
76. Musallam KM, Taher AT, Cappellini MD, Sankaran VG. Clinical experience with fetal
hemoglobin induction therapy in patients with β-thalassemia. Blood 2013; 121:2199.
35 of 45 6/6/2019, 12:35 AM
77. Perrine SP, Ginder GD, Faller DV, et al. A short-term trial of butyrate to stimulate fetal-globin-
gene expression in the beta-globin disorders. N Engl J Med 1993; 328:81.
78. Faller DV, Perrine SP. Butyrate in the treatment of sickle cell disease and beta-thalassemia.
Curr Opin Hematol 1995; 2:109.
79. Witt O, Monkemeyer S, Rönndahl G, et al. Induction of fetal hemoglobin expression by the
histone deacetylase inhibitor apicidin. Blood 2003; 101:2001.
80. Bauer DE, Kamran SC, Orkin SH. Reawakening fetal hemoglobin: prospects for new
therapies for the β-globin disorders. Blood 2012; 120:2945.
81. Fucharoen S, Inati A, Siritanaratku N, et al. A randomized phase I/II trial of HQK-1001, an
oral fetal globin gene inducer, in β-thalassaemia intermedia and HbE/β-thalassaemia. Br J
Haematol 2013; 161:587.
82. Inati A, Kahale M, Perrine SP, et al. A phase 2 study of HQK-1001, an oral fetal haemoglobin
inducer, in β-thalassaemia intermedia. Br J Haematol 2014; 164:456.
83. Patthamalai P, Fuchareon S, Chaneiam N, et al. A phase 2 trial of HQK-1001 in HbE-β

thalassemia demonstrates HbF induction and reduced anemia. Blood 2014; 123:1956.
84. Taher AT, Karakas Z, Cassinerio E, et al. Efficacy and safety of ruxolitinib in regularly
transfused patients with thalassemia: results from a phase 2a study. Blood 2018; 131:263.
85. Gabbianelli M, Morsilli O, Massa A, et al. Effective erythropoiesis and HbF reactivation
induced by kit ligand in beta-thalassemia. Blood 2008; 111:421.
86. Srivastava A, Shaji RV. Cure for thalassemia major - from allogeneic hematopoietic stem cell
transplantation to gene therapy. Haematologica 2017; 102:214.
87. Marktel S, Scaramuzza S, Cicalese MP, et al. Intrabone hematopoietic stem cell gene
therapy for adult and pediatric patients affected by transfusion-dependent ß-thalassemia. Nat
Med 2019; 25:234.
88. Thompson AA, Walters MC, Kwiatkowski J, et al. Gene Therapy in Patients with Transfusion-
Dependent β-Thalassemia. N Engl J Med 2018; 378:1479.
89. Miccio A, Cesari R, Lotti F, et al. In vivo selection of genetically modified erythroblastic
progenitors leads to long-term correction of beta-thalassemia. Proc Natl Acad Sci U S A
36 of 45 6/6/2019, 12:35 AM
2008; 105:10547.
90. May C, Rivella S, Chadburn A, Sadelain M. Successful treatment of murine beta-thalassemia

intermedia by transfer of the human beta-globin gene. Blood 2002; 99:1902.
91. Rivella S, May C, Chadburn A, et al. A novel murine model of Cooley anemia and its rescue
by lentiviral-mediated human beta-globin gene transfer. Blood 2003; 101:2932.
92. Persons DA, Allay ER, Sawai N, et al. Successful treatment of murine beta-thalassemia
using in vivo selection of genetically modified, drug-resistant hematopoietic stem cells. Blood
2003; 102:506.
93. Huo Y, McConnell SC, Ryan TM. Preclinical transfusion-dependent humanized mouse model
of beta thalassemia major. Blood 2009; 113:4763.
94. Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2

activation after gene therapy of human β-thalassaemia. Nature 2010; 467:318.
95. Baum C, Düllmann J, Li Z, et al. Side effects of retroviral gene transfer into hematopoietic
stem cells. Blood 2003; 101:2099.
96. Quek L, Thein SL. Molecular therapies in beta-thalassaemia. Br J Haematol 2007; 136:353.
97. Nienhuis AW. Development of gene therapy for blood disorders. Blood 2008; 111:4431.
98. Atweh GF, Forget BG. Clinical applications of gene therapy: anemias. In: Stem Cell Biology a
nd Gene Therapy, esenberry PJ, Stein GS, Forget BG (Eds), John Wiley, New York 1998.
p.411.
99. Nicolini FE, Imren S, Oh IH, et al. Expression of a human beta-globin transgene in erythroid
cells derived from retrovirally transduced transplantable human fetal liver and cord blood
cells. Blood 2002; 100:1257.
100. Puthenveetil G, Scholes J, Carbonell D, et al. Successful correction of the human beta-
thalassemia major phenotype using a lentiviral vector. Blood 2004; 104:3445.
101. May C, Rivella S, Callegari J, et al. Therapeutic haemoglobin synthesis in beta-thalassaemic

mice expressing lentivirus-encoded human beta-globin. Nature 2000; 406:82.
102. Persons DA, Allay ER, Sabatino DE, et al. Functional requirements for phenotypic correction
of murine beta-thalassemia: implications for human gene therapy. Blood 2001; 97:3275.
37 of 45 6/6/2019, 12:35 AM
103. Wilber A, Hargrove PW, Kim YS, et al. Therapeutic levels of fetal hemoglobin in erythroid
progeny of β-thalassemic CD34+ cells after lentiviral vector-mediated gene transfer. Blood
2011; 117:2817.
104. Liu Y, Yang Y, Kang X, et al. One-Step Biallelic and Scarless Correction of a β-Thalassemia
Mutation in Patient-Specific iPSCs without Drug Selection. Mol Ther Nucleic Acids 2017;
6:57.
105. Zhao HF, Abraham A, Kim YS, et al. Lentiviral Transfer of γ-Globin with Fusion Gene NUP98-
HOXA10HD Expands Hematopoietic Stem Cells and Ameliorates Murine β-Thalassemia. Mol
Ther 2017; 25:593.
106. Xu S, Luk K, Yao Q, et al. Editing aberrant splice sites efficiently restores β-globin expression
in β-thalassemia. Blood 2019; 133:2255.
107. Psatha N, Reik A, Phelps S, et al. Disruption of the BCL11A Erythroid Enhancer Reactivates
Fetal Hemoglobin in Erythroid Cells of Patients with β-Thalassemia Major. Mol Ther Methods
Clin Dev 2018; 10:313.
108. Wu Y, Zeng J, Roscoe BP, et al. Highly efficient therapeutic gene editing of human
hematopoietic stem cells. Nat Med 2019; 25:776.
109. Thein SL. Molecular basis of β thalassemia and potential therapeutic targets. Blood Cells Mol
Dis 2018; 70:54.
110. Algiraigri AH, Wright NAM, Paolucci EO, Kassam A. Hydroxyurea for nontransfusion-
dependent β-thalassemia: A systematic review and meta-analysis. Hematol Oncol Stem Cell
Ther 2017.
111. Foong WC, Ho JJ, Loh CK, Viprakasit V. Hydroxyurea for reducing blood transfusion in non-
transfusion dependent beta thalassaemias. Cochrane Database Syst Rev 2016;
10:CD011579.
112. Nassar AH, Usta IM, Rechdan JB, et al. Pregnancy in patients with beta-thalassemia
intermedia: outcome of mothers and newborns. Am J Hematol 2006; 81:499.
113. Jensen CE, Tuck SM, Wonke B. Fertility in beta thalassaemia major: a report of 16
pregnancies, preconceptual evaluation and a review of the literature. Br J Obstet Gynaecol
1995; 102:625.
114. Aessopos A, Karabatsos F, Farmakis D, et al. Pregnancy in patients with well-treated beta-
38 of 45 6/6/2019, 12:35 AM
thalassemia: outcome for mothers and newborn infants. Am J Obstet Gynecol 1999;
180:360.
115. Thompson AA, Kim HY, Singer ST, et al. Pregnancy outcomes in women with thalassemia in
North America and the United Kingdom. Am J Hematol 2013; 88:771.
116. ACOG Committee on Obstetrics. ACOG Practice Bulletin No. 78: hemoglobinopathies in
pregnancy. Obstet Gynecol 2007; 109:229. Reaffirmed 2018.
117. Russo V, Rago A, Papa AA, Nigro G. Electrocardiographic Presentation, Cardiac

Arrhythmias, and Their Management in β-Thalassemia Major Patients. Ann Noninvasive
Electrocardiol 2016; 21:335.
118. Vitrano A, Calvaruso G, Lai E, et al. The era of comparable life expectancy between
thalassaemia major and intermedia: Is it time to revisit the major-intermedia dichotomy? Br J
Haematol 2017; 176:124.
Topic 7118 Version 79.0
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GRAPHICS
Classical thalassemia syndromes (genotypes and laboratory findings)
Typical findings on Hemoglobin analysis (HPLC or

Syndrome Genotype
CBC electrophoresis)
Alpha thalassemias (reduction in alpha globin chains)
Hydrops fetalis with (- - / - - ) Severe microcytic anemia Hb Barts (γ globin tetramers); Hb Portland
Hb Barts with hydrops fetalis; usually (embryonic hemoglobin); no HbF, HbA, or
fatal in utero HbA 2
HbH disease (α - / - -) Moderate microcytic anemia HbH (up to 30%); HbA 2 (up to 4%)
or
(α t - / - -)*
Minor (α - /α - ) Mild microcytic anemia Hb Barts (3 to 8%, only in the newborn

or period)
(α α /- -)
Silent carrier (α α /α -) Normal hemoglobin, normal Normal

MCV
Beta thalassemias (reduction in beta globin chains) ¶
Major (transfusion- β0 / β0 Severe microcytic anemia HbA 2 (5% or more); HbF (up to 95%); no
dependent) or with target cells (typical Hb 3 HbA
to 4 g/dL)
β0 / β+
Intermedia (non- β+ / β+ Moderate microcytic anemia HbA 2 (4% or more); HbF (up to 50%)
transfusion-
dependent)
Minor (also called β / β0 Mild microcytic anemia HbA 2 (4% or more); HbF (up to 5%)
trait or carrier) or
β / β+
This table lists classical thalassemia syndromes; numerous other combina ons and phenotypes are possible.
Refer to UpToDate topics on thalassemia gene cs, pathophysiology, and diagnosis for more details.
CBC: complete blood count; HPLC: high-performance liquid chromatography; Hb: hemoglobin; HbF: fetal hemoglobin;
HbA: adult hemoglobin; MCV: mean corpuscular volume.
* The "t" stands for a mutant alpha globin such as Hb constant spring (eg, α cs – / – –).
¶ β 0 refers to no beta globin production; β + refers to decreased beta globin production; HbE is a β + mutation.
Prepared with data from: Brancaleoni V, Di Pierro E, Motta I, Cappellini MD. Laboratory diagnosis of thalassemia. Int J Lab
Hematol 2016; 38 Suppl 1:32.
Graphic 115337 Version 4.0
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Overview of the management of beta thalassemia
This algorithm applies to individuals with significant clinical manifestations from beta thalassemia.
Refer to UpToDate for additional details as well as for the care of individuals with alpha thalassemia
and less severe forms of beta thalassemia such as beta thalassemia minor. All individuals with
significant hemolysis are treated with daily folic acid.
HLA: human leukocyte antigen; MRI: magnetic resonance imaging; GVHD: graft-versus-host disease.
¶ Includes those with anemia, which may require transfusions (periodic or regular), as well as other
clinical manifestations as discussed in UpToDate. Does not include thalassemia trait.
Δ Refer to UpToDate for considerations in the decision to pursue hematopoietic cell transplantation and for
details such as donor selection, stem cell source (bone marrow, peripheral blood, or umbilical cord blood),
conditioning regimen, and GVHD prophylaxis.
◊ Refer to UpToDate for monitoring schedule and methods for measuring liver and cardiac iron.
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Calculation of the amount of blood to transfuse based on the hematocrit of

packed RBCs and the desired increase in hemoglobin level
Desired increase Hematocrit of donor red cells

in hemoglobin 50% 60% 75% 80%
2 g/dL 12 mL/kg 10 mL/kg 8 mL/kg 7.5 mL/kg
3 g/dL 18 mL/kg 15 mL/kg 12 mL/kg 11.2 mL/kg
4 g/dL 24 mL/kg 20 mL/kg 16 mL/kg 15 mL/kg
The amount of blood (volume or number of units) depends on the starting hemoglobin level, desired increase,
hematocrit of the packed RBCs, and size of the patient, and requires some empirical dose-finding for each
individual. Units with CPD-A tend to have hematocrits close to 75%; units with additive solutions tend to have
lower hematocrits. As an example calculation, to raise hemoglobin level by 4 g/dL in a patient weighing 40 kg and
receiving blood with the AS1 additive (with a hematocrit of 60%) would require 800 mL. This calculation assumes
a blood volume of 70 mL/kg body weight. In many cases, it may be easier to order a certain number of units
rather than a volume of blood, especially for adults.
RBCs: Red blood cells.
Reproduced with permission from: Trompeter S, Cohen A. Blood transfusion. In: Guidelines for the Management of
Transfusion Dependent Thalassaemia (TDT), 3rd ed, Cappellini MD, Cohen A, Porter J, et al (Eds), Thalassaemia
International Federation 2014. p.28. Copyright © 2014 Thalassaemia International Federation. All rights reserved.
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Checklist for routine monitoring in individuals with transfusion-dependent

thalassemia (TDT)
Category Children Adults
General health Testing prior to transfusion and possible Testing prior to transfusion and possible
transplant (all done once at initial evaluation): transplant (all done once if not already
HLA typing available):
DNA mapping (alpha and beta globin HLA typing
genes) DNA mapping (alpha and beta globin
RBC phenotyping genes)
RBC phenotyping
Assessment of iron overload: Assessment of iron overload:

Total volume of RBCs transfused – Assess Total volume of RBCs transfused –
every 6 to 12 months Assess every 6 to 12 months
Serum ferritin – Every 3 months Serum ferritin – Every 3 months
Iron, TIBC, TSAT – As clinically indicated Iron, TIBC, TSAT – As clinically indicated
(eg, if ferritin level is higher than (eg, if ferritin level is higher than
expected) expected)
Liver iron (eg, by MRI) annually Liver iron (eg, by MRI) annually
Chemistry panel including serum calcium every Chemistry panel including serum calcium
3 months every 3 to 6 months
Urinalysis every 6 months
Growth and development: Growth and development:

Weight monthly in infants, every 3 to 4 Weight every 3 to 6 months
months in older children and adolescents Standing height every 3 to 6 months
Head circumference every other month in
infants
Annual growth velocity in children
Tanner stage every 6 months in older
children and adolescents
Routine dental evaluation every 6 months Routine dental evaluation every 6 months
Vision screening every 3 months; ophthalmology Routine ophthalmology examination every 6

examination annually months
Audiology screen annually
Specific organ Hematology: Hematology:

systems CBC at any transfusion CBC at any transfusion
Blood type and antibody screen monthly if Blood type and antibody screen monthly
receiving chronic transfusions if receiving chronic transfusions
Direct antiglobulin test (DAT; direct Direct antiglobulin test (DAT; direct
Coombs) as clinically indicated Coombs) as clinically indicated
Hepatology: Hepatology:
Transaminases (AST, ALT) and bilirubin Transaminases (AST, ALT) and bilirubin
(direct and total) every 3 months (direct and total) every 3 to 6 months
Hepatitis A, B, and C serology and serum Hepatitis A, B, and C serology and
albumin annually serum albumin annually
Hepatitis B and C PCR as clinically Hepatitis B and C PCR as clinically
indicated indicated
PT and aPTT as clinically indicated PT and aPTT as clinically indicated
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Endocrinology: Endocrinology:
T3, free T4, TSH annually starting at age 5 T3, free T4, TSH annually
years PTH, calcium, and ionized calcium
PTH, calcium, and ionized calcium annually annually
starting at age 5 years Fasting glucose, HbA1c, or oral glucose
Fasting glucose, HbA1c, or oral glucose tolerance test* annually
tolerance test* at ages 10, 12, 14, and 16 IGF-1 and IGFBP-3 as clinically indicated
years (for growth delay)
IGF-1 and IGFBP-3 as clinically indicated
(for growth delay)
LH-ICMA, FSH, and estradiol as clinically
indicated (for delayed puberty in females)
Testosterone as clinically indicated (for
delayed puberty in males)
This is a general timetable for clinical and laboratory evaluations for individuals with transfusion-dependent
thalassemia (TDT). TDT includes conditions previously referred to as thalassemia major as well as some with
thalassemia intermedia; clinical judgment is used to determine the appropriate interval for all testing and the
specific testing and timetable in thalassemia intermedia phenotypes. Evaluations for delayed puberty are generally
done for girls at age 12 years and for boys at age 14 years. Refer to UpToDate for additional discussions of
thalassemia management.
HLA: human leukocyte antigen; RBC: red blood cell; TIBC: total iron binding capacity; TSAT: transferrin saturation; MRI:
magnetic resonance imaging; CBC: complete blood count; AST: aspartate aminotransferase; ALT: alanine
aminotransferase; PCR: polymerase chain reaction; PT: prothrombin time; aPTT: activated partial thromboplastin time;
TSH: thyroid-stimulating hormone; PTH: parathyroid hormone; HbA1c: glycosylated hemoglobin; IGF-1: insulin-like
growth factor-1; IGFBP-3: IGF binding protein 3; LH-ICMA: luteinizing hormone-immunochemiluminometric assay; FSH:
follicle-stimulating hormone.
* If there is a concern that hemolysis may falsely lower the HbA1c, the other methods (fasting glucose or oral glucose
tolerance test) may be preferred.
Modified with permission from: UCSF Benioff Children's Hospital Oakland, Northern California Comprehensive Thalassemia
Center. Treating Thalassemia: Checklist. Available at: http://thalassemia.com/treatment-timetable.aspx#gsc.tab=0
(Accessed on September 27, 2018). Copyright © 2017 Children's Hospital & Research Center Oakland.
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Contributor Disclosures
Edward J Benz, Jr, MD Consultant/Advisory Boards: Deciphera Pharmaceuticals; Advantagene; Knowledge
to Practice; Cure Sickle Cell Initiative, NIH, NHLBI, and Emmes Corp [Board of Directors]. Equity
Ownership/Stock Options: Deciphera; Advantagene; Knowledge to Practice. Equity Ownership/Stock Options
(Spouse): Multiple pharma company stocks held in trust [Thalassemia (Desferioxamine)]. Emanuele
Angelucci, MD Nothing to disclose Stanley L Schrier, MD Nothing to disclose Jennifer S Tirnauer,
MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
Conflict of interest policy
45 of 45 6/6/2019, 12:35 AM

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Official reprint from UpToDate®

Separate topic reviews discuss other issues in the thalassemias:

● Pathophysiology – (see "Pathophysiology of beta thalassemia" and "Molecular genetics of

● Prenatal screening – (see "Prenatal screening and testing for hemoglobinopathy")

● Hematopoietic cell transplantation – (see "Hematopoietic cell transplantation for

TERMINOLOGY AND DISEASE CLASSIFICATION

Thalassemia refers to a group of inherited hemoglobinopathies where there is a quantitative defect

● Beta thalassemia intermedia phenotypes – Individuals with thalassemia intermedia

● Anemia – We suggest folic acid supplementation if there is evidence of ongoing hemolysis

● Disease morbidity – We monitor for disease complications as appropriate to disease

Decision to initiate regular transfusions

● Thalassemia major – Individuals with thalassemia major are transfusion-dependent. For

● Thalassemia intermedia – Thalassemia intermedia phenotypes encompass a range of

As noted below, extended crossmatching to prevent alloimmunization, leukocyte depletion to

● At the same time that a chronic transfusion program is started

Reduction of alloimmunization and other complications of transfusion — Individuals

The prevalence of alloimmunization in thalassemia has been estimated to be in the range of 10 to

DECISION TO PURSUE ALLOGENEIC HCT

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for

MONITORING AND MANAGEMENT OF DISEASE COMPLICATIONS

At follow-up visits for transfusion-dependent thalassemia, once the transfusion schedule is

● Kidney – Renal function, on a regular basis (eg, with each CBC).

Management is directed at the underlying cause. Referral to a pain management consultant is

Cardiopulmonary complications — Individuals with thalassemia major or thalassemia intermedia

Additional management of chronic cardiopulmonary complications is discussed in separate topic

Endocrine complications — Thalassemia major and thalassemia intermedia confer an increased

Strategies to reduce the risk of osteoporosis include the following:

● Encouragement of moderate to high-impact physical activity

Rarely, surgical correction (eg, correction of maxillary expansion) may be needed.

Venous thromboembolism — The risk of venous thromboembolism (VTE) is increased in

Quality of life — Quality of life is an important consideration in individuals with thalassemia, as it

INVESTIGATIONAL DISEASE-MODIFYING APPROACHES

Luspatercept and sotatercept (ActRIIA ligand traps) — Luspatercept (previously called

● In an open-label dose-finding study, 64 patients with beta thalassemia (approximately half

• 81 percent of transfusion-dependent participants were able to reduce transfusions by 20

• 58 percent of non-transfusion-dependent participants had an increase in hemoglobin of

● A randomized, placebo-controlled trial in transfusion-dependent thalassemia (BELIEVE) has

Sotatercept (ActRIIA-Fc; previously called ACE-011) is another activin A sequestering compound

● Hypomethylating agents such as decitabine (5-aza-2'-deoxycytidine) may alter erythropoiesis

Other agents may act by stimulating erythropoiesis:

● The inadequate tissue oxygenation in thalassemia produces a compensatory increase in

• At a median of 26 months, 12 of 13 individuals with non-beta0/beta0 genotypes became

Combinations with hydroxyurea — Hydroxyurea alone is not particularly effective in modifying

The efficacy of hydroxyurea in reducing transfusion requirements in thalassemia was evaluated in

PRENATAL TESTING AND GENETIC COUNSELING

Pregnancy — Pregnancy is possible in individuals with thalassemia minor and thalassemia

[112-115]. As an example, a report of 129 pregnancies in 72 women with thalassemia (including

Surgery/anesthesia concerns — Surgical considerations in individuals with thalassemia include

● Preoperative hemoglobin level – We generally prefer to have a preoperative hemoglobin

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Basics topic (see "Patient education: Beta thalassemia (The Basics)")

SUMMARY AND RECOMMENDATIONS

restrictions and supplements' above.)

● Transfusion therapy is used in individuals with thalassemia to reduce symptoms and

• Thalassemia major – Individuals with thalassemia major are transfusion-dependent due

• Thalassemia intermedia phenotype – Decisions regarding transfusion in patients with

• Thalassemia minor – Chronic transfusion therapy is not required in patients with

● Patients receiving chronic transfusion therapy or periodic transfusions require regular

● Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for

2. Angelucci E, Barosi G, Camaschella C, et al. Italian Society of Hematology practice