Management of thalassemia

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 – (See "Public health issues in the thalassemic syndromes".)

●Pathophysiology – (See "Pathophysiology of thalassemia" and "Molecular genetics of the thalassemia syndromes" and "Hemoglobin variants including Hb C, Hb D, and Hb E".)

●Prenatal screening – (See "Prenatal screening and testing for hemoglobinopathy".)

●Diagnosis – (See "Diagnosis of thalassemia (adults and children)" and "Methods for hemoglobin analysis and hemoglobinopathy testing".)

●Iron chelation – (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 "Diagnosis of thalassemia (adults and children)" and "Molecular genetics of the thalassemia syndromes" and "Pathophysiology of 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.

●Transfusion-dependent beta thalassemia – Transfusion-dependent thalassemia (TDT) encompasses the previously used designations of beta thalassemia major and some beta thalassemia intermedia phenotypes. These individuals generally require chronic transfusions and are managed with a prespecified pretransfusion hemoglobin level. This helps to treat and prevent severe, symptomatic anemia and suppresses extramedullary hematopoiesis and its complications.

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 and/or benefit from luspatercept, similar to individuals with thalassemia major. (See 'Management of anemia' below and 'Pregnancy' below.)

Iron overload is inevitable; monitoring iron stores and use of iron chelation are integral components of therapy (see 'Management of anemia' below). Consideration of luspatercept, allogeneic hematopoietic stem cell transplantation (HSCT), or enrollment in a clinical trial testing other disease-modifying therapies may be appropriate for selected individuals with severe disease. (See 'Luspatercept for transfusion-dependent beta thalassemia' below and 'Decision to pursue allogeneic HSCT' below and 'Investigational approaches' below.)

●Non-transfusion-dependent beta thalassemia – Non-transfusion-dependent thalassemia phenotypes encompass the designations of beta thalassemia minor, thalassemia trait, or thalassemia minima. These individuals typically do not require any interventions for anemia or other deviations from routine medical care. However, it is important for them 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 "Pathophysiology of thalassemia", section on 'Terminology and disease classification'.)

Survival beyond the perinatal period for hydrops fetalis with hemoglobin Barts is rare. Those infants are absolutely transfusion-dependent throughout life. (See "Alpha thalassemia major: Prenatal and postnatal management".)

Individuals with hemoglobin H (Hb H) 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 "Pathophysiology of thalassemia", section on 'Terminology and disease classification'.)

In addition to the management issue noted for the beta thalassemia intermedia phenotype, it must be noted that Hb H 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 apply to all individuals, regardless of disease severity:

●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.)

●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 'Reproductive 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".)

●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 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, 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 "Diagnostic approach to anemia in adults".)

Individuals with thalassemia can develop anemia due to other causes that should be addressed and treated 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 "Diagnostic approach to anemia in adults".)

In some cases of severe disease, it may be appropriate to pursue other interventions for anemia such as splenectomy, hematopoietic stem cell transplantation (HSCT), or other therapies discussed below. (See 'Role of splenectomy' below and 'Decision to pursue allogeneic HSCT' below and 'Investigational approaches' below.)

The role of activin ligand traps such as luspatercept is evolving rapidly, as discussed below. (See 'Epigenetic and JAK2 regulators' 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, 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", 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.

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 patients have any of the following:

•Signs of cardiopulmonary compromise

•Functional deterioration

•Signs and symptoms of significant extramedullary hematopoiesis such as expanding bony masses, pathologic fractures, hypersplenism

•Growth failure

•Poor feeding

•Deterioration in quality of life

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. However, indefinite transfusions may not be necessary for individuals with thalassemia intermedia, and transfusion indications should be reassessed periodically.

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].

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 approximately 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.

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 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.)

Once an individual reaches 18 years of age, luspatercept becomes an option. (See 'Luspatercept for transfusion-dependent beta thalassemia' 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 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 (table 3). We typically use the serum ferritin level for serial 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. In beta thalassemia intermedia, serum ferritin may underestimate the total body iron. 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 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 RhD, 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: Indications and transfusion techniques", section on 'Transfusion techniques'.)

Transfusions also carry other risks such as allergic reactions, febrile nonhemolytic transfusion 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 "Immunologic transfusion reactions" and "Transfusion-related acute lung injury (TRALI)" and "Transfusion-associated circulatory overload (TACO)".)

LUSPATERCEPT FOR TRANSFUSION-DEPENDENT BETA THALASSEMIA

Luspatercept mechanism of action — Luspatercept (previously called ACE-536) belongs to a class of agents referred to as activin A traps or activin A receptor IIA (ActRIIA) ligands; these drugs sequester activin A and related members of the transforming growth factor (TGF)-beta family [38,39].

Luspatercept and related compounds improve red blood cell (RBC) maturation and reduce transfusion requirements by an incompletely understood mechanism that may involve effects on TGF-beta signaling. The effects on erythropoiesis and bone formation appear to be independent of erythropoietin, hepcidin, and growth differentiation factor 11 (GDF11) [39-41].

Sotatercept (ActRIIA-Fc; previously called ACE-011) is a related molecule developed before luspatercept that is not being pursued because it is less specific [38,39,42].

Indications for luspatercept — Chronic transfusions carry requirements for intravenous access, time spent receiving the transfusion, potential for transfusion reactions, and iron overload. For adults with transfusion-dependent beta thalassemia, luspatercept is a means of reducing these burdens. It was approved for the treatment of adults with transfusion-dependent beta-thalassemia in November 2019 [43].

Some individuals may choose to take luspatercept, and others may continue with regular transfusions while awaiting more information on long-term outcomes. Individuals who are tolerating regular transfusions and wish to continue them may reasonably do so. For those who do not have access to luspatercept, regular transfusions are the main alternative. Others may reasonably pursue potentially curative therapy with hematopoietic stem cell transplant or gene therapy. Gene therapy would typically be recommended in the context of a clinical trial. (See 'Stem cell transplant and gene therapy' below.)

We would avoid luspatercept in the following individuals:

●Children and adolescents under 18 years of age, as safety and efficacy have not been established. Off-label use might be considered in older adolescents with high transfusion burdens (16 to 18 years).

●Females who are pregnant, planning to become pregnant, or of childbearing potential not using birth control, due to concerns about potential teratogenicity.

●Splenectomized individuals. If use of luspatercept in a splenectomized individual is required, thromboembolism prophylaxis should be administered. (See 'Role of splenectomy' below.)

Dosing (luspatercept) — Women of childbearing potential should have a documented negative pregnancy test before starting luspatercept. Thromboembolic risk factors should be assessed, especially in individuals who have undergone splenectomy; luspatercept is generally avoided in splenectomized individuals but may be considered in selected cases. (See 'Indications for luspatercept' above and 'Evidence for efficacy and adverse effects (luspatercept)' below.)

Luspatercept dosing is initiated at 1 mg/kg subcutaneously once every three weeks [43]. The dose may be increased to 1.25 mg/kg daily if the transfusion requirement does not decline by at least one-third and by at least two units of packed RBCs. In some cases, the dose is increased if the transfusion requirement does not decline by at least one-half over six weeks (after two consecutive doses).

Transfusions and iron chelation are continued as needed during initial therapy and could be gradually reduced as transfusion requirement declines, provided that neutral or negative iron balance is maintained.

Monitoring during therapy includes regular complete blood counts (CBC) and other ongoing monitoring (eg, iron status).

Luspatercept is discontinued if the individual does not have a reduction in transfusion requirement despite maximum dosing after nine weeks, if toxicities are unacceptable, or if extramedullary masses develop.

Evidence for efficacy and adverse effects (luspatercept) — The primary evidence for the efficacy of luspatercept comes from the BELIEVE trial, published in early 2020 [44]. BELIEVE randomly assigned 336 adults with transfusion-dependent beta thalassemia to receive luspatercept or placebo in a 2:1 ratio for at least 48 weeks (median duration of treatment, 64 weeks). The median age of participants was 30 years, and slightly under 60 percent had undergone splenectomy. Compared with placebo, luspatercept significantly reduced transfusion requirements. As examples:

●Reduction in transfusions by one-half during any 12-week period – 40 versus 6 percent

●Reduction in transfusions by one-third and by at least 2 units during any 12-week period – 71 versus 30 percent

●Complete transfusion independence in any 8-week period – 11 versus 2 percent

Pretransfusion hemoglobin levels were not altered (ie, the benefit was not due to revised transfusion thresholds), and these benefits generally persisted across prespecified subgroup analyses related to patient age, prior splenectomy, baseline transfusion requirements, baseline hemoglobin level, and genotype. Median time to response was 12 to 24 days, and percentage with response was lower when calculated over any 24-week period. Subgroup analyses also suggested that the magnitude of response to luspatercept may be lower in patients with a beta⁰/beta⁰ genotype compared with those with a non-beta⁰/beta⁰ genotype.

Ferritin was slightly lower in the luspatercept group (decreased by 248 ng/mL, versus increase by 107 ng/mL with placebo), but liver iron concentration and cardiac MRI were unchanged. It is difficult to determine how much the reduction in ferritin was due to reduced transfusions and how much was due to improved erythropoiesis. Longer follow-up is necessary to determine the impact of luspatercept on iron overload and iron chelation.

Thromboembolic complications were more common in the luspatercept group (8 people [4 percent, including three ischemic strokes, three deep vein thromboses, two superficial thromboses, one portal vein thrombosis, and one pulmonary embolism; none were fatal]) versus 1 in the placebo group (1 percent; with phlebitis). All thromboembolic complications occurred in individuals who had undergone splenectomy and had at least one other risk factor such as a history of venous thrombosis or thrombocytosis at baseline. These findings emphasize the need for thorough evaluation of splenectomized patients for thromboembolic risk factors before considering luspatercept therapy, as well as the need to use anticoagulant prophylaxis if luspatercept is absolutely required due to transfusion or iron overload status.

Other adverse effects that were more common with luspatercept included bone pain or arthralgias (approximately 20 percent with luspatercept versus 8 percent with placebo), dizziness, hypertension, and hyperuricemia. Bone pain was manageable and declined over time. A total of 12 people in the luspatercept group discontinued therapy due to adverse events, versus one in the placebo group.

These results are consistent with preclinical data and an earlier open-label study in individuals with beta thalassemia, who had significant improvement in hemoglobin level [45,46]. Luspatercept also has the potential to decrease transfusion reactions and iron input [47].

Longer-term follow up of patients receiving luspatercept for beta thalassemia documented development of extramedullary hematopoietic masses in approximately 3 percent of individuals. In some cases, these masses have caused serious complications such as spinal cord compression [48]. Revised labeling for luspatercept states that patients should be monitored for extramedullary masses, and luspatercept should be discontinued if masses cause serious complications or cannot be controlled [49].

While luspatercept appears to be effective and was generally well-tolerated for an extended period in these studies, further observation will be needed to establish the very long-term efficacy and safety of luspatercept (or other ActRIIA ligand traps) in patients with lifelong anemias.

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

Luspatercept is generally avoided in individuals who have undergone splenectomy. If luspatercept is required in a splenectomized individual, thromboembolism prophylaxis should be used. (See 'Indications for luspatercept' above and 'Venous thromboembolism' below.)

Splenectomy may improve anemia and reduce transfusion requirements in some individuals, 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 [4,50,51]. 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. (See "Elective (diagnostic or therapeutic) splenectomy", section on 'Indications'.)

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 increased risks of thromboembolism, life-threatening infection, and pulmonary hypertension. 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 [52]. Case reports have described portal vein thrombosis after laparoscopic splenectomy in thalassemia [53,54]. 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" and "Elective (diagnostic or therapeutic) splenectomy", section on 'Indications'.)

STEM CELL TRANSPLANT AND GENE THERAPY

Decision to pursue allogeneic HSCT — Allogeneic hematopoietic stem cell transplantation (HSCT) 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 HSCT are both major barriers that eliminate the HSCT option for many individuals. A role for HSCT in alpha thalassemia (eg, hemoglobin H disease) has not been established but may be pursued for severe disease (hemoglobin Barts). (See "Alpha thalassemia major: Prenatal and postnatal management", section on 'Stem cell transplant'.)

Despite these barriers, HSCT 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 HSCT 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 HSCT are lowest if the HSCT 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. Individuals with hypersplenism usually undergo splenectomy before HSCT. 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 HSCT.

As investigational methods for performing HSCT 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 [55]. 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 HSCT in thalassemia; modifications such as the use of haploidentical transplant, matched unrelated donor transplant, and nonmyeloablative conditioning regimens; and potential complications and post-HSCT care, are presented separately. (See "Hematopoietic cell transplantation for transfusion-dependent thalassemia" and "Thalassemia: Management after hematopoietic cell transplantation".)

Gene therapy and other stem cell modifications — Autologous hematopoietic stem cell transplant using modified autologous hematopoietic stem cells (HSCs) to produce unaffected (or less-severely affected) RBCs is an alternative to allogeneic transplant.

●Gene therapy to introduce a functional beta globin gene – One approach for beta thalassemia uses viral transduction of a normally functioning beta globin gene into autologous HSCs that are then infused as an autologous HSCT [56]. Injection of the HSCs directly into bone but with a different cellular product has also been explored, as described in the clinical studies below [57].

In 2019, the European Medicines Agency (EMA) approved the gene therapy construct betibeglogene autotemcel (zynteglo), a lentiviral product containing approximately 24 to 400 million autologous CD34⁺ cells transduced with a beta globin variant (T87Q), for individuals 12 years and older who have transfusion-dependent beta thalassemia with a non-beta⁰/beta⁰ genotype (ie, they must have at least one beta⁺ variant). Myeloablative conditioning is required. Because of disagreements about cost coverage, this modality is not currently available in Europe despite regulatory approval.

In 2022, zynteglo was approved by the US Food and Drug Administration (FDA) for children and adults with transfusion-dependent beta thalassemia [58].

In early 2021, trials with lentiviral vectors and use of the EMA-approved product were suspended after three individuals with sickle cell disease who were participating in gene therapy trials developed myeloid malignancies (one of these was subsequently determined not to be due to malignancy) [59]. The National Heart, Lung, and Blood Institute (NHLBI) paused a clinical study of a different but related lentiviral vector gene therapy program in SCD "out of an abundance of caution" [60]. Subsequently, investigation of these cases determined that the gene therapy construct was very unlikely to cause AML/MDS, and the trials were resumed. An individual receiving a lentiviral vector gene therapy for adrenoleukodystrophy also developed MDS. Details are presented separately (See "Investigational therapies for sickle cell disease", section on 'Concern about myeloid malignancy in gene therapy studies' and "X-linked adrenoleukodystrophy and adrenomyeloneuropathy", section on 'Autologous HCT with ex vivo gene therapy'.)

Myeloid malignancies have not been reported in individuals with thalassemia who are receiving these therapies, but further study is needed to determine the mechanisms of carcinogenesis and how to address them. Contributing mechanisms may include the underlying disease, other medications, changes related to stem cell collection, the conditioning regimen, the viral vector, or others. One case of MDS was reported not to be due to the viral vector [61]; in one case the lentiviral vector was present inside leukemic cells.

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.

•Betibeglogene autotemcel – Betibeglogene autotemcel (beti-cel, zynteglo) consists of autologous hematopoietic stem and progenitor cells transduced with the BB305 vector. BB305 is a lentiviral vector containing the T87Q variant of the beta globin gene. T87Q is an antisickling variant similar to gamma globin; the distinct sequence that differs from wild-type beta globin allows quantification of the expression level of the variant hemoglobin (Hb A^T87Q) from the transgene. This test is not commercially available and must be performed in a specialized laboratory.

A pair of studies from 2018 described the use of this therapy in 22 patients with transfusion-dependent beta thalassemia [62]. Clinical benefits were impressive, especially in patients with some production of hemoglobin A at baseline (non-beta^0/beta⁰ genotypes). In the most severe patients, the results were positive but not curative, indicating the high quantitative bar that must be cleared to achieve cure:

-At a median of 26 months, 12 of 13 individuals with non-beta^0/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 beta^0/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 therapy construct.

A subsequent study from 2021 focused exclusively on patients with non-beta^0/beta⁰ genotypes [63]. Individuals with severe iron overload were excluded. At a median of 29.5 months follow-up (range, 13.0 to 48.2), 20 of 22 evaluable patients (91 percent) were transfusion-independent, including 6 of 7 children <12 years of age. The mean hemoglobin was 11.7 g/dL (range, 9.5 to 12.8 g/dL), mostly consisting of Hb A^T87Q (median, 8.7 g/dL; range, 5.2 to 10.6 g/dL). Iron reduction therapy was initiated in most of the participants (chelation in 11 and phlebotomy in seven). Adverse events were typical of busulfan myeloablation; there were no malignancies and no deaths.

•GLOBE vector with mini beta globin – A study from 2019 described the use of gene therapy in nine individuals with transfusion-dependent beta thalassemia (six children and three adults) [57]. HSCT 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 region [64].

The rationale for intra-bone injection was based on the experience with umbilical cord blood transplantation in malignancies, to overcome the lower number of HSCs in cord blood [65]. Direct injection into bone favors homing of HSCs to bone marrow spaces and avoids the trapping of HSCs in filter organs. With a median follow up of 18 months, all participants had reduced transfusion requirements, but only 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 BB305 vector has been modified to be replication incompetent and self-inactivating [63]. 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 [56,64,66-81].

●Gene editing to disrupt BCL11A – Gene editing involves use of molecular techniques to make permanent genetic changes in a cell's endogenous DNA. HSCs can be modified ex vivo and returned to an individual following hematopoietic stem cell transplant with myeloablative conditioning. In theory, it might be possible to inject the HSC gene editing vector directly, if it could be targeted exclusively to HSCs, but this has not been tested clinically. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Gene editing'.)

Gene editing to disrupt the BCL11A gene is under investigation as a means of increasing fetal hemoglobin (Hb F) to treat beta thalassemia. BCL11A encodes a transcriptional repressor that promotes globin gene switching from gamma globin to beta globin in early infancy, resulting in a decrease in Hb F and an increase in adult hemoglobin (Hb A). Disruption of BCL11A as a means of reactivating Hb F expression is an attractive approach to therapy [82-84]. This is based on the proven clinical benefit by increased levels of Hb F in patients with thalassemia and sickle cell disease patients.

Preliminary clinical studies of gene editing of the BCL11A system have described remarkable improvements in small numbers of patients with transfusion-dependent beta thalassemia who received autologous HSCs that had been edited to disrupt BCL11A [85].

In contrast to lentiviral gene therapy, which integrates at multiple random locations in each genome and has a potential risk of insertional mutagenesis, gene editing is a non-viral system and does not use a lentiviral vector. Gene editing uses a transient precise CRISPR/Cas9 editing system with a specific guide RNA. Gene editing trials have not been put on hold after the reported cases of myeloid malignancies after gene therapy in SCD mentioned above.

Use of gene editing to disrupt aberrant splice sites and restore normal beta globin expression is also under investigation [86].

●Alpha thalassemia – No effective means of gene therapy are in advanced stages of development for alpha thalassemia.

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 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, some patients eventually develop 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 [87]. 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 'Cardiac complications' below.)

●Pulmonary status – In individuals with chronic hemolysis and/or iron overload, echocardiography should be considered to evaluate pulmonary arterial hypertension and to assess cardiac status. (See 'Pulmonary hypertension' 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.)

●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 'Reproductive 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 "Diagnosis of thalassemia (adults and children)", section on 'Clinical manifestations'.)

Management is directed at the underlying cause. Referral to a pain management consultant is appropriate. (See "Pain in children: Approach to pain assessment and overview of management principles" and "Approach to the management of chronic non-cancer pain in adults".)

Cardiac 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. These may be due to combinations of hypoxemia, anemia, diabetic vascular disease, and iron overload. (See "Diagnosis of thalassemia (adults and children)", section on 'Heart failure and arrhythmias' and 'Pulmonary hypertension' below.)

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 kidney, liver, and thyroid function; searching for other precipitating factors such as infection; and initiation of chelation therapy (if indicated) [88]. Early involvement of specialist consultants is advised. (See "Treatment of acute decompensated heart failure: Specific therapies" and "Iron chelators: Choice of agent, dosing, and adverse effects".)

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 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 [88]. 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 [89]. 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 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 [88,90].

Additional management of chronic cardiac complications is discussed in separate topic reviews. (See "Determining the etiology and severity of heart failure or cardiomyopathy" and "Treatment and prognosis of heart failure with preserved ejection fraction" and "Overview of the management of heart failure with reduced ejection fraction in adults".)

Pulmonary hypertension — The risk of pulmonary arterial hypertension (PAH) may be increased in individuals with thalassemia due to chronic hemolysis, iron overload, and other manifestations. (See "Diagnosis of thalassemia (adults and children)", section on 'Pulmonary abnormalities and PH'.)

A 2022 study evaluated long-term outcomes in 24 patients with beta thalassemia who had documented PAH by right heart catheterization in the absence of chronic cardiopulmonary disease [91]. At a median age of 46.5 years and a median follow up of four years, 13 of the patients had died (all-cause mortality rate, 54 percent; 95% CI 33-75 percent). Ten of the deaths were attributed to PAH (9 right sided heart failure, 1 pulmonary embolism; PAH-related mortality rate, 42 percent; 95% CI 22-63 percent). Cumulative PAH-related mortality-free survival estimates at 1, 2, and 5 years were 78, 65, and 60 percent. Survival strongly correlated with PAH therapy.

An editorialist noted that many patients with thalassemia and PAH are undertreated and emphasized the need for routine monitoring and multidisciplinary treatment, including risk factor modification (treatment of iron overload, hypercoagulability, sleep apnea, and lung disease) and interventions for those with tricuspid jet velocity ≥3 m/sec [92]. Thalassemia-specific interventions including initiation or optimization of a chronic transfusion therapy regimen are warranted (see 'Regular transfusions' above). Use of phosphodiesterase type 5 inhibitors (eg, sildenafil) and the endothelin receptor antagonist bosentan have been reported [93-97].

Management should be directed by a clinician with expertise in treating PAH. Details are presented separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Liver disease — Iron overload can lead to impaired liver function and eventually cirrhosis if not 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 "Diagnosis of thalassemia (adults and children)", 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 hyperglycemia 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 [98]. (See "Diagnosis of thalassemia (adults and children)", 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:

●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 [98-101]. 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 [102].

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) [103-107].

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 "Diagnosis of thalassemia (adults and children)" and 'Role of splenectomy' above.)

For individuals who have undergone splenectomy and require luspatercept, we provide thromboembolism prophylaxis.

There are no randomized trials evaluating the benefit of prophylactic anticoagulation or antiplatelet therapy in individuals with thalassemia, 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 [108-111]. 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 [112].

INVESTIGATIONAL 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 HSCT and/or possibly gene therapy. Approaches that restore or improve production of healthy red blood cells (RBCs) in the bone marrow continue to be sought.

Mitapivat — Mitapivat is a small molecule allosteric activator of the RBC enzyme pyruvate kinase (PK). It was originally developed as a treatment for PK deficiency but has subsequently been shown to improve anemia in other hemolytic disorders, possibly by increasing ATP production [113]. (See "Pyruvate kinase deficiency", section on 'Mitapivat for symptomatic anemia'.)

In a study involving 20 adults with non-transfusion-dependent thalassemia and baseline hemoglobin ≤10 g/dL who were treated with mitapivat for 24 weeks, 16 (80 percent) had a hemoglobin response, defined as an increase from baseline of ≥1 g/dL [114]. This included 5 of 5 individuals with alpha thalassemia and 11 of 15 with beta thalassemia. The mean hemoglobin increase was 1.3 g/dL and the mean time to increase was 4.5 weeks; this was preceded by improvement in markers of hemolysis. Therapy was well-tolerated, with no serious adverse effects attributed to the drug. Future studies will address optimal dosing and predictors of response.

Epigenetic and JAK2 regulators — 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"):

●HDAC inhibitors – HDAC inhibitors such as butyrates (eg, arginine butyrate, sodium phenylbutyrate) activate gamma globin gene expression and could potentially raise Hb F levels and reduce anemia [115-119]. 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 Hb F 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 [120-122]. The use of HDAC inhibitors in combination with hydroxyurea has also been explored.

●Hypomethylating agents – 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 (Hb F) levels, and improve the hemoglobin level in beta thalassemia [118,123].

Other agents may act by stimulating erythropoiesis:

●JAK2 inhibitors – The inadequate tissue oxygenation in thalassemia produces a compensatory increase in erythropoietin, which accelerates erythropoiesis and may contribute to ineffective erythropoiesis (see "Pathophysiology of thalassemia", section on 'Ineffective erythropoiesis').

Upregulation of the kinase JAK2 may contribute to ineffective erythropoiesis, leading to the hypothesis that available JAK2 inhibitors could be used to reduce transfusion requirements or decrease spleen size. 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 [124]. Ruxolitinib reduced median spleen size by approximately 25 percent. Another series of four individuals treated with ruxolitinib showed reduction of spleen size, increased appetite, and improved quality of life in all four; transfusion requirement was reduced in one [125]. 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.

●Stem cell factor – Factors that act on hematopoietic stem cells such as stem cell factor (also called 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 Hb F levels [126].

●Hepcidin – Drugs that target hepcidin and other modulators of iron regulation are in early stages of investigation. (See "Regulation of iron balance".)

The ultimate benefit of these therapies may result from a combination of effects, including increased production of Hb F and decreased apoptosis. Other potential regulators of Hb F 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".)

It is important to point out that the therapies that increase gamma globin production (and Hb F levels) have no role in treating alpha thalassemia. Gamma globin is a beta-like chain; therapies for alpha thalassemia would have to induce production of more alpha or alpha-like chains.

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 (Hb F), 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 [127]. 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 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 [128].

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 Hb F-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 Hb F. (See "Pathophysiology of thalassemia".)

REPRODUCTIVE 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.

It is important for patients and clinicians to be aware that two parents with thalassemia trait can conceive a child with transfusion-dependent thalassemia [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 genetic (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 [129-132]. 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 [132]. 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 [133]. 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 [133]. 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 "Diagnosis of thalassemia (adults and children)", 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 "Diagnosis of thalassemia (adults and children)", section on 'Skeletal changes'.)

●Venous thromboembolism (VTE) prophylaxis – As noted above, we use the same guidelines for VTE prophylaxis as we use in individuals without thalassemia, although individuals who have undergone splenectomy are considered at increased risk for VTE. For splenectomized individuals who require luspatercept, we provide VTE prophylaxis. (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 adults undergoing hip fracture repair or hip or knee replacement".)

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.

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 [90,134]. 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 stem cell transplantation (HSCT), begun in the 1980s, is potentially curative, although many individuals will not have access to HSCT 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 [135].

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: Sickle cell disease and thalassemias".)

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 5^th to 6^th 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 10^th to 12^th 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

●Anemia – The main treatments for anemia are transfusions and luspatercept (algorithm 1). Transfusion therapy reduces symptoms and morbidities associated with anemia and ineffective erythropoiesis; ineffective erythropoiesis can impair growth and development and cause skeletal abnormalities, splenomegaly, and iron overload. Luspatercept can reduce transfusion requirements in adults with transfusion-dependent beta thalassemia.

For all individuals with hemolytic anemia, we also suggest folic acid (Grade 2C). It is reasonable to omit folic acid if especially burdensome or no clinical evidence of folate deficiency. (See 'Management of anemia' above.)

•Transfusion-dependent – For individuals with transfusion-dependent thalassemia (TDT, previously called thalassemia major phenotype), we suggest chronic transfusion to reduce symptoms of anemia and suppress extramedullary hematopoiesis (Grade 2C). (See "Diagnosis of thalassemia (adults and children)", section on 'Overview of subtypes and disease severity' and 'Regular transfusions' above.)

We generally suggest a pretransfusion hemoglobin of 9.5 to 10.5 g/dL rather than a higher or lower nadir (Grade 2C). Clinical experience and observational studies demonstrate reduced extramedullary hematopoiesis with this hemoglobin. Different hemoglobin nadirs may be appropriate in individuals with certain comorbidities or without clinically significant ineffective erythropoiesis. (See 'Decision to initiate regular transfusions' above and 'Typical chronic transfusion regimen' above.)

Some individuals may choose to take luspatercept, and others may continue with regular transfusions while awaiting more information on long-term outcomes. (See 'Luspatercept for transfusion-dependent beta thalassemia' above.)

•Non-transfusion-dependent – For non-transfusion-dependent thalassemia (NTDT, previously called thalassemia intermedia phenotype), management is individualized. Most patients need only periodic transfusions for symptomatic relief or during periods of stress (rapid growth, infection-associated bone marrow suppression, surgery, pregnancy). Some patients may become require regular transfusions (see 'Decision to initiate regular transfusions' above). The role of erythropoiesis-modifying agents is unknown.

•Thalassemia minor – Chronic transfusions are not required when anemia is very mild or absent.

●Excess iron stores – Patients receiving transfusions require regular assessment and treatment of excess iron stores. (See 'Assessment of iron stores and initiation of chelation therapy' above and "Iron chelators: Choice of agent, dosing, and adverse effects".)

●Splenectomy – Splenectomy is an option for severe anemia, hypersplenism, or other splenic complications; however, we try to avoid splenectomy if possible. The benefit may be transient and risks of thromboembolism and life-threatening infection are increased, especially thromboembolism risk in patients receiving luspatercept. When pursued, splenectomy is generally deferred until age four years. Pre-splenectomy vaccines, prophylactic antibiotics, and thromboembolism prophylaxis are required. (See 'Role of splenectomy' above.)

●Transplant – Allogeneic hematopoietic stem cell transplantation is potentially curative and may be appropriate for severe TDT (algorithm 1). The decision to pursue transplant is highly complex and should be made in consultation with a thalassemia specialist and an experienced high-volume transplant center. (See 'Decision to pursue allogeneic HSCT' above.)

●Monitoring – Individuals with TDT are typically cared for by a specialist at least two to four times a year for monitoring, including close attention to iron stores and other disease manifestations (table 3). (See 'Monitoring and management of disease complications' above.)

●Investigational approaches – Several drug therapies and gene therapy are under investigation. (See 'Investigational approaches' above and 'Gene therapy and other stem cell modifications' above.)

●Reproductive counseling – Genetic testing and reproductive counseling is routine for all individuals with thalassemia. (See 'Reproductive testing and genetic counseling' above and "Prenatal screening and testing for hemoglobinopathy".)

●Prognosis – Survival continues to improve into the fourth, fifth, and sixth decades of life. Cardiovascular complications are the major cause of death in TDT. (See 'Prognosis' above.)

ACKNOWLEDGMENT — We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.