Beta-Thalassemia

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Summary

Clinical characteristics.

Beta-thalassemia (β-thalassemia) is characterized by reduced synthesis of the hemoglobin subunit beta (hemoglobin beta chain) that results in microcytic hypochromic anemia, an abnormal peripheral blood smear with nucleated red blood cells, and reduced amounts of hemoglobin A (HbA) on hemoglobin analysis.

Individuals with thalassemia major have severe anemia and hepatosplenomegaly; they usually come to medical attention within the first two years of life. Without treatment, affected children have severe failure to thrive and shortened life expectancy. Treatment with a regular transfusion program and chelation therapy, aimed at reducing transfusion iron overload, allows for normal growth and development and may improve the overall prognosis.

Individuals with thalassemia intermedia present later and have milder anemia that does not require regular treatment with blood transfusion. These individuals are at risk for iron overload secondary to increased intestinal absorption of iron as a result of ineffective erythropoiesis.

Diagnosis/testing.

The diagnosis of β-thalassemia relies on measuring red blood cell indices that reveal microcytic hypochromic anemia, nucleated red blood cells on peripheral blood smear, hemoglobin analysis that reveals decreased amounts of HbA and increased amounts of hemoglobin F (HbF) after age 12 months, and the clinical severity of anemia. Identification of biallelic pathogenic variants in HBB (the gene encoding the hemoglobin subunit beta) on molecular genetic testing may be useful for diagnosis in at-risk individuals under age 12 months who have a positive or suggestive newborn screening result and/or unexplained microcytic hypochromic anemia with anisopoikilocytosis and nucleated red blood cells on peripheral blood smear.

Management.

Treatment of manifestations:

  • Thalassemia major. Regular transfusions correct the anemia, suppress erythropoiesis, and inhibit increased gastrointestinal absorption of iron. Bone marrow transplantation (BMT) from an HLA-identical sib represents an alternative to traditional transfusion and chelation therapy. Cord blood transplantation from a related donor offers a good probability of a successful cure and is associated with a low risk for graft-vs-host disease.
  • Thalassemia intermedia. Symptomatic therapy based on splenectomy in most affected individuals, sporadic red cell transfusions in some, folic acid supplementation, and iron chelation.

Prevention of secondary complications: Assessment of iron overload through one or more of the following: serum ferritin concentration, liver biopsy, magnetic biosusceptometry, and MRI techniques; prevention of transfusional iron overload with adequate iron chelation therapy (i.e., desferroxamine B, deferiprone, deferasirox); assessment of myocardial siderosis by MRI and monitoring of cardiac function; treatment of osteoporosis, including consideration of bisphosphonate therapy.

Surveillance: Thalassemia major: monitoring of the effectiveness/side effects of transfusion therapy and chelation therapy in affected individuals of all ages by monthly physical examination; trimonthly assessment of liver function tests, determination of serum ferritin concentration, and evaluation of growth and development (during childhood); annual evaluation of eyes, hearing, heart, endocrine function (thyroid, endocrine pancreas, parathyroid, adrenal, pituitary), liver (ultrasound examination), and myocardial and liver MRI. In adults: bone densitometry to assess for osteoporosis; serum alpha-fetoprotein concentration for early detection of hepatocarcinoma in those with hepatitis C and iron overload; regular gallbladder echography for early detection of cholelithiasis for those at risk.

Agents/circumstances to avoid: Alcohol consumption, iron-containing preparations.

Evaluation of relatives at risk: If the pathogenic variants have been identified in an affected family member, molecular genetic testing of at-risk sibs should be offered to allow for early diagnosis and appropriate treatment. Hematologic testing can be used if the pathogenic variants in the family are not known.

Pregnancy management: Women with thalassemia intermedia who have never received a blood transfusion or who received a minimal quantity of blood are at risk for severe alloimmune anemia if blood transfusions are required during pregnancy.

Genetic counseling.

The β-thalassemias are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (i.e., carriers) may be slightly anemic but are clinically asymptomatic. Carriers are often referred to as having thalassemia minor (or β-thalassemia minor). Carrier testing for individuals at risk (including family members, gamete donors, and members of at-risk ethnic groups) is possible. Once both HBB pathogenic variants have been identified in a couple at risk, prenatal testing and preimplantation genetic testing are possible.

Diagnosis

Suggestive Findings

Beta-thalassemia (β-thalassemia) major should be suspected in an infant or child younger than age two years with the following clinical or newborn screening findings:

  • Clinical findings
    • Severe microcytic anemia
    • Mild jaundice
    • Hepatosplenomegaly
    Note: If untreated, affected children usually manifest failure to thrive and expansion of the bone marrow to compensate for ineffective erythropoiesis.
  • Newborn screening findings. A positive or suggestive screen done through newborn screening (i.e., through capillary electrophoresis, isoelectric focusing, or high-performance liquid chromatography on newborn blood spots)

Thalassemia intermedia should be suspected in individuals who present at a later age with similar but milder clinical findings. Individuals with thalassemia intermedia do not require regular treatment with blood transfusion.

Thalassemia minor is usually clinically asymptomatic, but sometimes a mild anemia is present.

Establishing the Diagnosis

The diagnosis of β-thalassemia is established in a proband older than age 12 months based on the hematologic findings of microcytic hypochromic anemia (Table 1), anisopoikilocytosis with nucleated red blood cells on peripheral blood smear, and hemoglobin analysis that reveals decreased amounts or complete absence of hemoglobin A and increased amounts of hemoglobin F (Table 2).

The diagnosis of β-thalassemia is established in a proband younger than age 12 months based on the following findings:

  • Positive or suggestive newborn screening result
    • The diagnosis of β0-thalassemia (in which no beta-globin protein is produced) can be made at birth by detecting a complete absence of hemoglobin A.
    • Definitive diagnosis of β+-thalassemia (in which beta-globin protein is produced but at a reduced level) by these techniques is not possible in the newborn period because the diminished amount of hemoglobin A overlaps the range for normal babies.
  • Microcytic hypochromic anemia with anisopoikilocytosis and nucleated red blood cells on peripheral blood smear
  • Biallelic pathogenic variants in HBB identified on molecular genetic testing (see Table 3)

Hematologic Findings

Red blood cell indices show microcytic anemia (Table 1).

Table 1.

Red Blood Cell Indices in Beta-Thalassemia

Red Blood Cell IndexNormal 1AffectedCarrier 1
MaleFemaleβ-Thal Majorβ-Thal Minor
Mean corpuscular volume (MCV fl)89.1±5.0187.6±5.550-70<79
Mean corpuscular hemoglobin (MCH pg)30.9±1.930.2±2.112-20<27
Hemoglobin (Hb g/dL)15.9±1.014.0±0.9<7Males: 11.5-15.3
Females: 9.1-14
1.

Data from Galanello et al [1979]

Peripheral blood smear

  • Affected individuals demonstrate the red blood cell (RBC) morphologic changes of microcytosis, hypochromia, anisocytosis, poikilocytosis (spiculated tear-drop and elongated cells), and nucleated red blood cells (i.e., erythroblasts). The number of erythroblasts is related to the degree of anemia and is markedly increased following splenectomy.
  • Carriers demonstrate reduced mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) (Table 1), and RBC morphologic changes that are less severe than in affected individuals. Erythroblasts are normally not seen.

Qualitative and quantitative hemoglobin analysis (by cellulose acetate electrophoresis and DE-52 microchromatography or HPLC) identifies the amount and type of hemoglobin present. The following hemoglobin (Hb) types are most relevant to β-thalassemia:

  • Hemoglobin A (HbA): two globin alpha chains and two globin beta chains (α2β2)
  • Hemoglobin F (HbF): two globin alpha chains and two globin gamma chains (α2γ2)
  • Hemoglobin A2 (HbA2): two globin alpha chains and two globin delta chains (α2δ2)

The hemoglobin pattern in β-thalassemia varies by β-thalassemia type (Table 2).

Table 2.

Hemoglobin Patterns in Beta-Thalassemia (Age >12 Months)

Hemoglobin TypeNormal 1AffectedCarrier
βº-Thal Homozygotes 2β+-Thal Homozygotes or β+/βº Compound Heterozygotes 3β-Thal Minor
HbA96%-98%010%-30%92%-95%
HbF<1%95%-98%70%-90%0.5%-4%
HbA22%-3%2%-5%2%-5%>3.5%
1.

Data from Telen & Kaufman [1999]

2.

βº-thalassemia: complete absence of globin beta chain production

3.

β+-thalassemia: variable degree of reduction of globin beta chain synthesis

Hemoglobin electrophoresis and HPLC also detect other hemoglobinopathies (S, C, E, OArab, Lepore) that may interact with β-thalassemia.

Click here (pdf) for information on the results of in vitro synthesis of radioactive labeled globin chains in affected individuals.

Molecular Genetic Testing

The recommended molecular genetic testing approach for beta-thalassemia is single-gene testing:

  • Sequence analysis of HBB is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
    Note: Analysis of HBB is complicated by the presence of highly homologous gene family members as well as a pseudogene, HBBP1; therefore, any assay that examines HBB sequence must be validated to ensure specificity to the active gene (see Molecular Genetics).
  • In at-risk populations (see Table 4), targeted analysis for pathogenic variants can be performed first based on ancestry since the prevalent pathogenic variants are limited in each at-risk population.

Table 3.

Molecular Genetic Testing Used in Beta-Thalassemia

Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
HBBSequence analysis 3Almost 100%
Gene-targeted deletion/duplication analysis 4Rare 5
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.

Harteveld et al [2005], Shooter et al [2015], Reading et al [2016]

Clinical Characteristics

Clinical Description

Beta-thalassemia (β-thalassemia) is characterized by reduced synthesis of the hemoglobin subunit beta (hemoglobin beta chain) that results in microcytic hypochromic anemia, an abnormal peripheral blood smear with nucleated red blood cells, and reduced amounts of hemoglobin A (HbA) on hemoglobin analysis.

The phenotypes of the homozygous β-thalassemias include thalassemia major and thalassemia intermedia. The clinical severity of the β-thalassemia syndromes depends on the extent of alpha globin chain / non-alpha globin chain (i.e., β+ γ) imbalance. The non-assembled alpha globin chains that result from unbalanced alpha globin chain / non-alpha globin chain synthesis precipitate in the form of inclusions. These alpha globin chain inclusions damage the erythroid precursors in the bone marrow and in the spleen, causing ineffective erythropoiesis. The bone marrow is extremely cellular, mainly as a result of marked erythroid hyperplasia, with a myeloid/erythroid ratio reversed from the normal (3 or 4) to 0.1 or less. However, bone marrow examination is usually not necessary for diagnosis of affected individuals.

Individuals with thalassemia major usually come to medical attention within the first two years of life; they subsequently require regular red blood cell transfusions to survive. Those who present later and do not regularly require transfusion are said to have thalassemia intermedia.

β-Thalassemia Major

Presentation. Clinical presentation of thalassemia major occurs between ages six and 24 months.

  • Affected infants fail to thrive and become progressively paler.
  • Feeding problems, diarrhea, irritability, recurrent bouts of fever, and progressive enlargement of the abdomen caused by splenomegaly may occur.
  • If the diagnosis of thalassemia major is established at this stage and if a regular transfusion program that maintains a minimum Hb concentration of 95 to 105 g/L is initiated, growth and development are normal at least until age ten to 11 years.

Complications. After age ten to 11 years, affected individuals are at risk of developing severe complications related to iron overload, depending on their compliance with chelation therapy (see Management). In individuals who have been regularly transfused, iron overload results mainly from transfusions.

Complications of iron overload include the following:

  • In children, growth restriction and failure of sexual maturation
  • In adults, involvement of the heart (dilated cardiomyopathy), liver (fibrosis and cirrhosis), and endocrine glands (resulting in diabetes mellitus and insufficiency of the parathyroid, thyroid, pituitary, and, less commonly, adrenal glands)

Other complications:

  • Hypersplenism
  • Chronic hepatitis (resulting from infection with the viruses that cause hepatitis B and/or hepatitis C)
  • Cirrhosis (from iron overload and chronic hepatitis)
  • HIV infection
  • Venous thrombosis
  • Osteoporosis

The risk for hepatocellular carcinoma is increased secondary to liver viral infection, iron overload, and longer survival [Borgna-Pignatti et al 2014, Moukhadder et al 2017].

Prognosis. The prognosis for individuals with β-thalassemia major has dramatically improved over the last decades with the advent of noninvasive methods to measure organ iron before the appearance of clinical symptoms, new chelators, and increased blood safety measures.

After 2000, all of these developments have led to a significant trend in decreasing cardiac mortality, previously reported to cause 71% of the deaths in individuals with β-thalassemia major [Borgna-Pignatti et al 2004, Telfer et al 2006, Modell et al 2008]. Recent studies show that despite geographic differences, most individuals with transfusion-dependent thalassemia have normal cardiac iron, but a significant proportion have simultaneous liver iron overload [Aydinok et al 2015b].

Without treatment. The classic clinical picture of thalassemia major is presently only seen in some developing countries, in which the resources for carrying out long-term transfusion programs are not available. The most relevant features of untreated or poorly transfused individuals:

  • Growth restriction
  • Pallor
  • Jaundice
  • Brown pigmentation of the skin
  • Poor musculature
  • Genu valgum
  • Hepatosplenomegaly
  • Leg ulcers
  • Development of masses from extramedullary hematopoiesis
  • Skeletal changes that result from expansion of the bone marrow, including:
    • Deformities of the long bones of the legs
    • Typical craniofacial changes (frontal bossing, malar prominence, depressed nasal bridge, tendency toward upslanted palpebral fissures, and hypertrophy of the maxillae, which tends to expose the upper teeth)
    • Osteoporosis

Individuals who have not been regularly transfused usually die in the first two decades. Individuals who have been poorly transfused are also at risk for complications of iron overload.

β-Thalassemia Intermedia

Clinical features are pallor, jaundice, cholelithiasis, liver and spleen enlargement, moderate to severe skeletal changes, leg ulcers, extramedullary masses of hyperplastic erythroid marrow, a tendency to develop osteopenia and osteoporosis, and thrombotic complications resulting from iron accumulation and hypercoagulable state secondary to the lipid membrane composition of the abnormal red blood cells [Cappellini et al 2012].

  • By definition, transfusions are not required, or only occasionally required.
  • Iron overload occurs mainly from increased intestinal absorption of iron caused by deficiency of hepcidin, a 25-amino acid peptide produced by hepatocytes that plays a central role in the regulation of iron homeostasis [Nemeth & Ganz 2006, Origa et al 2007]. Hepcidin deficiency is associated with ineffective erythropoiesis. The associated complications of iron overload present later, but may be as severe as those seen in individuals with thalassemia major who depend on transfusions.

Genotype-Phenotype Correlations

βº variants and some β+ variants are associated with a severe phenotype and result in thalassemia major in the homozygous or compound heterozygous state; however, clinical severity may be modified to thalassemia intermedia if ameliorating genetic factors are present.

Some β+ variants have a mild phenotype; however, the clinical severity in the homozygous state or compound heterozygous state with other β0 or β+ variants is variable.

A few β+ silent variants (with a normal or borderline HbA2 and a normal MCH in the heterozygous state) result in very mild clinical severity in the homozygous state or compound heterozygous state with severe β0 or + variants.

Common mild and silent pathogenic variants are listed in Table 5.

Clinical presentation of compound heterozygosity for β-thalassemia and HbE ranges from severe to asymptomatic.

Ameliorating Genetic Factors

Clinical severity of β+- or βº-thalassemia may be ameliorated by coinheritance of pathogenic variants in HBA1 or HBA2, associated with α-thalassemia, which reduce alpha globin expression, thereby decreasing the alpha/non-alpha globin chain imbalance. Due to clinical variability, HBA1 and HBA2 genotypes cannot be used to predict clinical outcome.

The coinheritance of some genetic determinants able to sustain a continuous production of gamma globin chains (HbF) in adult life may also reduce the extent of alpha/non-alpha globin chain imbalance:

  • The β-thalassemia pathogenic variants that increase gamma globin chain (HbF) output:
    • δβº-thalassemia caused by deletions of variable size in the HBB gene cluster
    • Deletions that remove only the 5' region of the HBB promoter, which also results in high levels of HbA2
  • Co-transmission of hereditary persistence of fetal hemoglobin (HPFH), which is the result of single-nucleotide variants in the hemoglobin Gγ (HBG2) or hemoglobin Aγ (HBG1) promoter (most commonly c.-158C>T in HBG2 and c.-117G>A in HBG1; see Table 4 and Table 5), may result in a milder phenotype.
  • The c.-196C>T HBG1 variant in cis with p.Gln40Ter has been found on some Sardinian β-thalassemia chromosomes (Sardinian δβº-thalassemia).

Other genetic loci that are not linked to the HBB gene cluster and may have an ameliorating effect on clinical features of β-thalassemia have been suggested [Sankaran et al 2008, Uda et al 2008, Galanello et al 2009, Thein et al 2009, Borg et al 2010, Satta et al 2011, Gallienne et al 2012].

In some instances, heterozygous β-thalassemia may lead to the phenotype of thalassemia intermedia instead of the asymptomatic carrier state. Known molecular mechanisms include the following:

  • Heterozygosity for pathogenic variants in HBB that result in hyper-unstable hemoglobins (dominant β-thalassemia), which precipitate in the red cell membrane together with unassembled alpha globin chains, resulting in markedly ineffective erythropoiesis. Most of these HBB pathogenic variants lie in the third exon and lead to the production of a markedly unstable Hb variant often not detectable in peripheral blood.
  • Double heterozygosity for typical β-thalassemia pathogenic variants and the triple or (less frequently) quadruple alpha gene arrangement (ααα/αα or ααα/ααα or αααα/αα) may increase the imbalance in the ratio of alpha/non-alpha globin chains. Duplications of the entire alpha globin gene cluster have been reported to cause thalassemia intermedia in association with the β-thalassemia carrier state [Harteveld et al 2008, Sollaino et al 2009, Origa et al 2014].

Genetic determinants capable of sustaining continuous production of HbF in adult life outside the HBB gene cluster have been mapped to chromosome 2p16 and chromosome 6q23 [Uda et al 2008].

  • The 2p16 locus identified by GWAS mapped to BCL11A (rs11886868; c.386-24278C>T in intron 2) and was found strongly associated with HbF levels. The c.386-24278C allele was significantly more common in 0 homozygotes for p.Gln40Ter with a mild phenotype and in patients with mild sickle cell disease [Lettre et al 2008, Uda et al 2008]. The c.386-24278C>T genotype in young patients with homozygous β-thalassemia and sickle cell anemia may serve as a prognostic indication for the severity of the disease. Furthermore, targeted downregulation of BCL11A in patients could elevate HbF levels and thereby ameliorate the severity of these inherited anemias.
  • A genetic variant associated with HbF variation was mapped to the HBS1L-MYB region on chromosome 6 [Creary et al 2009]. Recent studies have shown that the HBS1L-MYB intergenic variants contain regulatory sequences controlling MYB expression. Coinheritance of these HPFH determinants and alpha-thalassemia contribute in the amelioration of the phenotype of homozygous β-thalassemia accounting for 75% of difference in clinical severity [Galanello et al 2009].

Recently, it was suggested that three factors – the type of pathogenic variant in HBB, HBA gene defects, and fetal hemoglobin production modulators (HBG2:c.-158C>T, HBS1L-MYB intergenic region, and the BCL11A: c.386-24278G>A) – combine to build a predictive score of disease severity, based on a representative cohort of 890 patients with non-transfusion-dependent and transfusion-dependent β-thalassemia. The effect of these loci on the transfusion-free survival probability and on the age at which the patient started regular transfusions was demonstrated [Danjou et al 2015].

Other modifying factors. The clinical phenotype of homozygous β-thalassemia may also be modified by the coinheritance of secondary genetic factors mapping outside the β-globin gene cluster, which influence the complications of the thalassemia phenotype [Origa et al 2008, Origa et al 2009].

Nomenclature

β-thalassemia includes three main forms:

  • β-thalassemia major, also referred as "Cooley’s anemia," "Mediterranean anemia," or "transfusion-dependent thalassemia (TDT);
  • β-thalassemia intermedia; and
  • Thalassemia minor, called "β-thalassemia carrier," "β-thalassemia trait," or "heterozygous β-thalassemia."

Non-transfusion-dependent thalassemias (NTDT) is a term used to label patients who do not require lifelong regular transfusions for survival; NTDT encompasses β-thalassemia intermedia, hemoglobin E/β-thalassemia (mild and moderate forms), and α-thalassemia intermedia (hemoglobin H disease).

Prevalence

β-thalassemia is prevalent in populations in the Mediterranean, the Middle East, the Transcaucasus, Central Asia, the Indian subcontinent, and the Far East. It is also common in populations of African heritage. The highest incidences are reported in Cyprus (14%), Sardinia (12%), and Southeast Asia.

The high gene frequency of β-thalassemias in these regions is most likely related to selective pressure from malaria. This distribution is quite similar to that of endemic Plasmodium falciparum malaria. However, because of population migration and (to a limited degree) the slave trade, β-thalassemia is now also common in northern Europe, North and South America, the Caribbean, and Australia.

Differential Diagnosis

β-thalassemia associated with other features. In rare instances the β-thalassemia defect does not lie in HBB or in the β-globin gene cluster. In instances in which the β-thalassemia trait is associated with other features, the molecular lesion has been found either in the gene encoding the transcription factor TFIIH (β-thalassemia trait associated with xeroderma pigmentosum and trichothiodystrophy) or in the X-linked transcription factor GATA-1 (X-linked thrombocytopenia with thalassemia) (see GATA1-Related X-Linked Cytopenia) [Viprakasit et al 2001, Freson et al 2002].

Few conditions share similarities with homozygous β-thalassemia.

  • The genetically determined sideroblastic anemias are easily differentiated because of ring sideroblasts in the bone marrow and variably elevated serum concentration of erythrocyte protoporphyrin. Most sideroblastic anemia is associated with defects in the heme biosynthetic pathway, especially δ-aminolevulinic acid synthase.
  • Congenital dyserythropoietic anemias do not have high HbF and do have other distinctive features, such as multinuclearity of the red blood cell precursors (see Congenital Dyserythropoietic Anemia Type I).
  • A few acquired conditions associated with high HbF (juvenile chronic myeloid leukemia, aplastic anemia) may be mistaken for β-thalassemia, even though they have very characteristic hematologic features.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with β-thalassemia, the following evaluations are recommended if they have not already been completed:

  • The initial step following diagnosis of β-thalassemia in an individual is to distinguish between those who have thalassemia intermedia (requiring intermittent transfusions on an as-needed basis) from those with thalassemia major (who need a regular transfusion program). See Establishing the Diagnosis.
    The following should be included in the investigations when deciding whom to transfuse:
    • Confirmed diagnosis of thalassemia; and
    • Hemoglobin level <7 g/dL on two occasions, more than two weeks apart (excluding all other contributory causes, such as infections), or presence of the following features, regardless of hemoglobin level:
      • Facial changes
      • Poor growth
      • Bony fractures
      • Clinically significant extramedullary hematopoiesis
  • Consultation with a clinical geneticist and/or genetic counselor is appropriate.

Treatment of Manifestations

Comprehensive reviews of the management of thalassemia major and thalassemia intermedia have been published by the Thalassemia International Federation [Taher et al 2013, Cappellini et al 2014] and are available at the TIF website.

Thalassemia major. Regular transfusions correct the anemia, suppress erythropoiesis, and inhibit increased gastrointestinal absorption of iron.

  • Before starting the transfusions, the following are absolutely necessary:
    • Hepatitis B vaccination
    • Extensive red blood cell antigen typing, including Rh, Kell, Kidd, and Duffy and serum immunoglobulin determination – the latter of which detects individuals with IgA deficiency, who need special (repeatedly washed) blood unit preparation before each transfusion
  • The transfusion regimen is designed to obtain a pre-transfusion Hb concentration of 95-100 g/L.
  • Transfusions are usually given every two to three weeks.

Thalassemia intermedia. Treatment of individuals with thalassemia intermedia is symptomatic and based on splenectomy and folic acid supplementation.

  • Treatment of extramedullary erythropoietic masses is based on radiotherapy, transfusions, or, in selected cases, hydroxyurea (with a protocol similar to that used for sickle cell disease).
    Hydroxyurea also increases globin gamma chains and may have other undefined effects.
  • Individuals with thalassemia intermedia may develop iron overload from increased gastrointestinal absorption of iron or from occasional transfusions; chelation therapy with deferasirox has been demonstrated to be safe and effective in persons age ten years or older with a liver iron concentration ≥5 mg Fe/g dry weight or serum ferritin ≥800 ng/mL (thresholds after which the risk of serious iron-related morbidity is increased) [Taher et al 2012].

Bone marrow transplantation

  • Bone marrow transplantation (BMT) from an HLA-identical sib represents an alternative to traditional transfusion and chelation therapy. If BMT is successful, iron overload may be reduced by repeated phlebotomy, thus eliminating the need for iron chelation.
  • The outcome of BMT is related to the pretransplantation clinical conditions, specifically the presence of hepatomegaly, extent of liver fibrosis, and magnitude of iron accumulation. In children who lack the above risk factors, disease-free survival is higher than 90%. Adults with beta-thalassemia are at increased risk for transplant-related toxicity due to an advanced phase of the disease and have a two-year overall survival of 80% and a two-year event-free survival of 76% with current treatment protocol [Baronciani et al 2016].
  • BMT from unrelated donors has been carried out on a limited number of individuals with β-thalassemia. Provided that selection of the donor is based on stringent criteria of HLA compatibility and that individuals have limited iron overload, results are comparable to those obtained when the donor is a compatible sib [La Nasa et al 2005, Gaziev et al 2013].
  • Severe acute graft-vs-host disease (GVHD) may occur in 9% of individuals, with a lower risk observed in those with an HLA-matched sib donor.
  • Affected individuals without matched donors could also benefit from haploidentical mother-to-child transplantation, the results of which appear encouraging [Sodani et al 2011, Anurathapan et al 2016].

Cord blood transplantation. Cord blood transplantation from a related donor offers a good probability of a successful cure and is associated with a low risk for GVHD [Pinto & Roberts 2008]. For couples who have already had a child with thalassemia and who undertake prenatal diagnosis in a subsequent pregnancy, prenatal identification of HLA compatibility between the affected child and an unaffected fetus allows collection of placental blood at delivery and the option of cord blood transplantation to cure the affected child [Orofino et al 2003]. Alternatively, in case of an affected fetus and a previous unaffected child, the couple may decide to continue the pregnancy and pursue BMT later, using the unaffected child as the donor.

Unrelated cord blood transplantation has been explored as an alternative option for affected individuals without a suitable HLA-matched unrelated adult donor. However, this strategy may be limited by less-than-adequate cell dose and higher rates of primary graft failure. One potential strategy may be the use of two cord blood units in order to achieve the desired cell dose, as has been done in individuals with malignancy – although this approach may be associated with a higher rate of acute GVHD, which may add to the burden of morbidity and mortality for this population.

For these reasons, unrelated cord blood transplantation would appear to be a suboptimal strategy for individuals with thalassemia [Ruggeri et al 2011]. However, others have found the outcome of unrelated cord blood transplantation to be more favorable. Jaing et al [2012] reported an overall survival of 88% and a thalassemia-free survival of 74% in 35 individuals with β-thalassemia.

Prevention of Primary Manifestations

Early detection of anemia, the primary manifestation of the disease, allows early appropriate treatment and monitoring.

Prevention of Secondary Complications

Transfusional Iron Overload

The most common secondary complications are those related to transfusional iron overload, which can be prevented by adequate iron chelation.

Assessment of iron overload

  • Serum ferritin concentration. In clinical practice, the effectiveness of chelators is monitored by routine determination of serum ferritin concentration. However, serum ferritin concentration is not always reliable for evaluating iron burden because it is influenced by other factors, the most important being the extent of liver damage.
  • Liver biopsy. Determination of liver iron concentration in a liver biopsy specimen shows a high correlation with total body iron accumulation and is the gold standard for evaluation of liver iron overload. However, (1) liver biopsy is an invasive technique involving the possibility (though low) of complications; (2) liver iron content can be affected by hepatic fibrosis, which commonly occurs in individuals with iron overload and hepatitis C virus infection; and (3) irregular iron distribution in the liver can lead to false negative results [Clark et al 2003].
  • Magnetic biosusceptometry (SQUID), which gives a reliable measurement of hepatic iron concentration, is another option [Fischer et al 2003]; however, magnetic susceptometry is presently available only in a limited number of centers worldwide.
  • MRI techniques for assessing