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    Thalassemia

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    Aug.02.2023

    Thalassemia

    Synopsis

    Key Points

    • Thalassemias are a group of blood disorders characterized by inadequate production of globin chains leading to ineffective erythropoiesis and anemia of varying degrees of severity r1
    • Thalassemia presents with symptoms typical of anemia (eg, fatigue, asthenia, dyspnea, exercise intolerance, anorexia)
    • Severe untreated cases of β-thalassemia major can present with signs of ineffective hematopoiesis (eg, bone deformities, pathologic fractures, hepatomegaly)
    • Screening of all infants is recommended, especially for those with an ethnic background with a higher incidence of thalassemia
    • Screen all individuals of African, Mediterranean, Middle Eastern, West Indian, or Southeast Asian heritage who are of childbearing age or pregnant r2
    • Initial workup employs CBC with RBC indices, reticulocytes, and peripheral blood smear plus biochemical tests (hemoglobin studies such as electrophoresis) to arrive at a presumptive diagnosis
    • Molecular genetics testing is used to characterize gene deletions and/or mutations to confirm clinical phenotype and to guide genetic counseling
    • Primary treatment for β-thalassemia major and for transfusion-dependent cases of β-thalassemia intermedia or α-thalassemia intermedia is transfusion of packed RBCs each time hemoglobin falls into the range of 9.5 to 10.5 g/dL r3
      • Transfusion promotes normal growth, facilitates normal functioning, and suppresses excessive bone marrow activity
      • Posttransfusion hemoglobin level should be over 10.5 g/dL, but not higher than 13 to 15 g/dL r4r5
    • Patients receiving routine transfusions require iron chelation each time ferritin level reaches 1000 mcg/L, which usually happens after 10 to 20 transfusions r5
      • Chelation agents that can be used are deferoxamine, deferiprone, or deferasirox
    • Cure is possible only with allogenic hematopoietic stem cell transplant or autologous hematopoietic stem cell transplant combined with gene therapy
    • Patients with transfusion-dependent thalassemia require regular follow-up and monitoring, ideally with a thalassemia specialist
    • Although life expectancy has markedly improved in recent decades, patients with transfusion-dependent thalassemia remain at increased risk for early mortality and continue to have high burden of iron overload and other disease-associated complications

    Pitfalls

    • Thalassemia minor (both α and β) is very easily mistaken for iron deficiency anemia; obtain iron studies (eg, ferritin) to differentiate

    Terminology

    Clinical Clarification

    • Thalassemias are a group of blood disorders characterized by inadequate production of globin chains leading to ineffective erythropoiesis and anemia of varying degrees of severity r1r6
      • Thalassemia is a quantitative hemoglobin disease; hemoglobin is normal but an insufficient amount is produced

    Classification

    • Classified according to genotype and clinical phenotype
      • β-Thalassemia r3
        • β-Thalassemia minima (silent carrier)
          • Clinically normal but β-globin synthesis is reduced
          • RBC indices normal or borderline for microcytosis (low mean corpuscular volume) and hypochromia (low MCHC)
        • β-Thalassemia minor (β-thalassemia carrier, β-thalassemia trait, heterozygous β-thalassemia)
          • β-Globin synthesis is reduced; patients are carriers and have β-thalassemia trait, manifesting as the following:
            • Mild anemia often present
            • RBC indices normal or borderline for microcytosis and hypochromia
            • Hemoglobin normal to slightly low
          • Does not require treatment for anemia
        • β-Thalassemia intermedia (non–transfusion-dependent β-thalassemia) r7r8
          • β-Globin synthesis is reduced, and patients show heterogeneous clinical profile with hemoglobin level ranging from 7 to 10 g/dL; sustainable without regular transfusions
          • May require intermittent or occasional transfusion (eg, during pregnancy)
        • β-Thalassemia major (transfusion-dependent β-thalassemia, Cooley anemia, or Mediterranean anemia) r5
          • β-Globin synthesis is absent, and patients present with severe microcytic anemia (hemoglobin under 7 g/dL), usually clinically evident by early childhood r5
          • Typically requires regular transfusions to manage symptomatic anemia
      • α-Thalassemia r9
        • α-Thalassemia minima (α-thalassemia-2 trait or α⁺-thalassemia)
          • Patient clinically unaffected
          • RBC indices normal or borderline for microcytosis (low mean corpuscular volume) and hypochromia (low MCHC)
        • α-Thalassemia minor (α-thalassemia-1 trait or α⁰-thalassemia)
          • α-Globin synthesis is reduced
          • Carrier status with mild symptoms and borderline to mildly reduced RBC indices
          • Does not require treatment for anemia
        • Hemoglobin H disease (α-thalassemia intermedia) r10
          • α-Globin synthesis is reduced
          • Presents with moderate to severe microcytic hypochromic hemolytic anemia, mild jaundice, and moderate hepatosplenomegaly
          • Spectrum of severity with some patients chronically transfusion dependent
        • α-Thalassemia major (hemoglobin Barts, hydrops fetalis syndrome) r5
          • α-Globin synthesis is absent
          • Presents with severe anemia, generalized edema, ascites, marked hepatosplenomegaly, and skeletal and cardiovascular malformations
          • Usually results in stillbirth; the few that survive are invariably transfusion dependent
    • Classified according to transfusion dependence
      • Non–transfusion-dependent thalassemias r5r8
        • β-Thalassemia intermedia
        • Hemoglobin H disease
        • Hemoglobin E/β-thalassemia
      • Transfusion-dependent thalassemias r5
        • β-Thalassemia major
        • Severe hemoglobin E/β-thalassemia
        • Some forms of hemoglobin H disease
        • Survivors with hemoglobin Barts hydrops
      • Designation of disease as non–transfusion-dependent or transfusion-dependent reflects current clinical status and may shift over time r8

    Diagnosis

    Clinical Presentation

    History

    • Patients may present with any of the following symptoms typical of anemia and/or extramedullary erythropoiesis:
      • Constitutional
        • Fatigue c1
        • Asthenia c2
        • Anorexia c3
        • Exercise intolerance c4
        • Symptoms specific to infants and young children
      • Respiratory
        • Dyspnea on exertion or at rest c13c14
      • Gastrointestinal
        • Diarrhea (infants and young children) c15c16
        • Abdominal pain c17
      • Genitourinary
      • Musculoskeletal
        • Bone pain or tenderness c19
      • Neurologic
    • Timing and acuity of symptomatic presentation varies depending on underlying hemoglobinopathy
      • Majority of patients who are not diagnosed as a result of newborn screening usually present after age 6 months (when fetal hemoglobin synthesis has ceased) with evidence of anemia r10
      • α-Thalassemia major produces a severely affected fetus, which typically is stillborn or dies in the neonatal period r11c21
      • α-Thalassemia intermedia (hemoglobin H disease) may be symptomatic from birth r12
      • α-Thalassemia minor may be mildly symptomatic, and those with α-thalassemia minima are asymptomatic; both are carriers of α-thalassemia trait r13
      • β-Thalassemia major usually presents between ages 6 and 24 months with failure to thrive r4c22
      • β-Thalassemia intermedia may present in children aged 2 to 6 years with growth and development retardation; others with β-thalassemia intermedia may remain asymptomatic until adulthood r4c23c24c25
      • β-Thalassemia minor may be mildly symptomatic, and those with β-thalassemia minima are asymptomatic; both are carriers of β-thalassemia trait r4
    • Rarely, α-thalassemia major (hydrops fetalis) is diagnosed during pregnancy, usually between 22 and 28 weeks of gestation by obstetric ultrasonography r11c26
      • In at-risk pregnancies (identified by screening individuals in high-incidence populations), ultrasonography findings of hydrops fetalis may be detected between 13 and 14 weeks of gestation c27
      • Parents involved in at-risk pregnancies can also choose to obtain an early prenatal diagnosis by chorionic villus sampling or amniocentesis r14

    Physical examination

    • Signs of anemia and RBC destruction
      • Pallor c28
      • Ejection murmur (midsystolic) c29
      • Leg ulcers c30
      • Signs of marrow overactivity
        • Bone tenderness suggesting pathologic fracture c31
        • Maxillary or frontal bone hyperplasia c32
          • Can present as frontal bossing or so-called chipmunk face c33
        • Dental malocclusion c34
    • Signs of extramedullary erythropoiesis
      • Abdominal distention c35
      • Hepatosplenomegaly c36
    • Signs of cholelithiasis
      • Jaundice c37
      • Scleral icterus c38
      • Right upper quadrant or epigastric tenderness on palpation c39c40
      • Abdominal distention c41
    • Signs of hydrops fetalis in neonate r11
      • Stillbirth or early neonatal death occurs c42c43
      • In a newborn
        • Generalized edema c44
        • Ascites c45
        • Pleural/pericardial effusions c46c47
        • Hepatosplenomegaly c48
        • Hydrocephaly c49

    Causes and Risk Factors

    Causes

    • β-Thalassemia c50
      • Reduced or absent synthesis of hemoglobin β-globin chains due to pathogenic variants in HBB gene (encoding hemoglobin β-globin chains), with resultant relative excess of α-globin chains r5r15c51
      • Excess α-globin chains accumulate and precipitate, leading to oxidative membrane damage and apoptotic cell destruction in RBC precursors in the bone marrow r5
    • α-Thalassemia r5r11c52
      • Reduced or absent synthesis of hemoglobin α-globin chains due to deletion or inactivation of 1 or more of the 4 α-globin alleles, with resultant relative excess of β-globin chains
        • α-Thalassemia major (hemoglobin Barts, hydrops fetalis syndrome): a severe form caused by deletion or inactivation of all 4 α-globin genes c53c54c55c56c57
        • α-Thalassemia intermedia (hemoglobin H disease): usually caused by deletion or inactivation of 3 α-globin genes and associated with recurrent episodes of hemolysis
      • Excess β-globin chains can form tetramers that precipitate, leading to oxidative membrane damage and decreased survival in RBCs r5

    Risk factors and/or associations

    Genetics
    • Autosomal recessive inheritance c58
      • A rare form of recessively inherited β-thalassemia can arise via spontaneous mutations not associated with geographic regions of malaria; suspect autosomal recessive inherited β-thalassemia in a clinically appropriate case when both parents are unaffected r16
    • More than 200 thalassemia mutations of the HBB gene are known but most are extremely rare; most cases are caused by a handful of common mutations and gene deletions r9c59
    • Genotypes correlate with β- and α-thalassemia classifications but with significant genotype/phenotype overlap due to a multitude of factors affecting how the genotypes manifest r9
      • Genotype/phenotype overlap is larger for β-thalassemia owing to variable presence of alternate globin chains that substitute for the usual adult β globin
      • α-Thalassemia genotypes correlate extremely closely with phenotypic classes (ie, minor, intermedia, major), but phenotype can be modified by coexisting conditions that reduce concentration of β chains, thereby reducing effects that otherwise result from α/β imbalance
    • β-Thalassemia c60
      • β-Globin genes: chromosome 11 (OMIM #141900,r18#613985r19) r17
        • Genome has 2 β-globin alleles, 1 each on maternal and paternal chromosome of the pair
        • 2 common abnormal gene variants cause the following β-thalassemia genotypes:
          • β/β⁺
            • 1 normal allele (β) produces normal amounts of β globin, and 1 abnormal allele produces reduced amounts of β globin (β⁺)
            • Corresponds to β-thalassemia minima or minor (trait)
          • β/β⁰
            • 1 normal allele (β) produces normal amounts of β globin, and 1 abnormal allele produces no β globin at all (β⁰)
            • Usually corresponds to β-thalassemia minor (trait) but also can manifest as β-thalassemia intermedia phenotype
          • β⁺/β⁺
            • Homozygosity of allele that produces reduced amounts of β globin (β+)
            • Corresponds to β-thalassemia intermedia or major
          • β⁺/β⁰
            • 1 allele that produces reduced amounts of β globin (β⁺) and 1 allele that produces no β globin at all (β⁰)
            • Corresponds to β-thalassemia intermedia or major
          • β⁰/β⁰
            • Homozygosity for allele that produces no β globin at all (β⁰)
            • Corresponds to β-thalassemia major
      • Point mutation causing hemoglobin E can also cause a form of β-thalassemia major (called E β-thalassemia) when inherited along with the hemoglobin-E gene, owing to compound heterozygosity (1 allele is β⁺ or β⁰ and the other is the hemoglobin-E gene) r20
        • Similarly, coinheritance of the sickle cell gene plus a β-thalassemia mutation causes sickle β-thalassemia
    • α-Thalassemia r8c61
      • α-Globin genes: chromosome 16 (OMIM *141800,r21*141850, r22*142310,r23 #604131r24)
        • Genome has 4 α-globin alleles, 2 each on maternal and paternal chromosome of the pair
        • α-Thalassemia results from deletion or inactivation of 1 or more of the 4 alleles, causing the following α-thalassemia genotypes:
          • -α/αα
            • Deletion of 1 α-globin gene with 3 normal genes present
            • Causes α-thalassemia minima phenotype (silent carrier)
          • -α/-α
            • 2 α-globin genes deleted in trans pattern (1 on each chromosome)
            • Patient has α-thalassemia minor
          • --/αα
            • 2 α-globin genes deleted in cis pattern (both on same chromosome)
            • Patient has α-thalassemia minor
            • Puts offspring at greater risk compared with trans pattern
          • -α/--
            • 3 α-globin genes are deleted, leaving only 1 normal gene
            • Manifests as hemoglobin H disease (α-thalassemia intermedia)
          • --/--
            • All 4 α-globin genes deleted
            • Causes hemoglobin Barts, leading to hydrops fetalis (α-thalassemia major)
        • Inheritance of 1 or 2 α-globin deletions is Mendelian; thus, a child receives paternal and maternal chromosomes with a singly deleted, doubly deleted, or normal α-globin alleles
          • This means that in populations in which only the singly deleted form is present, offspring cannot end up with anything worse than -α/-α (trans), manifesting as α-thalassemia minor
          • In populations in which the doubly deleted form exists in the gene pool, offspring can end up with α-thalassemia intermedia and major
    Ethnicity/race
    • α-Thalassemia occurs with increased incidence in people with the following ancestry in particular: r11
      • Southeast Asian c62
      • African c63
      • Central American c64
      • Mediterranean c65
      • Middle Eastern c66
    • β-Thalassemia occurs with increased incidence in people from the following regions: r3
    Other risk factors/associations
    • δ-Globin synthesis
      • Reduced/absent δ globin moves patient farther along severity spectrum by reducing hemoglobin A2 production that otherwise compensates r17c77c78
      • In contrast, increased expression of δ-globin gene or presence of a mixed δ-β globin (made from recombination of δ and β genes in some people [Lepore hemoglobin]) makes β-thalassemia more mild r3r7r16c79
    • Coinheritance of α- and β-thalassemia genes r17c80
      • This tends to moderate the condition by decreasing formation of either α or β tetramers that form owing to an imbalance of α- and β-globin synthesis
        • Occurs especially in β-thalassemia; coinheritance of α-thalassemia trait makes β-thalassemia less severe r7
    • Elevated hemoglobin F due to persistent production of γ-globin chain after birth c81
      • This moderates β-thalassemia; since γ chains substitute for β chains, hemoglobin F works as functional hemoglobin and also keeps α chains occupied so they do not form α tetramers (which are even worse than β or γ tetramers)
    • Resistance to Plasmodium falciparum r26r27
      • Point mutations of the β-globin gene are perpetuated in populations where Plasmodium falciparum malaria is endemic because people with thalassemia trait resist the organism and have a malaria survival advantage c82
      • As with β-globin point mutations, people with thalassemia trait due to reduced number of α-globin genes are resistant to Plasmodium falciparum

    Diagnostic Procedures

    Primary diagnostic tools

    • Other than α-thalassemia major (hydrops fetalis syndrome), most cases of thalassemia are detected through screening efforts (ie, all 50 of the US states screen for thalassemia at birth),r28 when patients develop symptomatic anemia, or incidentally when CBC demonstrates a mild microcytic anemia r10c83
      • Patients missed at birth screening usually present after age 6 months (when fetal hemoglobin synthesis has ceased) with evidence of anemia r10
    • Initial workup uses CBC with RBC indices, reticulocyte count, and peripheral blood smear r16c84c85c86
      • A very low mean corpuscular volume (under 75 fL) in a patient with normal or only slightly reduced hemoglobin is highly suggestive of thalassemia and warrants further biochemical testing r10
      • RBC distribution width is elevated in only 50% of thalassemia cases r10
        • Microcytic anemia with normal RBC distribution is almost always due to thalassemia; further biochemical testing will provide a diagnosis
        • Microcytic anemia with elevated RBC distribution requires further biochemical testing to differentiate from other causes of microcytic anemia
    • Obtain iron studies including ferritin level to exclude iron deficiency as a cause of hypochromic microcytic anemia r5c87
    • Biochemical testing with gel electrophoresis, high-performance liquid chromatography, or other technique is required for presumptive diagnosis of thalassemia; a hematologist can be helpful in guiding test selection and interpreting results r29c88c89
      • Each biochemical test has advantages and disadvantages; typically, a number of tests will be performed
    • Molecular genetics testing follows to characterize gene deletions and/or mutations, to confirm clinical phenotype, and/or to guide genetic counseling r30c90
    • Couples known by DNA analysis to be at risk for a child with thalassemia may elect prenatal testing r11
      • Chorionic villus sampling (usually performed between 10 and 12 weeks of gestation) or amniocentesis (usually performed between 15 and 18 weeks of gestation) can provide cells from which fetal DNA can be extracted, allowing molecular genetic testing

    Laboratory

    • CBC with RBC indices, reticulocyte count, and peripheral blood smear r16c91c92c93c94
      • Indicated for every patient with symptoms and signs of anemia, including those with suspected thalassemia
      • Shows microcytic, hypochromic anemia
        • β-Thalassemia major r10
          • Mean corpuscular volume less than 70 fL (typically 65 fL or lower) for patients aged 6 months to 6 years; less than 76 fL for patients between ages 6 and 12 years; less than 80 fL (typically 65 fL or lower) in patients older than 12 years
          • MCHC typically 12 to 18 pg
          • Hemoglobin: very low (typically 3-7 g/dL) in untreated people with β-thalassemia major
          • Target cells also common
        • β-Thalassemia intermedia r6
          • Mean corpuscular volume typically 50 to 80 fL
          • MCHC typically 16 to 24 pg
          • Hemoglobin 7 to 10 g/dL
        • β-Thalassemia trait r16
          • Typically shows mild hypochromic microcytic anemia, either with normal blood smear, or with anisopoikilocytosis, basophilic stippling, elevated reticulocytes, and/or target cells
        • α-Thalassemia intermedia (hemoglobin H disease) r16
          • Mean corpuscular volume typically 50 to 65 fL
          • MCHC typically 15 to 20 pg
          • Hemoglobin typically 7 to 10 g/dL
          • Smear may show anisopoikilocytosis, poor hemoglobinization, microcytes, macrocytes, fragmented cells, target cells, teardrop cells, and/or polychromasia
        • α-Thalassemia trait r10
          • Normocytic or mildly microcytic anemia
          • Mean corpuscular volume typically 70 to 80 fL
          • Hemoglobin can be normal or slightly low
    • Iron studies r9c95
      • Appropriate for differentiating thalassemia minor (especially β-thalassemia minor), thalassemia trait, and intermedia from iron deficiency anemia
      • In thalassemia, ferritin level is usually within reference range but can be high owing to increased iron uptake
        • Ferritin also increases after multiple transfusions and serves as a marker for iron overload
      • Iron studies (eg, serum iron, total iron binding capacity) are rarely needed beyond a serum ferritin, which is low in patients with iron deficiency, to differentiate iron deficiency from thalassemia
    • Biochemical tests c96c97c98
      • Qualitative and quantitative analyses of hemoglobin are required to determine the type and amount of hemoglobin present r30
        • β-Thalassemia
          • Minor r16
            • Hemoglobin A quantity is at or slightly below normal
            • Elevated hemoglobin A2 (due to δ-chain compensation)
            • Often (33%-50%r16 of cases) persistent hemoglobin F (fetal hemoglobin in which γ chains substitute for β chains of adult hemoglobin)
          • Intermedia
            • Hemoglobin-A level below reference range but major component present
            • Hemoglobin-A2 level elevated
            • Hemoglobin-F levels increased in 50% of patients r30
          • Major
            • Hemoglobin-A level below reference range or absent
            • Hemoglobin-A2 level higher than reference range
        • α-Thalassemia r16
          • Intermedia
            • In addition to reduced quantities of α globin, shows a small amount (generally up to 3%) of hemoglobin Barts (γ-chain tetramers) and 2% to 40% (usually 10%r16) hemoglobin H (β-chain tetramers)
              • Samples from those with α-thalassemia major show large amounts of hemoglobin Barts, but such patients usually do not survive
          • Minor
            • No abnormalities for these patients are found on this testing, which screens for abnormal hemoglobin r30
      • Gel electrophoresis or high-performance liquid chromatography is widely used for hemoglobin analysis r29c99c100
        • High-performance liquid chromatography can quantify most hemoglobin types r30
        • A type of gel electrophoresis, isoelectric focusing electrophoresis is often considered the biochemical gold standard for hemoglobin abnormalities r30
          • Drawback is inability to quantitate hemoglobin species; not sensitive enough to confirm the diagnosis of β-thalassemia or to compare ratios of hemoglobin A with other hemoglobins r30
      • Each technique for hemoglobin analysis has advantages and disadvantages; using only 1 (eg, high-performance liquid chromatography, gel electrophoresis) can lead to misdiagnosis r30
      • Capillary zone electrophoresis is a newer technique that can differentiate all major hemoglobin variants; there are few studies confirming its clinical value compared with more established tests r30
      • Mass spectrometry is also used to analyze hemoglobin but is most valuable in screening populations and selecting people who require definitive testing r30
    • Molecular genetics studies c101c102
      • Biochemical testing provides a presumptive diagnosis after which deletions and mutations must be characterized by molecular genetic testing, confirming the clinical phenotype and providing information for genetic counseling r30
      • Patient genome of chromosomes 11 and 16 is tested for mutations/deletions of β- and α-globin genes, respectively
        • Testing includes targeted analysis for pathogenic variants, sequence analysis, and gene-targeted deletion/duplication analysis
          • Positive results for β-globin mutations (β⁺ and β⁰) and Xmn1–Gγ (a genetic polymorphism that is prevalent among patients with β-thalassemia intermedia) confirm β-thalassemia diagnosis
          • Detection of α-globin gene deletions confirms α-thalassemia diagnosis
      • Most molecular studies are polymerase chain reaction based r30
      • Most tests are commercially available and are designed to target specific, characterized mutations r30
        • Other methodologies are used for screening, rather than identification of exact variants r30
      • Targeted analysis for pathogenic variants is often considered first, based on ancestry r4
        • There are a limited number of pathogenic variants to look for in each at-risk population (eg, Mediterranean, Middle Eastern)
      • Single-gene testing (of the sequence of HBB gene) is considered if the affected patient does not belong to an identified high-risk group or if targeted analysis only found 1 or no pathogenic variants r4
        • If after gene sequence analysis only 1 or no pathogenic variants have been identified, gene-targeted deletion/duplication analysis of the HBB gene is conducted

    Differential Diagnosis

    Most common

    • Iron deficiency anemia r9c103d1
      • Most common anemia presenting with fatigue, pallor, and hypochromic RBCs that may be slightly microcytic
        • Presentation is very similar to trait form of both α- and β-thalassemia
      • Differentiated from all thalassemias (symptomatic and trait) based on iron studies
        • Iron deficiency
          • Serum ferritin is best single test: results are low in patients with iron deficiency
          • Iron level is low and total iron binding capacity is elevated
        • Thalassemia
          • Ferritin is in reference range or high (the latter in severe cases of thalassemia intermedia or major)
          • In severe cases, transferrin is saturated
      • Differentiated from more severe thalassemias based on mean corpuscular volume
        • With β-thalassemia intermedia, α-thalassemia intermedia (hemoglobin H disease), and especially β-thalassemia major, mean corpuscular volume is very low, typically 65 fL or less
        • Iron deficiency: RBCs are normocytic (80-96 fL) or only slightly microcytic
    • Anemia of chronic disease r31c104
      • Presentation includes fatigue and pallor; CBC results can vary but can show microcytic hypochromic anemia similar to thalassemia
      • Differentiated from thalassemia based on the following:
        • Serum ferritin is best single test: results are high in patients with anemia of chronic disease
          • Total iron binding capacity is also low in patients with anemia of chronic disease
        • Thalassemia minor: iron study results tend to be within reference range
        • With thalassemia intermedia or major, differentiation requires molecular testing
    • Sideroblastic anemias c105
      • Presentation marked by fatigue, pallor, splenomegaly, and hypochromic RBCs, as in thalassemia
      • Sideroblastic anemia may be due to any of the following:
        • Lead toxicity
        • Alcohol abuse
        • Certain medications (eg, chemotherapy, antibiotics, antitubercular agents)
        • Supplement abuse (especially zinc)
        • Prolonged parenteral nutrition
        • Long-term dialysis, especially when dialysis fluid zinc levels are higher than reference range
      • Differentiated from thalassemia based on
        • Serum ferritin is best single test: results are high in patients with sideroblastic anemia
          • Serum iron is also high in patients with sideroblastic anemia
          • Basophilic stippling of RBCs in patients with sideroblastic anemia
        • Thalassemia: iron study results are normal in thalassemia trait/minor
          • In patients with thalassemia intermedia and major, ferritin can be high, but molecular testing can differentiate these cases

    Treatment

    Goals

    • Prevent or correct severe anemia
    • Sustain normal growth and development throughout childhood
    • Prevent iron overload

    Disposition

    Admission criteria

    Principal reasons for admission of patients with thalassemia r32

    • Infection
    • Severe complications of iron overload (eg, heart failure)
    Criteria for ICU admission
    • Cardiac, hepatic, or other organ failure due to iron overload
    • Sepsis

    Recommendations for specialist referral

    • Refer all patients suspected of having thalassemia to a hematologist
    • Refer family members of affected patients to a medical geneticist for assessment of carrier status and personal disease risk
    • Offer young adult patients with thalassemia or those at risk of being carriers (ie, family history) who desire to conceive referral to a prenatal genetic counselor

    Treatment Options

    β-Thalassemia major

    • Regular blood transfusions are required, generally every 2 to 5 weeks, to maintain a pretransfusion hemoglobin concentration of 9.5 to 10.5 g/dL r9r15
      • Transfusions serve to correct anemia, inhibit ineffective erythropoiesis, and suppress increased gastrointestinal absorption of iron
      • Need for transfusion may start as early as age 6 months
    • Erythropoiesis-enhancing agents
      • Luspatercept, which promotes late-stage erythropoiesis, can be used to treat anemia and reduce transfusion requirements for adult patients with transfusion-dependent β-thalassemia r5r33r34
        • Administered subcutaneously once every 3 weeks r35
        • Not yet approved for use in children or pregnant patients
      • Other agents targeting ineffective erythropoiesis and iron dysregulation are currently under investigation r5r35r36
    • Assess iron stores for iron overload, which will eventually develop r5r15
      • Serial serum ferritin provides an estimate of iron burden
      • Quantitative measurement of hepatic iron stores
        • Liver biopsy is the gold standard for determining iron stores but is invasive and impractical, and iron stores may be irregularly distributed in the liver (causing false-negative study results)
        • MRI techniques using T2 and T2* parameters are validated for determining liver iron stores; cardiac T2* is also valid
    • Iron chelation therapy is given to lower iron stores and prevent the complications of hemochromatosis r15
      • Usually is required to start between ages 5 and 8 years r10
        • Start chelation therapy when serum ferritin exceeds 1000 mcg/mL or iron overload is otherwise determined r4
        • Goal is to maintain hepatic iron concentration lower than 7.0 mg/g of dry-weight liver tissue r15
      • Deferoxamine (desferrioxamine) has been the treatment of choice but requires subcutaneous or IV administration (5-7 days per week with 12-hour continuous infusion) r15
        • Major drawback is low adherence to therapy
      • Deferiprone is given orally 2 to 3 times daily r15
        • Monitor patient for neutropenia and agranulocytosis, gastrointestinal symptoms, and arthropathy
        • Studies indicate that deferiprone is more cardioprotective than deferoxamine
      • Deferasirox, the newest iron chelator, is given orally once daily
        • Transient gastrointestinal complaints are usual, and agranulocytosis has not been seen
        • Monitor for hepatic failure, renal failure, cytopenias, and gastrointestinal hemorrhage, which have been reported in the postmarketing phase
      • A combination of deferoxamine and deferiprone has been used for severe iron overload with manageable toxicity
    • Splenectomy is often performed r6
      • Indications for splenectomy are the following: r5
        • Increased transfusion requirement that prevents adequate iron control with chelation therapy
        • Hypersplenism
        • Symptomatic splenomegaly
      • Requires prophylactic antibiotics after surgery for at least 2 to 5 years and possibly lifelong r5
    • Bone marrow transplant (hematopoietic stem cell transplant) is a potentially curative procedure r37
      • Offer for children before development of iron overload and its manifestations, using HLA-matched sibling donor
        • Excellent outcomes reported with low-risk patients (those with no hepatomegaly, with no portal fibrosis on liver biopsy, and who are receiving regular chelation therapy)
      • Also offer to adults whose iron stores have been controlled through regular chelation therapy
      • Less than 25% of patients will have access to an HLA-matched donor for an allogenic transplant
      • Disease-free survival up to 90% when an HLA-identical sibling donor is used
      • Newer methods that do not require irradiation are used for bone marrow ablation before transplant
    • Gene therapy r6
      • Use of a viral vector to introduce a fully functional gene into the patient's genome
      • Has eliminated transfusion requirement for treated patients r38
      • Betibeglogene autotemcel was recently approved by FDA for adult and pediatric patients with β-thalassemia who are transfusion dependent r39

    β-Thalassemia intermedia

    • Encompasses a range of clinical phenotypes; transfusions are given if and when necessary r4
      • Some patients require no transfusions or require transfusion only during periods of erythropoietic stress such as pregnancy or infection, while others require regular transfusions and are managed in the same way as patients with β-thalassemia major
      • Need for transfusions is determined by monitoring for symptoms and effects (if any) on growth and development over time r4
        • Indications for transfusion therapy in β-thalassemia intermedia r40
          • Hemoglobin level less than 5 g/dL
          • Decreasing hemoglobin level in concert with profound spleen enlargement (more than 3 cm growth per year)
          • Growth failure (height more indicative of growth pattern)
          • Decreased exercise tolerance
          • Failure of secondary sexual development (in parallel with bone age)
          • Severe bony changes
          • Pregnancy
          • Infection causing hemoglobin decrease
    • Assess iron load regularly and provide chelation therapy if indicated r4
      • Start chelation therapy when serum ferritin is above 1000 mcg/mL or iron overload is otherwise determined
      • Patients with β-thalassemia intermedia have excess gastrointestinal iron absorption due to ineffective erythropoiesis; iron overload can occur without receiving regular transfusion therapy
    • Hydroxyurea is recommended for some patients with non–transfusion-dependent β-thalassemia intermedia r41
      • In erythroid cells, hydroxyurea induces production of γ-globin chains, which can then combine with α-globin chains to form hemoglobin F r41
      • Has been shown to improve hemoglobin level, hematocrit, mean corpuscular volume, and mean corpuscular hemoglobin in patients with β-hemoglobinopathies r41
      • Can significantly decrease transfusion requirements for up to 79% of patients with non–transfusion-dependent β-thalassemia intermedia and reduce extramedullary hematopoiesis and splenomegaly r41
      • Studies on efficacy in other types of β-thalassemia are ongoing r41
    • Splenectomy may be required for the same indications as for β-thalassemia major r4
      • RBC requirements to maintain hemoglobin at over 9.5 to 10 g/dL exceed 200 mL/kg of packed RBCs per year r6
      • Symptomatic splenomegaly r6
      • Increased iron overload despite receiving iron chelation therapy r6
      • Leukopenia or thrombocytopenia r6
    • Provide supplementary folic acid to patients with β-thalassemia intermedia with no or low transfusion requirement to prevent deficiency due to hyperactive bone marrow r4

    β-Thalassemia minor and β-thalassemia minima r4

    • No therapy or ongoing monitoring is required

    α-Thalassemia major (hydrops fetalis) r11

    • Patients with hydrops fetalis not treated in utero are typically either stillborn or die in the neonatal period
      • Prenatal diagnosis and early pregnancy termination are usually considered
      • Parents may be offered the option of in utero transfusions, which can potentially prevent hydrops fetalis and permit survival until birth; lifelong transfusions or a hematopoietic stem cell transplant would then be required for continued survival, similar to patients with β-thalassemia major r14

    α-Thalassemia intermedia (hemoglobin H disease) r11

    • Most patients are clinically well and require no treatment
    • Occasional transfusion of RBCs may be required if hemoglobin suddenly drops owing to hemolysis or aplasia associated with febrile illness
    • Massive splenomegaly or hypersplenism is an indication for splenectomy

    α-Thalassemia minor and α-thalassemia minima r13

    • No therapy or ongoing monitoring is required

    Drug therapy

    • Iron chelators r5r16c106
      • Indicated to prevent hemochromatosis in transfusion-managed patients
      • Required when serum ferritin has reached 1000 mcg/L, which usually happens after 10 to 20 transfusions
      • Any of the following iron chelators can be used:
        • Deferoxamine (desferrioxamine) r42c107
          • Subcutaneous
            • In general, the subcutaneous route of administration is preferred for chronic iron overload.
            • Deferoxamine Mesylate Solution for injection; Infants† and Children 1 to 2 years†: 25 to 35 mg/kg/dose subcutaneously over 8 to 24 hours for 5 to 7 days/week.
            • Deferoxamine Mesylate Solution for injection; Children and Adolescents 3 to 17 years: 20 to 60 mg/kg/day subcutaneously over 8 to 24 hours for 5 to 7 days/week. Usual Max: 50 mg/kg/day except when very intensive chelation is needed in persons who have completed growth.
            • Deferoxamine Mesylate Solution for injection; Adults: 20 to 60 mg/kg/day subcutaneously over 8 to 24 hours for 5 to 7 days/week. Usual Max: 50 mg/kg/day except when very intensive chelation is needed in persons who have completed growth.
          • Intravenous
            • Deferoxamine Mesylate Solution for injection; Infants† and Children 1 to 2 years†: 25 to 35 mg/kg/dose IV over 8 to 12 hours for 5 to 7 days/week.
            • Deferoxamine Mesylate Solution for injection; Children and Adolescents 3 to 17 years: 20 to 40 mg/kg/day IV over 8 to 12 hours for 5 to 7 days/week. Max: 40 mg/kg/day until growth has stopped.
            • Deferoxamine Mesylate Solution for injection; Adults: 40 to 50 mg/kg/day IV over 8 to 12 hours for 5 to 7 days/week. Max: 60 mg/kg/day.
        • Deferiprone c108
          • Twice daily tablets (1000 mg)
            • Deferiprone Oral tablet; Children and Adolescents 8 to 17 years: 37.5 mg/kg/dose PO 2 times daily, initially. To minimize gastrointestinal upset, dosing may be initiated at 22.5 mg/kg/dose PO 2 times daily and increased by 15 mg/kg/day weekly. Adjust dose based on response and therapeutic goals. Max: 99 mg/kg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
            • Deferiprone Oral tablet; Adults: 37.5 mg/kg/dose PO 2 times daily, initially. To minimize gastrointestinal upset, dosing may be initiated at 22.5 mg/kg/dose PO 2 times daily and increased by 15 mg/kg/day weekly. Adjust dose based on response and therapeutic goals. Max: 99 mg/kg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Three times daily tablets (500 or 1000 mg)
            • Deferiprone Oral tablet; Children and Adolescents 8 to 17 years: 25 mg/kg/dose PO 3 times daily, initially. To minimize gastrointestinal upset, dosing may be initiated at 15 mg/kg/dose PO 3 times daily and increased by 15 mg/kg/day weekly. Adjust dose based on response and therapeutic goals. Max: 99 mg/kg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
            • Deferiprone Oral tablet; Adults: 25 mg/kg/dose PO 3 times daily, initially. To minimize gastrointestinal upset, dosing may be initiated at 15 mg/kg/dose PO 3 times daily and increased by 15 mg/kg/day weekly. Adjust dose based on response and therapeutic goals. Max: 99 mg/kg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Oral solution
            • Deferiprone Oral solution; Children and Adolescents 3 to 17 years: 25 mg/kg/dose PO 3 times daily, initially. To minimize gastrointestinal upset, dosing may be initiated at 15 mg/kg/dose PO 3 times daily and increased by 15 mg/kg/day weekly. Adjust dose based on response and therapeutic goals. Max: 99 mg/kg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
            • Deferiprone Oral solution; Adults: 25 mg/kg/dose PO 3 times daily, initially. To minimize gastrointestinal upset, dosing may be initiated at 15 mg/kg/dose PO 3 times daily and increased by 15 mg/kg/day weekly. Adjust dose based on response and therapeutic goals. Max: 99 mg/kg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
        • Deferasirox tablets or granules r43c109
          • Non-transfusion dependent-thalassemia syndromes
            • Deferasirox Oral granules; Children and Adolescents 10 to 17 years: 7 mg/kg/dose PO once daily, initially. Consider increasing the dose to 14 mg/kg/day after 4 weeks if the baseline liver iron (Fe) concentration is more than 15 mg Fe/g of dry weight. Adjust dose after 6 months based on liver iron concentration. Max: 14 mg/kg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
            • Deferasirox Oral tablet; Adults: 7 mg/kg/dose PO once daily, initially. Consider increasing the dose to 14 mg/kg/day after 4 weeks if the baseline liver iron (Fe) concentration is more than 15 mg Fe/g of dry weight. Adjust dose after 6 months based on liver iron concentration. Max: 14 mg/kg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Transfusional iron overload
            • Deferasirox Oral granules; Children and Adolescents 2 to 17 years: 14 mg/kg/dose PO once daily, initially. Titrate dose by 3.5 or 7 mg/kg/dose every 3 to 6 months based on serum ferritin concentrations. Usual Max: 21 mg/kg/day. Max: 28 mg/kg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
            • Deferasirox Oral tablet; Adults: 14 mg/kg/dose PO once daily, initially. Titrate dose by 3.5 or 7 mg/kg/dose every 3 to 6 months based on serum ferritin concentrations. Usual Max: 21 mg/kg/day. Max: 28 mg/kg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Erythropoiesis enhancer
      • Luspatercept r5r33r44c110
        • Luspatercept Solution for injection; Adults: 1 mg/kg/dose subcutaneously once every 3 weeks, initially. Increase the dose to 1.25 mg/kg/dose once every 3 weeks if there is no reduction in RBC transfusion burden after at least 2 consecutive doses. Max: 1.25 mg/kg/dose. Therapy interruption, a dosage reduction, or discontinuation may be necessary in patients who develop elevated hemoglobin concentrations or severe adverse reactions. Discontinue therapy if there is no reduction in RBC transfusion burden after at least 3 consecutive doses at 1.25 mg/kg/dose.
      • Hydroxyurea
        • Hydroxyurea Oral tablet; Children and Adolescents: 10 to 15 mg/kg/dose PO once daily, initially. Increase the dose by 2.5 to 5 mg/kg/day gradually. Usual dose: 15 to 30 mg/kg/day. Max 35 mg/kg/day.
        • Hydroxyurea Oral tablet; Adults: 10 to 15 mg/kg/dose PO once daily, initially. Increase the dose by 2.5 to 5 mg/kg/day gradually. Usual dose: 15 to 30 mg/kg/day. Max 35 mg/kg/day.
    • Gene therapy
      • Betibeglogene autotemcel
        • Betibeglogene autotemcel Suspension for injection; Children and Adolescents 4 to 17 years: 5 x 10 to the 6th power CD34+ cells/kg IV as a single dose is the minimum recommended dose.
        • Betibeglogene autotemcel Suspension for injection; Adults: 5 x 10 to the 6th power CD34+ cells/kg IV as a single dose is the minimum recommended dose.
    • Antibiotics
      • Provide for at least 2 to 5 years after splenectomy; consider lifelong prophylaxis, especially for high-risk patients r5
      • Amoxicillin r45c111
        • Amoxicillin Trihydrate Oral tablet; Infants and Children 1 month to 5 years: 20 to 40 mg/kg/day (Max: 500 mg/day) PO divided once or twice daily.
        • Amoxicillin Trihydrate Oral tablet; Children and Adolescents 6 to 17 years: 20 to 40 mg/kg/day (Max: 500 mg/day) PO divided once or twice daily.
        • Amoxicillin Trihydrate Oral tablet; Adults: 250 to 500 mg PO once daily.
      • Penicillin r5c112
        • Penicillin V Potassium Oral tablet; Infants and Children 1 month to 2 years: 125 mg PO twice daily.
        • Penicillin V Potassium Oral tablet; Children 3 to 5 years: 250 mg PO twice daily.
        • Penicillin V Potassium Oral tablet; Children and Adolescents 6 to 17 years: 250 mg PO twice daily.
        • Penicillin V Potassium Oral tablet; Adults: 500 mg PO once or twice daily.
    • Nutritional supplementation
      • Folic acid
        • Folic acid supplementation is indicated to prevent deficiency from hyperactive bone marrow in patients with β-thalassemia intermedia and α-thalassemia intermediar13r4c113
        • Folic Acid Oral tablet; Children and Adolescents: 1 mg PO once daily.
        • Folic Acid Oral tablet; Adults: 1 mg PO once daily.
      • Zinc r5
        • Zinc supplementation is indicated for proven deficiency, poor growth, and reduced bone mass
        • Zinc Oral tablet; Children and Adolescents: 15 to 40 mg PO once daily.
        • Zinc Oral tablet; Adults: 15 to 40 mg PO once daily.
      • Calcium r5
        • Calcium supplementation is indicated for prevention and treatment of thalassemia-associated osteoporosis in conjunction with vitamin D
        • Calcium Carbonate Oral tablet; Children and Adolescents: 1,000 mg/day elemental calcium (2,500 mg/day calcium carbonate) PO.
        • Calcium Carbonate Oral tablet; Adults: 1,000 mg/day elemental calcium (2,500 mg/day calcium carbonate) PO.
      • Vitamin D r5
        • Vitamin D supplementation is indicated for prevention and treatment of thalassemia-associated osteoporosis in conjunction with calcium
        • Vitamin D (Cholecalciferol) Oral tablet; Children and Adolescents: 50 mcg (2,000 International Units) PO once daily.
        • Vitamin D (Cholecalciferol) Oral tablet; Adults: 50 mcg (2,000 International Units) PO once daily.
      • Vitamin C (ascorbic acid)
        • Vitamin C (Ascorbic Acid) Oral tablet; Infants and Children 1 to 9 years: 50 to 100 mg PO once daily. Max 2 to 3 mg/kg/day.
        • Vitamin C (Ascorbic Acid) Oral tablet; Children and Adolescents 10 to 17 years: 100 mg PO once daily. Max 2 to 3 mg/kg/day.
        • Vitamin C (Ascorbic Acid) Oral tablet; Adults: 200 mg PO once daily. Max 2 to 3 mg/kg/day.

    Nondrug and supportive care

    Main therapy is transfusion of packed RBCs r9c114

    • Required routinely (eg, monthly, bimonthly, weekly) for patients with β-thalassemia major
    • Monitor patients with less severe forms of β- and α-thalassemia by CBC and transfuse when needed
      • Patients with the trait rarely or never require transfusion

    More advanced procedures are hematopoietic stem cell transplantr37 and gene therapyr46c115c116

    Calcium and vitamin D supplementation recommendations for all patients r5c117c118c119

    Patients with anemia: folic acid supplementation recommended for these patients; can be considered for all patients r5

    Patients with zinc deficiency: zinc supplementation recommended for these patients; can be considered in all patients r5r47

    Avoid iron-containing supplements unless patient has documented iron deficiency; dietary iron restriction may be necessary for some patients at risk of iron overload r5c120

    Diet rich in vitamin E is recommended r5

    Vitamin C supplementation is recommended with deferoxamine infusions or if deficiency is proven r5

    Counsel to avoid alcohol and tobacco use r5c121c122

    • Alcohol exacerbates the oxidative damage of iron; in conjunction with the hepatitis viruses, it significantly increases the risk of cirrhosis and hepatocarcinoma r5
    • Tobacco use affects bone remodeling and increases the risk of osteoporosis r5

    Psychological support may improve overall well-being and adherence to treatment r5

    Genetic counseling r11r15c123

    • Offer preconception genetic counseling and testing to people of childbearing age
    Procedures
    Transfusion r5c124
    General explanation
    • Lifelong regular blood transfusions are recommended for patients with transfusion-dependent thalassemia r5
    • Regular transfusion therapy is usually initiated in first 2 years of life for severe thalassemia genotypes; some patients with milder forms may need regular transfusions later in life r5
    • Transfusion promotes normal growth, facilitates normal functioning, and suppresses excessive bone marrow activity r5
    • Patients are given leuko-depleted packed RBCs that are matched appropriately with the patient's RBC antigen phenotype r9
      • Extended phenotype-matched RBCs should be used for patients who develop alloimmunization r48
      • Before a first transfusion, perform extended RBC antigen typing of at least ABO, C, c, D, E, e, and Kell, although preferably perform a full RBC phenotype/genotype panel
      • At each transfusion, give blood compatible for ABO, C, c, E, e, and Kell antigens
    • Obtain serum immunoglobulin determination to identify patients with IgA deficiency who may benefit from washed RBCs
    • Volume of packed RBCs required is calculated for children as follows: required increase in hemoglobin (g/L) × child's weight (kg) × 0.3 r5
      • Normal transfusion rate is 5 mL/kg/hour for children, completing transfusion within 4 hours r16
    • In adults, 1 unit of packed RBCs will typically raise the hemoglobin concentration by 1 g/dL and the hematocrit by 3% r49
      • Transfusion must be completed within 4 hours
    Indication
    • Criteria required to initiate transfusion therapy include confirmed thalassemia diagnosis and either or both of the following: r5
      • Hemoglobin less than 7 g/dL on 2 occasions spaced at least 2 weeks apart
      • Symptomatic anemia, poor growth/failure to thrive, complications from excessive intramedullary hematopoiesis, or clinically significant extramedullary hematopoiesis
    • Goals of therapy: r5
      • β-Thalassemia major
        • Goal of regular scheduled transfusion therapy is to maintain a pretransfusion target hemoglobin range of 9.5 to 10.5 g/dL
        • Consider higher pretransfusion target hemoglobin level (10-12 g/dL) in the setting of cardiac insufficiency or other cardiac complications
        • Typical posttransfusion target hemoglobin range is 13 to 15 g/dL
        • Transfusion approach aims to promote normal growth and activity, suppress ineffective erythropoiesis, and minimize iron overload
          • Suppressing erythropoiesis helps to prevent cardiac and endocrine complications and reduces splenomegaly and its consequences r50
      • Patients with α- and β-thalassemia intermedia are typically treated with sporadic transfusions, using the same approach as is taken with β-thalassemia major; some patients will become transfusion dependent r9
    Complications r51
    • Alloimmunization
    • Iron overload
    • Blood-borne infection
    • Transfusion reactions
    Interpretation of results
    • Treatment is successful if posttransfusion hemoglobin level is over 10.5 g/dL but not higher than 13 to 15 g/dL r4r5
    Splenectomy r6c125
    General explanation
    • Surgical removal of spleen
      • Decision to remove spleen must be balanced with increased risk of thrombosis and bacterial infection leading to sepsis
      • 1 Month or more before splenectomy, immunize the patient with the pneumococcal polysaccharide vaccine and vaccines against Haemophilus influenza and Neisseria meningitidisr5
        • Also give pneumococcal conjugate vaccine series to children
      • Patients who have undergone splenectomy should receive influenza immunization annually r5
      • Give antibiotic prophylaxis to all patients who have had a splenectomy for at least 2 to 5 years postoperatively, lifelong for high-risk patients r5
        • Lifelong prophylaxis is indicated after an episode of postsplenectomy sepsis
    Indication
    • Increased transfusion requirement that prevents adequate iron control with chelation therapy r6
    • Symptomatic splenomegaly r5
    • Hypersplenism r5
    Contraindications
    • Inability to tolerate general anesthesia
    • Uncontrollable coagulopathy
    Complications
    • Major long-term postsurgical risk is sepsis
    • Thromboembolism, particularly in postoperative period
    • Pulmonary hypertension
    Hematopoietic stem cell transplantation r37r52c126
    General explanation
    • Patient is implanted with hematopoietic stem cells obtained from any of the following:
      • Bone marrow from a matched sibling or other well-matched donor
      • Embryonic source
      • HLA-identical sibling umbilical cord cells
    • The transplanted stem cells have normal globin genes, so the patient begins making normal RBCs
    • Usually before transplant, the patient's own bone marrow is myeloablated (the bone marrow is suppressed with chemotherapy), but new methods allow for hematopoietic stem cell transplant without myeloablation
      • No controlled trials have compared effectiveness/safety of different types of hematopoietic stem cell transplantation r53
    • Potentially curative treatment option for transfusion-dependent thalassemia r5
    Indication
    • Thalassemia major with dependency on transfusion
    • Ideally offered at early age before complications from iron overload have developed r5
    • Patients aged 15 years or younger are the best candidates for hematopoietic stem cell transplantation methods that use myeloablation, but nonablative approaches allow more adults with thalassemia major to qualify as candidates r37
    Contraindications
    • No available matched donor
    Complications r54r55
    • Toxicity secondary to myeloablative regimen
    • Infection secondary to immunosuppression
    • Acute or chronic graft-versus-host disease
    • Late endocrine complications such as thyroid dysfunction, diabetes, and hypogonadism
    Interpretation of results
    • Development of normal CBC results indicates a successful procedure
    Gene therapy c127
    General explanation
    • Any or all of the following genetic modification approaches: r56
      • Gene for the deficient/absent globin is added to the genome of the patient's hematopoietic stem cells
      • Gene for alternate globin that can substitute for deficient chain is turned on or its expression is amplified
        • For β-thalassemia this means turning on γ-globin expression to replace deficient β globin
      • Expression of the other globin (α in the case of β-thalassemia) is decreased to prevent tetramer formation
    • Betibeglogene autotemcel is the only gene therapy currently approved by FDA for thalassemia r46
      • Production of the patient's hematopoietic stem cells is chemically stimulated; stem cells are then harvested via apheresis r46
      • A modified β-globin gene is added to the stem cells' genome ex vivo using lentiviral transduction r46
      • Chemotherapeutic agents are used to deplete the patient's hematopoietic stem and progenitor cells to facilitate engraftment (myeloablative bone marrow conditioning) r57
      • Genetically modified stem cells are infused back into the patient in a manner similar to hematopoietic stem cell transplant
    • Eliminates the need for a donor and the risks associated with allogenic hematopoietic stem cell transplant (graft rejection, graft-versus-host disease, infertility, and other treatment-related toxic effects) r58
    • Results in normal or near-normal hemoglobin levels in 91% of patients followed up for up to 4 years after transplant r59
    • Cost may limit use; distribution in Europe was halted following failed negotiations over price r60
    Indication
    • Thalassemia major with dependency on transfusion
    Contraindications
    • None
    Complications
    • Potential toxicities of hematopoietic stem cell gene therapy can result from the myeloablative conditioning and unintended effects of genetic manipulation; improved conditioning regimens are an active area of research r57
    Interpretation of results
    • Development of normal CBC results indicates a successful procedure

    Comorbidities

    • Iron deficiency c128
      • Can complicate the diagnosis of thalassemia minor, since the presentation is similar to iron deficiency anemia and is distinguished from the latter based on normal iron study results
        • Patient with mild anemia, abnormal iron study results, and ethnicity consistent with thalassemia will require hemoglobin analysis to rule out thalassemia minor
      • Complicates treatment because iron supplementation is detrimental to patients with thalassemia
        • Patients with thalassemia minor are given an occasional transfusion because this provides them with RBCs containing both globins and iron
    • Glucose-6-phosphate dehydrogenase deficiency c129
      • Common in same populations in which β-thalassemia is common
      • Does not usually worsen the anemia but can affect management by restricting patient from certain antibiotics and other drugs
    • Viral hepatitis r5
      • Hepatitis B and C virus can accelerate hepatic fibrosis in patients with thalassemia
      • Routine screening for hepatitis B and C virus chronic infection is recommended for patients with thalassemia
        • Offer hepatitis B virus vaccination to patients who are seronegative for the virus markers
        • Evaluate patients with hepatitis B and C virus chronic infection for treatment with antiviral drugs

    Special populations

    • Pregnant patients with β-thalassemia intermedia who have not received transfusions or only minimally so are at risk for severe alloimmune anemia if blood transfusions are required
    • Monitor pregnant patients with α-thalassemia intermedia for preeclampsia, threatened miscarriage, heart failure, and worsening anemia owing to their increased risk for these conditions

    Monitoring

    • All forms of transfusion-dependent thalassemia (eg, β-thalassemia major) r4r5
      • Require regular follow-up with a physician knowledgeable about the patient and illness, usually a thalassemia specialist c130
      • Recommended with each clinical visit:
        • Clinical history
        • Height, weight, BMI, and vital signs
        • Physical examination including assessment of liver size
        • Assessment of vaccination status
      • Recommended monthly:
        • CBC
        • Vital sign monitoring
        • Monitoring for transfusion reactions
      • Recommended every 3 months:
        • Serum ferritin and transferrin
        • Complete metabolic panel including liver function tests
        • Fasting blood glucose
        • Creatine kinase
        • Height and weight monitoring for children and adolescents
      • Recommended every 6 months:
        • Zinc, magnesium, and vitamin D levels
        • Lipid panel
        • Urinalysis
        • Ultrasonographic screening for hepatocellular carcinoma
        • Growth velocity and pubertal development monitoring for children and adolescents
      • Recommended annually:
        • Audiologic examination
        • Ophthalmologic examination
        • Dental examination
        • Serologies for hepatitis A, B, and C virus (unless vaccinated for A and/or B)
        • HIV screening
        • Complete cardiac evaluation and evaluation of endocrine, pancreas, thyroid, parathyroid, adrenal, and pituitary function (usually after 10 years of transfusion therapy)
          • Includes thyroid and parathyroid hormone levels, ECG, echocardiography, and glucose tolerance test
          • Ideally, cardiac assessment and management are performed by clinics or physicians with experience in thalassemia-associated cardiomyopathy, in collaboration with the patient's thalassemia specialist
        • MRI studies to assess cardiac and hepatic iron
        • Abdominal ultrasonogram and FibroScan; every 6 months if known liver disease
        • DXA scan
    • Non–transfusion-dependent thalassemia r8
      • Monitoring is similar to that of transfusion-dependent thalassemia
      • More frequent monitoring of CBC, renal function, and hepatic function is indicated for patients receiving hydroxyurea
      • Monitor closely during acute infection or pregnancy, as these may be associated with hemolytic/aplastic crises
    • Patients with α-thalassemia minor and minima and β-thalassemia minor and minima are all carriers and require no long-term monitoring r10

    Complications and Prognosis

    Complications

    • Splenomegaly and hypersplenism c131c132
      • These patients are at high risk for infection and often require splenectomy
      • Overactivity of the spleen causes a significant increase in transfusion requirements for a patient with thalassemia
      • Splenectomy, and thus need for long-term prophylactic antibiotics, can be avoided with early diagnosis and treatment, which typically occur in the developed world (disease is detected in early childhood)
      • Splenectomy increases risk of thrombosis and can be managed by:
        • Anticoagulation before high-risk procedures (eg, surgery)
        • Antiplatelet therapy if thrombocytosis develops (platelets more than 800,000/mm³) r61
        • Low-molecular-weight heparin if thrombosis occurs
    • Heart failure c133
      • Late complication of severe anemia
      • Can result from hemochromatosis due to long-term transfusion treatment and from the disease itself causing an increase in iron absorption (ie, β-thalassemia intermedia)
      • Can be avoided by early diagnosis and treatment, including iron chelation therapy
    • Hepatomegaly and hepatic failure c134c135
      • Results from extramedullary hematopoiesis and hemochromatosis
      • Can be avoided by early diagnosis and treatment, including iron chelation therapy
      • Only treatment is liver transplant
    • Pathologic fractures c136
      • From excessive hematopoiesis
      • Can be avoided by early diagnosis and treatment and using radiography to look for expanded medullary spaces
      • Also can be prevented by radiation therapy given at times of extreme anemia to stop hematopoiesis (since it is ineffective hematopoiesis)
    • Iron overload leading to hemochromatosis c137c138
      • Results mostly from numerous transfusions needed by patients with transfusion-dependent thalassemia (eg, β-thalassemia major and some patients with β-thalassemia intermedia or α-thalassemia intermedia)
        • Can also result from thalassemia directly due to inadequate globin production, resulting in insufficient binding of iron
      • Can also occur secondary to excessive iron absorption caused by abnormally low levels of hepcidin in thalassemia, even in the absence of transfusions r62
      • Excessive iron stores cause the following: r9
        • Endocrine dysfunction
          • Hypothyroidism c139
          • Hypogonadotrophic hypogonadism c140
          • Growth hormone deficiency c141
          • Hypoparathyroidism c142
          • Diabetes mellitus c143
        • Cardiac pathology
          • Congestive heart failure c144
          • Cardiac arrhythmias c145
      • Prevented with chelation therapy
    • Sepsis r9c146
      • Can result from splenectomy
    • Chelation therapy complications can include the following: r9
      • Hearing loss (deferoxamine) c147
      • Peripheral neuropathy (deferoxamine) c148
      • Poor growth (deferoxamine) c149
      • Renal dysfunction (deferasirox) c150
      • Transient agranulocytosis (deferiprone) c151
    • Growth failure
      • Multifactorial causes, including chronic anemia, transfusion-related iron overload, chelation toxicity, hormonal factors, and nutritional factors r5
      • Growth complications noted in nearly half of patients with β-thalassemia major r63

    Prognosis

    • Patients with α-thalassemia major are stillborn or die in the perinatal period
    • Patients with β-thalassemia major die by age 5 years without transfusions r29
    • Patients with transfusion-dependent thalassemia (β-thalassemia major and some patients with β-thalassemia intermedia and α-thalassemia intermedia) develop iron overload complications by age 10 years r3
      • Cardiac complications due to severe anemia or iron overload have been the leading cause of mortality; however, advances in screening for myocardial and hepatic iron overload have led to reductions in mortality from this heart disease r64
      • Average life expectancy for patients with β-thalassemia major (and others who are transfusion dependent) has markedly improved in recent decades owing to improved monitoring and chelation therapy, from 17 years in 1970, to 27 years in 1980, and to 37 years in 1990 r10r64
      • Hepatocellular carcinoma and infection are other leading causes of death
      • Recent data suggest that 63% of patients are expected to survive until age 50 years, many without any disease-related complications at all r64
      • Despite recent improvements in survival, patients with transfusion-dependent thalassemia remain at increased risk for early mortality and continue to have high burden of iron overload and other disease-associated complications r65
    • Patients with thalassemia trait have a normal life expectancy
    • Males with β-thalassemia trait may be less likely to develop arterial cardiovascular and cerebrovascular disease than the general population r66

    Screening and Prevention

    Screening

    At-risk populations

    • Newborns born to individuals of African, Mediterranean, Middle Eastern, West Indian, or Southeast Asian heritage r2r28
    • Siblings of an affected child r11

    Screening tests

    • All 50 of the US states screen for β-thalassemia and other hemoglobinopathies in all newborns r28c152
      • Testing by electrophoresis of cord blood or blood extracted from dried blood on paper c153
      • While not currently employed globally, screening for thalassemia is recommended to be expanded globally as newborn testing programs develop
    • American College of Obstetrics and Gynecology recommends screening for hemoglobinopathies for pregnant individuals based on ethnicity (African, Mediterranean, Middle Eastern, Southeast Asian, or West Indian descent) and for those in whom routine antenatal RBC indices indicate a low mean corpuscular hemoglobin or mean corpuscular volume r2
      • Obtain CBC with RBC indices plus hemoglobin electrophoresis c154c155c156
      • When screenings are positive, offer testing of the partner to assess reproductive risk
    • The National Society of Genetic Counselors recommends offering expanded carrier screening to all individuals considering reproduction and all pregnant reproductive pairs as a non–race-based medical practice r67
      • The goal of expanded carrier screening is to identify a person's reproductive chance for 100 plus autosomal recessive and X-linked conditions with infantile or early-childhood onset, which may affect reproductive management r67
    • Test siblings of an affected child as early as possible r11
      • If molecular study results have been obtained previously and pathogenic variants of the disease in the family are known, obtain molecular testing c157
      • If pathogenic variants of the disease in the family are not known, obtain hematologic testing
        • CBC with RBC indices and peripheral smear c158c159c160
        • Hemoglobin electrophoresis if CBC shows anemia with reduced mean corpuscular volume c161

    Prevention

    • Prevention is possible only through effective prenatal screening and determination of carrier status in the potential father and mother, who can then make reproductive decisions based on knowledge of the disease risk r68c162c163
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