Alpha Thalassemia 

Updated: Oct 16, 2018
Author: Alexandra C Cheerva, MD, MS; Chief Editor: Hassan M Yaish, MD 

Overview

Background

The alpha thalassemia (α-thalassemia) syndromes are a group of hereditary anemias of varying clinical severity. They are characterized by reduced or absent production of 1 or more of the globin chains of which human hemoglobin is composed.

The oxygen carrying capability of the red blood cells (RBCs) relies on hemoglobin, a tetramer protein that comprises 4 globin chains bound to the heme molecule. There are 4 major types of globins: alpha (α), beta (β), gamma (γ), and delta (δ). The dominant hemoglobin in adults (hemoglobin A) is composed of 2 alpha and 2 beta chains. Two minor forms of hemoglobin constitute a small percentage of normal blood: hemoglobin F (fetal), composed of 2 alpha chains and 2 gamma chains, and hemoglobin A2, composed of 2 alpha chains and 2 delta chains.

A very tightly controlled globin chain production process keeps the ratio of alpha chains to non-alpha chains at 1.00 (± 0.05). Thalassemia, by altering this process, disrupts this ratio. Decreased production of alpha-globin gene products, whether alpha1 globin or alpha2 globin (alpha-globin gene is present in duplicate on chromosome 16), yields a relative excess of beta chains, which results in less stable chains; this leads to the clinical disease known as alpha thalassemia.[1, 2] Similarly, impaired production of beta-globin gene products manifests with a more severe disease known as beta thalassemia.[3, 4]

Thalassemia is one of the world’s most common single-gene disorders. Individuals with thalassemia syndrome are most often of African, Asian, Mediterranean, or Middle Eastern descent. Mutations and gene deletions causing the various thalassemia genotypes have arisen independently in different populations but have subsequently propagated by means of natural selection.[5, 6, 7]

Thalassemia is more prevalent in regions in which malaria is endemic because the RBC phenotype confers some protection against malaria.[8] Individuals with beta thalassemia syndromes have somewhat better protection against malaria than individuals with alpha thalassemia syndromes.

Pathophysiology

Genes that regulate both the synthesis and the structure of different globins are organized into 2 separate clusters. The alpha-globin genes are encoded on chromosome 16, and the gamma-, delta-, and beta-globin genes are encoded on chromosome 11. Healthy individuals have 4 alpha-globin genes, 2 on each chromosome 16 (αα/αα; see the image below). Alpha thalassemia syndromes are caused by deficient expression of 1 or more of the 4 alpha-globin genes on chromosome 16 and are characterized by absent or reduced synthesis of alpha-globin chains.

Alpha-chain genes in duplication on chromosome 16 Alpha-chain genes in duplication on chromosome 16 pairing with non-alpha chains to produce various normal hemoglobins.

Abnormal production of alpha-globin chains results in a relative excess of gamma-globin chains in fetuses and newborns and of beta-globin chains in children and adults. Furthermore, the beta-globin chains are capable of forming soluble tetramers (β4, or hemoglobin H [HbH]); yet this form of hemoglobin is unstable and tends to precipitate within the cell, forming insoluble inclusions (Heinz bodies) that damage the red cell membrane.

In addition, diminished hemoglobinization of individual red blood cells results in damage to erythrocyte precursors and ineffective erythropoiesis in the bone marrow, as well as hypochromia and microcytosis of circulating red blood cells.

From a genetic standpoint, alpha thalassemia syndromes are extremely heterogeneous; however, their phenotypic expression may be described in simplified clinical terms related to the number of inherited alpha-globin genes. Alpha thalassemia may be broadly classified according to whether the loss of alpha-globin genes is complete or partial—that is, alpha(0) thalassemia or alpha(+) thalassemia. Some subclasses are present within the latter category, based on the number of genes affected. In all, there are four general forms of alpha thalassemia.

Alpha(0) thalassemia

More than 20 different genetic mutations resulting in the functional deletion of both pairs of alpha-globin genes (--/--) have been identified. The resulting disorder is referred to as hydrops fetalis, alpha thalassemia major, or hemoglobin Bart’s. Individuals with this disorder cannot produce any functional alpha globin and thus are unable to make any functional hemoglobin A, F, or A2. Hydrops fetalis is incompatible with extrauterine life, and fetuses with this condition characteristically died either in utero or shortly after birth because of severe anemia. While the mortality rate for hydrops fetalis is still high, medical advances have permitted a portion of these infants to survive.

Alpha(+) thalassemia

There are more than 15 different genetic mutations that result in decreased production of alpha globin, usually through functional deletion of 1 or more of the 4 alpha-globin genes. Alpha(+) thalassemia is subclassified into the following three general forms on the basis of the number of inherited alpha genes.

Silent carrier

Persons who inherit 3 normal alpha-globin genes (-α/αα) are referred to clinically as silent carriers. Other names for this condition are alpha thalassemia minima, alpha thalassemia-2 trait, and heterozygosity for alpha(+) thalassemia minor. The affected individuals exhibit no clinical abnormalities and may be hematologically normal or have slight reductions in RBC mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH).

Alpha thalassemia trait

Inheritance of 2 normal alpha-globin genes through either heterozygosity for alpha(0) thalassemia (αα/--) or homozygosity for alpha(+) thalassemia (-α/-α) results in the development of alpha thalassemia trait, also referred to as alpha thalassemia minor or alpha thalassemia-1 trait. If both alpha2- and alpha1-globin genes are deleted on the same chromosome (--/αα), the genotype is said to have the cis form; if the 2 alpha2 -globin genes of both alleles of chromosome 16 are deleted but the alpha1 -globin genes are intact (-α/-α), it is said to have the trans form.

The affected individuals are clinically normal but frequently have minimal anemia and reduced MCV and MCH. The RBC count is usually increased, typically exceeding 5.5 × 1012/L.

Hemoglobin H disease

Inheritance of only one out of the four normal alpha-globin genes (-α/--) leads to a condition known as HbH disease, or alpha thalassemia intermedia. The loss of 3 alpha-globin genes results in abundant formation of HbH, which is characterized by a high ratio of beta globin to alpha globin and a 2-fold to 5-fold excess in beta-globin production. The excess beta chains aggregate into tetramers, which account for 5-30% of the hemoglobin level in patients with HbH disease.[9]

HbH has a high affinity for oxygen and has no Bohr effect or heme-heme interaction; therefore, it is an ineffective supplier of oxygen to the tissues under physiologic conditions. Patients with significant amounts of HbH have a defect in oxygen-carrying capacity that is more severe than would be expected on the basis of the hemoglobin concentration alone. RBCs that contain HbH are sensitive to oxidative stress; thus, they may be more susceptible to hemolysis when oxidants such as sulfonamides are administered.

Aging erythrocytes contain more precipitated HbH than younger erythrocytes; consequently, they are removed from the circulation prematurely. Thus, HbH disease is primarily a hemolytic disorder. When bone marrow cells are examined, HbH inclusions are rare, and erythropoiesis is apparently effective. Erythroid hyperplasia can result in typical structural bone abnormalities with marrow hyperplasia, bone thinning, maxillary hyperplasia, and pathologic fractures.

An Iranian study, by Farashi et al, of 66 patients with HbH disease found that point mutations produced a more severe form of the condition than did deletional mutations.[10]  The clinical severity of HbH disease may depend on which alpha-globin gene is deleted, since one of the alpha genes may produce only 25% of the alpha-globin chains, while the other provides 75% of them.

A study by Xu et al found that in individuals with HbH disease, HbA1c values are significantly below those found in controls or in patients with two or three functional alpha-globin genes. This finding is significant because alpha thalassemia frequently occurs in patients with diabetes mellitus. Nondiabetic patients were used in the study.[11]

Etiology

Normal hemoglobin biosynthesis requires an intact gene, silencers, enhancers, promoters, and locus control region (LCR) sequences. Several hundred mutations causing thalassemia have been described. These may affect any step in globin gene expression, transcription, pre-mRNA splicing, mRNA translation and stability, and posttranslational assembly and stability of globin polypeptides.

The most common mechanism of aberrant alpha-globin production involves deletion of either portions of the alpha-globin genes themselves or the genetic regulatory elements that control their expression. Regulatory elements may be located on the same chromosome (cis -acting elements) or on separate chromosomes (trans -acting elements).

The (--SEA) type of alpha thalassemia deletion removes both alpha-globin genes in cis, is common in Southeast Asia, and is the most common cause of HbH disease and hydrops fetalis in that part of the world. Nondeletional forms of alpha thalassemia in which the alpha-globin genes are intact are caused by mutations similar to those causing beta thalassemia and are relatively uncommon.[12, 13]

Production of functional hemoglobin is also impaired in alpha thalassemia when point mutations, frame shift mutations, nonsense mutations, and chain termination mutations occur within or around the coding sequences of the alpha-globin gene cluster. These gene-level mutations may in turn affect RNA splicing, hinder initiation of mRNA translation, or result in the generation of unstable alpha-globin chain variants.

Mutations affecting transcription, pre-mRNA splicing, or canonical splice signals are rare causes of alpha thalassemia. Other forms of alpha thalassemia are caused by either premature or failed translation termination. More rare mutations have been found to cause thalassemia by interfering with the normal folding of otherwise normal globin peptide.

Epidemiology

United States statistics

The frequency of alpha thalassemia is low among whites. It is estimated that about 15% of American blacks are silent carriers for alpha thalassemia and about 3% have alpha thalassemia trait; HbH disease is rare in this population. In North America, many multicultural communities are growing, and these populations have increased frequencies of thalassemia syndromes.

In some ethnic groups, such as the Southeast Asian population (in particular) and Mediterranean populations, HbH disease and hemoglobin Bart’s (γ4) are common because of the frequent coinheritance of an allele lacking both alpha-globin genes and another allele lacking 1 alpha-globin gene. The high frequency of hemoglobin Constant Spring (CS) in the Southeast Asian population can lead to the HbH (--/-αCS) phenotype, which involves an elongated form of alpha-globin chain.[14, 1]

The results of one study suggested that HbH Constant Spring (HCS) should be identified as a distinct thalassemia syndrome with a high-risk of life-threatening anemia.[15] The study also found that HbH disease was managed without blood transfusions and was not associated with an increased rate of severe anemia. Because many patients with these disorders encompassed mixed ethnic backgrounds, the study emphasizes the need for extended newborn screening in populations that are customarily considered to be at low risk for HbH.[15]

According to the National Institutes of Health (NIH)-sponsored North American Thalassemia Clinical Research Network (TCRN) study of the epidemiology of thalassemia in North America, 59% of patients with alpha thalassemia have a single alpha-globin gene (-α/--), 8% have no alpha-globin genes (--/--), and 33% have gene deletions with structural mutations.

International statistics

Alpha thalassemia is perhaps the most common single-gene disorder in the world. It is estimated that there are 270 million carriers of mutant globin genes that can potentially cause severe forms of thalassemia. In addition, 300,000-400,000 severely affected infants are born every year, more than 95% of whom are in Asia, India, or the Middle East.

Before the introduction of DNA analysis, population surveys for alpha thalassemia were based entirely on the measurement of hemoglobin Bart’s levels in cord blood. However, single-gene-deletion heterozygotes do not always have detectable hemoglobin Bart’s in the neonatal period. As a result, reliable data on population frequencies for various types of alpha thalassemia are not always available.

Alpha thalassemia is common throughout parts of the world where malaria is endemic. Multiple studies have suggested that the presence of both single and double alpha-globin gene deletions has a protective effect against malaria.

The frequency of alpha thalassemia alleles is 5-10% in the Mediterranean basin, 20-30% in portions of West Africa, and as high as 60-80% in parts of Saudi Arabia, India, Thailand, Papua New Guinea, and Melanesia. In Thailand, which has a population of 62 million people, approximately 7000 infants are born each year with HbH disease. The frequency of heterozygote carrier status among the Chinese population has been reported to range from 5% to 15%. The frequency of alpha thalassemia is lower than 0.01% in Great Britain, Iceland, and Japan.[16, 17, 18, 19]

Age-related demographics

Abnormalities of alpha-globin chains are genetic, and individuals are born with the disorder.[20] The exception to this rule is patients with alpha thalassemia myelodysplastic syndrome (ATMDS), who are usually elderly, with a mean age of 68 years at diagnosis.

Sex-related demographics

In general, males and females are equally affected. However, there is a type of alpha thalassemia that is associated with mental retardation and affects only males. This condition is referred to as alpha thalassemia mental retardation-X syndrome (ATR-X).

However, a report by Haas et al identified 2 females in a single center with ATMDS and mutations in the ATR-X gene (ATRX).[21] The investigators observed that although it was possible that females may be less likely to develop ATMDS if the inactivated copy of ATRX is reactivated throughout life, this hypothesis was ruled out in their study by the use of a cross-sectional analysis of healthy females ranging in age from neonate to 90 years to examine the pattern of ATRX inactivation.

Race-related demographics

Alpha thalassemia occurs in individuals of all ethnic backgrounds but particularly those of African, Asian, Central American, Mediterranean, and Middle Eastern descent. Emigration from regions in which carrier frequency is high increases the presence of thalassemia syndromes in other parts of the world. The North American TCRN study showed that 85% of patients with alpha thalassemia are Asian, 4% are white, and 11% are of other ethnicities, including African, black, mixed ethnicity, and unknown.

Prognosis

For silent carriers and individuals with alpha thalassemia trait, the prognosis is excellent.

For individuals with HbH disease, the overall survival rate varies but is generally good, with most patients surviving into adulthood. However, some patients have a more complicated course and may not do as well. Patients with HbH disease are at risk for severe anemia and have a lifelong requirement for transfusions. One study suggests that the subtype of hemoglobin H Constant Spring (HCS) is associated with a high risk of life-threatening anemia.[15] Patients identified with this subtype of HbH disease require close follow-up. If anemia is well managed and iron overload is prevented with chelation therapy, individuals with HbH disease can live long and healthy lives.

Hydrops fetalis (alpha thalassemia major) is incompatible with life and requires identification in utero and in utero transfusions if the fetus is to survive and be born. To identify fetuses with this condition, family genetic studies must be done, high-risk couples identified, and the fetus tested in utero for the absence of alpha-globin chains.

Those rare fetuses that survive to be born, with the help of intrauterine transfusions, continue to require lifelong transfusions and medical care. They may be considered for hematopoietic stem cell transplantation, which is curative of their alpha thalassemia major syndrome.

A study by Joly et al supported the idea that alpha thalassemia reduces the risk of cerebral vasculopathy in children with sickle cell anemia. The report involved three groups of children with sickle cell anemia, including one group with cerebral vasculopathy (ie, stroke, silent infarct, or abnormal transcranial Doppler ultrasonography results), a second group without cerebral vasculopathy, and a third group with conditional transcranial Doppler ultrasonography results. The data indicated that alpha thalassemia has a protective effect against, and that glucose-6-phosphate dehydrogenase (G6PD) deficiency increases the risk for, cerebral vasculopathy in sickle cell anemia.[22]

Patient Education

Patients with a family history or a known carrier state for alpha thalassemia gene mutations should obtain genetic counseling to determine the genotype and assess the risk to offspring. This is especially true in cases of suspected concomitant hemoglobinopathy.

 

Presentation

History and Physical Examination

The history and physical findings in patients with alpha thalassemia vary according to the number of alpha-globin chains deleted. Additional beta-chain and other hemoglobin abnormalities may also contribute to the clinical presentation and course.

Silent carrier

Silent carriers (-α/αα) are essentially asymptomatic, and complete blood count (CBC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), peripheral smear, and hemoglobin electrophoresis are all typically normal. Slight hypochromia and microcytosis may be evident by microscopic evaluation. Silent carriers may be detected by alpha gene analysis. They may be identified when related carriers of the allele mate and have children with hemoglobin H (HbH) disease.

Alpha thalassemia trait

Individuals with alpha thalassemia trait (-α/-α or --/αα) are asymptomatic, with a normal CBC. The peripheral blood smear typically shows hypochromia, microcytosis, and target cells. The MCV is frequently less than 80 fL, and the MCH is always below 27 pg. RBC counts are usually higher than normal. Hemoglobin electrophoresis is normal. Although elevation of hemoglobin A2 does not occur, elevations of hemoglobin F have been reported.

Individuals of African origin usually carry a homozygous state of the alpha2 allele (the trans deletion, -α/-α), and deletion usually involves the less active of 2 normal alleles. Alpha thalassemia trait tends to be milder in this population. In Asia, the cis deletion ( --/αα) is common, and subpopulations exhibit more dramatic features of thalassemia trait. If patients have the hemoglobin Constant Spring (CS) mutation, a slowly migrating abnormal hemoglobin band is present on hemoglobin electrophoresis.

The condition is generally diagnosed as a result of incidental laboratory abnormalities and family studies to characterize a relative. Alpha-globin gene analysis can confirm the absence of 2 alpha-globin genes. Persons with this condition may be identified when a child is born with HbH disease.

Hemoglobin H disease

Symptoms of HbH disease (--/-α) are consistent with a chronic hemolytic anemia and include episodes of severe pallor and anemia. Patients are often symptomatic at birth; many others present with neonatal jaundice or anemia. Indirect hyperbilirubinemia, elevated lactate dehydrogenase levels, and reduced haptoglobin are all consistently seen with hemolytic anemia. Exacerbations of hemolysis may occur when patients are exposed to stressors such as infections, fever, ingestion of oxidative compounds, or drug use, and patients may require transfusions.

Generally, HbH disease is thought to be a mild disorder. However, because of the marked variability in degree of anemia, patients may range from asymptomatic to needing periodic transfusions to having severe anemia with hepatomegaly and splenomegaly. Some patients may also suffer hydrops fetalis syndrome in utero. Pregnancy may also be a special circumstance, in which patients may develop severe anemia and require transfusions.[14] The subset of patients with HbH Constant Spring (CS) may have a high risk of life-threatening anemia and require close follow-up.[15]

Complications occur in varying degrees and include the following:

  • Hepatosplenomegaly

  • Leg ulcers

  • Gallstones

  • Aplastic or hypoplastic crises

  • Skeletal, developmental, and metabolic changes due to ineffective erythropoiesis (these resemble the changes characteristic of beta thalassemia intermedia or beta thalassemia major)

  • Prominent frontal bossing (due to bone marrow expansion)

  • Delayed pneumatization of sinuses

  • Marked overgrowth of the maxillae

  • Ribs and long bones becoming boxlike and convex

  • Premature closure of epiphyses resulting in shortened limbs

  • Compression fracture of the spine (which may result in cord compression or other neurologic deficits)

  • Osteopenia and fractures

Splenectomy or transfusional support is often necessary in the second or third decade of life. Iron overload may also occur as a result of increased iron absorption and frequent transfusions.

Acquired cases are observed in myeloproliferative diseases (eg, acute myelogenous leukemia, erythroleukemia, refractory sideroblastic anemia, acute lymphocytic leukemia).

Hydrops fetalis (alpha thalassemia major)

Individuals with hydrops fetalis (--/--) have no functional alpha-globin chains and thus are unable to make functional hemoglobin. Usually, they die in utero or shortly after birth. Infants who survive to be born have massive total body edema with high-output congestive heart failure due to the severe anemia. They also have massive hepatomegaly due to heart failure and extramedullary hematopoiesis. An excess of hemoglobin Bart’s, which is unable to carry oxygen effectively, is usually present.

There have been several case reports of individuals with hemoglobin Bart’s who have survived for variable amounts of time, but many have developmental abnormalities, and all have undergone intrauterine transfusions and required regular blood transfusion and chelation therapy. In a study of nine patients with hydrops fetalis followed-up for a median period of 7 years, Chan et al noted the occurrence of hypospadias, growth retardation, global developmental delay, and residual neurologic deficits.[23]

Alpha thalassemia mental retardation syndromes

There are 2 clinical entities described in which patients are noted to have mild forms of alpha thalassemia in conjunction with mental retardation: the ATR-16 syndrome and the ATR-X syndrome.

In the ATR-16 syndrome, affected children have large chromosomal rearrangements involving the short arm of the chromosome 16 telomere, which includes the alpha-globin complex. This results in monosomy for the 16p telomere and the alpha-thalassemia phenotype. If an affected child also inherits a single alpha-globin gene deletion from the other parent, HbH disease results. These children may also have mental retardation and other congenital anomalies that are thought to be due to deletions of dose-sensitive genes on chromosome 16p.

The ATR-X syndrome is an X-linked disorder caused by mutations of the ATRX gene located on chromosome Xq13.3.[21] This gene acts as a regulator of alpha-globin gene expression. Patients who are affected have normal alpha-globin genes, but the expression of these genes is downregulated.

The ATR-X syndrome is more common than the ATR-16 syndrome. Males who are affected usually have severe intellectual and physical handicaps and other congenital anomalies. Skeletal deformities are present in as many as 90% of patients. The alpha-thalassemia phenotype varies, with HbH inclusion bodies found in 0-32% of circulating erythrocytes.

Alpha thalassemia myelodysplastic syndrome

A particularly severe acquired form of HbH disease may occur in elderly men with clonal myeloproliferative diseases, in whom HbH levels may be as high as 60%. This disease, commonly referred to as alpha thalassemia myelodysplastic syndrome (ATMDS), is characterized by marked hypochromic microcytic anemia and the presence of HbH as demonstrated by hemoglobin electrophoresis and supravital staining.

ATMDS patients are also found to have a very low ratio of alpha-globin chains to beta-globin chains (α/β ratio), often less than 0.2. This ratio is lower than would be expected for patients with a single functioning alpha-globin gene (--/-α), which suggests downregulation of all 4 alpha-globin genes by a trans -acting mutation. Low alpha-globin messenger RNA levels are found in bone marrow cells.

When archival blood and bone marrow from patients with ATMDS are studied, acquired ATR-X mutations are found in most patients. Hemolytic disease caused by HbH disease may wax and wane over the course of the myeloproliferative disease.

Complications

The morbidity and mortality of alpha thalassemia are related to the degree of imbalanced globin production and therefore correlate well with the number of affected alpha-globin genes.

Individuals who are silent carriers (-α/αα) or have alpha thalassemia trait (--/αα or -α/-α) are phenotypically normal or have mild anemia as the only major morbidity associated with their disease.[24]

In patients with HbH disease (--/-α), the degree of anemia varies, and morbidity and mortality are largely related to the degree. As a result of multiple blood transfusions, consequences of iron overload on the heart, liver, and other organs may be present; these can contribute to morbidity and mortality. Patients with HbH disease may develop hypersplenism, gallstones, leg ulcers, frequent infections, and various forms of venous thrombosis.

A study by Chou et al indicated that loss of ATR-X proteins in pancreatic neuroendocrine tumors, due to somatic inactivating mutations in ATRX, independently predicts poor overall survival in patients with these neoplasms.[25]

The most severe form of alpha thalassemia, hemoglobin Bart’s, is characteristic of individuals with no functional alpha-globin genes (--/--). After a gestation of about 33 weeks, these infants develop hydrops fetalis syndrome and may die in utero, during delivery, or shortly after birth. With medical advances, however, survival has been documented.

A study by Bahar et al indicated that persons with alpha thalassemia have a nearly three-fold greater risk for impaired glucose tolerance (ie, diabetes mellitus or prediabetes). The study included 80 alpha-thalassemia carriers and 80 controls, with fasting blood sugar and oral glucose tolerance tests indicating a relative risk of 2.78 for glucose tolerance impairment in the alpha-thalassemia group.[26]

A study by Winichakoon et al found that in nontransfusion-dependent thalassemia, complications associated with alpha thalassemia were less prevalent than, and different from, those related to beta thalassemia. While extramedullary hematopoiesis, cardiomyopathy, cholelithiasis, and pulmonary hypertension occurred more frequently in beta thalassemia, osteoporosis was a more common complication in alpha thalassemia.[27]

 

DDx

Diagnostic Considerations

During pregnancy, iron and folic acid deficiencies can alter the mean corpuscular volume (MCV). As a result, thalassemia may be difficult to diagnose or exclude during pregnancy. If a strong suspicion exists and if a definitive answer is required, polymerase chain reaction (PCR) evaluation should be performed for globin-chain analysis. Many laboratories now perform a panel for seven alpha thalassemia gene mutations, which could identify the precise genotypic status of the patient.

Pregnant women with hemoglobin H (HbH) disease require special care because women with severe anemia may have serious health problems during their pregnancy, and these problems may adversely affect the health of their fetuses. The incidence of low birth weight is also high in women with HbH disease and severe anemia.[28, 29]

Other problems to be considered include the following:

  • Autoimmune hemolytic anemia

  • Hemoglobin S thalassemia syndrome

  • Hemoglobin E thalassemia syndrome

  • Hemoglobinopathies

  • Hereditary persistence of hemoglobin F (fetal hemoglobin)

  • High hemoglobin F syndromes

  • Nonimmune hemolytic anemia

  • Sideroblastic anemia

Differential Diagnoses

 

Workup

Approach Considerations

Alpha thalassemia is frequently mistaken for iron deficiency anemia because both disorders have microcytic red blood cells. Iron therapy is not required for alpha thalassemia, and the procedures used to find a source of bleeding in patients with iron deficiency anemia have no value in patients with thalassemia. Measurements of serum iron and ferritin can provide laboratory evidence to exclude iron deficiency as the etiology for microcytosis.

Failure to exclude iron deficiency anemia in a patient with an alpha thalassemia syndrome may lead to continuation of supplemental iron therapy for an extended period, and the resulting iron overload may lead to secondary hemochromatosis. If iron overload continues longer than 1-2 years, it can lead to damage in multiple organs, including cardiac, hepatic, and endocrine dysfunction.

Workup relies primarily on laboratory evaluation, hemoglobin electrophoresis, and genetic testing (alpha thalassemia mutations panel). Bone marrow aspiration and biopsy are generally not helpful in diagnosing these conditions; they may be indicated if other confounding problems are noted.

Laboratory Studies

Silent carrier

The following findings are noted in silent carriers (-α/αα):

  • Hemoglobin level - Within the reference range

  • Reticulocyte count - Normal

  • Mean corpuscular volume (MCV) – 75-85 fL

  • Mean corpuscular hemoglobin (MCH) - Around 26 pg

Alpha thalassemia trait

The following findings are noted in individuals with alpha thalassemia trait (-α/-α or --/αα):

  • Hemoglobin level - Within the reference range

  • Reticulocyte count - Normal

  • MCV - 65-75 fL

  • MCH - Around 22 pg

Hemoglobin H disease

Individuals with hemoglobin H (HbH) disease (-α/--) have moderate-to-severe anemia. The following findings are noted:

  • Hemoglobin level - 7-10 g/dL

  • Reticulocyte count - 5-10% (the higher the reticulocyte count, the more severe the hemolysis)

  • MCV - 55-65 fL

  • MCH - 20 pg

  • Peripheral blood smear - Small misshapen red cells, hypochromia, microcytosis, and targeting

  • Brilliant cresyl blue stain - HbH inclusion bodies

Hydrops fetalis (alpha thalassemia major)

Individuals with hydrops fetalis (--/--) have severe anemia. The following findings are noted:

  • Hemoglobin - 4-10 g/dL

  • MCV - 110-120 fL

  • Peripheral blood smear - Severe anisopoikilocytosis, severe hypochromia, and nucleated red blood cells (RBCs)

Alpha thalassemia with sickle-cell anemia

Alpha thalassemia combined with sickle-cell anemia results in a higher hemoglobin concentration and improved RBC survival. The alpha-globin gene deletion is associated with improved RBC deformability, but the improved rheologic benefits often are overcome by the greater viscosity of a higher hematocrit. Clinically, this scenario is evidenced by a greater number of painful vaso-occlusive crises. It is noteworthy, however, that the incidence of stroke is lower than that seen in sickle-cell disease alone.

Hemoglobin Electrophoresis

Although hemoglobin electrophoresis is not sensitive enough to diagnose alpha thalassemia syndromes, it can be very useful in quantitating and identifying different hemoglobin types.

Hemoglobin Bart’s is elevated at birth in patients with alpha thalassemia. In persons with HbH disease, 20-40% of total hemoglobin is hemoglobin Bart’s, along with typical findings of adult hemoglobin A, hemoglobin A2, and hemoglobin F. In silent carriers, however, the percentage is only 1-2%, with low or normal amounts of hemoglobin A2.[30] In persons with alpha thalassemia trait, hemoglobin Bart’s accounts for about 5-15% of total hemoglobin.

The thalassemias were initially defined in terms of the ratio between the quantities of alpha-globin and beta-globin chains (α/β ratio). Altered α/β synthetic ratios occur in both alpha and beta thalassemias. The α/β ratios progressively decrease from silent carrier state to alpha thalassemia trait to HbH disease. Tests are performed by incubating red blood cells with radiolabeled amino acid and subsequently separating alpha- and beta-globin chains with urea carboxymethyl cellulose (CMC) chromatography.

Imaging Studies

In general, imaging studies are not useful in alpha thalassemia. However, because hepatosplenomegaly and gallstones are common in HbH disease, some imaging of these organs can be useful. Ultrasonography of the liver, gallbladder, and spleen frequently reveals gallstones, which consist of pigment resulting from hemolysis.

Hepatomegaly was seen in 70% of 502 patients in Thailand, 60% of 153 patients in Sardinia, and 14% of 88 patients in Taiwan. Splenomegaly is also common in HbH disease and was found in 79% of patients in Thailand, 60% in Sardinia, and 47% in Taiwan.

Genetic Testing

Genetic testing is currently available to establish the diagnosis and clarify the genetic abnormalities in patients with a family history or laboratory results suggestive of an alpha thalassemia syndrome.[31] Polymerase chain reaction (PCR) and restriction endonuclease testing may be used. Recombinant DNA technology can be diagnostic, but is still considered research. Other genetic tests include gene mapping and anti-L globin monoclonal antibodies.

Genetic techniques can be helpful in some cases in which both the patient’s and the parents’ alpha-chain configurations are elucidated exactly, which can be useful in predicting the risk that a couple’s future offspring will be affected.

Histologic Findings

Peripheral blood smear may reveal target cells, microcytosis, hypochromia, and anisopoikilocytosis. Most silent carriers have only mild microcytosis, which can be differentiated from other common causes of microcytosis on the basis of serum iron and ferritin concentrations within the reference range.

Peripheral smear from patient with hemoglobin H di Peripheral smear from patient with hemoglobin H disease showing target cells, microcytosis, hypochromia, and anisopoikilocytosis. Morphologic abnormalities are similar to those observed in beta thalassemia. In silent carriers, only mild microcytosis is observed.
 

Treatment

Approach Considerations

Individuals with mild forms of alpha thalassemia may not require specific treatment except as needed for management of low hemoglobin levels. In some patients, supplementation of iron or folic acid may be useful. Patients with more severe anemia may require lifelong transfusion therapy. Surgical therapy is considered only in selected cases.

Iron and Folic Acid Supplementation

Iron deficiency must be documented carefully with laboratory testing before supplemental iron is given. Iron supplementation does not improve hematologic values in alpha thalassemia. Many patients with apparent iron deficiency actually have iron overload (hemochromatosis), the effects of which can contribute to morbidity and mortality. Iron overload is a particular concern in patients with hemoglobin H (HbH) disease or those rare surviving patients with alpha thalassemia major. In patients with elevated ferritin levels, the diet should be low in iron.

Folic acid supplementation may be beneficial in patients with elevated reticulocyte counts, indicating increased utilization resulting from the hemolytic process and the high bone marrow turnover rate.

General Supportive Care

General supportive care in HbH disease, including transfusions, may be needed periodically or in periods of severe anemia, such as during parvovirus infections. Guidelines for transfusion in neonates and older children have been established.[32] Blood transfusions should be administered only if necessary.

Usually, patients with HbH disease live fairly normal lives and require few transfusions. Hemoglobin levels usually range from 7-10 g/dL. Transfusion therapy is reserved for patients with severe anemia (usually < 7 g/dL) and symptomatic anemia. If chronic transfusion therapy is needed, iron chelation therapy should be considered to prevent iron overload. Even patients who have not received a large number of transfusions may have elevated total body iron loads and may require chelation therapy.

Hemolytic episodes may be triggered either by drug use or by infection. The use of special red blood cell units (eg, washed, irradiated, or leukocyte-depleted) is usually unnecessary.

Other Medical Measures

Be aware of the risk of infections, particularly in children who have undergone splenectomy. Administer appropriate vaccines to these individuals.

In very severe cases, allogeneic hematopoietic stem cell transplantation may be considered. This measure is curative because the hematopoietic system of the patient is replaced by that of the donor. A sibling who is fully matched for human leukocyte antigen (HLA) and who is, at most, a carrier for alpha thalassemia (deletion of 2 alpha-globin genes) is the most suitable donor. However, because of the toxicity of the procedure, bone marrow transplantation should be limited to the most severely affected patients.

A study by Kreger et al combining a retrospective review of three cases of alpha thalassemia major and a literature review of 17 cases found that in utero transfusion (IUT) can lead to favorable outcomes. All 20 patients in the study received IUT, with neurodevelopmental deficits reported in four of 14 patients (29%) and anatomic abnormalities reported in 11 of 20 of them (55%). Successful hematopoietic cell transplantation was eventually carried out in four patients.[33]

Splenectomy and Orthopedic Surgery

Surgical care is not needed for silent carriers or persons with alpha thalassemia trait. However, splenectomy may be beneficial for some patients with HbH disease.[34] Usually, splenectomy is reserved for patients with symptoms of hypersplenism (as reflected by leukopenia, thrombocytopenia, and worsening anemia) or for patients who were previously stable and have developed a transfusion requirement. Orthopedic or orthodontic surgery may be necessary to correct skeletal abnormalities due to erythroid hyperplasia.

Prevention

Prenatal testing is available for families at risk (eg, families in which the parents are members of ethnic groups with the highest carrier rates). Globin-chain analysis can be performed by means of polymerase chain reaction (PCR) testing.[35]

Although neonatal screening is not sufficient in the diagnosis of HbH disease, patients who have the disease at birth have large amounts of hemoglobin Bart’s, which is detectable by neonatal screening.

Consultations

Patients usually undergo evaluation by a hematologist for initial diagnosis. Patients who are silent carriers or have the alpha thalassemia trait generally need no further hematology follow-up.

Patients with HbH disease usually undergo close follow-up monitoring by a hematologist who can coordinate care and treat the patient during acute hemolytic and anemic episodes.

 

Medication

Medication Summary

No medications are needed for silent carriers or individuals with alpha thalassemia trait. In general, no medications are needed for patients with hemoglobin H (HbH) disease; however, if the reticulocyte count is elevated, the diet should be supplemented with folic acid. If a patient has an elevated ferritin level, chelation therapy with deferoxamine or deferasirox should be considered. Deferasirox is preferred because it is orally administered, whereas deferoxamine is administered intravenously (IV) or subcutaneously (SC).

Vitamins

Class Summary

This agent is a supplement with folic acid, a vitamin necessary for red blood cell (RBC) production.

Folic acid (Folacin-800)

Folic acid is a necessary coenzyme for nucleoprotein synthesis and maintenance in patients with erythropoiesis.

Chelation agents

Class Summary

Iron overload (usually from multiple transfusions) may require chelation therapy, which usually begins when the ferritin level is greater than 1000 ng/mL.

Deferoxamine mesylate (Desferal)

Deferoxamine is freely soluble in water. Approximately 8 mg of iron is bound by 100 mg of deferoxamine. Deferoxamine is excreted in urine and bile and discolors the urine red. It readily chelates iron from ferritin and hemosiderin but not from transferrin. It is most effective when provided to the circulation continuously by means of infusion. Deferoxamine may be administered by intramuscular (IM) injection, slow infusion, SC bolus, or continuous infusion. It does not effectively chelate other trace metals of nutritional importance.

Deferasirox (Exjade, Jadenu)

Deferasirox is available as a tablet for oral suspension. It is an oral iron-chelating agent that reduces liver iron concentration and serum ferritin levels. Deferasirox binds iron with high affinity in a 2:1 ratio. It is approved for treatment of treat chronic iron overload due to multiple blood transfusions and nontransfusion-dependent thalassemia.

Jadenu is a newer form of Exjade that is supposed to be easier to administer and better tolerated. The dose is usually 30% lower than Exjade rounded to the nearist whole tablet.

 

Questions & Answers

Overview

What are alpha thalassemia (?-thalassemia) syndromes?

What is the pathophysiology of alpha thalassemia (?-thalassemia)?

What is the pathophysiology of alpha(0) thalassemia?

What is the pathophysiology of alpha(+) thalassemia syndromes?

What are silent carrier alpha(+) thalassemia syndromes?

What is the pathophysiology of alpha thalassemia (?-thalassemia) trait?

What is the pathophysiology of hemoglobin H disease (alpha thalassemia intermedia)?

What causes alpha thalassemia (?-thalassemia) syndromes?

What is the prevalence of alpha thalassemia (?-thalassemia) syndromes in the US?

What is the global prevalence of alpha thalassemia (?-thalassemia) syndromes?

What are the age-related predilections of alpha thalassemia (?-thalassemia) syndromes?

What are the sexual predilections of alpha thalassemia (?-thalassemia) syndromes?

What are the racial predilections of alpha thalassemia (?-thalassemia) syndromes?

What is the prognosis of alpha thalassemia (?-thalassemia) syndromes?

What is included in patient education about alpha thalassemia (?-thalassemia) syndromes?

Presentation

What are the characteristic clinical history and physical findings of alpha thalassemia (?-thalassemia) silent carrier?

Which factors affect the clinical presentation of alpha thalassemia (?-thalassemia) syndromes?

What are the characteristic clinical history and physical findings of alpha thalassemia (?-thalassemia) trait?

What are the characteristic clinical history and physical findings of hemoglobin H disease (alpha thalassemia intermedia)?

What are the possible complications of hemoglobin H disease (alpha thalassemia intermedia)?

What are the characteristic clinical history and physical findings of hydrops fetalis (alpha thalassemia major)?

What are the characteristic clinical history and physical findings of alpha thalassemia (?-thalassemia) mental retardation syndromes?

What are the characteristic clinical history and physical findings of alpha thalassemia (?-thalassemia) myelodysplastic syndrome?

What is the morbidity and mortality associated with alpha thalassemia (?-thalassemia) syndromes?

DDX

How is alpha thalassemia (?-thalassemia) diagnosed and treated during pregnancy?

Which conditions should be considered in the differential diagnosis of alpha thalassemia (?-thalassemia) syndromes?

What are the differential diagnoses for Alpha Thalassemia?

Workup

How is alpha thalassemia (?-thalassemia) differentiated from iron deficiency anemia?

Which lab findings suggest alpha thalassemia (?-thalassemia) silent carrier?

Which lab findings suggest alpha thalassemia (?-thalassemia) trait?

Which lab findings suggest hemoglobin H disease (alpha thalassemia intermedia)?

Which lab findings suggest hydrops fetalis (alpha thalassemia major)?

Which lab findings suggest alpha thalassemia (?-thalassemia) with sickle-cell anemia?

What is the role of hemoglobin electrophoresis in the workup of alpha thalassemia (?-thalassemia) syndromes?

What is the role of imaging studies in the diagnosis of alpha thalassemia (?-thalassemia) syndromes?

What is the role of genetic testing in the workup of alpha thalassemia (?-thalassemia) syndromes?

Which histologic findings are characteristic of alpha thalassemia (?-thalassemia) syndromes?

Treatment

How are alpha thalassemia (?-thalassemia) syndromes treated?

What is the role of iron supplementation in the treatment of alpha thalassemia (?-thalassemia) syndromes?

What is the role of folic acid supplementation in the treatment of alpha thalassemia (?-thalassemia) syndromes?

What is included in general supportive care for hemoglobin H disease (alpha thalassemia intermedia)?

How is the risk of infection reduced in patients with alpha thalassemia (?-thalassemia) syndromes?

What is the role of hematopoietic stem cell transplantation (HSCT) in the treatment of alpha thalassemia (?-thalassemia) syndromes?

What is the role of surgery in the treatment of alpha thalassemia (?-thalassemia) syndromes?

How are alpha thalassemia (?-thalassemia) syndromes prevented?

Which specialist consultations are beneficial to patients with alpha thalassemia (?-thalassemia) syndromes?

Medications

Which medications are used in the treatment of alpha thalassemia (?-thalassemia) syndromes?

Which medications in the drug class Chelation agents are used in the treatment of Alpha Thalassemia?

Which medications in the drug class Vitamins are used in the treatment of Alpha Thalassemia?