THALASSEMIA

THALASSEMIA

Current Diagnosis

• Complete blood count: anemia (very severe in β-thalassemia major, mild in β-thalassemia minor and α-thalassemia trait), low mean corpuscular volume, variable leukocytosis, thrombocytopenia (secondary to splenomegaly) or thrombocythemia (after splenectomy)

• Peripheral blood smear: hypochromia, microcytosis, anisocytosis, poikilocytosis, target cells, Heinz bodies, nucleated red blood cells

• Evidence of hemolytic anemia: indirect hyperbilirubinemia, elevated lactate dehydrogenase, decreased haptoglobin

•   Hemoglobin electrophoresis pattern:

β-Thalassemia minor: elevated HbA2 (α2δ2)

β-Thalassemia intermedia: elevated HbA2, elevated HbF (α2γ2), and decreased HbA (α2β2)

β-Thalassemia major: absence of HbA, markedly elevated HbF, and elevated HbA2

α-Thalassemia trait: normal

Hemog lobin H disease: decreased HbA, presence of HbH (β4) and HbBart (γ4)

Hemoglobin Barts hydrops fetalis: HbBart, absence of HbA, HbA2, and HbF

•   Timing of symptomatic disease:

β-Thalassemia minor: asymptomatic β-Thalassemia intermedia: variable

β-Thalassemia major: within first year of life α-Thalassemia trait: asymptomatic

Hemoglobin H disease: symptomatic at time of birth Hemoglobin Barts hydrops fetalis: death during gestation

Current Therapy

• Chronic packed red blood cell transfusions for β-thalassemia major (1–3 units of packed leukoreduced erythrocytes every 3–5 weeks) with a target hemoglobin concentration of 9 to 10.5 g/dL; variable transfusion needs for β-thalassemia intermedia and hemoglobin H disease

•   Splenectomy with antibiotic prophylaxis and vaccination

• Iron chelation: deferoxamine (Desferal), or deferasirox (Exjade); deferiprone (Ferriprox)

• Osteoporosis management: calcium with vitamin D supplementation; bisphosphonates

• Allogeneic hematopoietic cell transplantation for β-thalassemia major

Globin Gene Arrangements

Thalassemia syndromes encompass a spectrum of hemoglobin disorders that arise from impaired production of globin chains. The genes that encode globins are located in two clusters: the β gene cluster on chromosome 11 and the α gene cluster on chromosome 16 (Figure 1). The β gene cluster includes the adult globin genes (β and δ) as well as the fetal Aγ and Gγ genes and the embryonic ɛ gene. The arrangement of the 5′ to 3′ sequence of these genes parallels the order of their developmental expression. Functional hemoglobin is a tetramer that includes two α and two β globin units. The α gene cluster includes two fetal/adult α genes (α1 and α2) and the embryonic ζ genes. In the embryo, three hemoglobins are found (ζ2ɛ2, α2ɛ2, and ζ2γ2). Fetal hemoglobin (HbF) is composed of two α chains and two γ chains (α2γ2). In adults, the predominant hemoglobin is hemoglobin A (HbA), consisting of two α chains and two β chains (α2β2) (see Figure 1). Hemoglobin A2, consisting of two α chains and two δ chains (α2δ2), is a normal variant in adults and typically represents less than 3% of the total hemoglobin (see Figure 1).

FIGURE 1    Representation of the β and α globin gene clusters.  Also shown are the globin tetramers produced during embryonic development.

In β-thalassemia, there is diminished production of β globin genes, resulting in an excess of α globin chains. Conversely, in α-thalassemia there is impaired production of α globin genes, resulting in an excess of β globin chains. This imbalance of globin production is variable, and the degree of accumulation of unpaired globin chains is directly related to the severity of the disease phenotype. The genetic basis of thalassemia is heterogeneous, and several hundred mutations have been identified. These mutations may affect any level of globin gene expression, including arrangement of the globin gene complex, gene deletion, splicing, transcription, translation, and protein stability. In general, β-thalassemia occurs as a result of mutations, whereas α- thalassemia occurs as a result of gene deletion.

It has been estimated that there are 270 million carriers of thalassemia in the world, including 80 million β-thalassemia carriers. The frequency of β-thalassemia carriers is highest in the malarial tropical and subtropical regions of Asia, the Mediterranean, and the Middle East. The term thalassemia, derived from Greek, refers to the Mediterranean Sea. This distribution is secondary to the selective advantage of heterozygotes against malaria. β-Thalassemia is subdivided into major, intermedia, and minor types (Table 1). α- Thalassemia is classified into four syndromes: α-thalassemia trait 2 (loss of one α globin gene [αα/α−]); α-thalassemia trait 1, also referred to as α-thalassemia minor (loss of two α globin genes [αα/−− or α−/α−]); hemoglobin H (HbH) disease (loss of three alleles [α−/−−]); and hemoglobin Barts hydrops fetalis (loss of all four α globin loci [−−/−−]).

Table 1

Summary of Hematologic and Clinical Features of the Thalassemias

Abbreviations: Hb = hemoglobin; RBCs = red blood  cells.

Pathophysiology

The clinical manifestations of thalassemia and their severity are a consequence of the relative excess of unpaired globin chains. In particular, excess α globin chains are unstable and insoluble and therefore precipitate inside the red blood cell (RBC). These inclusions (precipitated hemoglobin) may be visualized as Heinz bodies. The accumulation of α globin chains leads to a variety of insults to the erythrocyte, including changes in membrane deformability and increased fragility. Free β chains are more soluble than free α chains and are able to form a homotetramer (HbH). The hallmark of thalassemia is an anemia that is a consequence of both increased destruction (i.e., hemolysis) and decreased production (i.e., ineffective erythropoiesis). The bone marrow typically displays erythroid hyperplasia.

Oxidant injury is closely linked with the pathology of thalassemia. Under normal conditions, a small amount of methemoglobin (Fe3+) is formed via oxidation and can then be reduced back to hemoglobin (Fe2+). However, isolated globin chains can be oxidized to hemichromes, some forms of which are irreversibly oxidized. The hemichromes can then generate reactive oxygen species, which can oxidize membrane components, leading to cell injury. There is an increase in membrane rigidity in β-thalassemia, and this appears to be secondary to the binding of partially oxidized α globin chains to components of the membrane skeleton. Increased membrane rigidity in turn leads to decreased membrane deformability and increased destruction. In α-thalassemia, HbH has a left-shifted oxygen disassociation curve and therefore does not readily transport oxygen. HbH erythrocytes have increased rigidity, which is thought to be secondary to interactions between excess β globin chains and the membrane. Unlike with β-thalassemia, HbH erythrocytes have increased membrane stability. Inclusion bodies have been identified in HbH cells, and there appears to be a correlation between RBC age and solubility of HbH. As cells age, the amount of soluble HbH decreases, and the level of inclusions increases.

It has also been recognized that there is increased phagocytosis of thalassemia RBCs compared to normal controls. The etiology is not completely understood, but it may be a consequence of reduction in surface levels of sialic acid, increase in surface immunoglobulin G binding, and changes in phosphatidylserine localization.

Despite the pronounced hemolysis and marrow erythroid hyperplasia, patients with thalassemia generally do not display the compensatory reticulocytosis that is indicative of the other basis for anemia, ineffective erythropoiesis. Accumulation of α chain aggregates is thought to lead to death of erythrocyte precursors.

Furthermore, abnormal assembly of membrane proteins in erythroid precursors has been demonstrated.

Iron overload is one of the primary causes of morbidity. Even without transfusion, the long-standing anemia, however mild, leads to increased iron absorption in the gut and eventual chronic iron overload. Excessive iron deposition causes devastating damage to multiple organs, particularly affecting the heart, liver, and endocrine organs.

β-Thalassemia Major

Symptoms of β-thalassemia major are not present at birth, because HbF (α2γ2) is present. However, as HbF levels decline over the first year, the signs and symptoms of severe hemolytic anemia begin to manifest. Affected individuals display hepatosplenomegaly from expansion of the reticuloendothelial system as well as extramedullary hematopoiesis, pallor, growth retardation, and abnormal skeletal development. If left untreated, 80% of children with β-thalassemia major will die before the age of 5 years.

Laboratory Features

Thalassemia major is characterized by a severe microcytic anemia. Hemoglobin levels may be as low as 3 to 4 g/dL. The peripheral blood smear is markedly abnormal and is notable for hypochromia, microcytosis, anisocytosis, poikilocytosis, target cells, and tear drop cells. Routine stains show the presence of precipitated α globin chains as Heinz bodies. The reticulocyte count is often low. The white blood cell count is often high but may be artifactually elevated as a consequence of automated inclusion of high numbers of circulating nucleated RBCs. The platelet count is typically normal, but progressive hypersplenism can result in decreased platelet counts.

Patients who have undergone splenectomy often have increased white blood cell and platelet counts. Iron studies reveal elevated serum iron, transferrin saturation, and ferritin. Consistent with hemolysis and ineffective erythropoiesis, indirect bilirubin and lactate dehydrogenase levels are increased and haptoglobin levels are low.

Clinical Features

Unique to β-thalassemia major is the development of extramedullary erythropoiesis. This may be so severe that the masses of bone marrow lead to broken bones and spinal cord compression. Sites of involvement include the sinuses and the thoracic and pelvic cavities. The expansion of the erythroid bone marrow can lead to a number of skeletal changes. In particular, characteristic changes in the facial bones and skull result in frontal bossing, overgrowth of the maxillae, and malocclusion. This has sometimes been referred to as chipmunk facies. Other bones are also affected, and premature fusion of the epiphyses results in shortened limbs. Compression fractures of the spine may occur. Even if the disease is managed appropriately with transfusions and iron chelation, patients will still suffer from osteopenia and osteoporosis. Possible mechanisms include changes secondary to hypogonadism or increased bone resorption secondary to vitamin D deficiency.

Hepatomegaly and splenomegaly, secondary to extramedullary erythropoiesis and RBC destruction, are prominent. Injury to Kupffer cells and hepatocytes from chronic overload leads to fibrosis and end- stage liver disease. Hepatic iron overload is probably caused in part by comparatively high levels of transferrin receptors. Iron overload, and perhaps other factors, increase susceptibility to viral hepatitis.

Laboratory studies show indirect hyperbilirubinemia, hypergammaglobulinemia, and elevated liver markers. The chronic hemolysis leads to formation of bilirubin gallstones, although cholecystitis or cholangitis is not common. Splenic dysfunction results in immune dysfunction. The shortened erythrocyte survival time leaves patients susceptible to aplastic crisis induced by parvovirus B19 infection. Extramedullary hematopoiesis may also affect the kidneys, and patients often have large kidneys. Rapid cell turnover leads to hyperuricemia, and children may develop gouty nephropathy.

A number of endocrine abnormalities are commonly seen in β- thalassemia major, including hypogonadism, growth failure, diabetes, and hypothyroidism. These abnormalities occur even in chronically transfused patients and may be in part related to iron overload.

Endocrine glands, like liver and heart, have high levels of transferrin- receptor and therefore are more susceptible to iron overload. The typical growth pattern for a child with β-thalassemia major is relatively normal until the age of 9 to 10 years. After that time, the growth velocity slows, and the pubertal growth spurt is either absent or reduced. Although secretion of growth hormone does not appear to be altered in thalassemic patients, a reduction in peak amplitude and nocturnal levels of growth hormone has been observed. Amenorrhea is quite common, with 50% of girls presenting with primary amenorrhea. Secondary amenorrhea also develops, particularly in patients who do not receive regular chelation therapy. In males, impotence and azoospermia is common. Primary hypothyroidism typically appears during the second decade of life. The prevalence of diabetes mellitus and impaired glucose intolerance has been estimated at 4% to 20%. Unlike type 1 diabetes mellitus, diabetes associated with thalassemia is rarely complicated by diabetic ketoacidosis. The risk of diabetic retinopathy is lower, but the risk of diabetic nephropathy is higher. Patients with a high ferritin level (above 1800 µg/L) experience a faster progression to hypothyroidism, hypogonadism, and other endocrinopathies.

Thalassemic patients suffer from extensive cardiac abnormalities.

Chronic anemia causes cardiac dilatation. Although chronic transfusion can help prevent cardiac dilatation, the resulting iron overload leads to cardiac hemosiderosis. Pericarditis, ventricular and supraventricular arrhythmias, and end-stage cardiomyopathy can develop. Ventricular arrhythmia is a common cause of death. Patients may also develop pulmonary hypertension. The degree of iron overload in the heart has traditionally been assessed by cardiac biopsy, but cardiac magnetic resonance imaging (MRI) is increasingly being used.

Vitamin and mineral deficiencies may occur. Folic acid deficiency may develop in patients, presumably as a consequence of increased cell turnover. Although the cause is unknown, patients with β- thalassemia major often have very low serum zinc levels. Serum levels of vitamin E and vitamin C may also be low.

Management of β-Thalassemia Major

Transfusion

The key intervention for the management of β-thalassemia major is chronic transfusion therapy. In particular, during the first decade of life, regular transfusion results in improvements in hepatosplenomegaly, skeletal abnormalities, and cardiac dilatation. Patients typically require 1 to 3 units of packed RBCs every 3 to 5 weeks. The optimal target total hemoglobin level has yet to be determined. Alloimmunization does occur, and some blood centers try to leukodeplete their products, match donors by ethnicity, and limit the donor pool for any particular patient. Although the risk of blood-borne infections is now quite small, regular transfusion of blood products still carries a risk for infections such as HIV and hepatitis C.

Splenectomy

The general indication for splenectomy is an increase of more than 50% in the RBC transfusion requirement over the period of 1 year. Splenectomy may initially yield a decrease in the RBC transfusion requirement. It has been noted that thalassemia patients are at higher risk for infection after splenectomy than are those patients splenectomized for other reasons. The bacteria that most frequently cause infections in these patients include Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Klebsiella, Escherichia coli, and Staphylococcus aureus. The increased susceptibility to infection compared with other splenectomized patients is thought to be a result of greater immune dysfunction secondary to iron overload. In particular, it has been reported that iron-overloaded macrophages lose the ability to kill intracellular pathogens. Antibiotic prophylaxis with penicillin, amoxicillin, or erythromycin is recommended for children up to the age of 16 years. In addition, patients should receive immunizations, including the pneumococcal, influenza, and Haemophilus influenzae vaccines.

Iron Chelation Therapy

Because of increased iron absorption and chronic transfusion therapy, iron overload develops. As noted earlier, iron overload causes damage to multiple organs. Because iron is poorly excreted, removal must be accomplished by phlebotomy (not an option in thalassemic patients) or by chelation therapy. Historically, deferoxamine (Desferal) has been the most widely used chelator. This agent may be administered subcutaneously, intramuscularly, or intravenously. The dosing for chronic iron overload is 20 to 40 mg/kg/day SQ or 500 to 1000 mg/day IM + 2 g IV per unit transfused blood. The IV-only route is indicated for patients with cardiovascular collapse. Multiple studies have shown that deferoxamine therapy improves long-term survival. In addition, intensive therapy with deferoxamine has been shown to improve cardiac function in patients with severe iron overload.

However, compliance with daily injections has been a particular problem, and, unless regular therapy is given, iron will reaccumulate.

Deferiprone (Ferriprox) was the first orally active chelator to be introduced. It is given three times daily (total of 75 mg/kg/day).

Studies have indicated that deferiprone may be as effective as deferoxamine in lowering iron levels. A recent Cochrane Review concluded that deferiprone is indicated in the treatment of iron overload in thalassemia major if deferoxamine therapy is contraindicated or inadequate. Agranulocytosis associated with deferiprone has been reported, and, because of this risk, the drug is currently not available in the United States except through the FDA Treatment Use Program. Deferiprone is available in Europe and Asia. There has also been interest in combined therapy with deferiprone and deferoxamine, and one study showed that the combination was more effective in removing cardiac and hepatic iron but did not further improve cardiac function.

Deferasirox (Exjade) is the first orally active agent approved for use in the United States. Its longer half-life in comparison to deferiprone allows this drug to be given once daily (total of 20–40 mg/kg/day). A phase III trial comparing deferasirox to deferoxamine in patients with thalassemia revealed similar decreases in liver iron concentrations.

Side effects include gastrointestinal complaints (abdominal pain, nausea, vomiting, diarrhea) and skin rash. There have been postmarketing reports of acute renal failure, hepatic failure, and cytopenias. It is recommended that serum creatinine, ferritin, and alanine aminotransferase be monitored monthly during therapy. A prospective, randomized study comparing deferipronre and deferoxamine vs deferipronre and deferasirox in 96 patients with β- thalassemia major demonstrated that both regimens reduced iron overload. However, the latter regimen was found to be superior with respect to improving cardiac iron, patient compliance, and patient satisfaction.

The gold standard for measurement of liver iron concentration has been liver biopsy with iron measurement by atomic absorption spectrometry. More recently, there has been increasing use of MRI technology to measure liver iron levels. In general, iron content determined by MRI methodology correlates with liver iron concentration determined by biopsy. However, the precision of liver MRI measurement appears to be dependent on iron levels, liver fibrosis, and calibration. Hepatic iron concentration has also been measured using a superconducting quantum interference device (SQUID), although reported consistency has varied and widespread use of this technique has been limited by expense and complexity.

Management of Osteoporosis

Even with calcium and vitamin D supplementation, iron chelation, transfusion therapy, and hormonal therapy, bone loss continues to be a significant problem for thalassemia patients. Recently, there has been interest in the use of bisphosphonates. This class of drugs, which includes clodronate (Bonefos),2 alendronate (Fosamax), pamidronate (Aredia), zoledronate (Zometa), and neridronate (Nerixia),2 inhibit osteoclastic bone resorption and have found extensive use in the management of Paget’s disease, osteoporosis, and skeletal metastases. Small studies performed in thalassemia patients have failed to show benefit with clodronate 100 mg IM every 10 days or 300 mg IV every 3 weeks. A very small study using alendronate (Fosamax)1 10 mg PO daily revealed an increase in bone mineral density only at the femoral level. Conversely, in a study involving pamidronate (Aredia)1 30 or 60 mg IV every month, there was an increase in bone density only at the lumbar level. The most promising results have been achieved with the most potent member of the class, zoledronate. Several trials demonstrated that zoledronate (Zometa)1 4 mg IV every 3 or 4 months results in significant improvement in femoral and lumbar bone mineral density and reduces bony pain. The largest randomized trial involved 118 β-thalassemia patients who received calcium plus vitamin D with or without neridronate (given every 90 days). At 6 and 12 months, there was increased bone mineral density as well as decreased back pain and analgesic use in the neridronate arm. Larger, long-term trials are necessary before this agent finds widespread use in the management of thalassemia-induced osteoporosis.

Hematopoietic Cell Transplantation

Hematopoietic cell transplantation is the only curative strategy for patients with hemoglobinopathies. Patients are assigned to a risk class (Pesaro class) based on adherence to regular iron chelation therapy, presence or absence of hepatomegaly, and presence or absence of portal fibrosis. Those children with no or little hepatomegaly, no portal fibrosis, and regular iron chelation therapy (class I) have a better than 90% chance of cure, whereas those with both hepatomegaly and portal fibrosis (class III) have long-term survival rates of about 60% in older studies. More recent reports indicate that class III survival has improved to 90%.

The use of human leukocyte antigen (HLA)-identical sibling donors has been preferred, because the use of HLA-mismatched donors has produced inferior results and is associated with increased graft rejection, graft-versus-host disease, and infection. However, it is estimated that only one-third of patients will have a matched donor.

The use of unrelated donors has been explored, and initial studies showed poorer outcomes. However, more recent data suggest that matched unrelated donors might be a viable option if a suitable sibling donor is lacking, thanks to improved donor selection and transplantation techniques. The use of partially HLA-matched unrelated cord blood has been reported, although 4 out of 9 children did not engraft.

Another emerging technique is the use of reduced-intensity conditioning regimens, although long-term success has yet to be achieved. However, no randomized controlled studies have been performed evaluating the role of transplant in thalassemia patients.

Gene Therapy

Globin gene therapy, achieved through manipulation of autologous stem cells, is an attractive alternative to allogeneic transplantation. There are three major scientific hurdles that must be overcome: design of vectors that yield therapeutic levels of globin gene expression, ability to isolate and transduce autologous stem cells, and development of transplantation conditions that will permit host repopulation. In addition, the safety of viral and nonviral transfection is an issue. Initial studies involved ex vivo transduction of autologous hematopoietic stem cells with a lentiviral vector carrying the transgene. Most of the treated patients achieved sufficient transgene expression to result in an increase in hemoglobin by 4–6 g/dL within 2–5 months. Another approach which is currently under investigation involves the use of genome editing techniques such as CRISPR.

Pharmacologic Induction of Fetal Hemoglobin

Induction of HbF expression has been proposed as a therapeutic strategy. For β-thalassemia, induced γ globin gene expression would be predicted to decrease globin chain imbalance by complexing with free α chains. Hydroxyurea (Hydrea)1 is an antimetabolite thought to interfere with DNA synthesis. It is well established in the management of sickle cell disease, where it has been shown to increase levels of HbF. The use of hydroxyurea in β-thalassemia is much less well established. In the United States, hydroxyurea has been approved for use in sickle cell disease but not for thalassemia.

Studies published elsewhere in the world have generally shown improvements in hemoglobin levels in thalassemia intermedia patients, with some patients becoming transfusion independent. A recent meta-analysis on the use of hydroxyurea in patients with transfusion dependent β-thalassemia concluded that this agent might offer some benefit but that double-blinded placebo-controlled studies are lacking.

5-Azacytidine (azacitidine [Vidaza]),1 an inhibitor of DNA methyltransferase, has been shown to induce HbF. However, concerns regarding long-term use have prevented further evaluation in thalassemia. Decitabine (Dacogen),1 an analogue of 5-azacytidine, has been shown to increase HbF levels in patients with sickle cell disease refractory to hydroxyurea. A small pilot study of low-dose decitabine in β-thalassemia intermedia patients demonstrated an increase in total hemoglobin and hemoglobin F levels. Butyrate,5  an inhibitor of histone deacetylases, is another agent capable of inducing HbF. However, butyrate and its derivatives (arginine butyrate,5 sodium isobutyramide,5 and sodium phenylbutyrate [Buphenyl]1) have failed to show significant clinical benefit in thalassemia patients. Therefore, at this time, no agent has been approved for use in thalassemia patients. A number of hypotheses have been proposed to explain the lack of success of inducers of HbF in thalassemia: there is simply too little γ globin production to significantly affect globin chain balance; these agents decrease expression of partially active β-thalassemia genes; these agents increase expression of α-globin genes; chronic transfusions appear to reduce HbF levels; and these agents suppress erythropoiesis.

Antioxidants

Oxidative damage is believed to be an important cause of tissue damage, and there has been interest in the use of antioxidants in thalassemia patients. A variety of substances have been investigated, including ascorbate,1 vitamin E,1N-acetylcysteine (Mucomyst),1 flavonoids, and indicaxanthin.5 A variety of antioxidant effects have been observed in vitro with these agents, but none has been shown to improve anemia in patients with thalassemia.

β-Thalassemia Intermedia

Given the underlying genetic heterogeneity, it is not surprising that the clinical manifestations of β-thalassemia intermedia are also quite varied. Some patients with more mild forms of β-thalassemia intermedia do not require chronic transfusion therapy. There is not a clear consensus as to when chronic transfusion should be initiated.

Factors that are considered for children include growth patterns, spleen size, and bone development. Transfusion may be necessary during infection-induced aplastic crises. In some instances, transfusions are begun in childhood to help with growth and then discontinued after puberty. Some adults gradually become more anemic and eventually require transfusion. Some authors have argued that starting transfusions early in life is advantageous, because the prevalence of alloimmunization appears to increase if transfusion is started after the first few years of life.

Splenomegaly usually develops in all patients, including those who do not require transfusion. With progression of splenomegaly and the accompanying sequestration and hemolysis, there is usually worsening of anemia, to the point at which transfusions may be required. Most patients achieve transfusion independence after splenectomy. Gallstones may develop, and a prophylactic cholecystectomy is sometimes performed at the same time as the splenectomy. As with β-thalassemia major patients, intermedia patients are at increased risk for infection and should be appropriately vaccinated.

For reasons that are not entirely clear, there is an increased risk of thromboembolic complications in intermedia patients compared with thalassemia major patients. An Italian study reported that 10% of thalassemia intermedia and 4% of thalassemia major patients experienced a thromboembolic event. Another study reported that thromboembolism occurred four times more frequently in patients with intermedia versus major disease. This report noted that venous events were more common in the thalassemia intermedia population, whereas arterial events were more common in the thalassemia major population. An even higher rate of venous thrombotic events (29%) was reported in a population of splenectomized patients with thalassemia intermedia. It has been suggested that exposed anionic phospholipids on the surface of damaged RBCs may induce a procoagulant effect. There is no consensus regarding the prophylactic use of antiplatelet agents or anticoagulants in this population.

Patients with thalassemia intermedia may develop iron overload, although it is less severe than in patients with thalassemia major. Even those that are not regularly transfused may develop a degree of iron overload, because there is increased iron absorption. Iron overload may be managed with the iron chelating agents as described earlier.

Cardiac toxicity, including congestive heart failure, valvular problems, and pulmonary hypertension (leading to secondary right- sided heart failure), resulting from iron overload is not infrequent in the thalassemia intermedia population.

Bone abnormalities and osteoporosis may develop in thalassemia intermedia patients. In a North American study, the prevalence of fractures in these patients was 12%. Leg ulcers involving the medial malleolus are common and are often difficult to treat. Hypogonadism, hypothyroidism, and diabetes may occur, with frequency related to the severity of anemia and iron overload. Pseudoxanthoma elasticum, a syndrome consisting of skin lesions, angioid streaks in the retina, calcified retinal walls, and aortic valve disease, is more common in thalassemia intermedia than in thalassemia major. Currently, no effective therapy exists, although it has been reported that aluminum hydroxide (Alternagel)1 reduces skin calcification.

β-Thalassemia Minor

Most patients with β-thalassemia minor are asymptomatic. However, they have an abnormal complete blood count that may sometimes lead to the misdiagnosis of iron deficiency. Although these patients have a microcytic anemia, it is much less severe than in patients with β-thalassemia major. In general, the hematocrit is greater than 30%.

The mean corpuscular volume is typically less than 75 fL and the RBC distribution width index is normal, in contrast to iron deficiency, in which the degree of microcytosis is less and the distribution width index is usually increased. The peripheral blood smear shows the presence of target cells. Hemoglobin electrophoresis typically reveals an increase in HbA2. The normal anemia experienced during pregnancy may sometimes be exacerbated in patients with β- thalassemia minor, necessitating transfusion. Otherwise, no long-term effects of β-thalassemia minor have been described, and no interventions are required.

α-Thalassemia

Laboratory and Clinical Features

Patients with α-thalassemia trait 2 are asymptomatic and have normal laboratory values, including complete blood count, peripheral smear, and hemoglobin electrophoresis. Individuals with α-thalassemia trait 1 are asymptomatic, and the disease resembles β-thalassemia minor.

The peripheral smear shows a hypochromic microcytic anemia with the presence of target cells. Hemoglobin electrophoresis is normal.

HbH disease does produce symptoms. Unlike β-thalassemia major, in which HbF production protects the fetus, individuals with HbH disease develop hemolytic anemia during gestation and are symptomatic at birth. This is because α globin production is required for HbF (α2γ2). As with β-thalassemia major, patients with HbH disease suffer from the consequences of chronic hemolytic anemia, although the severity is somewhat less. The transfusion requirements for HbH patients resemble those for patients with β-thalassemia intermedia, with transfusion support initiated in the second and third decades of life. These patients also develop iron overload, necessitating treatment with chelation therapy.

Hydrops fetalis with hemoglobin Barts is usually fatal in utero. The utter lack of α globin chain production results in absence of HbF. Hemoglobin Barts, a homotetramer consisting of four γ globin genes, is unable to deliver oxygen to tissues. Severe tissue hypoxia develops, leading to widespread tissue ischemia. High cardiac output failure leads to massive edema (hydrops). In most cases, death occurs in the third trimester or late second trimester. There have been reports of live births after intrauterine transfusion, but survival beyond the perinatal period is exceedingly rare. Prenatal diagnosis of hemoglobin Barts hydrops fetalis may be achieved through DNA-based testing using amniocytes from amniocentesis or chorionic villi sampling.

Noninvasive testing is under development, including methods that isolate circulating fetal DNA in maternal peripheral blood.

Management

Patients with α-thalassemia 2 and 1 traits do not require treatment. The management of HbH disease is similar to that described for β- thalassemia.

References 

1.   Angelucci E., Matthes-Martin S., Baronciani D., et al. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica. 2014;99:811–820.

2.    Bayanzay K, Khan R. Meta-analysis on effectiveness of hydroxyurea to treat transfusion-dependent beta-thalassemia, Hematology 20(8):469–476, 2015.

3.     Bhardawj A., Swe K.M., Sinha N.K., Osunkwo I. Treatment for osteoporosis in people with b-thalassaemia. Cochrane Database Syst Rev. 2016;3:CD010429.

4.    Finotti A., Gambari R. Recent trends for novel options in experimental biological therapy of β-thalassemia. Expert Opin Biol Ther. 2014;14:1443–1454.

5.     Giusti A. Bisphosphonates in the management of thalassemiaassociated osteoporosis: a systematic review of randomized controlled trials. J Bone Miner Metab. 2014;32:606– 615.

6.    Jagannath V.A., Fedorowicz Z., Al Hajeri A., et al. Hematopoietic stem cell transplantation for people with β- thalassaemia major. Cochrane Database Syst Rev. 2014;10: CD008708.

7.    Karimi M., Cohan N., De Sanctic V., et al. Guidelines for diagnosis and management of beta-thalassemia intermedia. Pediatr Hematol Oncol. 2014;31:583–596.

8.    Marsella M., Borgna-Pignatti C. Transfusional iron overload and iron chelation therapy in thalassemia major and sickle cell disease. Hematol Oncol Clin North Am. 2014;28:703–727.

9.       Saliba A.N., Harb A.R., Taher A.T. Iron chelation therapy in transfusion-dependent thalassemia patients: current strategies and future directions. J Blood Med. 2015;6:197–209.

10.       Srivastava A, Shaji RV. Cure for thalassemia major: from allogeneic hematopoietic stem cell transplantation to gene therapy, Haematologica 102(2):214–223, 2017.

11.    Toumba M., Sergis A., Kanaris C., et al. Endocrine complications in patients with thalassaemia major. Pediatr Endocrinol Rev.  2007;5:642–648.

1  Not FDA approved for this  indication.

5  Investigational drug in the United  States.

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