Approach

The vast majority of alpha-thalassemia patients are clinically well and most are asymptomatic. Many patients with hemoglobin H (Hb H) are also clinically well, but are at risk for acute hemolytic episodes, aplastic crises, iron overload (even in the absence of chronic transfusions), hypersplenism, and endocrine disease.[5][44]

Education is an important part of management and should cover the risks of acute events and, in genetic counseling, the risks of conceiving a child with Hb H disease or the potentially devastating alpha-thalassemia major.[4]

Alpha-thalassemia silent carrier and alpha-thalassemia trait

Alpha-thalassemia silent carrier (1 affected alpha-globin gene) status is generally associated with normal Hb levels; patients with alpha-thalassemia trait (2 affected alpha-globin genes) may have a mild asymptomatic anemia. It is important to avoid unnecessary and potentially harmful iron supplementation in this population and to provide education, particularly with regard to genetic counseling.[16]​[68]​ Iron therapy is needed only if the patient develops iron deficiency as confirmed by the standard diagnostic methods (serum iron, transferrin saturation level, serum ferritin). See Iron deficiency anemia.

Patients who are homozygous for Hb Constant Spring (Hb CS/CS; a subtype of alpha-thalassemia trait) have a more serious clinical phenotype than those who are homozygous for deletional alpha(+) thalassemia. They have a mild anemia and frequently have jaundice and splenomegaly with a normal mean corpuscular volume (MCV) and slightly low mean corpuscular hemoglobin (MCH).[6]

Women with alpha-thalassemia trait: pregnancy

Pregnancy leads to a relative increase in plasma volume greater than red cell mass, which results in a decrease in Hb. This decrease is more pronounced in individuals with alpha-thalassemia trait than in those without.[69]​ However, in alpha-thalassemia trait, the Hb does not usually decline below 9 g/dL and intervention is not typically required.[70]​​

Hb H disease

Patients with Hb H disease are at risk for complications, including transient episodes of severe anemia (secondary to increased oxidant stress from medication or illness), aplastic crisis due to parvovirus B19 or other viral infections, cholelithiasis, leg ulcers, splenomegaly, calcium and vitamin D deficiency, osteopenia, and growth retardation.[5][44][71][72]​​​​​​​​ Patients with Hb H CS are at particularly high risk for infection-related anemia leading to urgent red blood cell transfusion.[56] See Complications.

Patients and their families must be informed of the need to seek medical attention if they notice symptoms such as increased fatigue, shortness of breath, jaundice, or dark urine.

Patients should avoid medications associated with oxidant injury in G6PD deficiency, such as sulfonamides and nitrofurantoin.[73] These patients are also given multivitamins without iron and oral folate supplementation.[71]

Hb H disease: iron overload status

All patients should be monitored for iron overload. Iron overload develops over time in a high proportion of patients with Hb H disease, even in the absence of chronic red blood cell transfusions.[5][74][75]​​​​​​​​​​  Suppression of hepcidin by erythropoiesis and other factors leads to increased absorption of iron and increased release of reticuloendothelial iron.[16][76][77]​​​​​​​​​​ Iron overload may lead to hepatic, endocrine, vascular, and (less commonly) cardiac complications.​[5][16]

Iron overload may begin at an earlier age, and may be of greater severity, in patients with nondeletional Hb H disease (such as Hb H/Constant Spring) than in those with deletional Hb H disease.​[56][78]​​​​​​​ Patients with nondeletional Hb H disease are more likely to require transfusion than patients with deletional Hb H disease.[5][56] In one report, one third of patients with nondeletional Hb H disease required regular transfusions.[8]

Iron status can be followed by serum ferritin, liver iron (R2 or R2* magnetic resonance imaging [MRI], superconducting quantum interference devices [SQUID], or liver biopsy [less preferred]), and cardiac iron (assessed by T2* cardiac MRI).[16]​​[54][55]​​​ Cardiac iron loading is uncommon in nontransfused patients.

For patients with nontransfusion-dependent thalassemia, regular evaluation of ferritin (at least every 6-12 months) should start at age 10 years, with MRI evaluation of liver iron if ferritin >300 nanograms/mL.[16] For patients with transfusion-dependent thalassemia, evaluation of ferritin should be carried out at each transfusion, with annual MRI evaluation of liver iron starting after 8-10 transfusions.[16]

Cardiac iron MRI monitoring is recommended annually for transfusion-dependent patients and should be considered periodically (annually if ferritin levels >2000 nanograms/mL) for those with nontransfusion-dependent disease.[16] Serum ferritin levels may underestimate iron concentration.[56]

Hb H disease: iron chelation therapy

The goal of iron chelation is to prevent end-organ damage secondary to iron overload.

Guidelines recommend that iron chelation therapy should be initiated in nontransfusion-dependent alpha-thalassemia patients if liver iron concentration is >5 mg Fe/g dry weight (or serum ferritin level is >500 nanograms/mL). Transfusion-dependent patients begin chelation therapy if liver iron concentration is >3.5 mg Fe/g dry weight (or serum ferritin level is >800 nanograms/mL).[16] 

Liver iron concentration should be maintained at 2 mg to 5 mg Fe/g dry weight in alpha-thalassemia patients.[16] Data are, however, limited. In nontransfusion-dependent beta-thalassemia intermedia, liver iron concentration ≥5 mg Fe/g dry weight is associated with increased risk of vascular events, hypothyroidism, osteoporosis, and hypogonadism.[79] 

Two oral iron chelators, deferasirox and deferiprone, and one parenteral iron chelator, deferoxamine, are available in the US and Europe. One meta-analysis of randomized controlled trials that evaluated these three agents in patients with severe thalassemia failed to identify one iron chelator that was consistently superior to the others.[80]

Deferasirox

Approved by the US Food and Drug Administration (FDA) for use in transfusion-dependent patients ≥2 years, and in nontransfusion-dependent thalassemia patients ≥10 years with liver iron concentrations ≥5 mg Fe/g dry weight and serum ferritin levels >300 nanograms/mL. In Europe, deferasirox is approved for patients ≥2 years with transfusion-dependent thalassemia and patients ≥10 years with nontransfusion-dependent thalassemia where deferoxamine cannot be used or is inadequate.

In one 12-month randomized double-blind placebo-controlled trial, deferasirox significantly decreased iron overload in nontransfusion-dependent thalassemia patients ≥10 years of age (166 patients randomized, 22 of whom had alpha-thalassemia) with an R2-MRI measured liver iron concentration of at least 5 mg Fe/g dry weight.[81] The most common adverse events were nausea, rash, and diarrhea. In a 1-year extension of the trial, liver iron concentration levels continued to decrease with deferasirox use.[82]

Deferasirox carries a warning related to the risk of renal failure, hepatic failure, and gastrointestinal hemorrhage.[83] Additional adverse effects include auditory and ocular impairment, rash, and bone marrow suppression. Serum creatinine, liver function, and auditory and ophthalmic function should be monitored before initiation of and during therapy.[84]

Deferiprone

Approved by the FDA for use in treatment of iron overload due to blood transfusions in patients ages ≥3 years with thalassemia and other anemias. In Europe, deferiprone is licensed for use in patients with thalassemia major when current chelation therapy is contraindicated or inadequate.

One phase 3 randomized controlled trial found deferiprone to be noninferior to deferasirox in pediatric patients with transfusion-dependent hemoglobinopathies.[85] The majority (90%) of enrolled patients had beta-thalassemia major; however, similar efficacy and safety is expected in patients with alpha-thalassemia major.[85] Deferiprone may improve cardiac parameters (myocardial MRI T2* and left ventricular ejection fraction) to a greater extent than deferoxamine.[80] Deferiprone increases risk for agranulocytosis; complete blood count (CBC) with differential must be monitored regularly while undergoing treatment.[86][87]​​​​​​​​​ Deferiprone can cause gastrointestinal and joint adverse effects.

Deferoxamine

Deferoxamine has a very short half-life and is administered as a slow subcutaneous or intravenous infusion. This limits acceptability to patients and can impede adherence. Deferoxamine effectively reduces both liver and cardiac iron.[88][89]​​ Deferoxamine carries a risk of auditory and ophthalmic toxicity, requiring regular monitoring.[16]

Hb H disease: splenectomy

Splenomegaly is common in patients with Hb H disease; more often in nondeletional than deletional Hb H disease. In select patients, splenectomy may increase hemoglobin levels and/or relieve symptoms.

Guidelines suggest considering splenectomy for patients with the following features:[16]

  • Moderately severe anemia

  • Episodes of acute hemolysis requiring frequent transfusions

  • Long-term complications of chronic hemolytic anemia

  • Symptomatic splenomegaly

​ Splenectomy is not recommended for patients with Hb H disease with severe anemia, who may be at higher risk of complications and still require transfusions postsplenectomy.[16] Splenectomy is not recommended in young children because of the risk of sepsis.[16]

Splenectomy may be particularly effective in raising the hemoglobin level and avoiding transfusions in patients with Hb H CS.[56] However, the potential for serious complications, including infection, thrombosis, and pulmonary hypertension, requires careful consideration before proceeding.[90][91]​​​​​​ Discuss risks and benefits of splenectomy, and alternative treatment options, with the patient.

Antiplatelet agents can be given to minimize the risk of thrombosis following splenectomy.[54][92]​​​​​​​ Patients should be vaccinated against pneumococcus, meningococcus, and Haemophilus influenzae prior to splenectomy.[16][93]​​​​​ Following splenectomy, children are given prophylactic oral penicillin for at least 2 years.[54][94]​​​

Patients and caregivers must be educated regarding the risks of postsplenectomy sepsis and the need for immediate medical evaluation in the case of febrile illness. Patients undergoing splenectomy may undergo concomitant cholecystectomy if there is evidence of cholelithiasis.​[16]

Hb H disease: red blood cell transfusion

The small proportion of patients who may need chronic red blood cell transfusion therapy should be carefully evaluated and managed in a thalassemia center with appropriate expertise.[54] The decision to initiate a chronic transfusion program should take into account multiple variables including the severity of anemia, the patient's cardiovascular status, and associated complications.

Guidelines suggest consideration of regular red blood cell transfusion in the following situations:[16]

  • Baseline hemoglobin <7 g/dL, declining hemoglobin levels, development of symptomatic anemia, or poor quality of life due to anemia.

  • To prevent or reduce long-term complications of chronic hemolytic anemia or to suppress ineffective erythropoiesis.

  • When frequent transfusions are required for acute hemolytic events.

  • Growth failure, poor educational performance, diminished exercise tolerance, or delayed puberty in children and young people.

Decisions about starting chronic transfusion should be individualized. A severity scoring system has been developed and validated to help guide transfusion decisions in pediatric nondeletional Hb H disease.[95]

Prior to transfusion, red cell antigen phenotyping should be performed, and patients should be transfused with appropriately matched blood to minimize the risk of alloimmunization.[96]

Patients must be carefully monitored for iron overload, and iron chelation therapy must be initiated as indicated.[16] Cardiac, endocrine, and hepatic function must also be carefully monitored.[54][97]

Adverse effects and intensive demands of iron chelation therapy may contribute to reduced adherence in transfusion-dependent patients with thalassemia.[98]​ Further research is required to assess adherence to iron chelation therapy, to identify suboptimal adherence, and to evaluate strategies that contribute to increased adherence.[98][99][100] [ Cochrane Clinical Answers logo ] ​​​​​​​​​

Hb H disease: hematopoietic stem cell transplant

The only curative therapy available for alpha-thalassemia, and can be considered in patients with severe transfusion-dependent disease. Overall survival rates may be up to 91%; outcomes are more favorable in children <16 years.[101][102]​​​​

Hb H disease: pregnancy

Pregnancy leads to a relative increase in plasma volume greater than red cell mass, which results in a decrease in Hb. Women with Hb H disease who are not iron overloaded should receive the same prenatal supplementation as pregnant women without thalassemia; however, they should be followed closely and transfusion may be required, particularly if the Hb declines below 8 g/dL.

Alpha-thalassemia major

Following diagnosis of alpha-thalassemia major, the mother may choose to terminate the pregnancy. Counseling should, however, recognize that intrauterine transfusion (IUT) is an option for expectant parents who receive a prenatal diagnosis of alpha-thalassemia major.[37][103]​ Fetuses (diagnosed prenatally) with homozygous alpha(0) variants that spare the zeta-globin gene, or (--(FIL)/--(SEA) or --(THAI)/--(SEA)) genotypes, will survive into the second or third trimester, or, occasionally, to birth.

IUT can be offered to families who wish to pursue fetal intervention for alpha-thalassemia major.[37] If desired, IUT should begin as soon as technically possible, generally at 18 weeks' gestation, to mitigate the long-term impact of fetal hypoxia. A similar protocol to standard protocols for alloimmunization should be followed.[37]

A review of data from the alpha-thalassemia registry (International Registry of Patients With Alpha Thalassemia) indicates that fetuses with alpha-thalassemia major who received at least two IUTs had delivery near term, resolution of hydrops, normal neurodevelopmental outcomes, and excellent survival.[103] Case reports and case series report similar outcomes.[104][105]​​​

Patients who survive alpha-thalassemia major in utero will require lifelong transfusion (with the attendant requirement for iron chelation), or hematopoietic stem cell transplantation.[37]​ Patients with alpha-thalassemia major are not likely to benefit from splenectomy, and it is not recommended in these patients.[16]

Genotype analysis

The alpha-globin gene cluster is made up of an embryonic zeta-globin gene and two coexpressed alpha-globin genes, designated alpha-2 and alpha-1. Among the most common alpha(0) variants, --(SEA), --(MED), and -(alpha)(20.5) lead to deletion of both alpha-2 and alpha-1 in cis (where gene variants are on the same chromosome), while sparing the embryonic zeta-globin gene. In contrast, in the --(THAI) and --(FIL) deletions, the zeta-globin gene is deleted in addition to both alpha-globin genes in cis. Therefore, embryos with homozygous --(THAI) and --(FIL) deletions, incapable of making normal embryonic hemoglobins, will die very early in gestation, leading to early miscarriage.[11]

Those with homozygous alpha(0) variants that spare the zeta-globin gene, or (--(FIL)/--(SEA) or --(THAI)/--(SEA)) genotypes, will survive into the second or third trimester, or, occasionally, to birth. Without intervention, the fetus is subject to severe hypoxia, leading to the hydrops fetalis presentation.[11] These infants are also at risk for severe congenital anomalies, although intervention may lessen anomaly severity.[11]

Rarely, patients with Hb H disease may also present with hydrops fetalis.[106][107]​ There is an increased incidence of severe maternal complications associated with a hydrops fetalis presentation, including placentomegaly, hypertension, severe preeclampsia, and hemorrhage.[11][108]

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