Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

acute hemolytic episodes: pregnant or nonpregnant

1st line – identification of cause + monitoring + folic acid supplementation

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ACUTE
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acute hemolytic episodes: pregnant or nonpregnant
1st line – 

identification of cause + monitoring + folic acid supplementation

Treatment for acute hemolytic episodes includes investigation as to the cause of the hemolytic event (including evaluation for coexisting G6PD deficiency), monitoring (for severe anemia, assessment of cardiovascular status, and transfusions, depending on the severity of anemia and tolerance to transfusions), and folic acid supplementation.

Primary options

folic acid (vitamin B9): children and adults: 1 mg orally once daily until response, then 0.4 mg orally once daily

Consider – red blood cell transfusion

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ACUTE
|
acute hemolytic episodes: pregnant or nonpregnant
Consider – 

red blood cell transfusion

Treatment recommended for SOME patients in selected patient group

Depending on the severity and tolerance of anemia, a patient with severe anemia may be hospitalized to have red blood cell transfusion. There is no absolute threshold at which acute transfusion should be initiated. In general, patients with a hemoglobin <7 g/dL may require transfusion, with the aim of restoring hemoglobin to 8-9 g/dL.​[16][54]

transient aplastic crisis: pregnant or nonpregnant

1st line – red blood cell transfusion

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ACUTE
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transient aplastic crisis: pregnant or nonpregnant
1st line – 

red blood cell transfusion

Transient aplastic crises are most commonly due to infection with parvovirus B19 infection, which infects erythroid progenitor cells.[109] The resultant reticulocytopenia may lead to a severe anemia, particularly in patients with chronic hemolysis. Transient aplastic crises are self-limited (1-2 weeks), and treatment is supportive, with bridging red blood cell transfusions until erythroid recovery.

There is no absolute threshold at which acute transfusion should be initiated. In general, patients with a hemoglobin <7 g/dL may require transfusion, with the aim of restoring hemoglobin to 8-9 g/dL.[16][54]​​

ONGOING

nonpregnant

1st line – avoidance of unnecessary iron supplementation + supportive care

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ONGOING
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nonpregnant
|
alpha-thalassemia silent carrier
1st line – 

avoidance of unnecessary iron supplementation + supportive care

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]

1st line – avoidance of unnecessary iron supplementation + supportive care

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ONGOING
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nonpregnant
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alpha-thalassemia trait
1st line – 

avoidance of unnecessary iron supplementation + supportive care

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]

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] Patients should be followed regularly for assessment of degree of anemia and hemolysis as well as for assessment of the development or worsening of splenomegaly.

1st line – folic acid supplementation + supportive care

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ONGOING
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nonpregnant
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Hb H disease
1st line – 

folic acid supplementation + supportive care

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 hemoglobin H (Hb H) disease or the potentially devastating alpha-thalassemia major.

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]​ 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 folic acid supplementation.[71]

Hb H disease refers to both the more common deletional and the less common nondeletional Hb H disease. Patients with nondeletional Hb H disease tend to have a more severe clinical course, with younger age at diagnosis, more symptoms, and greater degrees of splenomegaly, and are more likely to require transfusion than are patients with deletional Hb H disease.[5] In one report, one third of patients with nondeletional Hb H disease required regular transfusions.[8]

All patients should be monitored for iron overload. 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 mg/mL.[16]​ For patients with transfusion-dependent thalassemia, evaluation of ferritin should be carried out at each transfusion, with annual MRI for liver iron concentration 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]

Primary options

folic acid (vitamin B9): children and adults: 1 mg orally once daily

Consider – red blood cell transfusion

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ONGOING
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nonpregnant
|
Hb H disease
Consider – 

red blood cell transfusion

Treatment recommended for SOME patients in selected patient group

Patients with nondeletional Hb H, such as Hb H/Constant Spring, are more likely to require both acute and chronic red blood cell transfusions than patients with deletional Hb H disease.[5][56]​ 

There is no absolute threshold at which acute transfusions should be initiated. In general, patients with a hemoglobin <7 g/dL may require transfusion, with the aim of restoring hemoglobin to 8-9 g/dL.​[16][54]

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 comorbid conditions (including cardiovascular status, which, if impaired, can lead to intolerance of even moderate anemia), and associated complications.

Guidelines suggest consideration of regular red blood cell transfusion in the following situations: 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.[16]​ Cardiac, endocrine, and hepatic function must also be carefully monitored.[54][97]​ 

Consider – iron chelation therapy

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ONGOING
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nonpregnant
|
Hb H disease
Consider – 

iron chelation therapy

Treatment recommended for SOME patients in selected patient group

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

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]

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]

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 for liver iron concentration 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]

Guidelines recommend that iron chelation therapy should be initiated in nontransfusion-dependent 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]

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]​ Adverse effects and intensive demands of iron chelation therapy may contribute to reduced adherence in transfusion-dependent patients with thalassemia.[98]

Deferasirox is approved by the US Food and Drug Administration (FDA) for use in transfusion-dependent patients ≥2 years, and in nontransfusion-dependent thalassemia patients ages ≥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. 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 is approved by the FDA for 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. 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 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.

Primary options

deferasirox: consult specialist for guidance on dose

OR

deferoxamine: consult specialist for guidance on dose

Secondary options

deferiprone: consult specialist for guidance on dose

Consider – splenectomy + preoperative vaccination + postoperative penicillin and antiplatelet agent

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ONGOING
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nonpregnant
|
Hb H disease
Consider – 

splenectomy + preoperative vaccination + postoperative penicillin and antiplatelet agent

Treatment recommended for SOME patients in selected patient group

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: moderately severe anemia; episodes of acute hemolysis requiring frequent transfusions; long-term complications of chronic hemolytic anemia; symptomatic splenomegaly.[16]

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 the risks and benefits of splenectomy, and alternative treatment options, with the patient.

Antiplatelet agents such as low-dose aspirin can be given to try 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 post-splenectomy 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]

Primary options

penicillin V potassium: children <5 years of age: 125 mg orally twice daily; children ≥5 years of age: 250 mg orally twice daily

and/or

aspirin: adults: 81 mg orally once daily

Consider – hematopoietic stem cell transplant for severe transfusion-dependent disease

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ONGOING
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nonpregnant
|
Hb H disease
Consider – 

hematopoietic stem cell transplant for severe transfusion-dependent disease

Treatment recommended for SOME patients in selected patient group

Hematopoietic stem cell transplant is 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]

pregnant

1st line – routine prenatal supplementation if not iron overloaded and close follow-up

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ONGOING
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pregnant
|
alpha-thalassemia silent carrier
1st line – 

routine prenatal supplementation if not iron overloaded and close follow-up

In alpha-thalassemia silent carrier, the Hb does not usually decline below 9 g/dL and intervention is not typically required.[70]​

Routine prenatal supplementation with prenatal vitamins (if not iron overloaded) and close follow-up are usually sufficient.

1st line – routine prenatal supplementation if not iron overloaded and close follow-up

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ONGOING
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pregnant
|
alpha-thalassemia trait
1st line – 

routine prenatal supplementation if not iron overloaded and close follow-up

In alpha-thalassemia trait, the Hb does not usually decline below 9 g/dL and intervention is not typically required.[70]

Routine prenatal supplementation with prenatal vitamins (if not iron overloaded) and close follow-up are usually sufficient.

1st line – routine prenatal supplementation + close follow-up + supportive care

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ONGOING
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pregnant
|
with Hb H disease
1st line – 

routine prenatal supplementation + close follow-up + supportive care

Pregnancy leads to a relative increase in plasma volume greater than red cell mass, which results in a decrease in Hb.

Pregnant 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.

Iron chelation therapy is avoided during pregnancy to minimize potential teratogenicity and iron deficiency in the fetus.[110]

It is important to avoid medications associated with oxidant injury in G6PD deficiency, such as sulfonamides and nitrofurantoin, and to provide education, particularly with regard to genetic counseling.

Consider – red blood cell transfusion

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ONGOING
|
pregnant
|
with Hb H disease
Consider – 

red blood cell transfusion

Treatment recommended for SOME patients in selected patient group

Transfusion may be required, particularly if the Hb declines below 8 g/dL. Red blood cell transfusion may be given, even if there is a concern for iron overload.[110]

1st line – maternal support + monitoring for and management of complications

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ONGOING
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pregnant
|
fetus with alpha-thalassemia major
1st line – 

maternal support + monitoring for and management of complications

Embryos with homozygous --(THAI) and --(FIL) deletions are incapable of making normal embryonic hemoglobins and will die very early in gestation, leading to early miscarriage.[11]

Fetuses 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] There is an increased incidence of severe maternal complications associated with a hydrops fetalis presentation, including placentomegaly, hypertension, severe preeclampsia, and hemorrhage.[11][108]

Following diagnosis of alpha-thalassemia major, the mother may choose to terminate the pregnancy. It is very important that the complications are managed appropriately and maternal support is provided.

Consider – intrauterine red blood cell transfusion

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ONGOING
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pregnant
|
fetus with alpha-thalassemia major
Consider – 

intrauterine red blood cell transfusion

Treatment recommended for SOME patients in selected patient group

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]

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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