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 haemolytic episodes: pregnant or non-pregnant

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

Back
ACUTE
|
acute haemolytic episodes: pregnant or non-pregnant
1st line – 

identification of cause + monitoring + folic acid supplementation

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

Primary options

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

Consider – red blood cell transfusion

Back
ACUTE
|
acute haemolytic episodes: pregnant or non-pregnant
Consider – 

red blood cell transfusion

Additional treatment recommended for SOME patients in selected patient group

Depending on the severity and tolerance of anaemia, a patient with severe anaemia may be hospitalised to have red blood cell transfusion. There is no absolute threshold at which transfusion should be initiated, with the exception of patients with very severe anaemia (haemoglobin level <50 g/L [<5 g/dL]).[72] In general, patients with a haemoglobin <70 g/L (<7 g/dL) may require transfusion.[50]

transient aplastic crisis: pregnant or non-pregnant

1st line – red blood cell transfusion

Back
ACUTE
|
transient aplastic crisis: pregnant or non-pregnant
1st line – 

red blood cell transfusion

Transient aplastic crises are most commonly due to infection with parvovirus B19 infection, which infects erythroid progenitor cells.[102] The resultant reticulocytopenia may lead to a severe anaemia, particularly in patients with chronic haemolysis. Transient aplastic crises are self-limiting (1-2 weeks), and treatment is supportive, with bridging red blood cell transfusions until erythroid recovery.

There is no absolute threshold at which transfusion should be initiated, with the exception of patients with very severe anaemia (haemoglobin level <50 g/L [<5 g/dL]).[72] In general, patients with a haemoglobin <70 g/L (<7 g/dL) may require transfusion.[50]

ONGOING

non-pregnant

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

Back
ONGOING
|
non-pregnant
|
alpha-thalassaemia silent carrier
1st line – 

avoidance of unnecessary iron supplementation + supportive care

Alpha-thalassaemia silent carrier (1 affected alpha-globin gene) status is generally associated with normal Hb levels; patients with alpha-thalassaemia trait (2 affected alpha-globin genes) may have a mild asymptomatic anaemia. It is important to avoid unnecessary and potentially harmful iron supplementation in this population and to provide education, particularly with regard to genetic counselling.[103]

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

Back
ONGOING
|
non-pregnant
|
alpha-thalassaemia trait
1st line – 

avoidance of unnecessary iron supplementation + supportive care

Alpha-thalassaemia silent carrier (1 affected alpha-globin gene) status is generally associated with normal Hb levels; patients with alpha-thalassaemia trait (2 affected alpha-globin genes) may have a mild asymptomatic anaemia. It is important to avoid unnecessary and potentially harmful iron supplementation in this population and to provide education, particularly with regard to genetic counselling.[103]

Patients who are homozygous for Hb Constant Spring (Hb CS/CS; a sub-type of alpha-thalassaemia trait) have a more serious clinical phenotype than those who are homozygous for deletional alpha(+) thalassaemia. They have a mild anaemia and frequently have jaundice and splenomegaly with a normal mean corpuscular volume (MCV) and slightly low mean corpuscular haemoglobin (MCH).[6] Patients should be followed regularly for assessment of degree of anaemia and haemolysis as well as for assessment of the development or worsening of splenomegaly.

1st line – folic acid supplementation + supportive care

Back
ONGOING
|
non-pregnant
|
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 counselling, the risks of conceiving a child with haemoglobin H (Hb H) disease or the potentially devastating alpha-thalassaemia major.

Patients with Hb H disease are at risk for complications, including transient episodes of severe anaemia (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][43][65][66]​ 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.[67] These patients are also given multivitamins without iron and oral folic acid supplementation.[65]

Hb H disease refers to both the more common deletional and the less common non-deletional Hb H disease. Patients with non-deletional 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 non-deletional Hb H disease required regular transfusions.[8]

All patients ≥10 years of age with non-transfusion-dependent thalassaemia syndromes (≥15 years in patients with deletional Hb H disease) should undergo magnetic resonance evaluation for iron overload status at 1- to 2-year intervals; serum ferritin levels should be measured every 3 months.[72] Serum ferritin levels may underestimate iron concentration.[52]

Primary options

folic acid: children and adults: 1 mg orally once daily

Consider – red blood cell transfusion

Back
ONGOING
|
non-pregnant
|
Hb H disease
Consider – 

red blood cell transfusion

Additional treatment recommended for SOME patients in selected patient group

Patients with non-deletional Hb H, such as Hb H/Constant Spring, are more likely to require both acute and chronic transfusions than patients with deletional Hb H disease.[5][52] The decision to provide either acute or chronic transfusions depends on age, severity of anaemia, and the patient's ability to tolerate anaemia. Tolerance of anaemia will be influenced by the presence or absence of comorbidities such as cardiovascular disease.

There is no absolute threshold at which transfusions should be initiated, with the exception of patients with very severe anaemia (haemoglobin level <50 g/L [<5 g/dL]).[72] In general, patients with a haemoglobin <70g/L (7 g/dL) may require transfusion.[50]

The small proportion of patients who may need chronic transfusion therapy should be carefully evaluated and managed in a thalassaemia centre with appropriate expertise.[50] The decision to initiate a chronic transfusion programme should take into account multiple variables including the severity of anaemia, the patient's comorbid conditions (including cardiovascular status, which, if impaired, can lead to intolerance of even moderate anaemia), and associated complications. Prior to transfusion, red cell antigen phenotyping should be performed, and patients should be transfused with appropriately matched blood to minimise the risk of alloimmunisation.[89]

Patients must be carefully monitored for iron overload. Cardiac, endocrine, and hepatic function must also be carefully monitored.[50]

Consider – iron chelation therapy

Back
ONGOING
|
non-pregnant
|
Hb H disease
Consider – 

iron chelation therapy

Additional treatment recommended for SOME patients in selected patient group

Iron overload develops over time in a high proportion of patients with Hb H disease, even in the absence of chronic red cell transfusions.[5][68][69]​ The goal of iron chelation is to prevent end-organ damage secondary to iron overload.

Iron status can be followed by serum ferritin, and quantification of liver iron by MRI, superconducting quantum interference devices, or liver biopsy.[51] Although data are limited for alpha-thalassaemia, liver iron concentrations of ≥5 mg Fe/g dry weight in non-transfusion-dependent beta-thalassaemia intermedia patients are associated with increased risk of vascular events, hypothyroidism, osteoporosis, and hypogonadism.[72][73]​​ Serum ferritin levels of ≥1797.6 picomol/L (≥800 nanograms/mL) appear to correlate with liver iron concentrations of ≥5 mg Fe/g dry weight.[72][104]​​ In patients with the more severe forms of alpha-thalassaemia at risk of iron overload, such as those with Hb H disease, iron levels should be evaluated regularly. All patients aged ≥10 years with non-transfusion-dependent thalassaemia syndromes (≥15 years in patients with deletional Hb H disease) should have magnetic resonance evaluation for iron overload status at 1- to 2-year intervals; serum ferritin levels should be measured every 3 months.[72] Serum ferritin levels may underestimate iron concentration.[52]

Guidelines recommend that iron chelation therapy should be initiated in non-transfusion-dependent thalassaemia patients aged ≥10 years (≥15 years in patients with deletional Hb H disease) if liver iron concentration is ≥5 mg Fe/g dry weight (or serum ferritin level is ≥1797.6 picomol/L [≥800 nanograms/mL] when liver iron concentration measurement is unavailable).[72]

Two oral iron chelators, deferasirox and deferiprone, and one parenteral iron chelator, desferrioxamine, are available in the US and Europe. One meta-analysis of randomised controlled trials that evaluated these three agents in patients with severe thalassaemia failed to identify one iron chelator that was consistently superior to the others.[74]​ Adverse effects and intensive demands of iron chelation therapy may contribute to reduced adherence in transfusion-dependent patients with thalassaemia.[91]

Deferasirox is approved by the US Food and Drug Administration (FDA) for use in transfusion-dependent patients ≥2 years, and in non-transfusion-dependent thalassaemia patients aged ≥10 years with liver iron concentrations ≥5 mg Fe/g dry weight and serum ferritin levels >674.1 picomol/L (>300 nanograms/mL). In Europe, deferasirox is approved for patients ≥2 years with transfusion-dependent thalassaemia and patients ≥10 years with non-transfusion-dependent thalassaemia where desferrioxamine cannot be used or is inadequate. Deferasirox carries a warning related to the risk of renal failure, hepatic failure, and gastrointestinal haemorrhage.[77] 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.[78]

Deferiprone is approved by the FDA for treatment of iron overload due to blood transfusions in patients aged ≥3 years with thalassaemia and other anaemias. In Europe, deferiprone is licensed for use in patients with thalassaemia major when current chelation therapy is contraindicated or inadequate. Deferiprone increases risk for agranulocytosis; full blood count (FBC) with differential must be monitored regularly while undergoing treatment.[80][81]​​​ Deferiprone can cause gastrointestinal and joint adverse effects.

Desferrioxamine 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. Desferrioxamine effectively reduces both liver and cardiac iron.[82][83]​ It is renally and hepatically cleared, and carries a risk of auditory and ophthalmic toxicity, requiring regular monitoring.

Primary options

deferasirox: consult specialist for guidance on dose

OR

desferrioxamine: consult specialist for guidance on dose

Secondary options

deferiprone: consult specialist for guidance on dose

Consider – splenectomy + preoperative vaccination + postoperative phenoxymethylpenicillin and antiplatelet agents

Back
ONGOING
|
non-pregnant
|
Hb H disease
Consider – 

splenectomy + preoperative vaccination + postoperative phenoxymethylpenicillin and antiplatelet agents

Additional treatment recommended for SOME patients in selected patient group

Splenectomy is often considered if a patient develops painful splenomegaly, hypersplenism with associated pancytopenia, an increase in transfusion requirement, poor growth and development due to worsening anaemia, or lack of availability of transfusion or iron chelation therapy.[72][84] It may be particularly effective in raising the haemoglobin level and avoiding transfusions in patients with Hb H CS.[52] However, the potential for serious complications, including infection, thrombosis, and pulmonary hypertension, requires careful consideration before proceeding.[85][86]

Antiplatelet agents such as low-dose aspirin can be given to try to minimise the risk of thrombosis following splenectomy.[50][87]

Patients should be vaccinated against pneumococcus, meningococcus, and Haemophilus influenzae prior to splenectomy.[16][88]​​​​

Following splenectomy, children only should be given prophylactic phenoxymethylpenicillin (penicillin-VK) for at least 2 years.[50][105]

Patients 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.[72]

Primary options

phenoxymethylpenicillin: children <5 years of age: 125 mg orally twice daily; children ≥5 years of age: 250 mg orally twice daily

and/or

aspirin: adults: 75 mg orally once daily

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

Back
ONGOING
|
non-pregnant
|
Hb H disease
Consider – 

haematopoietic stem cell transplant for severe transfusion-dependent disease

Additional treatment recommended for SOME patients in selected patient group

Haematopoietic stem cell transplant is the only curative therapy available for alpha-thalassaemia, and can be considered in patients with severe transfusion-dependent disease.

Overall survival rates may be up to 91%; outcomes are more favourable in children <16 years.[94][95]

pregnant

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

Back
ONGOING
|
pregnant
|
alpha-thalassaemia silent carrier
1st line – 

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

In alpha-thalassaemia silent carrier, the Hb does not usually decline below 90 g/L (9 g/dL) and intervention is not typically required.[64]​ Routine antenatal supplementation with antenatal vitamins (if not iron overloaded) and close follow-up are usually sufficient.

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

Back
ONGOING
|
pregnant
|
alpha-thalassaemia trait
1st line – 

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

In alpha-thalassaemia trait, the Hb does not usually decline below 90 g/L (9 g/dL) and intervention is not typically required.[64] Routine antenatal supplementation with antenatal vitamins (if not iron overloaded) and close follow-up are usually sufficient.

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

Back
ONGOING
|
pregnant
|
with Hb H disease
1st line – 

routine antenatal 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 antenatal supplementation as pregnant women without thalassaemia; however, they should be followed closely and transfusion may be required, particularly if the Hb declines below 80 g/L (8 g/dL).

Iron chelation therapy is avoided during pregnancy to minimise potential teratogenicity and iron deficiency in the fetus.[106]

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 counselling.

Consider – red blood cell transfusion

Back
ONGOING
|
pregnant
|
with Hb H disease
Consider – 

red blood cell transfusion

Additional treatment recommended for SOME patients in selected patient group

Transfusion may be required, particularly if the Hb declines below 80 g/L (8 g/dL). Red cell transfusion may be given, even if there is a concern for iron overload.[106]

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

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

maternal support + monitoring for and management of complications

Embryos with homozygous --(THAI) and --(FIL) deletions are incapable of making normal embryonic haemoglobins 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.[99] There is an increased incidence of severe maternal complications associated with a hydrops fetalis presentation, including placentomegaly, hypertension, severe pre-eclampsia, and haemorrhage.[11][101]

Following diagnosis of alpha-thalassaemia 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

Back
ONGOING
|
pregnant
|
fetus with alpha-thalassaemia major
Consider – 

intrauterine red blood cell transfusion

Additional treatment recommended for SOME patients in selected patient group

Following diagnosis of alpha-thalassaemia major, the mother may choose to terminate the pregnancy. Counselling should, however, recognise that intrauterine transfusion (IUT) is an option for expectant parents who receive an antenatal diagnosis of alpha-thalassaemia major.[96]​ Fetuses (diagnosed antenatally) 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.

The American Society of Hematology recommends offering IUT to all families who wish to pursue fetal intervention for alpha-thalassaemia major. 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 alloimmunisation should be followed.[37]

A review of data from the alpha-thalassaemia registry (International Registry of Patients With Alpha Thalassemia) indicates that fetuses with alpha-thalassaemia major who received at least two IUTs had delivery near term, resolution of hydrops, normal neurodevelopmental outcomes, and excellent survival.[96] Case reports and case series report similar outcomes.[97][98]

Patients who survive alpha-thalassaemia major in utero will require lifelong transfusion (with the attendant requirement for iron chelation), or haematopoietic stem cell transplantation.[37]

back arrow

Choose a patient group to see our recommendations

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

Use of this content is subject to our disclaimer