Introduction

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Once an infant with α-thalassaemia major (haemoglobin Bart’s hydrops foetalis) survives the neonatal period, they will become lifelong transfusion-dependent, unless they are cured by haematopoietic stem cell transplantation. Generally, (more...)

1. Due to the physiologic switching of γ-to-β globin synthesis within the first few months of life, tetramers of β-globin (β₄, HbH) gradually replace the Hb Bart’s (γ4), which was the predominant haemoglobin in a foetus with haemoglobin Bart’s hydrops foetalis. Consequently, endogenous erythrocytes of a patient with α-thalassaemia major are almost completely composed of HbH [1]. These HbH-containing erythrocytes are susceptible to early haemolysis leading to intramedullary erythroid cell death (ineffective erythropoiesis), but more prominently, haemolysis in peripheral circulation [2, 3]. As a result, patients with transfusion-dependent α-thalassaemia major exhibit significant reticulocytosis in contrast to patients with β-thalassaemia major [3].
2. Similar to Hb Bart’s, HbH has an extremely high oxygen affinity and does not participate in transportation of oxygen to the tissues [4]. Thus, in patients with transfusion-dependent α-thalassaemia major, the total haemoglobin concentration does not accurately represent tissue oxygenation. When regularly transfused according to protocol that are developed for β-thalassaemia major, patients with α-thalassaemia major continue to have a high proportion of circulating non-functional HbH and display features of hypoxia, haemolysis, and ineffective erythropoiesis [3]. Ultimately, the resulting tissue hypoxia and increased haemolysis lead to chronic organ dysfunction and clinical complications. As the result, patients with α-thalassaemia major require a more aggressive transfusion regimen. This “hypertransfusion” approach aims to reduce the production of endogenous HbH-containing erythrocytes and improve “functional” haemoglobin (non-HbH haemoglobin). This approach has been shown to be associated with reduced haemolysis and improved tissue oxygenation. However, such a regimen results in a higher degree of iron load and its associated costs and complications [3].
3. All infants with α-thalassaemia major are transfusion-dependent from birth, and most likely they have already received transfusions in the prenatal period. This is in contrast to the majority of patients with β-thalassaemia major who do not require transfusion until at least six to nine months of age. The early initiation of blood transfusions, coupled with the need for more aggressive transfusion, results in early iron overload and inevitably the need for early iron chelation [5, 6]. Both early iron overload and early initiation of iron chelation at a young age have been shown to be associated with long-term complications [7–9]. In a small cohort of adolescents with α-thalassaemia major, a high rate of endocrinopathies and growth failure has been observed [5].
4. Patient with α-thalassaemia major exhibit an increased rate of congenital birth defects and almost all males have genitourinary abnormalities with a varying degree of severity. In addition, a higher rate of neurodevelopmental compromise has been observed in patients with α-thalassaemia major [10].

Transfusion for patients with α-thalassaemia major

Due to preserved reticulocytosis and high proportion of circulating non-functional HbH, patients with α-thalassaemia major require a more aggressive transfusion strategy as compared to patients with β-thalassaemia major. However, the best transfusion targets for these patients are not well defined. One case-series has suggested that maintaining pre-transfusion functional haemoglobin (non-HbH haemoglobin) > 105 g/L and HbH proportion < 15% are required to suppress ineffective erythropoiesis. These targets however were associated with significant increase in the required transfusion volume and consequently transfusional iron load, thus its haematological benefit may be offset by complications of iron overload [11]. It is likely that pre-transfusion functional haemoglobin of 90-100 g/L and HbH at < 15% are sufficient to offer long-term clinical benefit without excessive iron load. Nevertheless, it is important to calculate the non-functional haemoglobin periodically (ideally with every transfusion) and adjust transfusions as required. Functional haemoglobin can be calculated as follows:

Functional Hb = Total Hb x (1- [HbH % + Hb Bart’s %] / 100)

We recommend HbH (and HbH Bart’s) be measured using capillary zone electrophoresis, ideally on a fresh sample. HPLC can also be used; however, it is less accurate as bilirubin may interfere with the measurement of HbH or Hb Bart’s on HPLC [12]. If an automated haemoglobin analyzer is not available, peripheral blood smear using a supravital stain can be used to calculate the proportion of endogenous HbH-containing cells vs. HbA-containing transfused red blood cells. This method is not completely accurate as HbH-containing red blood cells have lower mean corpuscular haemoglobin (MCH) as compared to transfused red cells; nevertheless, this can be helpful.

If HbH cannot be reduced to < 15% with simple transfusions, sessions of exchange transfusion can be considered. Alternatively, some centres have used regular exchange transfusions to reduce the burden of iron overload [13]. Such an approach is associated with higher volume of blood consumption and may not be feasible in most settings. Centres lacking access to precise HbH measurements and, as a result, are unable to calculate functional haemoglobin may consider maintaining pre-transfusion total haemoglobin at 105-110 g/L and reticulocyte count < 500 x 10e9/L.

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Some centres have advocated for a more aggressive transfusion protocol for the first few months of life, in order to effectively supress erythropoiesis and reduce splenomegaly with the intention to eventually decreased the volume of transfusions in the (more...)

Finally, RBC antigens should be determined by DNA testing so that antigen-matched blood can be provided to reduce the risk of alloimmunization. For detailed review of principles of transfusions, please refer to the Thalassaemia International Federation Guidelines for the Management of Transfusion Dependent Thalassaemia [15].

Iron overload and chelation

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As reviewed previously, in patients with α-thalassaemia major, transfusional iron overload occurs early, within a few months of birth. The management of iron overload in α-thalassaemia major, especially in younger infants and children (more...)

We recommend starting iron chelation with deferasirox at low dose (Jadenu, 3 to 5 mg/kg, usually 45 mg, crushed tablet, or equivalent dosing for Exjade) and increase the dose by 45 mg every two months as long as transaminases are stable. The dose is increased up to a maximum of 14 mg/kg until the child is 2 years old, following which the general guidelines for deferasirox are followed. Please refer to Chapter 11 (Iron Overload in α-thalassaemia) and the Thalassaemia International Federation Guidelines for the Management of Transfusion Dependent Thalassaemia for more detailed review [15]. We do not recommend aggressive iron chelation before 2 years of life.

Deferiprone should be reserved for where deferasirox is not available or accessible, or when deferasirox is not tolerated at therapeutic doses. Dosing of deferiprone in young children follows the same approach as for deferasirox, as reviewed above. Deferiprone can be added as a second chelator at a dose of 50 to 75 mg/kg. Safety and efficacy of deferiprone in children <2 years with β-thalassaemia major, sickle cell disease, and other anaemias have been reported [17, 18] but no data are available for patients with α-thalassaemia major.

Deferoxamine can be used in combination with one of the other chelators in children with severe hepatic iron overload however, it is not the preferable chelation in infants and toddlers given potential long-term side effects. The dose of deferoxamine is limited to 20 to 30 mg/kg as a subcutaneous infusion on three to five days per week to reduce the risk of toxicity affecting bones and growth [8, 9, 19].

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Once on iron chelation, patients should be monitored regularly for changes associated with iron overload or chelation. Liver enzymes and biochemical markers of kidney function should be checked with every interaction. Urinalysis for measurement of urine (more...)

Other issues

Management of neurodevelopmental compromise

Emerging evidence suggests that children treated with intrauterine transfusions (IUT) generally exhibit improved long-term neurodevelopmental outcomes compared to those who did not receive IUT [5, 20]. However, it’s important to note that even children treated with IUT may have experienced a period of severe anaemia early in gestation. This early anaemia could potentially have an adverse impact on neurocognitive development [10]. Additionally, suboptimal post-natal transfusions can lead to a state of chronic hypoxia and haemolysis, which may affect neurodevelopment. In fact, a high rate of ischemic white matter changes has been observed in children and adolescents with α-thalassaemia major [5].

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All infants with α-thalassaemia major should be closely monitored by developmental specialists and undergo neurologic assessments. Neurodevelopmental assessments should be repeated during school-age or if there are concerns regarding academic (more...)

If a child with α-thalassaemia major is diagnosed with neurodevelopmental compromise, they should be promptly referred for specialized intervention and appropriate support. The management plan will depend on the extent of intellectual disability and whether any visual, hearing, or motor deficits are present.

Haematopoietic stem cell transplant

As discussed earlier, patients with α-thalassaemia major necessitate more intensive transfusion and iron chelation regimens and experience higher rate of thalassaemia or treatment-related complications compared to individuals with transfusion-dependent β-thalassaemia. Consequently, the option of haematopoietic stem cell transplant should be considered early as a potential curative option for patients with α-thalassaemia major (please refer to Chapter 12: Curative therapies for α-thalassaemia for further details).

Summary and recommendations

References

1.

Vichinsky EP. Alpha thalassaemia major--new mutations, intrauterine management, and outcomes. Haematology Am Soc Hematol Educ Program. 2009:35–41. [PubMed: 20008180]

2.

Chui DH, Fucharoen S, Chan V. Haemoglobin H disease: not necessarily a benign disorder. Blood. 2003 Feb 1;101(3):791–800. [PubMed: 12393486]

3.

Amid A, Chen S, Brien W, Kirby-Allen M, Odame I. Optimizing chronic transfusion therapy for survivors of haemoglobin Barts hydrops foetalis. Blood. 2016 Mar 3;127(9):1208–11. [PubMed: 26732098]

4.

Imai K, Tientadakul P, Opartkiattikul N, Luenee P, Winichagoon P, Svasti J, Fucharoen S. Detection of haemoglobin variants and inference of their functional properties using complete oxygen dissociation curve measurements. Br J Haematol. 2001 Feb;112(2):483–7. [PubMed: 11167851]

5.

Zhang HJ, Amid A, Janzen LA, Segbefia CI, Chen S, Athale U, Charpentier K, Merelles-Pulcini M, Seaward G, Kelly EN, Odame I, Waye JS, Ryan G, Kirby-Allen M. Outcomes of haemoglobin Bart’s hydrops foetalis following intrauterine transfusion in Ontario, Canada. Arch Dis Child Fetal Neonatal Ed. 2021 Jan;106(1):51–6. [PubMed: 32616558]

6.

Denton C, Carson S, Veluswamy S, Wood JC, Coates TD. Pituitary and pancreatic iron is present at an early age in transfused patients with alpha thalassaemia major. Blood. 2023;141 Abst 2477.

7.

Kwiatkowski JL, Porter JB. Transfusion and Iron Chelation Therapy. In: Steinberg MH, Forget BG, Higgs DR, Weatherall DJ, editors. Disorders of Haemoglobin. Vol. 1. New York, NY: Cambridge University Press; 2009. pp. 689–744.

8.

De Virgiliis S, Congia M, Frau F, Argiolu F, Diana G, Cucca F, Varsi A, Sanna G, Podda G, Fodde M, et al. Deferoxamine-induced growth retardation in patients with thalassaemia major. J Pediatr. 1988 Oct;113(4):661–9. [PubMed: 3171791]

9.

De Sanctis V, Pinamonti A, Di Palma A, et al. Growth and development in thalassaemia major patients with severe bone lesions due to desferrioxamine. Eur J Pediatr. 1996;155(5):368–372. [PubMed: 8741032]

10.

Songdej D, Babbs C, Higgs DR., BHFS International Consortium. An international registry of survivors with Hb Bart’s hydrops foetalis syndrome. Blood. 2017 Mar 9;129(10):1251–9.56. [PMC free article: PMC5345731] [PubMed: 28057638]

11.

Amid A, Barrowman N, Odame I, Kirby-Allen M. Optimizing transfusion therapy for survivors of Haemoglobin Bart’s hydrops foetalis syndrome: Defining the targets for haemoglobin-H fraction and “functional” haemoglobin level. Br J Haematol. 2022 May;197(3):373–6. [PubMed: 35176810]

12.

Kar R, Sharma CB. Bilirubin peak can be mistaken as Hb Bart’s or Hb H on High-performance liquid chromatography. Haemoglobin. 2011;35(2):171–4. [PubMed: 21417577]

13.

Ong J, Bowden D, Kaplan Z. Management of haemoglobin Barts hydrops foetalis syndrome with exchange transfusions. Intern Med J. 2020 May;50(5):638–39. [PubMed: 32431038]

14.

Lal A, Lianoglou BR, Velez JM. Alpha thalassaemia major: Prenatal and postnatal management. In: Post TW, editor. UpToDate. UpToDate; Waltham, MA, USA: 2022.