Introduction

Clinical phenotypes are diverse among affected individuals with non-deletional haemoglobin H (HbH) disease (--/α^Tα). This mainly depends on the type of mutation in α-globin genes, whether the mutation is in the HBA1 or the HBA2 gene, as well as co-inheritance of β-thalassaemia. Nevertheless, patients with non-deletional HbH disease with identical genotypes can exhibit substantially different clinical severity. Homozygosity for non-deletional α-globin mutations and compound heterozygosity of two different non-deletional mutations (α^Tα/α^Tα) or non-deletional mutation and deletional α⁺-thalassaemia (-α/α^Tα) can also result in HbH disease.

In the past, HbH disease was generally thought to be a mild form of thalassaemia. A number of patients with more severe phenotypes, especially those with non-deletional HbH disease, were left undertreated. In this chapter, clinical presentations of common and less common non-deletional HbH disease, as well as special forms of non-deletional α-thalassaemia will be described. In addition, management of affected individuals with non-deletional HbH disease and monitoring of the disease-associated complications from early childhood to adulthood will be covered.

General clinical presentation of non-deletional HbH disease

A variable extent of anaemia, ranging from mild asymptomatic anaemia to the most severe foetal anaemia (hydrops foetalis), can be observed in individuals with non-deletional HbH disease. This is unlike patients with deletional HbH disease, in which the degree of anaemia is generally mild and uniform. Haemoglobin Constant Spring (CS) appears to be the most prevalent form of non-deletional α-globin variant worldwide [1, 2]. This results in HbH-CS (--/α^CSα) being the most common form of non-deletional HbH disease, of which clinical phenotypes were extensively described. Clinical symptoms of non-deletional HbH are generally more severe than those of deletional forms. This is because some of the common non-deletional mutations affect expression of the HBA2 gene which produces the majority of the α-globin chains [2, 3]. Some mutations lead to production of highly unstable α-globin chains that precipitate in red blood cell precursors, leading to more pronounced ineffective erythropoiesis and haemolysis [4, 5]. Comparison of clinical and laboratory characteristics between individuals with deletional and non-deletional HbH disease is shown in Table 1. The data were derived from multiple key publications on paediatric [2, 6, 7] and adult patients with HbH disease [8, 9] and from a recent study of 246 patients with HbH disease from Thailand [10]. Neonates with non-deletional HbH disease can develop haemolytic jaundice and anaemia. In rare cases, hydrops foetalis is observed.

Table 1

Clinical and laboratory characteristics of individuals with deletional and non-deletional HbH

Coinheritance of HbE with HbH-CS or HbH Pakse (HbH-PS) are often identified in Southeast Asia. Coinheritance of HbH with heterozygous HbE has been referred to as AEBart’s disease, whereas coinheritance of HbH with homozygous HbE has been called EFBart’s disease. Clinical presentation of individuals with non-deletional AEBart’s and EFBart’s disease is comparable to non-deletional HbH without coinherited E trait or EE [11, 12]. However, patients with non-deletional AEBart’s and EFBart’s diseases have lower mean corpuscular volume as compared to their non-deletional HbH counterparts (MCV of ~50-60 fL vs. 65-75 fL), although the Hb levels are comparable [11, 12]. Acute haemolytic episodes following infection or inflammation were reported to be less frequently observed in patients with non-deletional HbH disease who coinherited HbE [13]. Unlike coinheritance of E trait or EE, coinheritance of non-deletional HbH disease with HbE/β-thalassaemia results in severe anaemia [13]. The severity of anaemia in patients with non-deletional HbH disease who are also carriers for β-thalassaemia mutations is generally less than those with non-deletional HbH disease alone [9].

Uncommon non-deletional HbH diseases

Box

To date, up to 400 non-deletional α-globin mutations have been reported in the database of Hb variants (https://globin.bx.psu.edu/hbvar/menu.html). The vast majority of these mutations are extremely rare and were reported as family-specific mutations (more...)

All of these non-deletional mutations can result in various forms of α-thalassaemia, depending on whether they interact with deletional or other non-deletional α-globin mutations in trans or whether they are inherited in homozygous form. Non-deletional HbH (--/α^Tα) occurs in the regions where these non-deletional variants and centres-thalassaemia alleles (--/αα) are both prevalent. Table 2 summarizes clinical phenotypes of selected uncommon non-deletional HbH. Non-deletional mutations leading to other forms of α-thalassaemia are described at the end of this chapter.

Table 2

Summary of selected non-deletional HbH (--/α^Tα) phenotypes

Individuals with certain uncommon genotypes of non-deletional HbH present with very severe clinical course that includes life-long transfusion dependency and hydrops foetalis (HbH hydrops foetalis syndrome). Foetuses affected with HbH hydrops foetalis syndrome almost always harbour α⁰-thalassaemia on one allele and a non-deletional mutation involving the HBA2 gene on the other allele producing an extremely unstable Hb variant in utero [17]. These foetuses suffer from severe intrauterine anaemia and hypoxia, which result in various degrees of oedema, ascites, pleural and pericardial effusions, as well as foetal growth restriction. Additionally, associated congenital anomalies, such as hypospadias, ambiguous genitalia and undescended testes, were observed in HbH hydrops foetalis syndrome [17] similar to that found in Hb Bart’s hydrops foetalis syndrome (BHFS), which is caused by deletion of all four α-globin genes (18). The affected foetuses are typically born premature and die shortly after birth, unless given prenatal and postnatal transfusions. Most survivors with HbH hydrops foetalis syndrome become transfusion-dependent from early infancy [17]. Rare non-deletional HbH genotypes reported to cause hydrops foetalis include --^Tot/α^CD30(^delGAG)α, --^SEA/α^CD66(^CTG->CCG)α, --^FIL/α^CD35(^TCC->CCC)α, --^MED/α^TSaudiα and --^SEA/α^{Zurich-Albisrieden}α [17, 19-22]. More frequently observed genotypes causing such hydrops include --^SEA/α^Adanaα [17], --^FIL/α^Adanaα [23] and --^SEA/α^QSα [24, 25]. Affected foetuses with HbH-CS and HbH-PS were previously thought to not develop severe hydrops foetalis, despite having severe anaemia in utero [17, 26]. However, very rare cases of HbH hydrops foetalis associated with compound heterozygosity of SEA deletion and HbCS [27] or HbPS [28] have recently been described.

Management of non-deletional HbH disease during childhood

General management and follow-up monitoring

Supplementation with folic acid ranging from 1 to 5 mg per day is generally recommended for all patients with non-deletional HbH disease, as it is required for increased erythropoietic activity [6]. Non-iron-containing multivitamin is suggested [6, 7] especially in paediatric patients who may not attain proper dietary intakes. Iron accumulation occurs from early life in non-deletional HbH disease [7], mainly from increased gastrointestinal iron absorption, regardless of whether they have received blood transfusions. Iron supplements should therefore be avoided. Although specific dietary restrictions are not deemed necessary, it is recommended to exercise moderation when consuming iron-rich foods and excessive intake is not advisable.

As compared to patients with deletional HbH disease, those with non-deletional forms are more likely to experience acute worsening of anaemia during infection/inflammation, leading to an urgent need of blood transfusion [7]. This more commonly occurs during childhood; therefore, care should be provided to avoid such events. These preventive measures include prompt treatment of acute illness and alertness to symptoms of severe anaemia. Furthermore, it is advisable to follow scheduled immunizations in accordance with the national guidelines for each individual (see Chapter 10).

Box

As most patients with non-deletional HbH disease are non-transfusion dependent (NTD), the follow-up interval for the affected paediatric subgroup may be considered according to baseline Hb levels. Ideally, those with Hb>80 g/L should be seen in (more...)

Transfusion management

Patients should receive blood transfusions in cases of acute exacerbation of anaemia, typically occurring after episodes of acute illness. This intervention is recommended when the haemoglobin level drops below 70 g/L or when there is accompanying symptoms of anaemia, with an aim to restore Hb to 80-90 g/L [2].

Box

The decision to initiate regular transfusions in non-deletional HbH disease should be approached differently in children and adults. Failing to provide adequate transfusion support for children with more severe anaemia or ineffective erythropoiesis can (more...)

Recent observational study shows the beneficial role of regular transfusion therapy on the growth parameter of severely affected paediatric patients with non-deletional HbH disease [10]. Nevertheless, careful assessment of individual patients before initiation of regular blood transfusion is essential to avoid overtreatment. In general, a regular transfusion regimen should be considered in patients with the following condition: declining Hb level in parallel with progressive enlargement of spleen, failure of growth or secondary sexual development, poor performance at school, decreased exercise tolerance, presence of bone changes, frequent haemolytic crisis, or poor quality of life [31]. Since paediatric patients with non-deletional HbH disease might be cared for by general paediatricians or less-experienced haematologists in many countries, a simple objective score to aid the decision to initiate regular transfusions is shown in Table 3. A transfusion regimen is recommended for those patients with a persistent score of ≥4 (severe phenotype) over a period of 3 to 6 months [10].

Table 3

Score for paediatrics non-deletional HbH severity classification (10).

For each criterion, a score is given according to the value. Total sum of all scores is interpreted as follows: severity score <4, non-severe disease; severity score ≥4, severe disease likely requiring regular blood transfusion for better outcomes.

Box

Once initiated, blood transfusions should be scheduled, usually every 3 to 6 weeks, with pre-transfusion haemoglobin aimed at a slightly lower level (80-90 g/L) in comparison to that aimed for β-TM [32]. This is because there is generally less (more...)

It is important to keep in mind that transfusion requirements of individual patients can be dynamic. Children and adolescents who do not require transfusions initially may later become transfusion dependent. Therefore, regular assessment of clinical symptoms and haemoglobin (Hb) levels at each visit (every 3–6 months, as discussed earlier) is imperative during childhood and early adulthood. By contrast, affected patients who are born with hydrops foetalis or require frequent transfusions during the first 6 months of life usually remain transfusion-dependent, unless cured through haematopoietic stem cell transplantation.

In certain transfusion-dependent patients with rare genotypes of non-deletional HbH, the proportion of non-functional Hb Bart’s and HbH can remain high (>20%), even when following a conventional transfusion regimen [34, 35]. Similar to that identified in survivors of BHFS [36], these patients exhibited subtle improvements in growth and the persistence of massive hepatosplenomegaly despite standard transfusion treatments. Such cases may necessitate a more aggressive transfusion regimen, akin to that employed in BHFS survivors, which aims to achieve a pre-transfusion functional Hb level of 90-100 g/L [37]. Functional Hb is calculated as total Hb x (1- [HbH % + Hb Bart’s %] / 100). In BHFS survivors, maintaining this level of pre-transfusion functional Hb was found to reduce haemolysis and enhance tissue oxygenation, resulting in improved clinical symptoms [36, 37]. However, it is of utmost importance to carefully evaluate whether the benefits of this aggressive transfusion regimen outweigh the increased risk of iron overload for individual patients with severe non-deletional HbH disease.

Management of adult patients with non-deletional HbH disease

Splenectomy

Box

Splenectomy is a traditional treatment option for patients with β-thalassaemia, but its use has declined due to the risk of postoperative complications, such as hypercoagulability, thrombotic events, and infections [38]. However, in patients with (more...)

Complications in non-deletional HbH diseases

Special forms of non-deletional α-thalassaemia

Homozygous HbCS

In certain regions with a high prevalence of HbCS, such as Southeast Asia, homozygous HbCS (α^CSα/α^CSα) is often encountered. Adults affected by this condition typically exhibit mild HbH phenotypes, which may include normocytic or mild microcytic haemolytic anaemia, jaundice, and splenomegaly [76, 77].

Acute episodes of increased haemolysis following infection/inflammation can occur during childhood [78]. While some patients may be diagnosed incidentally in their adulthood, some present in utero with hydrops foetalis [76, 79-81]. Premature birth and associated congenital anomalies, including urogenital and mild cardiac defects similar to those identified in BHFS and HbH hydrops foetalis, can be observed. Neonatal jaundice is common and often requires treatment. Some infants may experience severe haemolytic anaemia necessitating blood transfusions in the first few months of life [80]. After the stormy pre- and post-natal periods, the infants spontaneously recover, usually after the age of 3–4 months, and by the time the patients reach 1–2 years of age, they often have haemoglobin levels exceeding 90 g/L, and no longer require blood transfusions [80]. This is unlike the survivors of BHFS and other HbH hydrops foetalis who almost always remain transfusion-dependent. The mechanisms underlying such clinical courses of affected infants with homozygous HbCS remain unclear. Compound heterozygosity for HbCS and HbPS has also been reported to exhibit a clinical course similar to that observed in individuals with homozygous HbCS [81].

Box

Therefore, homozygous HbCS should be one of the differential diagnoses in foetuses and neonates presenting non-immune hydrops foetalis or haemolytic jaundice/anaemia requiring treatments, especially in the areas where the variant is prevalent. Once diagnosed (more...)

Less common non-deletional variants in homozygosity or compound heterozygosity with α⁺-thalassaemia

Polyadenylation site (poly A) mutations in the HBA2 gene affect the polyadenylation signal site and impede the efficiency of globin protein synthesis. Poly A site mutations also interfere with the expression of the HBA1 gene in cis, contributing to the severity of the phenotype observed [82, 83]. There are two common poly A site mutations, namely α-Poly A1 (AATAAA > AATAAG) and α-Poly A2 (AATAAA > AATGAA) [82, 84]. Clinical disease is observed in individuals who are homozygous for poly A mutation (α^Tα/α^Tα) or compound heterozygous with α⁰ deletion (--/α^Tα).

The α-^5nt mutation is a pentanucleotide deletion in the intron 1 region of the HBA2 gene. This mutation has a significant impact on mRNA processing, and affected patients have a phenotype similar to α⁺-thalassaemia. Since poly A and α-^5nt mutations are regional common variants, their homozygosity and compound heterozygosity with other α⁺-thalassaemia are often identified in the areas. Table 4 summarizes clinical phenotypes of such combinations of selected non-deletional α-globin mutations.

Table 4

Summary of clinical phenotypes of selected less common non-deletional variants in homozygosity (α^Tα/α^Tα) or compound heterozygosity with α⁺-thalassaemia (-α⁺/α^Tα)

Summary and recommendations

References

1.

Vichinsky EP. Changing patterns of thalassaemia worldwide. Ann N Y Acad Sci. 2005;1054:18–24. [PubMed: 16339647] [CrossRef]

2.

Fucharoen S, Viprakasit V. Hb H disease: clinical course and disease modifiers. Haematology Am Soc Hematol Educ Program. 2009:26–34. [PubMed: 20008179] [CrossRef]

3.

Liebhaber SA, Cash FE, Ballas SK. Human alpha-globin gene expression. The dominant role of the alpha 2-locus in mRNA and protein synthesis. J Biol Chem. 1986;261(32):15327–33. [PubMed: 3771577]

4.

Pootrakul P, Sirankapracha P, Hemsorach S, Moungsub W, Kumbunlue R, Piangitjagum A, et al. A correlation of erythrokinetics, ineffective erythropoiesis, and erythroid precursor apoptosis in thai patients with thalassaemia. Blood. 2000;96(7):2606–12. [PubMed: 11001918]

5.

Taher AT, Weatherall DJ, Cappellini MD. Thalassaemia. Lancet. 2018;391(10116):155–67. [PubMed: 28774421] [CrossRef]

6.

Vichinsky E. Advances in the treatment of alpha-thalassaemia. Blood Rev. 2012;26 Suppl 1:S31–4. [PubMed: 22631041] [CrossRef]

7.

Lal A, Goldrich ML, Haines DA, Azimi M, Singer ST, Vichinsky EP. Heterogeneity of haemoglobin H disease in childhood. N Engl J Med. 2011;364(8):710–8. [PubMed: 21345100] [CrossRef]

8.

Chen FE, Ooi C, Ha SY, Cheung BM, Todd D, Liang R, et al. Genetic and clinical features of haemoglobin H disease in Chinese patients. N Engl J Med. 2000;343(8):544–50. [PubMed: 10954762] [CrossRef]

9.

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

10.

Songdej D, Tandhansakul M, Wongwerawattanakoon P, Sirachainan N, Charoenkwan P, Chuansumrit A. Severity scoring system to guide transfusion management in pediatric non-deletional HbH. Pediatr Int. 2023;65(1):e15568. [PubMed: 37475523] [CrossRef]

11.

Traivaree C, Boonyawat B, Monsereenusorn C, Rujkijyanont P, Photia A. Clinical and molecular genetic features of Hb H and AE Bart’s diseases in central Thai children. Appl Clin Genet. 2018;11:23–30. [PMC free article: PMC5892615] [PubMed: 29662324] [CrossRef]

12.

Songdej D, Fucharoen S. Alpha-Thalassaemia: Diversity of Clinical Phenotypes and Update on the Treatment. Thalassaemia Reports. 2022;12:157–72. Thalass. Rep. 2022, 12(4), 157–172; https://doi​.org/10.3390​/thalassrep12040020.

13.

Fucharoen S, Weatherall DJ. The haemoglobin E thalassaemias. Cold Spring Harb Perspect Med. 2012;2(8) [PMC free article: PMC3405827] [PubMed: 22908199] [CrossRef]

14.

Harteveld CL, Higgs DR. Alpha-thalassaemia. Orphanet J Rare Dis. 2010;5:13. [PMC free article: PMC2887799] [PubMed: 20507641] [CrossRef]

15.

Hamid M, Keikhaei B, Galehdari H, Saberi A, Sedaghat A, Shariati G, et al. Genotype-phenotype correlation in patients with deletional and nondeletional mutations of Hb H disease in Southwest of Iran. Sci Rep. 2022;12(1):e4856. [PMC free article: PMC8941133] [PubMed: 35319015] [CrossRef]

16.

Kalle Kwaifa I, Lai MI, Md Noor S. Non-deletional alpha thalassaemia: a review. Orphanet J Rare Dis. 2020;15(1):e166. [PMC free article: PMC7322920] [PubMed: 32600445] [CrossRef]

17.

Lorey F, Charoenkwan P, Witkowska HE, Lafferty J, Patterson M, Eng B, et al. Hb H hydrops foetalis syndrome: a case report and review of literature. Br J Haematol. 2001;115(1):72–8. [PubMed: 11722414] [CrossRef]

18.

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

19.

Viprakasit V, Green S, Height S, Ayyub H, Higgs DR. Hb H hydrops foetalis syndrome associated with the interaction of two common determinants of alpha thalassaemia (--MED/(alpha)TSaudi(alpha)). Br J Haematol. 2002;117(3):759–62. [PubMed: 12028055] [CrossRef]

20.

Yang X, Yan JM, Li J, Xie XM, Zhou JY, Li Y, et al. Hydrops foetalis Associated with Compound Heterozygosity for Hb Zurich-Albisrieden (HBA2: C.178G > C) and the Southeast Asian (- -(SEA)/) Deletion. Haemoglobin. 2016;40(5):353–5. [PubMed: 27686733] [CrossRef]

21.

Chan V, Chan TK, Liang ST, Ghosh A, Kan YW, Todd D. Hydrops foetalis due to an unusual form of Hb H disease. Blood. 1985;66(1):224–8. [PubMed: 2988669]

22.

Chan V, Chan VW, Tang M, Lau K, Todd D, Chan TK. Molecular defects in Hb H hydrops foetalis. Br J Haematol. 1997;96(2):224–8. [PubMed: 9029003]

23.

Henderson S, Pitman M, McCarthy J, Molyneux A, Old J. Molecular prenatal diagnosis of Hb H hydrops foetalis caused by haemoglobin Adana and the implications to antenatal screening for alpha-thalassaemia. Prenat Diagn. 2008;28(9):859–61. [PubMed: 18615546] [CrossRef]

24.

Li DZ, Liao C, Li J, Xie XM, Huang YN, Wu QC. Haemoglobin H hydrops foetalis syndrome resulting from the association of the - -SEA deletion and the alphaQuong Szealpha mutation in a Chinese woman. Eur J Haematol. 2005;75(3):259–61. [PubMed: 16104884] [CrossRef]

25.

Liao C, Li J, Xie XM, Zhou JY, Li DZ. Diversity in clinical presentation of haemoglobin H disease induced by the SEA deletion and the haemoglobin Quong Sze. Ann Hematol. 2009;88(11):1145–7. [PubMed: 19259674] [CrossRef]

26.

Weatherall DJ, Clegg JB. The Thalassaemia Syndromes. 4th ed. Oxford, UK: Blackwell Science; 2001.

27.

He S, Zheng C, Meng D, Chen R, Zhang Q, Tian X, et al. Hb H Hydrops foetalis Syndrome Caused by Association of the - - (SEA) Deletion and Hb Constant Spring (HBA2: c.427T > C) Mutation in a Chinese Family. Haemoglobin. 2015;39(3):216–9. [PubMed: 25897478] [CrossRef]

28.

Luewan S, Sirichotiyakul S, Charoenkwan P, Phirom K, Tongsong T. Hydrops foetalis Associated with Fetal Haemoglobin H-Pakse Disease. Fetal Diagn Ther. 2022;49(11-12):528–35. [PubMed: 36574766] [CrossRef]

29.

Allen A, Fisher C, Premawardhena A, Peto T, Allen S, Arambepola M, et al. Adaptation to anemia in haemoglobin E-ß thalassaemia. Blood. 2010;116(24):5368–70. [PubMed: 20833979] [CrossRef]

30.

O’Donnell A, Premawardhena A, Arambepola M, Allen SJ, Peto TE, Fisher CA, et al. Age-related changes in adaptation to severe anemia in childhood in developing countries. Proc Natl Acad Sci U S A. 2007;104(22):9440–4. [PMC free article: PMC1890513] [PubMed: 17517643] [CrossRef]

31.

Taher AT, Musallam K, Cappellini MD. Splenectomy. In: Taher AT, Musallam K, Cappellini MD, editors. Guidelines for the Management of Non-Transfusion Dependent Thalassaemia (NTDT). 2nd ed. Strovolos, Cyprus: Thalassaemia International Federation; 2017. pp. 19–24. [PubMed: 24672826]

32.

Cazzola M, Borgna-Pignatti C, Locatelli F, Ponchio L, Beguin Y, De Stefano P. A moderate transfusion regimen may reduce iron loading in beta-thalassaemia major without producing excessive expansion of erythropoiesis. Transfusion. 1997;37(2):135–40. [PubMed: 9051086]

33.

Cazzola M, De Stefano P, Ponchio L, Locatelli F, Beguin Y, Dessi C, et al. Relationship between transfusion regimen and suppression of erythropoiesis in beta-thalassaemia major. Br J Haematol. 1995;89(3):473–8. [PubMed: 7734344]

34.

Viprakasit V, Tanphaichitr VS, Veerakul G, Chinchang W, Petrarat S, Pung-Amritt P, et al. Co-inheritance of Hb Pak Num Po, a novel alpha1 gene mutation, and alpha0 thalassaemia associated with transfusion-dependent Hb H disease. Am J Hematol. 2004;75(3):157–63. [PubMed: 14978697] [CrossRef]

35.

Surapolchai P, Sirachainan N, So CC, Hongeng S, Pakakasama S, Anurathapan U, et al. Curative Stem Cell Transplantation for Severe Hb H Disease Manifesting From Early Infancy: Phenotypic and Genotypic Analyses. Haemoglobin. 2016;40(1):70–3. [PubMed: 26575104] [CrossRef]

36.

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

37.

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;197(3):373–6. [PubMed: 35176810] [CrossRef]

38.

Cappellini MD, Robbiolo L, Bottasso BM, Coppola R, Fiorelli G, Mannucci AP. Venous thromboembolism and hypercoagulability in splenectomized patients with thalassaemia intermedia. Br J Haematol. 2000;111(2):467–73. [PubMed: 11122086] [CrossRef]

39.

Bisharat N, Omari H, Lavi I, Raz R. Risk of infection and death among post-splenectomy patients. J Infect. 2001;43(3):182–6. [PubMed: 11798256] [CrossRef]

40.

Singer ST, Kim HY, Olivieri NF, Kwiatkowski JL, Coates TD, Carson S, et al. Haemoglobin H-constant spring in North America: an alpha thalassaemia with frequent complications. Am J Hematol. 2009;84(11):759–61. [PMC free article: PMC4254706] [PubMed: 19787795] [CrossRef]

41.

Zhou YL, Zhang XH, Liu TN, Wang L, Yin XL. Splenectomy improves anaemia but does not reduce iron burden in patients with haemoglobin H Constant Spring disease. Blood Transfus. 2014;12(4):471–8. [PMC free article: PMC4212026] [PubMed: 24960653] [CrossRef]

42.

Musallam KM, Rivella S, Vichinsky E, Rachmilewitz EA. Non-transfusion-dependent thalassaemias. Haematologica. 2013;98(6):833–44. [PMC free article: PMC3669437] [PubMed: 23729725] [CrossRef]

43.

Tso SC, Chan TK, Todd D. Venous thrombosis in haemoglobin H disease after splenectomy. Aust N Z J Med. 1982;12(6):635–8. [PubMed: 6962715]

44.

Taher AT, Musallam KM, Karimi M, El-Beshlawy A, Belhoul K, Daar S, et al. Overview on practices in thalassaemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study. Blood. 2010;115(10):1886–92. [PubMed: 20032507] [CrossRef]

45.

Musallam KM, Taher AT, Karimi M, Rachmilewitz EA. Cerebral infarction in β-thalassaemia intermedia: breaking the silence. Thromb Res. 2012;130(5):695–702. [PubMed: 22857801] [CrossRef]

46.

Ekwattanakit S, Siritanaratkul N, Viprakasit V. A prospective analysis for prevalence of complications in Thai nontransfusion-dependent Hb E/β-thalassaemia and α-thalassaemia (Hb H disease). Am J Hematol. 2018;93(5):623–9. [PubMed: 29359464] [CrossRef]

47.

Chuncharunee S, Teawtrakul N, Siritanaratkul N, Chueamuangphan N. Review of disease-related complications and management in adult patients with thalassaemia: A multi-centerstudy in Thailand. PLoS One. 2019;14(3):e0214148. [PMC free article: PMC6426207] [PubMed: 30893381] [CrossRef]

48.

Teawtrakul N, Jetsrisuparb A, Pongudom S, Sirijerachai C, Chansung K, Wanitpongpun C, et al. Epidemiologic study of major complications in adolescent and adult patients with thalassaemia in Northeastern Thailand: the E-SAAN study phase I. Haematology. 2018;23(1):55–60. [PubMed: 28759343] [CrossRef]

49.

Chansai S, Yamsri S, Fucharoen S, Fucharoen G, Teawtrakul N. Phosphatidylserine-exposed red blood cells and ineffective erythropoiesis biomarkers in patients with thalassaemia. Am J Transl Res. 2022;14(7):4743–56. [PMC free article: PMC9360869] [PubMed: 35958503]

50.

Dore F, Pardini S, Gaviano E, Longinotti M, Bonfigli S, Rovasio S, et al. Recurrence of spinal cord compression from extramedullary hematopoiesis in thalassaemia intermedia treated with low doses of radiotherapy. Am J Hematol. 1993;44(2):148. [PubMed: 8266922]

51.

Karimi M, Cohan N, Pishdad P. Hydroxyurea as a first-line treatment of extramedullary hematopoiesis in patients with beta thalassaemia: Four case reports. Haematology. 2015;20(1):53–7. [PubMed: 24717020] [CrossRef]

52.

Chehal A, Aoun E, Koussa S, Skoury H, Koussa S, Taher A. Hypertransfusion: a successful method of treatment in thalassaemia intermedia patients with spinal cord compression secondary to extramedullary hematopoiesis. Spine (Phila Pa 1976). 2003;28(13):E245–9. [PubMed: 12838112] [CrossRef]

53.

Ang AL, Le TT, Tan RS. HbH Constant Spring disease has lower serum ferritin relative to liver iron concentration (LIC): importance of LIC measurement and potential impact on serum ferritin thresholds for iron chelation. Br J Haematol. 2017;176(6):986–8. [PubMed: 26991009] [CrossRef]

54.

Teawtrakul N, Sirijerachai C, Chansung K, Jetsrisuparb A. The serum ferritin levels and liver iron concentrations in patients with alpha-thalassaemia: is there a good correlation? Haematology. 2021;26(1):473–7. [PubMed: 34238133] [CrossRef]

55.

Surapolchai P, Songdej D, Hantaweepant C, Tantiworawit A, Charoenkwan P, Lauhasurayotin S, et al. Thalassaemia-related complications in pediatric, adolescent, and young adult patients with transfusion-dependent thalassaemia: A multicenterstudy in Thailand. Pediatr Blood Cancer. 2023;70(10):e30599. [PubMed: 37488065] [CrossRef]

56.

Tiosano D, Hochberg Z. Endocrine complications of thalassaemia. J Endocrinol Invest. 2001;24(9):716–23. [PubMed: 11716158] [CrossRef]

57.

De Sanctis V, Soliman AT, Yassin MA, Di Maio S, Daar S, Elsedfy H, et al. Hypogonadism in male thalassaemia major patients: pathophysiology, diagnosis and treatment. Acta Biomed. 2018;89 2-s:6–15. [PMC free article: PMC6179033] [PubMed: 29451224] [CrossRef]

58.

De Sanctis V, Eleftheriou A, Malaventura C. Prevalence of endocrine complications and short stature in patients with thalassaemia major: a multicenterstudy by the Thalassaemia International Federation (TIF). Pediatr Endocrinol Rev. 2004;2 Suppl 2:249–55. [PubMed: 16462705]

59.

Srisukh S, Ongphiphadhanakul B, Bunnag P. Hypogonadism in thalassaemia major patients. J Clin Transl Endocrinol. 2016;5:42–5. [PMC free article: PMC5644428] [PubMed: 29067234] [CrossRef]

60.

De Sanctis V, Soliman AT, Elsedfy H, Di Maio S. Current practice in treating adult female thalassaemia major patients with hypogonadism: An International Network of Clinicians for Endocrinopathies in Thalassaemia and Adolescence Medicine survey from Italy. Indian J Endocrinol Metab. 2016;20(6):880–1. [PMC free article: PMC5105578] [PubMed: 27867897] [CrossRef]

61.

Noetzli LJ, Mittelman SD, Watanabe RM, Coates TD, Wood JC. Pancreatic iron and glucose dysregulation in thalassaemia major. Am J Hematol. 2012;87(2):155–60. [PubMed: 22120775] [CrossRef]

62.

De Sanctis V, Soliman A, Yassin M. Iron overload and glucose metabolism in subjects with β-thalassaemia major: an overview. Curr Diabetes Rev. 2013;9(4):332–41. [PubMed: 23687960] [CrossRef]

63.

Luo HC, Luo QS, Huang FG, Wang CF, Wei YS. Impact of genotype on endocrinal complications of Children with Alpha-thalassaemia in China. Sci Rep. 2017;7(1):e2948. [PMC free article: PMC5462763] [PubMed: 28592815] [CrossRef]

64.

De Sanctis V, Soliman AT, Candini G, Yassin M, Raiola G, Galati MC, et al. Insulin-like Growth Factor-1 (IGF-1): Demographic, Clinical and Laboratory Data in 120 Consecutive Adult Patients with Thalassaemia Major. Mediterr J Hematol Infect Dis. 2014;6(1):e2014074. [PMC free article: PMC4235482] [PubMed: 25408860] [CrossRef]

65.

Soliman AT, De Sanctis V, Elalaily R, Yassin M. Insulin-like growth factor- I and factors affecting it in thalassaemia major. Indian J Endocrinol Metab. 2015;19(2):245–51. [PMC free article: PMC4319264] [PubMed: 25729686] [CrossRef]

66.

Soliman AT, Al Yafei F, Al-Naimi L, Almarri N, Sabt A, Yassin M, et al. Longitudinal study on thyroid function in patients with thalassaemia major: High incidence of central hypothyroidism by 18 years. Indian J Endocrinol Metab. 2013;17(6):1090–5. [PMC free article: PMC3872691] [PubMed: 24381890] [CrossRef]

67.

Cappellini MD, Musallam KM, Poggiali E, Taher AT. Hypercoagulability in non-transfusion-dependent thalassaemia. Blood Rev. 2012;26 Suppl 1:S20–3. [PubMed: 22631037] [CrossRef]

68.

Schrier SL. Thalassaemia: pathophysiology of red cell changes. Annu Rev Med. 1994;45:211–8. [PubMed: 8198378]

69.

Gottlieb Y, Topaz O, Cohen LA, Yakov LD, Haber T, Morgenstern A, et al. Physiologically aged red blood cells undergo erythrophagocytosis in vivo but not in vitro. Haematologica. 2012;97(7):994–1002. [PMC free article: PMC3396668] [PubMed: 22331264] [CrossRef]

70.

Borenstain-Ben Yashar V, Barenholz Y, Hy-Am E, Rachmilewitz EA, Eldor A. Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassaemia patients may explain the chronic hypercoagulable state and thrombotic episodes. Am J Hematol. 1993;44(1):63–5. [PubMed: 8342566]

71.

Succar J, Musallam KM, Taher AT. Thalassaemia and venous thromboembolism. Mediterr J Hematol Infect Dis. 2011;3(1):e2011025. [PMC free article: PMC3113280] [PubMed: 21713079] [CrossRef]

72.

Atichartakarn V, Angchaisuksiri P, Aryurachai K, Chuncharunee S, Thakkinstian A. In vivo platelet activation and hyperaggregation in haemoglobin E/beta-thalassaemia: a consequence of splenectomy. Int J Hematol. 2003;77(3):299–303. [PubMed: 12731676] [CrossRef]

73.

Cappellini MD, Musallam KM, Marcon A, Taher AT. Coagulopathy in Beta-thalassaemia: current understanding and future perspectives. Mediterr J Hematol Infect Dis. 2009;1(1):e2009029. [PMC free article: PMC3033163] [PubMed: 21415997] [CrossRef]

74.

Taher A, Isma’eel H, Mehio G, Bignamini D, Kattamis A, Rachmilewitz EA, et al. Prevalence of thromboembolic events among 8,860 patients with thalassaemia major and intermedia in the Mediterranean area and Iran. Thromb Haemost. 2006;96(4):488–91. [PubMed: 17003927]

75.

Chansai S, Fucharoen S, Fucharoen G, Jetsrisuparb A, Chumpia W. Elevations of Thrombotic Biomarkers in Haemoglobin H Disease. Acta Haematol. 2018;139(1):47–51. [PubMed: 29402840] [CrossRef]

76.

Charoenkwan P, Sirichotiyakul S, Chanprapaph P, Tongprasert F, Taweephol R, Sae-Tung R, et al. Anemia and hydrops in a fetus with homozygous haemoglobin constant spring. J Pediatr Hematol Oncol. 2006;28(12):827–30. [PubMed: 17164653] [CrossRef]

77.

Pootrakul P, Winichagoon P, Fucharoen S, Pravatmuang P, Piankijagum A, Wasi P. Homozygous haemoglobin Constant Spring: a need for revision of concept. Hum Genet. 1981;59(3):250–5. [PubMed: 7327587] [CrossRef]

78.

Viprakasit V, Veerakul G, Sanpakit K, Pongtanakul B, Chinchang W, Tanphaichitr VS. Acute haemolytic crisis in a Thai patient with homozygous haemoglobin Constant Spring (Hb CS/CS): a case report. Ann Trop Paediatr. 2004;24(4):323–8. [PubMed: 15720889] [CrossRef]

79.

He Y, Zhao Y, Lou JW, Liu YH, Li DZ. Fetal Anemia and Hydrops foetalis Associated with Homozygous Hb Constant Spring (HBA2: c.427T > C). Haemoglobin. 2016;40(2):97–101. [PubMed: 26757782] [CrossRef]

80.

Komvilaisak P, Jetsrisuparb A, Fucharoen G, Komwilaisak R, Jirapradittha J, Kiatchoosakun P. Clinical Course of Homozygous Haemoglobin Constant Spring in Pediatric Patients. J Pediatr Hematol Oncol. 2018;40(5):409–12. [PubMed: 29668548] [CrossRef]

81.

Komvilaisak P, Komvilaisak R, Jetsrisuparb A, Wiangnon S, Jirapradittha J, Kiatchoosakun P, et al. Fetal Anemia Causing Hydrops foetalis From an Alpha-Globin Variant: Homozygous Haemoglobin Constant Spring. J Pediatr Hematol Oncol. 2018;40(5):405–8. [PubMed: 29240037] [CrossRef]

82.

Higgs DR, Goodbourn SE, Lamb J, Clegg JB, Weatherall DJ, Proudfoot NJ. Alpha-thalassaemia caused by a polyadenylation signal mutation. Nature. 1983;306(5941):398–400. [PubMed: 6646217] [CrossRef]

83.

Harteveld CL, Losekoot M, Haak H, Heister GA, Giordano PC, Bernini LF. A novel polyadenylation signal mutation in the alpha 2-globin gene causing alpha thalassaemia. Br J Haematol. 1994;87(1):139–43. [PubMed: 7947237] [CrossRef]

84.

Yüregir GT, Aksoy K, Cürük MA, Dikmen N, Fei YJ, Baysal E, et al. Hb H disease in a Turkish family resulting from the interaction of a deletional alpha-thalassaemia-1 and a newly discovered poly A mutation. Br J Haematol. 1992;80(4):527–32. [PubMed: 1581238] [CrossRef]