Impact of HbE mutation on the clinical severity of HbH disease: A multicentre study from Thailand
Duantida Songdej
Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Search for more papers by this authorNattiya Teawtrakul
Division of Hematology, Department of Internal Medicine, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
Search for more papers by this authorNapat Laoaroon
Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
Search for more papers by this authorPatcharee Komvilaisak
Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
Search for more papers by this authorPornpun Sripornsawan
Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
Search for more papers by this authorPacharapan Surapolchai
Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
Search for more papers by this authorChattree Hantaweepant
Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
Search for more papers by this authorAdisak Tantiworawit
Division of Hematology, Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand
Thalassemia and Hematology Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Search for more papers by this authorSasinee Hantrakool
Division of Hematology, Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand
Thalassemia and Hematology Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Search for more papers by this authorSupanun Lauhasurayotin
Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
Search for more papers by this authorKitti Torcharus
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Phramongkutklao College of Medicine, Bangkok, Thailand
Search for more papers by this authorPranee Sutcharitchan
Division of Hematology, Department of Internal Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
Search for more papers by this authorNoppacharn Uaprasert
Division of Hematology, Department of Internal Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
Search for more papers by this authorKrissana Panrong
Division of Hematology, Department of Internal Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
Search for more papers by this authorPanachai Silpsamrit
Division of Hematology, Department of Medicine, Phramongkutklao College of Medicine, Bangkok, Thailand
Search for more papers by this authorArunotai Meekaewkunchorn
Queen Sirikit National Institute of Child Health, Bangkok, Thailand
Search for more papers by this authorPimlak Charoenkwan
Thalassemia and Hematology Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Division of Hematology and Oncology, Department of Pediatrics, Chiang Mai University, Chiang Mai, Thailand
Search for more papers by this authorCorresponding Author
Bunchoo Pongtanakul
Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
Correspondence
Bunchoo Pongtanakul, Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok 10700, Thailand.
Email: [email protected]
Search for more papers by this authorRed Blood Cell Disorders Study Group
Search for more papers by this authorDuantida Songdej
Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
Search for more papers by this authorNattiya Teawtrakul
Division of Hematology, Department of Internal Medicine, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
Search for more papers by this authorNapat Laoaroon
Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
Search for more papers by this authorPatcharee Komvilaisak
Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
Search for more papers by this authorPornpun Sripornsawan
Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
Search for more papers by this authorPacharapan Surapolchai
Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
Search for more papers by this authorChattree Hantaweepant
Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
Search for more papers by this authorAdisak Tantiworawit
Division of Hematology, Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand
Thalassemia and Hematology Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Search for more papers by this authorSasinee Hantrakool
Division of Hematology, Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand
Thalassemia and Hematology Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Search for more papers by this authorSupanun Lauhasurayotin
Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
Search for more papers by this authorKitti Torcharus
Division of Pediatric Hematology/Oncology, Department of Pediatrics, Phramongkutklao College of Medicine, Bangkok, Thailand
Search for more papers by this authorPranee Sutcharitchan
Division of Hematology, Department of Internal Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
Search for more papers by this authorNoppacharn Uaprasert
Division of Hematology, Department of Internal Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
Search for more papers by this authorKrissana Panrong
Division of Hematology, Department of Internal Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
Search for more papers by this authorPanachai Silpsamrit
Division of Hematology, Department of Medicine, Phramongkutklao College of Medicine, Bangkok, Thailand
Search for more papers by this authorArunotai Meekaewkunchorn
Queen Sirikit National Institute of Child Health, Bangkok, Thailand
Search for more papers by this authorPimlak Charoenkwan
Thalassemia and Hematology Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Division of Hematology and Oncology, Department of Pediatrics, Chiang Mai University, Chiang Mai, Thailand
Search for more papers by this authorCorresponding Author
Bunchoo Pongtanakul
Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
Correspondence
Bunchoo Pongtanakul, Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok 10700, Thailand.
Email: [email protected]
Search for more papers by this authorRed Blood Cell Disorders Study Group
Search for more papers by this authorSummary
Haemoglobin (Hb) H disease and HbH disease with co-inherited HbE mutation are the most prevalent forms of α-thalassaemia in Southeast Asia. Data were limited when comparing clinical phenotypes between these two patient groups. We conducted a Thai multicentre study and enrolled 588 patients [median (IQR) age 13.0 (6.7–20.3) years], including those with deletional HbH disease with (n = 47) and without (n = 187) co-inherited HbE mutation and non-deletional HbH disease with (n = 101) and without (n = 253) co-inherited HbE mutation. Patients with HbH disease with co-inherited HbE mutation suffered more severe manifestations than those without. This observation was more pronounced in patients with non-deletional HbH disease. A greater proportion of patients with non-deletional HbH disease with co-inherited HbE mutation (43.6%) eventually required regular transfusions compared to those without (30.4%, p = 0.019). Among those with non-deletional HbH disease who did not require regular transfusions, Hb levels were lower in patients with co-inherited HbE mutation [8.1 (7.2–8.6) vs. 8.8 (8.2–9.5) g/dL, p < 0.001]. Among patients requiring regular transfusions who underwent splenectomy, 11/12 patients with non-deletional HbH disease stopped transfusion compared with 1/3 in non-deletional HbH disease with co-inherited HbE mutation group (p = 0.024). These findings provide insights for the clinical monitoring and management of HbH disease in the region.
Graphical Abstract
Haemoglobin H (HbH) disease with co-inheritance of HbE mutation is frequently found in Southeast Asia. This large multicentre study with a total of 588 enrolled patients demonstrated that co-inheritance of HbE mutation was associated with a higher rate of on-demand or chronic transfusions compared to those with HbH disease alone. The impact of HbE co-inheritance was mainly observed in patients with non-deletional HbH disease. The graph shows the proportion of patients in each diagnosis group becoming transfusion-dependent at different ages.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
The anonymized data obtained and analysed in this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
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| bjh19869-sup-0001-AppendixS1.docxWord 2007 document , 14.8 KB |
Appendix S1. |
| bjh19869-sup-0002-AppendixS2.docxWord 2007 document , 14.7 KB |
Appendix S2. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Fucharoen S, Winichagoon P. Problems of thalassemia in Thailand. ICMR Ann. 1988; 8: 29–33.
- 2Hockham C, Ekwattanakit S, Bhatt S, Penman BS, Gupta S, Viprakasit V, et al. Estimating the burden of α-thalassaemia in Thailand using a comprehensive prevalence database for Southeast Asia. elife. 2019; 8:e40580.
- 3Chui DH, Fucharoen S, Chan V. Hemoglobin H disease: not necessarily a benign disorder. Blood. 2003; 101(3): 791–800.
- 4Lal A, Goldrich ML, Haines DA, Azimi M, Singer ST, Vichinsky EP. Heterogeneity of hemoglobin H disease in childhood. N Engl J Med. 2011; 364(8): 710–718.
- 5Fucharoen S, Viprakasit V. Hb H disease: clinical course and disease modifiers. Hematol Am Soc Hematol Educ Program. 2009; 26–34.
- 6Charoenkwan P, Taweephon R, Sae-Tung R, Thanarattanakorn P, Sanguansermsri T. Molecular and clinical features of Hb H disease in northern Thailand. Hemoglobin. 2005; 29(2): 133–140.
- 7Laosombat V, Viprakasit V, Chotsampancharoen T, Wongchanchailert M, Khodchawan S, Chinchang W, et al. Clinical features and molecular analysis in Thai patients with HbH disease. Ann Hematol. 2009; 88(12): 1185–1192.
- 8He S, Zhang Q, Chen BY, Huang P, Tang YQ, Wei Y, et al. Genotypes and clinical features of 595 children with HbH disease in Guangxi, China. Zhongguo Dang Dai Er Ke Za Zhi. 2015; 17(9): 908–911.
- 9Lal A, Vichinsky E. The clinical phenotypes of alpha thalassemia. Hematol Oncol Clin North Am. 2023; 37(2): 327–339.
- 10Singer ST, Kim HY, Olivieri NF, Kwiatkowski JL, Coates TD, Carson S, et al. Hemoglobin H-constant spring in North America: an alpha thalassemia with frequent complications. Am J Hematol. 2009; 84(11): 759–761.
- 11Lorey 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): 72–78.
- 12Luewan S, Sirichotiyakul S, Charoenkwan P, Phirom K, Tongsong T. Hydrops fetalis associated with fetal hemoglobin H-Pakse disease. Fetal Diagn Ther. 2022; 49(11–12): 528–535.
- 13Vichinsky EP. Clinical manifestations of α-thalassemia. Cold Spring Harb Perspect Med. 2013; 3(5):a011742.
- 14Fucharoen S, Weatherall DJ. Progress toward the control and management of the thalassemias. Hematol Oncol Clin North Am. 2016; 30(2): 359–371.
- 15Chaibunruang A, Karnpean R, Fucharoen G, Fucharoen S. Genetic heterogeneity of hemoglobin AEBart's disease: a large cohort data from a single referral center in northeast Thailand. Blood Cells Mol Dis. 2014; 52(4): 176–180.
- 16Fucharoen S, Winichagoon P, Thonglairuam V, Wasi P. EF Bart's disease: interaction of the abnormal alpha- and beta-globin genes. Eur J Haematol. 1988; 40(1): 75–78.
- 17Fucharoen S, Weatherall DJ. The hemoglobin E thalassemias. Cold Spring Harb Perspect Med. 2012; 2(8):a011734.
- 18Traivaree 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.
- 19Boonsa S, Sanchaisuriya K, Fucharoen G, Wiangnon S, Jetsrisuparb A, Fucharoen S. The diverse molecular basis and hematological features of Hb H and AEBart's diseases in Northeast Thailand. Acta Haematol. 2004; 111(3): 149–154.
- 20Prayalaw P, Teawtrakul N, Jetsrisuparb A, Pongudom S, Fucharoen G, Fucharoen S. Phenotype and genotype in a cohort of 312 adult patients with nontransfusion-dependent thalassemia in Northeast Thailand. Acta Haematol. 2016; 135(1): 15–20.
- 21Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O'Neal L, et al. The REDCap consortium: building an international community of software platform partners. J Biomed Inform. 2019; 95:103208.
- 22Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009; 42(2): 377–381.
- 23Taher AT, Musallam K, Cappellini MD. Guidelines for the Management of non transfusion dependent thalassemia (NTDT). 2nd ed. Nicosia, Cyprus: Thalassemia International Federation; 2017.
- 24Cappellini MD, Farmakis D, Porter J, Taher AT. 2021 guidelines for the management of transfusion dependent thalassemia (TDT). 4th ed. Nicosia, Cyprus: Thalassemia International Federation; 2021.
- 25Songdej 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.
- 26Pootrakul 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 thalassemia. Blood. 2000; 96(7): 2606–2612.
- 27Atichartakarn V, Likittanasombat K, Chuncharunee S, Chandanamattha P, Worapongpaiboon S, Angchaisuksiri P, et al. Pulmonary arterial hypertension in previously splenectomized patients with beta-thalassemic disorders. Int J Hematol. 2003; 78(2): 139–145.
- 28Rahav G, Volach V, Shapiro M, Rund D, Rachmilewitz EA, Goldfarb A. Severe infections in thalassaemic patients: prevalence and predisposing factors. Br J Haematol. 2006; 133(6): 667–674.
- 29Sakran W, Levin C, Kenes Y, Colodner R, Koren A. Clinical spectrum of serious bacterial infections among splenectomized patients with hemoglobinopathies in Israel: a 37-year follow-up study. Infection. 2012; 40(1): 35–39.
- 30Taher AT, Musallam KM, Karimi M, El-Beshlawy A, Belhoul K, Daar S, et al. Splenectomy and thrombosis: the case of thalassemia intermedia. J Thromb Haemost. 2010; 8(10): 2152–2158.
- 31Yin XL, Zhang XH, Wu ZK, Zhao DH, Zhou YL, Yu YH, et al. Pulmonary hypertension risk in patients with hemoglobin h disease: low incidence and absence of correlation with splenectomy. Acta Haematol. 2013; 130(3): 153–159.
- 32Hirsh J, Dacie JV. Persistent post-splenectomy thrombocytosis and thrombo-embolism: a consequence of continuing anaemia. Br J Haematol. 1966; 12(1): 44–53.
- 33Singer ST, Kuypers F, Fineman J, Gildengorin G, Larkin S, Sweeters N, et al. Elevated tricuspid regurgitant jet velocity in subgroups of thalassemia patients: insight into pathophysiology and the effect of splenectomy. Ann Hematol. 2014; 93(7): 1139–1148.
- 34Tso SC, Chan TK, Todd D. Venous thrombosis in haemoglobin H disease after splenectomy. Aust NZ J Med. 1982; 12(6): 635–638.
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