Increased endothelial activation in α-thalassemia disease

  • Pankamol Sirivadhanakul
  • Ampaiwan Chuansumrit
  • Duantida Songdej
  • Praguywan Kadegasem
  • Pakawan Wongwerawattanakoon
  • Nongnuch SirachainanEmail author
Original Article


One complication of thalassemia is thromboembolism (TE), which is caused by an abnormal red blood cell surface, as well as endothelial and platelet activation. These findings are commonly observed in severe β-thalassemia. However, limited information on α-thalassemia exists. This study enrolled subjects with deletional and non-deletional α-thalassemia and normal controls (NC). Plasma and serum of subjects were tested for endothelial activation markers including thrombomodulin (TM), vascular cell adhesion molecule-1 (VCAM-1), and von Willebrand factor antigen as well as platelet activation markers including thromboxane B2 and platelet factor 4. A total of 179 subjects were enrolled: 29 in the deletional group (mean age 13.3 ± 4.4 years), 31 in the non-deletional group (mean age 12.9 ± 4.8 years), and 119 in the NC group (mean age 13.6 ± 3.0 years). Twenty nine percent of subjects in the non-deletional group received regular red blood cell transfusion and iron chelator administration. Serum ferritin level was higher in the non-deletional group than that in the deletional group. Multivariate analysis demonstrated that VCAM-1 and TM levels were increased significantly in α-thalassemia compared with NC group (816.8 ± 131.0 vs 593.9 ± 49.0 ng/ml, and 4.9 ± 0.7 vs 4.0 ± 0.4 ng/ml, P < 0.001 respectively). VCAM-1 and TM levels in the non-deletional group were significantly higher than that in the deletional group. The present study demonstrated endothelial activation in children with α-thalassemia disease, especially those in the non-deletional group, which might be one risk factor for TE in α-thalassemia disease.


α-Thalassemia Children Endothelial activation Thromboembolism 



Body mass index




Complete blood count


Circulating endothelial cells


Hb constant spring


Deoxyribonucleic acid




Prothrombin fragment 1 + 2




High-performance liquid chromatography


Intercellular adhesion molecule-1


Mean corpuscular hemoglobin


Mean corpuscular volume


Normal controls


Non-transfusion dependent thalassemia


Platelet factor 4


Hb Paksé


Red blood cell


Red cell distribution width


Thrombin-antithrombin complex


Thromboxane B2


Transfusion-dependent thalassemia






Vascular cell adhesion molecule-1


Vascular endothelial growth factor


Von Willebrand factor antigen



NC designed the study and reviewed the manuscript. PS performed the study and wrote the manuscript. AC, DS, and PW involved in the care of patients. PK performed the laboratory.

Funding information

This work was supported by a Grant from the Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. We thank Edanz Group ( for editing a draft of this manuscript.

Compliance with ethical standards

Ethical approval for the study protocol was obtained from the Ethical Clearance Committee on Human Rights Related to Research to Research Involving Human Subjects, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand (ID 12-59-09).

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Fucharoen S, Winichagoon P (1992) Thalassemia in Southeast Asia: problems and strategy for prevention and control. Southeast Asian J Trop Med Public Health 23:647–655Google Scholar
  2. 2.
    Kohne E (2011) Hemoglobinopathies: clinical manifestations, diagnosis, and treatment. Dtsch Arztebl Int 108:532–540. Google Scholar
  3. 3.
    Kelly N (2012) Thalassemia. Pediatr Rev 33:434–435. CrossRefGoogle Scholar
  4. 4.
    Vichinsky EP (2005) Changing patterns of thalassemia worldwide. Ann N Y Acad Sci 1054:18–24. CrossRefGoogle Scholar
  5. 5.
    Williams TN, Weatherall DJ (2012) World distribution, population genetics, and health burden of the hemoglobinopathies. Cold Spring Harb Perspect Med 2:1–14. CrossRefGoogle Scholar
  6. 6.
    Wasi P, Na-Nakorn S, Pootrakul S, Sookanek M, Disthasongchan P, Pornpatkul M, Pornpatkul M (1969) Alpha- and beta-thalassemia in Thailand. Ann N Y Acad Sci 165:60–82. CrossRefGoogle Scholar
  7. 7.
    Vichinsky E (2010) Complexity of alpha thalassemia: growing health problem with new approaches to screening, diagnosis, and therapy. Ann N Y Acad Sci 1202:180–187. CrossRefGoogle Scholar
  8. 8.
    Fucharoen S, Viprakasit V (2009) Hb H disease: clinical course and disease modifiers. Am Soc Hematol Educ Program 2009:26–34. CrossRefGoogle Scholar
  9. 9.
    Vichinsky EP (2013) Clinical manifestations of α-thalassemia. Cold Spring Harb Perspect Med 3:1–10. CrossRefGoogle Scholar
  10. 10.
    Laosombat V, Viprakasit V, Chotsampancharoen T, Wongchanchailert M, Khodchawan S, Chinchang W, Sattayasevana B (2009) Clinical features and molecular analysis in Thai patients with HbH disease. Ann Hematol 88:1185–1192. CrossRefGoogle Scholar
  11. 11.
    Chui DH, Fucharoen S, Chan V (2003) Hemoglobin H disease: not necessarily a benign disorder. Blood 101:791–800. CrossRefGoogle Scholar
  12. 12.
    Harteveld CL, Higgs DR (2010) α-Thalassaemia. Orphanet J Rare Dis 5:13.
  13. 13.
    Sirachainan N (2013) Thalassemia and the hypercoagulable state. Thromb Res 132:637–641. CrossRefGoogle Scholar
  14. 14.
    Tso SC, Chan TK, Todd D (1982) Venous thrombosis in haemoglobin H disease after splenectomy. Aust NZ J Med 12:635–638. CrossRefGoogle Scholar
  15. 15.
    Singer ST, Kim HY, Olivieri NF, Kwiatkowski JL, Coates TD, Carson S, Neufeld E, Cunningham MJ, Giardina PJ, Mueller BU, Quinn CT, Fung E, Vichinsky E, for the Thalassemia Clinical Research Network (2009) Hemoglobin H-constant spring in North America: an alpha thalassemia with frequent complications. Am J Hematol 84:759–761. CrossRefGoogle Scholar
  16. 16.
    Sun NA, Cheng P, Deng DH, Liu RR, Lai YR (2016) Analysis of the genetic variants associated with recurrent thromboembolism in a patient with hemoglobin H disease following splenectomy: a case report. Biomed Rep 5:23–26. CrossRefGoogle Scholar
  17. 17.
    Sonakul D, Fucharoen S (1992) Pulmonary thromboembolism in thalassemic patients. Southeast Asian J Trop Med Public Health 23:25–28Google Scholar
  18. 18.
    Winichakoon P, Tantiworawit A, Rattanathammethee T, Hantrakool S, Chai-Adisaksopha C, Rattarittamrong E, Norasetthada L, Charoenkwan P (2015) Prevalence and risk factors for complications in patients with nontransfusion dependent alpha-and beta-thalassemia. Anemia 2015:793025. CrossRefGoogle Scholar
  19. 19.
    Bunyaratvej A, Fucharoen S, Butthep P, Sae-ung N, Kamchonwongpaisan S, Khuhapinant A (1995) Alterations and pathology of thalassemic red cells: comparison between alpha-and beta-thalassemia. Southeast Asian J Trop Med Public Health 26:257–260Google Scholar
  20. 20.
    Butthep P, Bunyaratvej A, Funahara Y, Kitaguchi H, Fucharoen S, Sato S, Bhamarapravati N (1995) Alterations in vascular endothelial cell-related plasma proteins in thalassaemic patients and their correlation with clinical symptoms. Thromb Haemost 74:1045–1049. CrossRefGoogle Scholar
  21. 21.
    Carlos TM, Harlan JM (1994) Leukocyte-endothelial adhesion molecules. Blood 84:2068–2101Google Scholar
  22. 22.
    Butthep P, Bunyaratvej A, Funahara Y, Kitaguchi H, Fucharoen S, Sato S, Bhamarapravati N (1997) Possible evidence of endothelial cell activation and disturbance in thalassemia: an in vitro study. Southeast Asian J Trop Med Public Health 28:141–148AGoogle Scholar
  23. 23.
    Butthep P, Rummavas S, Wisedpanichkij R, Jindadamrongwech S, Fucharoen S, Bunyaratvej A (2002) Increased circulating activated endothelial cells, vascular endothelial growth factor, and tumor necrosis factor in thalassemia. Am J Hematol 70:100–106. CrossRefGoogle Scholar
  24. 24.
    Chansai S, Fucharoen S, Fucharoen G, Jetsrisuparb A, Chumpia W (2018) Elevations of thrombotic biomarkers in hemoglobin H disease. Acta Haematol 139:47–51. CrossRefGoogle Scholar
  25. 25.
    Sirachainan N, Chuansumrit A, Kadegasem P, Sasanakul W, Wongwerawattanakoon P, Mahaklan L, Mahaklan L (2016) Normal hemostatic parameters in children and young adults with α-thalassemia diseases. Thromb Res 146:35–42. CrossRefGoogle Scholar
  26. 26.
    Taher A, Vichinsky E, Musallam K, Cappellini MD, Viprakasit V, Weatherall D, editor (2013) Guidelines for the Management of Non Transfusion Dependent Thalassaemia (NTDT) [Internet]. Thalassaemia International Federation, Nicosia. Available from Accessed 4 April 2019
  27. 27.
    Prasartkaew S, Bunyaratvej A, Fucharoen S, Wasi P (1986) Comparison of erythrocyte antioxidative enzyme activities between two types of haemoglobin H disease. J Clin Pathol 39:1299–1303. CrossRefGoogle Scholar
  28. 28.
    Bunyaratvej A, Butthep P, Fucharoen S, Saw D (1992) Erythrocyte volume and haemoglobin concentration in haemoglobin H disease: discrimination between the two genotypes. Acta Haematol 87:1–5. CrossRefGoogle Scholar
  29. 29.
    Fucharoen S, Winichagoon P (2002) Thalassemia and abnormal hemoglobin. Int J Hematol 76:83–89. CrossRefGoogle Scholar
  30. 30.
    Boonsa S, Sanchaisuriya K, Fucharoen G, Wiangnon S, Jetsrisuparb A, Fucharoen S (2004) The diverse molecular basis and hematological features of Hb H and AE Bart’s diseases in Northeast Thailand. Acta Haematol 111:149–154. CrossRefGoogle Scholar
  31. 31.
    Bastyr EJ, Kadrofske MM, Vinik AI (1990) Platelet activity and phosphoinositide turnover increase with advancing age. Am J Med 88:601–606. CrossRefGoogle Scholar
  32. 32.
    Trichero A, Marchetti M, Giaccherini C, Tartari CJ, Russo L, Falango A (2017) Platelet haemostatic properties in β-thalassemia: the effect of blood transfusion. Blood Transfus 15(5):413–421. Google Scholar
  33. 33.
    Steiner M, Anastasi J, Vitamin E (1976) An inhibitor of the platelet release reaction. J Clin Invest 57(3):732–737. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pediatrics, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
  2. 2.Department of Nursing, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand

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