Thalassaemia as a Hypercoagulable State

European Oncology & Haematology, 2011;7(3):214-6 DOI:


Although the life expectancy of thalassaemia patients has markedly improved over the last few decades, patients still suffer from many complications of this congenital disease. The presence of a high incidence of thromboembolic events, mainly in thalassaemia intermedia, has led to the identification of a hypercoagulable state in these patients. In this article, the molecular and cellular mechanisms leading to hypercoagulability in thalassaemia are highlighted, with a special focus on thalassaemia intermedia, being the type with the highest incidence of thrombotic events as compared with other types of thalassaemia. Clinical experience and available clues regarding optimal management are also discussed.
Keywords: Thalassaemia, hypercoagulability, thromboembolism, stroke, splenectomy, transfusion
Disclosure: The authors have no conflicts of interest to declare.
Received: April 06, 2011 Accepted May 23, 2011
Correspondence: Maria Domenica Cappellini, Professor of Medicine, Department of Internal Medicine, Fondazione IRCSS “Ca’ Granda” Ospedale Policlinico, Università di Milano, Via Francesco Sforza 35, 20122 Milano, Italy. E:

Phenotypic diversity within the β-thalassaemia syndromes has traditionally received considerable interest, with several molecular and environmental modifiers of disease severity so far described.1 Patients with transfusion-dependent β-thalassaemia major (TM) suffer the most severe form and show the highest mortality rates.1 Nevertheless, the introduction of safe transfusion practices and effective iron chelation therapy continues to improve patient survival, allowing for several clinical complications to have time to manifest.2 The term β-thalassaemia intermedia (TI) was first suggested to describe patients who have milder anaemia compared with patients with TM and who usually present to medical attention later in childhood and remain largely transfusion-independent. However, recent evidence suggests that the diagnosis of TI carries higher morbidity than previously recognised, especially in the transfusion-independent patient, where the mechanism of disease remains largely unbalanced.3

Three main factors highlight the pathophysiology of TI: ineffective erythropoiesis, chronic anaemia/haemolysis, and iron overload secondary to increased intestinal absorption.3 The extreme diversity in phenotypic expression within the diagnosis of TI itself led to a wide variation in observed clinical complications and management practices.3,4 Among the medical complications of TI that were found to occur at high rates, even more frequently than in patients with TM, are thromboembolic events (TEE).5 Here, we review current evidence on TEE in thalassaemia patients, with special emphasis on TI.

Hypercoagulability in patients with thalassaemia has been attributed to several factors (see Figure 1).5,6 It is often a combination of these factors that leads to TEE.

It is widely accepted that patients with thalassaemia have chronically activated platelets and enhanced platelet aggregation,7 as confirmed by the increased expression of CD62P (P-selectin) and CD63, markers of in vivo platelet activation.8,9 Splenectomised thalassaemia patients have high platelet counts,10,11 but with a shorter lifespan due to enhanced consumption.12 It has also been shown that splenectomised TM and non-splenectomised TI patients have four to 10 times higher levels of metabolites of prostacyclin (PGI2) and thromboxane A2, both markers of haemostatic activity, than controls. However, no significant difference was found between TM and TI patients.13
  1. Steinberg MH, Forget BG, Higgs DR, Weatherall DJ, Disorders of hemoglobin: genetics, pathophysiology, and clinical management, 2nd edn, Cambridge: Cambridge University Press, 2009.
  2. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al., Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine, Haematologica, 2004;89:1187–93.
  3. Taher AT, Musallam KM, Cappellini MD, Weatherall DJ, Optimal management of beta thalassaemia intermedia, Br J Haematol, 2011;152:512–23.
  4. Taher AT, Musallam KM, Karimi M, et al., Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study, Blood, 2010;115:1886–92.
  5. Cappellini MD, Motta I, Musallam KM, Taher AT, Redefining thalassemia as a hypercoagulable state, Ann N Y Acad Sci, 2010;1202:231–6.
  6. Taher AT, Otrock ZK, Uthman I, Cappellini MD, Thalassemia and hypercoagulability, Blood Rev, 2008;22:283–92.
  7. Winichagoon P, Fucharoen S, Wasi P, Increased circulating platelet aggregates in thalassaemia, Southeast Asian J Trop Med Public Health, 1981;12:556–60.
  8. Del Principe D, Menichelli A, Di Giulio S, et al., PADGEM/GMP-140 expression on platelet membranes from homozygous beta thalassaemic patients, Br J Haematol, 1993;84:111–7.
  9. Ruf A, Pick M, Deutsch V, et al., In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major, Br J Haematol, 1997;98:51–6.
  10. Cappellini MD, Grespi E, Cassinerio E, et al., Coagulation and splenectomy: an overview, Ann N Y Acad Sci, 2005;1054:317–24.
  11. telet activation and hyperaggregation in hemoglobin E/beta-thalassemia: a consequence of splenectomy, Int J Hematol, 2003;77:299–303.
  12. Eldor A, Krausz Y, Atlan H, et al., Platelet survival in patients with beta-thalassemia, Am J Hematol, 1989;32:94–9.
  13. Eldor A, Lellouche F, Goldfarb A, et al., In vivo platelet activation in beta-thalassemia major reflected by increased plateletthromboxane urinary metabolites, Blood, 1991;77:1749–53.
  14. Rund D, Rachmilewitz E, Beta-thalassemia, N Engl J Med, 2005;353:1135–46.
  15. Hershko C, Graham G, Bates GW, Rachmilewitz EA, Non-specific serum iron in thalassaemia: an abnormal serum iron fraction of potential toxicity, Br J Haematol, 1978;40:255–63.
  16. Kuypers FA, de Jong K, The role of phosphatidylserine in recognition and removal of erythrocytes, Cell Mol Biol (Noisy-le-grand), 2004;50:147–58.
  17. Tavazzi D, Duca L, Graziadei G, et al., Membrane-bound iron contributes to oxidative damage of beta-thalassaemia intermedia erythrocytes, Br J Haematol, 2001;112:48–50.
  18. Borenstain-Ben Yashar V, Barenholz Y, Hy-Am E, et al., Phosphatidylserine in the outer leaflet of red blood cells from beta-thalassemia patients may explain the chronic hypercoagulable state and thrombotic episodes, Am J Hematol, 1993;44:63–5.
  19. Helley D, Eldor A, Girot R, et al., Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and beta-thalassemia, Thromb Haemost, 1996;76:322–7.
  20. Atichartakarn V, Angchaisuksiri P, Aryurachai K, et al., Relationship between hypercoagulable state and erythrocyte phosphatidylserine exposure in splenectomized haemoglobin E/beta-thalassaemic patients, Br J Haematol, 2002;118:893–8.
  21. Cappellini MD, Robbiolo L, Bottasso BM, et al., Venous thromboembolism and hypercoagulability in splenectomized patients with thalassaemia intermedia, Br J Haematol, 2000;111:467–73.
  22. Habib A, Kunzelmann C, Shamseddeen W, et al., Elevated levels of circulating procoagulant microparticles in patients with beta-thalassemia intermedia, Haematologica, 2008;93:941–2.
  23. Butthep P, Bunyaratvej A, Funahara Y, et al., Alterations in vascular endothelial cell-related plasma proteins in thalassaemic patients and their correlation with clinical symptoms, Thromb Haemost, 1995;74:1045–9.
  24. Butthep P, Bunyaratvej A, Funahara Y, et al., Possible evidence of endothelial cell activation and disturbance in thalassemia: an in vitro study, Southeast Asian J Trop Med Public Health, 1997;28(Suppl. 3):141–8A.
  25. Hovav T, Goldfarb A, Artmann G, et al., Enhanced adherence of beta-thalassaemic erythrocytes to endothelial cells, Br J Haematol, 1999;106:178–81.
  26. Zalloua PA, Shbaklo H, Mourad YA, et al., Incidence of thromboembolic events in Lebanese thalassemia intermedia patients, Thromb Haemost, 2003;89:767–8.
  27. Iolascon A, Giordano P, Storelli S, et al., Thrombophilia in thalassemia major patients: analysis of genetic predisposing factors, Haematologica, 2001;86:1112–3.
  28. Borgna-Pignatti C, Carnelli V, Caruso V, et al., Thromboembolic events in beta thalassemia major: an Italian multicenter study, Acta Haematol, 1998;99:76–9.
  29. Zurlo MG, De Stefano P, Borgna-Pignatti C, et al., Survival and causes of death in thalassaemia major, Lancet, 1989;2:27–30.
  30. Taher A, Isma’eel H, Mehio G, et al., Prevalence of thromboembolic events among 8,860 patients with thalassaemia major and intermedia in the Mediterranean area and Iran, Thromb Haemost, 2006;96:488–91.
  31. Manfre L, Giarratano E, Maggio A, et al., MR imaging of the brain: findings in asymptomatic patients with thalassemia intermedia and sickle cell-thalassemia disease, AJR Am J Roentgenol, 1999;173:1477–80.
  32. Taher AT, Musallam KM, Nasreddine W, et al., Asymptomatic brain magnetic resonance imaging abnormalities in splenectomized adults with thalassemia intermedia, J Thromb Haemost, 2010;8:54–9.
  33. Karimi M, Bagheri H, Rastgu F, Rachmilewitz EA, Magnetic resonance imaging to determine the incidence of brain ischaemia in patients with beta-thalassaemia intermedia, Thromb Haemost, 2010;103:989–93.
  34. Taher AT, Musallam KM, El-Beshlawy A, et al., Age-related complications in treatment-naive patients with thalassaemia intermedia, Br J Haematol, 2010;150:486–9.
  35. Taher AT, Musallam KM, Karimi M, et al., Splenectomy and thrombosis: the case of thalassemia intermedia, J Thromb Haemost, 2010;8:2152–8.
  36. Taher A, Hershko C, Cappellini MD, Iron overload in thalassaemia intermedia: reassessment of iron chelation strategies, Br J Haematol, 2009;147:634–40.
  37. Crary SE, Buchanan GR, Vascular complications after splenectomy for hematologic disorders, Blood, 2009;114:2861–8.
  38. Cadili A, de Gara C, Complications of splenectomy, Am J Med, 2008;121:371–5.
  39. Sumiyoshi A, Thakerngpol K, Sonakul D, Pulmonary microthromboemboli in thalassemic cases, Southeast Asian J Trop Med Public Health, 1992;23(Suppl. 2):29–31.
  40. Tripodi A, Cappellini MD, Chantarangkul V, et al., Hypercoagulability in splenectomized thalassemic patients detected by whole-blood thromboelastometry, but not by thrombin generation in platelet-poor plasma, Haematologica, 2009;94:1520–7.
Keywords: Thalassaemia, hypercoagulability, thromboembolism, stroke, splenectomy, transfusion