Annals of Hematology

, Volume 93, Issue 7, pp 1139–1148

Elevated tricuspid regurgitant jet velocity in subgroups of thalassemia patients: insight into pathophysiology and the effect of splenectomy

  • Sylvia T. Singer
  • Frans Kuypers
  • Jeffery Fineman
  • Ginny Gildengorin
  • Sandra Larkin
  • Nancy Sweeters
  • Howard Rosenfeld
  • Gregory Kurio
  • Annie Higa
  • Michael Jeng
  • James Huang
  • Elliott P. Vichinsky
Original Article


A high tricuspid regurgitant jet velocity (TRV) signifies a risk for or established pulmonary hypertension (PH), which is a serious complication in thalassemia patients. The underlying pathophysiology in thalassemia subgroups and potential biomarkers for early detection and monitoring are not well defined, in particular as they relate to spleen removal. To better understand some of these unresolved aspects, we examined 76 thalassemia patients (35 non-transfused), 25 splenectomized non-thalassemia patients (15 with hereditary spherocytosis), and 12 healthy controls. An elevated TRV (>2.5 m/s) was found in 25/76 (33 %) of the patients, confined to non-transfused or those with a late start of transfusions, including patients with hemoglobin H-constant spring, a finding not previously described. These non or late-transfused patients (76 % splenectomized) had significantly increased platelet activation (sCD40L), high platelet count, endothelial activation (endothelin-1), and hemolysis (LDH, plasma-free Hb), while hypercoagulable and inflammatory markers were not significantly increased. The same markers were increased in the seven patients with confirmed PH on cardiac catheterization, suggesting their possible role for screening patients at risk for PH. A combination of hemolysis and absence of spleen is necessary for developing a high TRV, as neither chronic hemolysis in the non-splenectomized thalassemia patients nor splenectomy without hemolysis, in the non-thalassemia patients, resulted in an increase in TRV.


Thalassemia Splenectomy Hereditary spherocytosis Platelet activation TRV Pulmonary hypertension 


  1. 1.
    Morris CR, Kim HY, Trachtenberg F, Wood J, Quinn CT, Sweeters N, Kwiatkowski JL, Thompson AA, Giardina PJ, Boudreaux J, Olivieri NF, Porter JB, Neufeld EJ, Vichinsky EP (2011) Risk factors and mortality associated with an elevated tricuspid regurgitant jet velocity measured by Doppler-echocardiography in thalassemia: a Thalassemia Clinical Research Network report. Blood 118(14):3794–3802. doi:10.1182/blood-2010-11-319152 PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Taher AT, Musallam KM, Karimi M, El-Beshlawy A, Belhoul K, Daar S, Saned MS, El-Chafic AH, Fasulo MR, Cappellini MD (2010) Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study. Blood 115(10):1886–1892. doi:10.1182/blood-2009-09-243154 PubMedCrossRefGoogle Scholar
  3. 3.
    Aessopos A, Stamatelos G, Skoumas V, Vassilopoulos G, Mantzourani M, Loukopoulos D (1995) Pulmonary hypertension and right heart failure in patients with beta-thalassemia intermedia. Chest 107(1):50–53 [see comments]PubMedCrossRefGoogle Scholar
  4. 4.
    Karimi M, Musallam KM, Cappellini MD, Daar S, El-Beshlawy A, Belhoul K, Saned MS, Temraz S, Koussa S, Taher AT (2011) Risk factors for pulmonary hypertension in patients with beta thalassemia intermedia. Eur J Intern Med 22(6):607–610. doi:10.1016/j.ejim.2011.05.013 PubMedCrossRefGoogle Scholar
  5. 5.
    Cappellini MD, Robbiolo L, Bottasso BM, Coppola R, Fiorelli G, Mannucci AP (2000) Venous thromboembolism and hypercoagulability in splenectomized patients with thalassaemia intermedia. Br J Haematol 111(2):467–473PubMedCrossRefGoogle Scholar
  6. 6.
    Aessopos A, Farmakis D, Karagiorga M, Voskaridou E, Loutradi A, Hatziliami A, Joussef J, Rombos J, Loukopoulos D (2001) Cardiac involvement in thalassemia intermedia: a multicenter study. Blood 97(11):3411–3416PubMedCrossRefGoogle Scholar
  7. 7.
    Atichartakarn V, Angchaisuksiri P, Aryurachai K, Onpun S, Chuncharunee S, Thakkinstian A, Atamasirikul K (2002) Relationship between hypercoagulable state and erythrocyte phosphatidylserine exposure in splenectomized haemoglobin E/beta-thalassaemic patients. Br J Haematol 118(3):893–898PubMedCrossRefGoogle Scholar
  8. 8.
    Taher AT, Musallam KM, Karimi M, El-Beshlawy A, Belhoul K, Daar S, Saned M, Cesaretti C, Cappellini MD (2010) Splenectomy and thrombosis: the case of thalassemia intermedia. J Thromb Haemost 8(10):2152–2158. doi:10.1111/j.1538-7836.2010.03940.x PubMedCrossRefGoogle Scholar
  9. 9.
    Taher A, Isma'eel H, Mehio G, Bignamini D, Kattamis A, Rachmilewitz EA, Cappellini MD (2006) Prevalence of thromboembolic events among 8,860 patients with thalassaemia major and intermedia in the Mediterranean area and Iran. Thromb Haemost 96(4):488–491PubMedGoogle Scholar
  10. 10.
    Angchaisuksiri P, Atichartakarn V, Aryurachai K, Archararit N, Chuncharunee S, Tiraganjana A, Rattanasiri S (2007) Hemostatic and thrombotic markers in patients with hemoglobin E/beta-thalassemia disease. Am J Hematol 82(11):1001–1004. doi:10.1002/ajh.20945 PubMedCrossRefGoogle Scholar
  11. 11.
    Tripodi A, Cappellini MD, Chantarangkul V, Padovan L, Fasulo MR, Marcon A, Mannucci PM (2009) Hypercoagulability in splenectomized thalassemic patients detected by whole-blood thromboelastometry, but not by thrombin generation in platelet-poor plasma. Haematologica 94(11):1520–1527. doi:10.3324/haematol.2009.010546 PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Aessopos A, Farmakis D, Deftereos S, Tsironi M, Tassiopoulos S, Moyssakis I, Karagiorga M (2005) Thalassemia heart disease: a comparative evaluation of thalassemia major and thalassemia intermedia. Chest 127(5):1523–1530PubMedCrossRefGoogle Scholar
  13. 13.
    Du ZD, Roguin N, Milgram E, Saab K, Koren A (1997) Pulmonary hypertension in patients with thalassemia major. Am Heart J 134(3):532–537PubMedCrossRefGoogle Scholar
  14. 14.
    El-Beshlawy A, Youssry I, El-Saidi S, El Accaoui R, Mansi Y, Makhlouf A, Taher A (2008) Pulmonary hypertension in beta-thalassemia major and the role of L-carnitine therapy. Pediatr Hematol Oncol 25(8):734–743. doi:10.1080/08880010802244035 PubMedCrossRefGoogle Scholar
  15. 15.
    Kiter G, Balci YI, Ates A, Hacioglu S, Sari I (2010) Frequency of pulmonary hypertension in asymptomatic beta-thalassemia major patients and the role of physiological parameters in evaluation. Pediatr Hematol Oncol 27(8):597–607. doi:10.3109/08880018.2010.503338 PubMedCrossRefGoogle Scholar
  16. 16.
    Farmakis D, Aessopos A (2011) Pulmonary hypertension associated with hemoglobinopathies: prevalent but overlooked. Circulation 123(11):1227–1232. doi:10.1161/circulationaha.110.988089 PubMedCrossRefGoogle Scholar
  17. 17.
    Morris CR, Kuypers FA, Kato GJ, Lavrisha L, Larkin S, Singer T, Vichinsky EP (2005) Hemolysis-associated pulmonary hypertension in thalassemia. Ann N Y Acad Sci 1054:481–485. doi:10.1196/annals.1345.058 PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Derchi G, Galanello R, Bina P, Cappellini MD, Piga A, Lai ME, Quarta A, Casu G, Perrotta S, Pinto V, Musallam KM, Forni GL, on behalf of the Webthal Pulmonary Arterial Hypertension G (2013) Prevalence and risk factors for pulmonary arterial hypertension in a large group of beta-Thalassemia patients using right heart catheterization: a Webthal(R) study. Circulation. doi:10.1161/CIRCULATIONAHA.113.002124 PubMedGoogle Scholar
  19. 19.
    Janda S, Shahidi N, Gin K, Swiston J (2011) Diagnostic accuracy of echocardiography for pulmonary hypertension: a systematic review and meta-analysis. Heart 97(8):612–622. doi:10.1136/hrt.2010.212084 PubMedCrossRefGoogle Scholar
  20. 20.
    Nathan DG (2011) Guilt by association. Blood 118(14):3758–3759. doi:10.1182/blood-2011-08-370338 PubMedCrossRefGoogle Scholar
  21. 21.
    Kuypers FA, Larkin SK, Emeis JJ, Allison AC (2007) Interaction of an annexin V homodimer (Diannexin) with phosphatidylserine on cell surfaces and consequent antithrombotic activity. Thromb Haemost 97(3):478–486PubMedGoogle Scholar
  22. 22.
    Lal A, Goldrich ML, Haines DA, Azimi M, Singer ST, Vichinsky EP (2011) Heterogeneity of hemoglobin H disease in childhood. N Engl J Med 364(8):710–718. doi:10.1056/NEJMoa1010174 PubMedCrossRefGoogle Scholar
  23. 23.
    Atichartakarn V, Chuncharunee S, Chandanamattha P, Likittanasombat K, Aryurachai K (2004) Correction of hypercoagulability and amelioration of pulmonary arterial hypertension by chronic blood transfusion in an asplenic hemoglobin E/beta-thalassemia patient. Blood 103(7):2844–2846PubMedCrossRefGoogle Scholar
  24. 24.
    Hassell KL (2011) Pulmonary hypertension, tricuspid regurgitant velocity screening, and the nitric oxide pathway. Hematol Am Soc Hematol Educ Program 2011:419–426. doi:10.1182/asheducation-2011.1.419 CrossRefGoogle Scholar
  25. 25.
    Goldfarb A, Grisaru D, Gimmon Z, Okon E, Lebensart P, Rachmilewitz EA (1990) High incidence of cholelithiasis in older patients with homozygous beta-thalassemia. Acta Haematol 83(3):120–122PubMedCrossRefGoogle Scholar
  26. 26.
    Habib A, Kunzelmann C, Shamseddeen W, Zobairi F, Freyssinet JM, Taher A (2008) Elevated levels of circulating procoagulant microparticles in patients with beta-thalassemia intermedia. Haematologica 93(6):941–942. doi:10.3324/haematol.12460 PubMedCrossRefGoogle Scholar
  27. 27.
    Atichartakarn V, Angchaisuksiri P, Aryurachai K, Chuncharunee S, Thakkinstian A (2003) In vivo platelet activation and hyperaggregation in hemoglobin E/beta-thalassemia: a consequence of splenectomy. Int J Hematol 77(3):299–303PubMedCrossRefGoogle Scholar
  28. 28.
    Eldor A, Lellouche F, Goldfarb A, Rachmilewitz EA, Maclouf J (1991) In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites. Blood 77(8):1749–1753PubMedGoogle Scholar
  29. 29.
    Borenstain-Ben Yashar V, Barenholz Y, Hy-Am E, Rachmilewitz EA, Eldor A (1993) 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 44(1):63–65PubMedCrossRefGoogle Scholar
  30. 30.
    Ruf A, Pick M, Deutsch V, Patscheke H, Goldfarb A, Rachmilewitz EA, Guillin MC, Eldor A (1997) In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major. Br J Haematol 98(1):51–56PubMedCrossRefGoogle Scholar
  31. 31.
    Goldschmidt N, Spectre G, Brill A, Zelig O, Goldfarb A, Rachmilewitz E, Varon D (2008) Increased platelet adhesion under flow conditions is induced by both thalassemic platelets and red blood cells. Thromb Haemost 100(5):864–870PubMedGoogle Scholar
  32. 32.
    Amer J, Fibach E (2004) Oxidative status of platelets in normal and thalassemic blood. Thromb Haemost 92(5):1052–1059. doi:10.1267/thro04051052 PubMedGoogle Scholar
  33. 33.
    Newman PJ, Newman DK (2003) Signal transduction pathways mediated by PECAM-1: new roles for an old molecule in platelet and vascular cell biology. Arterioscler Thromb Vasc Biol 23(6):953–964. doi:10.1161/01.atv.0000071347.69358.d9 PubMedCrossRefGoogle Scholar
  34. 34.
    Varon D, Jackson DE, Shenkman B, Dardik R, Tamarin I, Savion N, Newman PJ (1998) Platelet/endothelial cell adhesion molecule-1 serves as a costimulatory agonist receptor that modulates integrin-dependent adhesion and aggregation of human platelets. Blood 91(2):500–507PubMedGoogle Scholar
  35. 35.
    Chaichompoo P, Kumya P, Khowawisetsut L, Chiangjong W, Chaiyarit S, Pongsakul N, Sirithanaratanakul N, Fucharoen S, Thongboonkerd V, Pattanapanyasat K (2012) Characterizations and proteome analysis of platelet-free plasma-derived microparticles in beta-thalassemia/hemoglobin E patients. J Proteome 76(Spec No):239–250. doi:10.1016/j.jprot.2012.06.004 CrossRefGoogle Scholar
  36. 36.
    Sinauridze EI, Kireev DA, Popenko NY, Pichugin AV, Panteleev MA, Krymskaya OV, Ataullakhanov FI (2007) Platelet microparticle membranes have 50- to 100-fold higher specific procoagulant activity than activated platelets. Thromb Haemost 97(3):425–434PubMedGoogle Scholar
  37. 37.
    Gladwin MT, Barst RJ, Castro OL, Gordeuk VR, Hillery CA, Kato GJ, Kim-Shapiro DB, Machado R, Morris CR, Steinberg MH, Vichinsky EP (2010) Pulmonary hypertension and NO in sickle cell. Blood 116(5):852–854. doi:10.1182/blood-2010-04-282095 PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Bunn HF, Nathan DG, Dover GJ, Hebbel RP, Platt OS, Rosse WF, Ware RE (2010) Pulmonary hypertension and nitric oxide depletion in sickle cell disease. Blood 116(5):687–692. doi:10.1182/blood-2010-02-268193 PubMedCrossRefGoogle Scholar
  39. 39.
    Rother RP, Bell L, Hillmen P, Gladwin MT (2005) The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA: J Am Med Assoc 293(13):1653–1662. doi:10.1001/jama.293.13.1653 CrossRefGoogle Scholar
  40. 40.
    Balla J, Vercellotti GM, Jeney V, Yachie A, Varga Z, Eaton JW, Balla G (2005) Heme, heme oxygenase and ferritin in vascular endothelial cell injury. Mol Nutr Food Res 49(11):1030–1043. doi:10.1002/mnfr.200500076 PubMedCrossRefGoogle Scholar
  41. 41.
    Jeney V, Balla J, Yachie A, Varga Z, Vercellotti GM, Eaton JW, Balla G (2002) Pro-oxidant and cytotoxic effects of circulating heme. Blood 100(3):879–887PubMedCrossRefGoogle Scholar
  42. 42.
    Bohm F, Pernow J (2007) The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovasc Res 76(1):8–18. doi:10.1016/j.cardiores.2007.06.004 PubMedCrossRefGoogle Scholar
  43. 43.
    Vizza CD, Letizia C, Petramala L, Badagliacca R, Poscia R, Zepponi E, Crescenzi E, Nona A, Benedetti G, Ferrante F, Sciomer S, Fedele F (2008) Venous endotelin-1 (ET-1) and brain natriuretic peptide (BNP) plasma levels during 6-month bosentan treatment for pulmonary arterial hypertension. Regul Pept 151(1–3):48–53. doi:10.1016/j.regpep.2008.08.002 PubMedCrossRefGoogle Scholar
  44. 44.
    Anthi A, Tsangaris I, Hamodraka ES, Lekakis J, Armaganidis A, Orfanos SE (2012) Treatment with bosentan in a patient with thalassemia intermedia and pulmonary arterial hypertension. Blood 120(7):1531–1532. doi:10.1182/blood-2012-04-422568 PubMedCrossRefGoogle Scholar
  45. 45.
    Crary SE, Ramaciotti C, Buchanan GR (2011) Prevalence of pulmonary hypertension in hereditary spherocytosis. Am J Hematol 86(12):E73–E76. doi:10.1002/ajh.22182 PubMedCrossRefGoogle Scholar
  46. 46.
    Riondino S, Martini F, La Farina F, Spila A, Guadagni F, Ferroni P (2010) Increased plasma levels of soluble CD40 ligand correlate with platelet activation markers and underline the need for standardized pre-analytical conditions. Clin Biochem 43(7–8):666–670. doi:10.1016/j.clinbiochem.2009.12.021 PubMedCrossRefGoogle Scholar
  47. 47.
    Damas JK, Otterdal K, Yndestad A, Aass H, Solum NO, Froland SS, Simonsen S, Aukrust P, Andreassen AK (2004) Soluble CD40 ligand in pulmonary arterial hypertension: possible pathogenic role of the interaction between platelets and endothelial cells. Circulation 110(8):999–1005. doi:10.1161/01.cir.0000139859.68513.fc PubMedCrossRefGoogle Scholar
  48. 48.
    Allanore Y, Borderie D, Meune C, Lemarechal H, Weber S, Ekindjian OG, Kahan A (2005) Increased plasma soluble CD40 ligand concentrations in systemic sclerosis and association with pulmonary arterial hypertension and digital ulcers. Ann Rheum Dis 64(3):481–483. doi:10.1136/ard.2003.020040 PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Mannucci PM (2010) Red cells playing as activated platelets in thalassemia intermedia. J Thromb Haemost 8(10):2149–2151. doi:10.1111/j.1538-7836.2010.04030.x PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Sylvia T. Singer
    • 1
  • Frans Kuypers
    • 3
  • Jeffery Fineman
    • 7
  • Ginny Gildengorin
    • 4
  • Sandra Larkin
    • 3
  • Nancy Sweeters
    • 4
  • Howard Rosenfeld
    • 2
  • Gregory Kurio
    • 2
  • Annie Higa
    • 4
  • Michael Jeng
    • 6
  • James Huang
    • 5
  • Elliott P. Vichinsky
    • 1
  1. 1.Department of Hematology-OncologyChildren’s Hospital and Research Center OaklandOaklandUSA
  2. 2.Department of CardiologyChildren’s Hospital and Research Center OaklandOaklandUSA
  3. 3.Children’s Hospital Oakland Research InstituteOaklandUSA
  4. 4.Pediatric Clinical Research CenterChildren’s Hospital and Research Center OaklandOaklandUSA
  5. 5.Department of Hematology-OncologyUniversity of CaliforniaSan FranciscoUSA
  6. 6.Department of Hematology-OncologyStanford School of MedicinePalo AltoUSA
  7. 7.Department of PediatricsUniversity of California, San FranciscoSan FranciscoUSA

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