Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: update on defibrotide and other current investigational therapies

Abstract

Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), remains one of the most serious and common complications after myeloablative hematopoietic stem cell transplantation (HSCT). Clinical diagnosis of hepatic VOD is based on the clinical triad of (1) painful hepatomegaly, (2) hyperbilirubinemia and (3) unexplained fluid retention. While milder cases usually resolve spontaneously, severe VOD is associated with a grim prognosis. Defibrotide (DF), a polydisperse mixture of single-stranded oligonucleotide with antithrombotic and fibrinolytic effects on microvascular endothelium, has emerged as an effective and safe therapy for patients with severe VOD. Multiple studies, including a recent large international multicenter phase II clinical trial, have demonstrated 30–60% complete remission rates with DF, even among patients with severe VOD and multiorgan failure. This article will review our current understanding of hepatic VOD, and update the clinical trial experience with DF and other potential therapies for this feared transplant complication.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Bearman SI, Appelbaum FR, Buckner CD, Petersen FB, Fisher LD, Clift RA et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1988; 6: 1562–1568.

    Article  CAS  PubMed  Google Scholar 

  2. McDonald GB, Hinds MS, Fisher LD, Schoch HG, Wolford JL, Banaji M et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 1993; 118: 255–267.

    Article  CAS  PubMed  Google Scholar 

  3. Carreras E, Bertz H, Arcese W, Vernant JP, Tomas JF, Hagglund H et al. Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: a prospective cohort study of the European Group for Blood and Marrow Transplantation. European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party. Blood 1998; 92: 3599–3604.

    CAS  PubMed  Google Scholar 

  4. Lee JL, Gooley T, Bensinger W, Schiffman K, McDonald GB . Veno-occlusive disease of the liver after busulfan, melphalan, and thiotepa conditioning therapy: incidence, risk factors, and outcome. Biol Blood Marrow Transplant 1999; 5: 306–315.

    CAS  PubMed  Google Scholar 

  5. Hogan WJ, Maris M, Storer B, Sandmaier BM, Maloney DG, Schoch HG et al. Hepatic injury after nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation: a study of 193 patients. Blood 2004; 103: 78–84.

    CAS  PubMed  Google Scholar 

  6. Bearman SI . The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood 1995; 85: 3005–3020.

    CAS  PubMed  Google Scholar 

  7. Pihusch R, Salat C, Schmidt E, Gohring P, Pihusch M, Hiller E et al. Hemostatic complications in bone marrow transplantation: a retrospective analysis of 447 patients. Transplantation 2002; 74: 1303–1309.

    PubMed  Google Scholar 

  8. Richardson P, Bearman SI . Prevention and treatment of hepatic venocclusive disease after high-dose cytoreductive therapy. Leuk Lymphoma 1998; 31: 267–277.

    CAS  PubMed  Google Scholar 

  9. Chopra R, Eaton JD, Grassi A, Potter M, Shaw B, Salat C et al. Defibrotide for the treatment of hepatic veno-occlusive disease: results of the European compassionate-use study. Br J Haematol 2000; 111: 1122–1129.

    Article  CAS  PubMed  Google Scholar 

  10. Richardson PG, Murakami C, Jin Z, Warren D, Momtaz P, Hoppensteadt D et al. Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood 2002; 100: 4337–4343.

    Article  CAS  PubMed  Google Scholar 

  11. Corbacioglu S, Greil J, Peters C, Wulffraat N, Laws HJ, Dilloo D et al. Defibrotide in the treatment of children with veno-occlusive disease (VOD): a retrospective multicentre study demonstrates therapeutic efficacy upon early intervention. Bone Marrow Transplant 2004; 33: 189–195.

    Article  CAS  PubMed  Google Scholar 

  12. Chalandon Y, Roosnek E, Mermillod B, Newton A, Ozsahin H, Wacker P et al. Prevention of veno-occlusive disease with defibrotide after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2004; 10: 347–354.

    CAS  PubMed  Google Scholar 

  13. Corbacioglu S, Honig M, Lahr G, Stohr S, Berry G, Friedrich W et al. Stem cell transplantation in children with infantile osteopetrosis is associated with a high incidence of VOD, which could be prevented with defibrotide. Bone Marrow Transplant 2006; 38: 547–553.

    CAS  PubMed  Google Scholar 

  14. Dignan F, Gujral D, Ethell M, Evans S, Treleaven J, Morgan G et al. Prophylactic defibrotide in allogeneic stem cell transplantation: minimal morbidity and zero mortality from veno-occlusive disease. Bone Marrow Transplant 2007; 40: 79–82.

    CAS  PubMed  Google Scholar 

  15. DeLeve LD, Kaplowitz N . Selective susceptibility of hepatic endothelial cells to dacarbazine toxicity, a model for hepatic venoocclusive disease. Hepatology 1991; 14: 161A.

    Google Scholar 

  16. DeLeve LD . Cellular target of cyclophosphamide toxicity in the murine liver: role of glutathione and site of metabolic activation. Hepatology 1996; 24: 830–837.

    CAS  PubMed  Google Scholar 

  17. Hassan M, Ljungman P, Ringden O, Hassan Z, Oberg G, Nilsson C et al. The effect of busulphan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite: time interval influence on therapeutic efficacy and therapy-related toxicity. Bone Marrow Transplant 2000; 25: 915–924.

    CAS  PubMed  Google Scholar 

  18. de Jonge ME, Huitema AD, Beijnen JH, Rodenhuis S . High exposures to bioactivated cyclophosphamide are related to the occurrence of veno-occlusive disease of the liver following high-dose chemotherapy. Br J Cancer 2006; 94: 1226–1230.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Salat C, Holler E, Reinhardt B, Kolb HJ, Seeber B, Ledderose G et al. Parameters of the fibrinolytic system in patients undergoing BMT: elevation of PAI-1 in veno-occlusive disease. Bone Marrow Transplant 1994; 14: 747–750.

    CAS  PubMed  Google Scholar 

  20. Richardson P, Krishnan A, Wheeler C, Hoppensteadt D, Tuchin J, Fyfe H et al. Elevation of PAI-1 levels in BMT-associated VOD and changes seen with the use of defibrotide. Blood 1996; 88: 458a.

    Google Scholar 

  21. Richardson P, Hoppensteadt D, Elias A, Frei III E, Iacobelli M, Guinan E et al. Elevation of tissue factor pathway inhibitor [TFPI], thrombomodulin [TM] and plasminogen activator inhibitor-1 [PAI-1] levels in stem cell transplant [SCT]-associated veno-occlusive disease [VOD] and changes seen with the use of defibrotide [DF]. Blood 1997; 90: 219a.

    Google Scholar 

  22. Richardson PG, Hoppensteadt D, Elias AD, Kinchla N, Warren D, Iacobelli M et al. Elevation of endothelial stress products and trends seen in patients with severe veno-occlusive disease treated with defibrotide. Thromb Hemost 1999; 3185 (Suppl): 628.

    Google Scholar 

  23. Nurnberger W, Michelmann I, Burdach S, Gobel U . Endothelial dysfunction after bone marrow transplantation: increase of soluble thrombomodulin and PAI-1 in patients with multiple transplant-related complications. Ann Hematol 1998; 76: 61–65.

    CAS  PubMed  Google Scholar 

  24. Salat C, Holler E, Kolbe HJ, Brigitte R, Pihusch R, Wolfgang W et al. Plasminogen activator inhibitor-1 confirms the diagnosis of hepatic veno-occlusive disease in patients with hyperbilirubinemia after bone marrow transplant. Blood 1997; 89: 2184–2188.

    CAS  PubMed  Google Scholar 

  25. Lee JH, Lee KH, Kim S, Seol M, Park CJ, Chi HS et al. Plasminogen activator inhibitor-1 is an independent diagnostic marker as well as severity predictor of hepatic veno-occlusive disease after allogeneic bone marrow transplantation in adults conditioned with busulphan and cyclophosphamide. Br J Haematol 2002; 118: 1087–1094.

    CAS  PubMed  Google Scholar 

  26. Richardson P, Krishnan A, Wheeler C, Fyfe H, Hoppensteadt D, Fareed J et al. The use of defibrotide (DF) in BMT-associated veno-occlusive disease (VOD) (Meeting abstract). Proc Annu Meet Am Soc Clin Oncol 1996; 15: A13 1996.

    Google Scholar 

  27. Pihusch V, Pihusch M, Penovici M, Kolb HJ, Hiller E, Pihusch R . Transforming growth factor beta-1 released from platelets contributes to hypercoagulability in veno-occlusive disease following hematopoietic stem cell transplantation. Thromb Res 2005; 116: 233–240.

    CAS  PubMed  Google Scholar 

  28. Anscher MS, Peters WP, Reisenbichler H, Petros WP, Jirtle RL . Transforming growth factor beta as a predictor of liver and lung fibrosis after autologous bone marrow transplantation for advanced breast cancer. N Engl J Med 1993; 328: 1592–1598.

    CAS  PubMed  Google Scholar 

  29. DeLeve LD, Wang X, Kanel GC, Ito Y, Bethea NW, McCuskey MK et al. Decreased hepatic nitric oxide production contributes to the development of rat sinusoidal obstruction syndrome. Hepatology 2003; 38: 900–908.

    CAS  PubMed  Google Scholar 

  30. Kuroki I, Miyazaki T, Mizukami I, Matsumoto N, Matsumoto I . Effect of sodium nitroprusside on ischemia-reperfusion injuries of the rat liver. Hepatogastroenterology 2004; 51: 1404–1407.

    CAS  PubMed  Google Scholar 

  31. Smith LH, Dixon JD, Stringham JR, Eren M, Elokdah H, Crandall DL et al. Pivotal role of PAI-1 in a murine model of hepatic vein thrombosis. Blood 2006; 107: 132–134.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. DeLeve L, Shulman HM, McDonald GB . Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis 2002; 22: 27–42.

    PubMed  Google Scholar 

  33. Kumar S, DeLeve LD, Kamath PS, Tefferi A . Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation. Mayo Clin Proc 2003; 78: 589–598.

    Article  PubMed  Google Scholar 

  34. McDonald GB . Venocclusive disease of the liver following marrow transplantation. Marrow Transplant Rev 1993; 3: 49–56.

    Google Scholar 

  35. Rozman C, Carreras E, Qian C, Gale RP, Bortin MM, Rowlings PA et al. Risk factors for hepatic veno-occlusive disease following HLA-identical sibling bone marrow transplants for leukemia. Bone Marrow Transplant 1996; 17: 75–80.

    CAS  PubMed  Google Scholar 

  36. Moscardo F, Urbano-Ispizua A, Sanz GF, Brunet S, Caballero D, Vallejo C et al. Positive selection for CD34 reduces the incidence and severity of veno-occlusive disease of the liver after HLA-identical sibling allogeneic peripheral blood stem cell transplantation. Exp Hematol 2003; 31: 545–550.

    PubMed  Google Scholar 

  37. Nevill TJ, Barnett MJ, Klingemann HG, Reece DE, Shepherd JD, Phillips GL . Regimen-related toxicity of a busulfan-cyclophosphamide conditioning regimen in 70 patients undergoing allogeneic bone marrow transplantation. J Clin Oncol 1991; 9: 1224–1232.

    CAS  PubMed  Google Scholar 

  38. Matute-Bello G, McDonald GD, Hinds MS, Schoch HG, Crawford SW . Association of pulmonary function testing abnormalities and severe veno-occlusive disease of the liver after marrow transplantation. Bone Marrow Transplant 1998; 21: 1125–1130.

    CAS  PubMed  Google Scholar 

  39. Cesaro S, Pillon M, Talenti E, Toffolutti T, Calore E, Tridello G et al. A prospective survey on incidence, risk factors and therapy of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Haematologica 2005; 90: 1396–1404.

    PubMed  Google Scholar 

  40. Ringden O, Ruutu T, Remberger M, Nikoskelainer L, Volin L, Vindelov T et al. A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group. Blood 1994; 83: 2723–2730.

    CAS  PubMed  Google Scholar 

  41. Copelan EA, Bechtel TP, Avalos BR, Elder PJ, Ezzone SA, Scholl MD et al. Busulfan levels are influenced by prior treatment and are associated with hepatic veno-occlusive disease and early mortality but not with delayed complications following marrow transplantation. Bone Marrow Transplant 2001; 27: 1121–1124.

    CAS  PubMed  Google Scholar 

  42. McDonald GB, Slattery JT, Bouvier ME, Ren S, Batchelder AL, Kalhorn TF et al. Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood 2003; 101: 2043–2048.

    CAS  PubMed  Google Scholar 

  43. Lee JH, Choi SJ, Kim SE, Park CJ, Chi HS, Lee MS et al. Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan+cyclophosphamide for allogeneic bone marrow transplantation. Ann Hematol 2005; 84: 321–330.

    CAS  PubMed  Google Scholar 

  44. Clopes A, Sureda A, Sierra J, Queralto JM, Broto A, Farre R et al. Absence of veno-occlusive disease in a cohort of multiple myeloma patients undergoing autologous stem cell transplantation with targeted busulfan dosage. Eur J Haematol 2006; 77: 1–6.

    CAS  PubMed  Google Scholar 

  45. McCune JS, Batchelder A, Deeg HJ, Gooley T, Cole S, Phillips B et al. Cyclophosphamide following targeted oral busulfan as conditioning for hematopoietic cell transplantation: pharmacokinetics, liver toxicity, and mortality. Biol Blood Marrow Transplant 2007; 13: 853–862.

    CAS  PubMed  Google Scholar 

  46. Wadleigh M, Richardson PG, Zahrieh D, Lee SJ, Cutler C, Ho V et al. Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood 2003; 102: 1578–1582.

    CAS  PubMed  Google Scholar 

  47. Arceci RJ, Sande J, Lange B, Shannon K, Franklin J, Hutchinson R et al. Safety and efficacy of gemtuzumab ozogamicin in pediatric patients with advanced CD33+ acute myeloid leukemia. Blood 2005; 106: 1183–1188.

    CAS  PubMed  Google Scholar 

  48. McKoy JM, Angelotta C, Bennett CL, Tallman MS, Wadleigh M, Evens AM et al. Gemtuzumab ozogamicin-associated sinusoidal obstructive syndrome (SOS): an overview from the research on adverse drug events and reports (RADAR) project. Leuk Res 2007; 31: 599–604. E-pub 7 September 2006.

    CAS  PubMed  Google Scholar 

  49. Soiffer RJ, Dear K, Rabinowe SN, Anderson KC, Freedman AS, Murray C et al. Hepatic dysfunction following T-cell-depleted allogeneic bone marrow transplantation. Transplantation 1991; 52: 1014–1019.

    CAS  PubMed  Google Scholar 

  50. Moscardo F, Sanz GF, de La Rubia J, Jimenez C, Saavedra S, Regadera A et al. Marked reduction in the incidence of hepatic veno-occlusive disease after allogeneic hematopoietic stem cell transplantation with CD34(+) positive selection. Bone Marrow Transplant 2001; 27: 983–988.

    CAS  PubMed  Google Scholar 

  51. Moscardo F, Urbano-Ispizua A, Sanz GF, Brunet S, Caballero D, Vallejo C et al. Positive selection for CD34+ reduces the incidence and severity of veno-occlusive disease of the liver after HLA-identical sibling allogeneic peripheral blood stem cell transplantation. Exp Hematol 2003; 31: 545–550.

    PubMed  Google Scholar 

  52. Antin JH, Kim HT, Cutler C, Ho VT, Lee SJ, Miklos DB et al. Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation. Blood 2003; 102: 1601–1605.

    CAS  PubMed  Google Scholar 

  53. Cutler C, Henry NL, Magee C, Li S, Kim HT, Alyea E et al. Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11: 551–557.

    CAS  PubMed  Google Scholar 

  54. Eissner G, Multhoff G, Gerbitz A, Kirchner S, Bauer S, Haffner S et al. Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide. Blood 2002; 100: 334–340.

    CAS  PubMed  Google Scholar 

  55. Bianchi G, Barone D, Lanzarotti E, Tettamanti R, Porta R, Moltrasio D et al. Defibrotide, a single-stranded polydeoxyribonucleotide acting as an adenosine receptor agonist. Eur J Pharmacol 1993; 238: 327–334.

    CAS  PubMed  Google Scholar 

  56. Bracht F, Schror K . Isolation and identification of aptamers from defibrotide that act as thrombin antagonists in vitro. Biochem Biophys Res Commun 1994; 200: 933–936.

    CAS  PubMed  Google Scholar 

  57. Coccheri S, Biagi G, Legnani C, Bianchini B, Grauso F . Acute effects of defibrotide, an experimental antithrombotic agent, on fibrinolysis and blood prostanoids in man. Eur J Clin Pharmacol 1988; 35: 151–156.

    CAS  PubMed  Google Scholar 

  58. Berti F, Rossoni G, Biasi G, Buschi A, Mandelli V . Defibrotide by enhancing prostacyclin generation prevents endothelin-I induced contraction in human saphenous veins. Prostaglandins 1990; 40: 337–350.

    CAS  PubMed  Google Scholar 

  59. Zhou Q, Chu X, Ruan C . Defibrotide stimulates expression of thrombomodulin in human endothelial cells. Thromb Hemost 1994; 71: 507–510.

    CAS  Google Scholar 

  60. Fareed J . Modulation of endothelium by heparins and defibrotide. In: Nicolaides A, Novo S (eds). Advances in Vascular Pathology 1997. Elsevier Science B.V.: Amsterdam, 1997, pp 25–32.

    Google Scholar 

  61. Ulutin ON . Antithrombotic effect and clinical potential of defibrotide. Sem Thromb Hemost 1993; 19: 186–191.

    Google Scholar 

  62. Jamieson A, Alcock P, Tuffin DP . The action of polyanionic agents defibrotide and pentosan sulphate on fibrinolytic activity in the laboratory rat. Fibrinolysis 1996; 10: 27–35.

    Google Scholar 

  63. Falanga A, Marchetti M, Vignoli A, Barbui T . Defibrotide (DF) modulates tissue factor expression by microvascular endothelial cells. Blood 1999; 94: 146a.

    Google Scholar 

  64. Falanga A, Marchetti M, Vignoli A, Barbui T . Impact of defibrotide on the fibrinolytic and procoagulant properties of endothelial cell macro- and micro-vessels. Blood 2000; 96: 53a.

    Google Scholar 

  65. Richardson PG, Elias AD, Krishnan A, Wheeler C, Nath R, Hoppensteadt D et al. Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. Blood 1998; 92: 737–744.

    CAS  PubMed  Google Scholar 

  66. Richardson P, Murakami C, Jin Z, Warren D, Momtaz P, Hoppensteadt DA et al. Multi-institutional use of defibrotide in 88 patients post stem cell transplant with severe veno-occlusive disease and multi-system organ failure; response without significant toxicity in a high risk population and factors predictive of outcome. Blood 2002; 100: 4337–4343.

    CAS  PubMed  Google Scholar 

  67. Bulley SR, Strahm B, Doyle J, Dupuis LL . Defibrotide for the treatment of hepatic veno-occlusive disease in children. Pediatr Blood Cancer 2007; 48: 700–704.

    PubMed  Google Scholar 

  68. Richardson P, Soiffer R, Antin J, Jin Z, Kurtzberg J, Martin P et al. Defibrotide (DF) for the treatment of severe veno-occlusive disease (sVOD) and multi-organ failure (MOF) post SCT: final results of a multi-center, randomized, dose-finding trial. Blood 2006; 108: 178.

    Google Scholar 

  69. Vangelista A, Frasca GM, Raimondi C, Liviano-D'Arcangelo G, Bonomini V . Effects of defibrotide in acute renal failure due to thrombotic microangiopathy. Haemostasis 1986; 16 (Suppl 1): 51–54.

    PubMed  Google Scholar 

  70. Bearman SI, Anderson GL, Mori M, Hinds MS, Shulman HM, McDonald GB . Venoocclusive disease of the liver: development of a model for predicting fatal outcome after marrow transplantation. J Clin Oncol 1993; 11: 1729–1736.

    CAS  PubMed  Google Scholar 

  71. Versluys B, Bhattacharaya R, Steward C, Cornish J, Oakhill A, Goulden N . Prophylaxis with defibrotide prevents veno-occlusive disease in stem cell transplantation after gemtuzumab ozogamicin exposure. Blood 2004; 103: 1968; letter to editor.

    CAS  PubMed  Google Scholar 

  72. Baglin TP, Harper P, Marcus RE . Veno-occlusive disease of the liver complicating ABMT successfully treated with recombinant tissue plasminogen activator (rt-PA). Bone Marrow Transplant 1990; 5: 439–441.

    CAS  PubMed  Google Scholar 

  73. Bearman SI, Lee JL, Baron AE, McDonald GB . Treatment of hepatic venocclusive disease with recombinant human tissue plasminogen activator and heparin in 42 marrow transplant patients. Blood 1997; 89: 1501–1506.

    CAS  PubMed  Google Scholar 

  74. Laporte JP, Lesage S, Tilleul P, Najman A, Gorin NC . Alteplase for hepatic veno-occlusive disease complicating bone-marrow transplantation [letter] [see comments]. Lancet 1992; 339: 1057.

    CAS  PubMed  Google Scholar 

  75. Rosti G, Bandini G, Belardinelli A, Calori E, Tura S, Gherlinzoni F et al. Alteplase for hepatic veno-occlusive disease after bone-marrow transplantation [letter; comment] [see comments]. Lancet 1992; 339: 1481–1482.

    CAS  PubMed  Google Scholar 

  76. Ringden O, Wennberg L, Ericzon BG, Kallman R, Astrom M, Duraj F et al. Alteplase for hepatic veno-occlusive disease after bone marrow transplantation [letter; comment]. Lancet 1992; 340: 546–547.

    CAS  PubMed  Google Scholar 

  77. Leahey AM, Bunin NJ . Recombinant human tissue plasminogen activator for the treatment of severe hepatic veno-occlusive disease in pediatric bone marrow transplant patients. Bone Marrow Transplant 1996; 17: 1101–1104.

    CAS  PubMed  Google Scholar 

  78. Feldman L, Gabai E, Milovic V, Jaimovich G . Recombinant tissue plasminogen activator (rTPA) for hepatic veno-occlusive disease after allogeneic BMT in a pediatric patient. 1995; 16: 727–731.

  79. Goldberg SL, Shubert J, Rao AK, Redei I, Klumpp TR, Mangan KF . Treatment of hepatic veno-occlusive disease with low-dose tissue plasminogen activator: impact on coagulation profile. Bone Marrow Transplant 1996; 18: 633–636.

    CAS  PubMed  Google Scholar 

  80. Higashigawa M, Watanabe M, Nishihara H, Tabata N, Azuma E, Ido M et al. Successful treatment of an infant with veno-occlusive disease developed after allogeneic bone marrow transplantation by tissue plasminogen activator, heparin and prostaglandin E1. Leuk Res 1995; 19: 477–480.

    CAS  PubMed  Google Scholar 

  81. Hagglund H, Ringden O, Ljungman P . No beneficial effects, but severe side effects caused by recombinant human tissue plasminogen activator for treatment of hepatic veno-occlusive disease after allogeneic bone marrow transplantation. Transplantation 1995; 27: 3535.

    CAS  Google Scholar 

  82. Lee JH, Lee KH, Choi JS, Zang DY, Kim SB, Kim SW et al. Veno-occlusive disease (VOD) of the liver in Korean patients following allogeneic bone marrow transplantation (BMT): efficacy of recombinant human tissue plasminogen activator (rt-PA) treatment. J Korean Med Sci 1996; 11: 118–126.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Yu LC, Malkani I, Regueira O, Ode DL, Warrier RP . Recombinant tissue plasminogen activator (rt-PA) for veno-occlusive liver disease in pediatric autologous bone marrow transplant patients. Am J Hematol 1994; 46: 194–198.

    CAS  PubMed  Google Scholar 

  84. Schriber J, Milk B, Shaw D, Christiansen N, Baer M, Slack J et al. Tissue plasminogen activator (tPA) as therapy for hepatotoxicity following bone marrow transplantation. Bone Marrow Transplant 1999; 24: 1311–1314.

    CAS  PubMed  Google Scholar 

  85. Kulkarni S, Rodriguez M, Lafuente A, Mateos P, Mehta J, Singhal S et al. Recombinant tissue plasminogen activator (rtPA) for the treatment of hepatic veno-occlusive disease (VOD). Bone Marrow Transplant 1999; 23: 803–807.

    CAS  PubMed  Google Scholar 

  86. Morris JD, Harris RE, Hashmi R, Sambrano JE, Gruppo RA, Becker AT et al. Antithrombin-III for the treatment of chemotherapy-induced organ dysfunction following bone marrow transplantation. Bone Marrow Transplant 1997; 20: 871–878.

    CAS  PubMed  Google Scholar 

  87. Mertens R, Brost H, Granzen B, Nowak-Gottl U . Antithrombin treatment of severe hepatic veno-occlusive disease in children with cancer. Eur J Pediatr 1999; 158 (Suppl 3): S154–S158.

    CAS  PubMed  Google Scholar 

  88. Ibrahim RB, Peres E, Dansey R, Abidi MH, Abella EM, Klein J . Anti-thrombin III in the management of hematopoietic stem-cell transplantation-associated toxicity. Ann Pharmacother 2004; 38: 1053–1059.

    CAS  PubMed  Google Scholar 

  89. Haussmann U, Fischer J, Eber S, Scherer F, Seger R, Gungor T . Hepatic veno-occlusive disease in pediatric stem cell transplantation: impact of pre-emptive antithrombin III replacement and combined antithrombin III/defibrotide therapy. Haematologica 2006; 91: 795–800.

    PubMed  Google Scholar 

  90. Vaughan DE, Plavin SR, Schafer AI, Loscalzo J . PGE1 accelerates thrombolysis by tissue plasminogen activator. Blood 1989; 73: 1213–1217.

    CAS  PubMed  Google Scholar 

  91. Schlegel PG, Haber HP, Beck J, Krumpelmann S, Handgretinger R, Bader P et al. Hepatic veno-occlusive disease in pediatric stem cell recipients: successful treatment with continuous infusion of prostaglandin E1 and low-dose heparin. Ann Hematol 1998; 76: 37–41.

    CAS  PubMed  Google Scholar 

  92. Bearman SI, Shen DD, Hinds MS, Hill HA, McDonald GB . A phase I/II study of prostaglandin E1 for the prevention of hepatic venocclusive disease after bone marrow transplantation. Br J Haematol 1993; 84: 724–730.

    CAS  PubMed  Google Scholar 

  93. Attal M, Huguet F, Rubie H, Huynh A, Charlet JP, Payen JL et al. Prevention of hepatic veno-occlusive disease after bone marrow transplantation by continuous infusion of low-dose heparin: a prospective, randomized trial. Blood 1992; 79: 2834–2840.

    CAS  PubMed  Google Scholar 

  94. Bearman SI, Hinds MS, Wolford JL, Petersen FB, Nugent DL, Slichter SJ et al. A pilot study of continuous infusion heparin for the prevention of hepatic veno-occlusive disease after bone marrow transplantation. Bone Marrow Transplant 1990; 5: 407–411.

    CAS  PubMed  Google Scholar 

  95. Marsa-Vila L, Gorin NC, Laporte JP . Prophylactic heparin does not prevent liver veno-occlusive disease following autologous bone marrow transplantation. Eur J Haematol 1991; 47: 346–352.

    CAS  PubMed  Google Scholar 

  96. Or R, Nagler A, Shpilberg O, Elad S, Naparstek E, Kapelushnik J et al. Low molecular weight heparin for the prevention of veno-occlusive disease of the liver in bone marrow transplantation patients. Transplantation 1996; 61: 1067–1071.

    CAS  PubMed  Google Scholar 

  97. Simon M, Hahn T, Ford LA, Anderson B, Swinnich D, Baer MR et al. Retrospective multivariate analysis of hepatic veno-occlusive disease after blood or marrow transplantation: possible beneficial use of low molecular weight heparin. Bone Marrow Transplant 2001; 27: 627–633.

    CAS  PubMed  Google Scholar 

  98. Park SH, Lee MH, Lee H, Kim HS, Kim K, Kim WS et al. A randomized trial of heparin plus ursodiol vs heparin alone to prevent hepatic veno-occlusive disease after hematopoietic stem cell transplantation. Bone Marrow Transplant 2002; 29: 137–143.

    CAS  PubMed  Google Scholar 

  99. Forrest DL, Thompson K, Dorcas VG, Couban SH, Pierce R . Low molecular weight heparin for the prevention of hepatic veno-occlusive disease (VOD) after hematopoietic stem cell transplantation: a prospective phase II study. Bone Marrow Transplant 2003; 31: 1143–1149.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Forrest DL, Thompson K, Dorcas VG, Couban SH, Pierce R . Low molecular weight heparin for the prevention of veno-occlusive disease (VOD) after hematopoietic stem cell transplantation: a prospective phase II study. Bone Marrow Transplant 2003; 31: 1143–1149.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Ohashi K, Tanabe J, Watanabe R, Tanaka T, Sakamaki H, Maruta A et al. The Japanese multicenter open randomized trial of ursodeoxycholic acid prophylaxis for hepatic veno-occlusive disease after stem cell transplantation. Am J Hematol 2000; 64: 32–38.

    CAS  PubMed  Google Scholar 

  102. Essell JH, Thompson JM, Harman GS, Halvorson RD, Snyder MJ, Callander NS et al. Pilot trial of prophylactic ursodiol to decrease the incidence of veno-occlusive disease of the liver in allogeneic bone marrow transplant patients. Bone Marrow Transplant 1992; 10: 367–372.

    CAS  PubMed  Google Scholar 

  103. Essell JH, Schroeder MT, Harman GS, Halvorson R, Lew V, Callander N et al. Ursodiol prophylaxis against hepatic complications of allogeneic bone marrow transplantation. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998; 128 (12 Part 1): 975–981.

    CAS  PubMed  Google Scholar 

  104. Ruutu T, Eriksson B, Remes K, Juvonen E, Volin L, Remberger M et al. Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation. Blood 2002; 100: 1977–1983.

    CAS  PubMed  Google Scholar 

  105. Schlitt HJ, Tischler HJ, Ringe B, Raddatz G, Maschek H, Dietrich H et al. Allogeneic liver transplantation for hepatic veno-occlusive disease after bone marrow transplantation—clinical and immunological considerations. Bone Marrow Transplant 1995; 16: 473–478.

    CAS  PubMed  Google Scholar 

  106. Smith FO, Johnson MS, Scherer LR et al. Transjugular intrahepatic portosystemic shunting (TIPS) for the treatment of severe hepatic veno-occlusive disease. Bone Marrow Transplant 1996; 18: 643–646.

    CAS  PubMed  Google Scholar 

  107. Alvarez R, Banares R, Casariego J, Echenagusia A, Simo G, Alvarez E et al. Percutaneous intrahepatic portosystemic shunting in the treatment of veno-occlusive disease of the liver after bone marrow transplantation. Gastroenterol Hepatol 2000; 23: 177–180.

    CAS  PubMed  Google Scholar 

  108. Tefferi A, Kumar S, Wolf RC, Lacy MQ, Inwards DJ, Gloor JM et al. Charcoal hemofiltration for hepatic veno-occlusive disease after hematopoietic stem cell transplantation. Bone Marrow Transplant 2001; 28: 997–999.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to V T Ho.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ho, V., Revta, C. & Richardson, P. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: update on defibrotide and other current investigational therapies. Bone Marrow Transplant 41, 229–237 (2008). https://doi.org/10.1038/sj.bmt.1705899

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705899

Keywords

This article is cited by

Search

Quick links