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.

  • Original Article
  • Published:

Post-Transplant Events

Use of prophylactic anticoagulation and the risk of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation: a systematic review and meta-analysis

Bone Marrow Transplantation volume 37, pages 677–686 (2006)Cite this article

Abstract

Hepatic veno-occlusive disease is a serious regimen-related toxicity in patients undergoing hematopoietic stem cell transplantation. We performed a systematic review and meta-analysis of the literature on the effect of anticoagulation in preventing veno-occlusive disease. Several databases and online journals were searched for randomized controlled trials and cohort studies. Twelve studies (2782 patients) were eligible. Anticoagulation prophylaxis was associated with a statistically nonsignificant decrease in risk of veno-occlusive disease (pooled relative risk (RR), 0.90; 95% confidence interval (CI), 0.62–1.29). Results of one of three randomized controlled trials may have been affected by delayed introduction of anticoagulation. A second trial enrolled patients who received conventional chemoradiotherapy for early-stage disease (RR, 0.18; 95% CI, 0.04–0.78). The third trial was a pilot study with a small sample size (RR, 0.74; 95% CI, 0.53–1.04). Significant heterogeneity and methodologic weaknesses preclude drawing a meaningful conclusion from the pooled analysis. Despite some limitations, results of two of three eligible randomized controlled trials suggest that prophylactic anticoagulation may help prevent veno-occlusive disease. However, a large randomized controlled trial is needed for confirmation. Additionally, in future studies, owing to the wide spectrum of severity of veno-occlusive disease, outcomes such as 100-day mortality should strongly be considered.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Carreras E, Granena A, Rozman C . Hepatic veno-occlusive disease after bone marrow transplant. Blood Rev 1993; 7: 43–51.

    Article  CAS  PubMed  Google Scholar 

  2. McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED . Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology 1984; 4: 116–122.

    Article  CAS  PubMed  Google Scholar 

  3. 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 

  4. Jones RJ, Lee KS, Beschorner WE, Vogel VG, Grochow LB, Braine HG et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 1987; 44: 778–783.

    Article  CAS  PubMed  Google Scholar 

  5. 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 

  6. 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 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. 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 

  10. 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.

    Article  CAS  PubMed  Google Scholar 

  11. Yoshimi A, Kato K, Maeda N, Matsuyama T, Kojima S . Treatment of hepatic veno-occlusive disease after bone marrow transplantation with recombinant human tissue plasminogen activator (rh-tPA) [Japanese]. Rinsho Ketsueki 2000; 41: 103–108.

    CAS  PubMed  Google Scholar 

  12. Bearman SI, Shuhart MC, Hinds MS, McDonald GB . Recombinant human tissue plasminogen activator for the treatment of established severe venocclusive disease of the liver after bone marrow transplantation. Blood 1992; 80: 2458–2462.

    CAS  PubMed  Google Scholar 

  13. Nattakom TV, Charlton A, Wilmore DW . Use of vitamin E and glutamine in the successful treatment of severe veno-occlusive disease following bone marrow transplantation. Nutr Clin Pract 1995; 10: 16–18.

    Article  CAS  PubMed  Google Scholar 

  14. Teicher BA, Crawford JM, Holden SA, Lin Y, Cathcart KN, Luchette CA et al. Glutathione monoethyl ester can selectively protect liver from high dose BCNU or cyclophosphamide. Cancer 1988; 62: 1275–1281.

    Article  CAS  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. Shapira MY, Resnick IB, Bitan M, Ackerstein A, Samuel S, Elad S et al. Low transplant-related mortality with allogeneic stem cell transplantation in elderly patients. Bone Marrow Transplant 2004; 34: 155–159.

    Article  CAS  PubMed  Google Scholar 

  17. Schetelig J, Kroger N, Held TK, Thiede C, Krusch A, Zabelina T et al. Allogeneic transplantation after reduced conditioning in high risk patients is complicated by a high incidence of acute and chronic graft-versus-host disease. Haematologica 2002; 87: 299–305.

    PubMed  Google Scholar 

  18. Kroger N, Schetelig J, Zabelina T, Kruger W, Renges H, Stute N et al. A fludarabine-based dose-reduced conditioning regimen followed by allogeneic stem cell transplantation from related or unrelated donors in patients with myelodysplastic syndrome. Bone Marrow Transplant 2001; 28: 643–647.

    Article  CAS  PubMed  Google Scholar 

  19. de Lima M, Couriel D, Thall PF, Wang X, Madden T, Jones R et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood 2004; 104: 857–864. [E-pub 2004 Apr 8].

    Article  CAS  PubMed  Google Scholar 

  20. 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.

    Article  CAS  PubMed  Google Scholar 

  21. Attal M, Huguet F, Rubie H, Charlet JP, Schlaifer D, Huynh A et al. Prevention of regimen-related toxicities after bone marrow transplantation by pentoxifylline: a prospective, randomized trial. Blood 1993; 82: 732–736.

    CAS  PubMed  Google Scholar 

  22. 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: 975–981.

    Article  CAS  PubMed  Google Scholar 

  23. Cahn JY, Flesch M, Brion A, Deconinck E, Leconte Des Floris MF, Voillat L et al. Prevention of veno-occlusive disease of the liver after bone marrow transplantation: heparin or no heparin? Blood 1992; 80: 2149–2150.

    CAS  PubMed  Google Scholar 

  24. 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 

  25. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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.

    Article  CAS  PubMed  Google Scholar 

  27. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D et al. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA 2000; 283: 2008–2012.

    Article  CAS  PubMed  Google Scholar 

  28. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF . Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement: quality of reporting of meta-analyses. Lancet 1999; 354: 1896–1900.

    Article  CAS  PubMed  Google Scholar 

  29. McDonald GB, Sharma P, Matthews DE, Shulman HM, Thomas ED . The clinical course of 53 patients with venocclusive disease of the liver after marrow transplantation. Transplantation 1985; 39: 603–608.

    Article  CAS  PubMed  Google Scholar 

  30. Juni P, Altman DG, Egger M . Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ 2001; 323: 42–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M et al. The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. The Ottawa Health Research Institute: Ottawa, Canada. [2005 cited Jun 2]. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm.

  32. DerSimonian R, Laird N . Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–188.

    Article  CAS  PubMed  Google Scholar 

  33. Higgins JP, Thompson SG . Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539–1558.

    Article  PubMed  Google Scholar 

  34. Altman DG, Bland JM . Interaction revisited: the difference between two estimates. BMJ 2003; 326: 219.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Yannaki E, Batsis I, Kaloyannidis P, Smias C, Sakellari I, Georgoulis I et al. Fresh frozen plasma (FFP) during conditioning in addition to heparin, has a possible beneficial effect in veno-occlusive disease (VOD) prophylaxis [abstract #2613]. Blood 2003; 102: 706a.

    Google Scholar 

  36. Styler M, Crilley P, Topolsky D, Rubin S, Sabol P, King R et al. Low molecular weight heparin prophylaxis for veno-occlusive disease in unrelated marrow transplant recipients. Blood 1996; 88 (Suppl 1): 259B.

    Google Scholar 

  37. 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.

    Article  CAS  PubMed  Google Scholar 

  38. Rosenthal J, Sender L, Secola R, Killen R, Millerick M, Murphy L et al. Phase II trial of heparin prophylaxis for veno-occlusive disease of the liver in children undergoing bone marrow transplantation. Bone Marrow Transplant 1996; 18: 185–191.

    CAS  PubMed  Google Scholar 

  39. Marsa-Vila L, Gorin NC, Laporte JP, Labopin M, Dupuy-Montbrun MC, Fouillard L et al. Prophylactic heparin does not prevent liver veno-occlusive disease following autologous bone marrow transplantation. Eur J Haematol 1991; 47: 346–354.

    Article  CAS  PubMed  Google Scholar 

  40. Horn B, Reiss U, Matthay K, McMillan A, Cowan M . Veno-occlusive disease of the liver in children with solid tumors undergoing autologous hematopoietic progenitor cell transplantation: a high incidence in patients with neuroblastoma. Bone Marrow Transplant 2002; 29: 409–415.

    Article  CAS  PubMed  Google Scholar 

  41. Hagglund H, Remberger M, Klaesson S, Lonnqvist B, Ljungman P, Ringden O . Norethisterone treatment, a major risk-factor for veno-occlusive disease in the liver after allogeneic bone marrow transplantation. Blood 1998; 92: 4568–4572.

    CAS  PubMed  Google Scholar 

  42. Feldman L, Milovic V, Jaimovich G, Requejo A, Altclas J, Brioschi S . Prevention of hepatic veno-occlusive disease after bone marrow transplantation (BMT) by continuous infusion of low-dose heparin. Blood 1996; 88 (Suppl 1): 254B.

    Google Scholar 

  43. Carreras E, Bertz H, Arcese W, Vernant JP, Tomas JF, Hagglund H, et al., European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party. 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. Blood 1998; 92: 3599–3604.

    CAS  PubMed  Google Scholar 

  44. Reiss U, Cowan M, McMillan A, Horn B . Hepatic venoocclusive disease in blood and bone marrow transplantation in children and young adults: incidence, risk factors, and outcome in a cohort of 241 patients. J Pediatr Hematol Oncol 2002; 24: 746–750.

    Article  PubMed  Google Scholar 

  45. Cahn JY, Flesch M, Plouvier E, Herve P, Rozenbaum A . Venous occlusive disease of the liver and autologous bone marrow transplantation: preventive role for heparin? [French]. Nouv Rev Fr Hematol 1985; 27: 27–28.

    CAS  PubMed  Google Scholar 

  46. Demuynck H, Vandenberghe P, Verhoef GEG, Zachee P, Boogaerts MA . Prevention of veno-occlusive disease (VOD) of the liver after marrow and blood progenitor cell transplantation: a prospective, randomized study of different prophylactic regimens [abstract]. Blood 1995; 86 (Suppl 1): 620a.

    Google Scholar 

  47. 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 

  48. 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 

  49. Dulley FL, Kanfer EJ, Appelbaum FR, Amos D, Hill RS, Buckner CD et al. Venocclusive disease of the liver after chemoradiotherapy and autologous bone marrow transplantation. Transplantation 1987; 43: 870–873.

    Article  CAS  PubMed  Google Scholar 

  50. Carreras E, Granena A, Navasa M, Bruguera M, Marco V, Sierra J et al. On the reliability of clinical criteria for the diagnosis of hepatic veno-occlusive disease. Ann Hematol 1993; 66: 77–80.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We extend our thanks to the authors of the primary studies who responded to our queries5, 24, 25, 26, 35, 36, 37, 38, 40, 41, 42, 44 and we are indebted to those who provided us with additional data that were not available in their respective publications.26, 35, 36, 37, 42

Author information

Authors and Affiliations

  1. Division of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN, USA

    H Imran, V Rodriguez & S P Khan

  2. Division of Infectious Diseases, Mayo Clinic, Rochester, MN, USA

    I M Tleyjeh

  3. Division of General Internal Medicine, Mayo Clinic, Rochester, MN, USA

    A Zirakzadeh

Authors
  1. H Imran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I M Tleyjeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Zirakzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S P Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Imran.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Imran, H., Tleyjeh, I., Zirakzadeh, A. et al. Use of prophylactic anticoagulation and the risk of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation: a systematic review and meta-analysis. Bone Marrow Transplant 37, 677–686 (2006). https://doi.org/10.1038/sj.bmt.1705297

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705297

Keywords

This article is cited by

Search

Advanced search

Quick links