Diagnostic Considerations

Two conflicting definitions of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), the Seattle criteria and the Baltimore criteria, have been in use since the 1980s. These criteria predict VOD/SOS with an accuracy of more than 90% but have a relatively low sensitivity of 56%.^[27]

According to the modified Seattle criteria, 2 or more of the following must be present prior to 20 days after hematopoietic stem cell transplantation (HSCT) for a diagnosis of VOD/SOS:

Bilirubin level of more than 2 mg/dL (34 µmol/L)
Hepatomegaly and upper right quadrant pain of liver origin
Ascites and/or unexplained weight gain of more than 2% above the reference range

According to the Baltimore criteria, hyperbilirubinemia (≥2 mg/dL) and 2 or more of the following must be present prior to 21 days after HSCT:

Hepatomegaly (usually painful)
Ascites
Weight gain of more than 5% above the reference range

More recently, the European Society for Blood and Marrow Transplantation (EBMT) has proposed new diagnostic criteria for VOD/SOS, with separate criteria for pediatric and adult patients.^{[20, 28]}For hepatic VOD/SOS in children, the EBMT includes no limitation for time of onset after HSCT.^[28]Diagnosis requires the presence of two or more of the following:

Unexplained consumptive and transfusion-refractory thrombocytopenia
Otherwise unexplained weight gain on 3 consecutive days despite the use of diuretics or a weight gain > 5% above baseline value
Hepatomegaly above baseline value
Ascites above baseline value
Rising bilirubin from a baseline value on 3 consecutive days or bilirubin increase of ≥2 mg/dL within 72 h

The EBMT advises that hepatomegaly and ascites values are best confirmed by imaging. To determine baseline imaging values, the EBMT recommends performing ultrasonography, computed tomography, or magnetic resonance imaging immediately before HSCT.

For VOD/SOS in adult patients, the EBMT proposed separate criteria for classical and late-onset cases. For classical VOD/SOS in the first 21 days after HSCT, the criteria are bilirubin ≥2 mg/dL and two of the following:

Painful hepatomegaly
Weight gain > 5%
Ascites

For late-onset VOD/SOS in adults developing beyond 21 days after HSCT, the EBMT diagnostic criteria are as follows^[20]:

Presence of the classical VOD/SOS criteria or
Histologically proven SOS/VOD or
Two or more of the following: Bilirubin ≥2 mg/dL (34 μmol/L), painful hepatomegaly, weight gain > 5%, ascites and
Hemodynamic and/or ultrasonographic evidence of VOD/SOS

Differential Diagnoses

Antithrombin III Deficiency
Budd-Chiari Syndrome
Cholestasis
Gastrointestinal Bleeding: Surgical Perspective
Heart Failure, Congestive
Hematopoietic Stem Cell Transplantation (HSCT)
Hospital-Acquired Infections
Hypoprothrombinemia
Long-Term Effects of Bone Marrow Transplantation
Oncologic Emergencies
Pediatric Aspergillosis
Pediatric Biliary Atresia
Pediatric Cholecystitis
Pediatric Cytomegalovirus Infection
Pediatric Enteroviral Infections
Pediatric Gallstones (Cholelithiasis)
Pediatric Gastroenteritis
Pediatric Graft Versus Host Disease
Pediatric Hepatitis A
Pediatric Hepatitis B
Pediatric Hepatitis C
Pediatric Hepatorenal Syndrome
Pediatric Mononucleosis and Epstein-Barr Virus Infection
Pediatric Sepsis
Pediatric Surgery for Ascites
Pediatric Thromboembolism
Vasculitis and Thrombophlebitis

Workup

Barker CC, Butzner JD, Anderson RA, Brant R, Sauve RS. Incidence, survival and risk factors for the development of veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2003 Jul. 32(1):79-87. [QxMD MEDLINE Link].
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 Dec. 24(9):746-50. [QxMD MEDLINE Link].
Cesaro S, Pillon M, Talenti E, 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 Oct. 90(10):1396-404. [QxMD MEDLINE Link]. [Full Text].
Corbacioglu S, Honig M, Lahr G, 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 Oct. 38(8):547-53. [QxMD MEDLINE Link].
Coppell JA, Brown SA, Perry DJ. Veno-occlusive disease: cytokines, genetics, and haemostasis. Blood Rev. 2003 Jun. 17(2):63-70. [QxMD MEDLINE Link].
Jones RJ, Lee KS, Beschorner WE, et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation. 1987 Dec. 44(6):778-83. [QxMD MEDLINE Link].
Carreras E, Bertz H, Arcese W, 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 Nov 15. 92(10):3599-604. [QxMD MEDLINE Link]. [Full Text].
Cecen E, Uysal KM, Ozguven A, Gunes D, Irken G, Olgun N. Veno-occlusive disease in a child with rhabdomyosarcoma after conventional chemotherapy: report of a case and review of the literature. Pediatr Hematol Oncol. 2007 Dec. 24(8):615-21. [QxMD MEDLINE Link].
Cesaro S, Spiller M, Sartori MT, Alaggio R, Peruzzo M, Saggiorato G, et al. Veno-occlusive disease in pediatric patients affected by Wilms tumor. Pediatr Blood Cancer. 2011 Aug. 57(2):258-61. [QxMD MEDLINE Link].
Miyata D, Fukushima T, Matsunaga M, Saito N, Kato Y, Takahashi-Igari M, et al. Fatal pulmonary veno-occlusive disease after chemotherapy for Burkitt's lymphoma. Pediatr Int. 2011 Jun. 53(3):403-5. [QxMD MEDLINE Link].
Shulman HM, Gown AM, Nugent DJ. Hepatic veno-occlusive disease after bone marrow transplantation. Immunohistochemical identification of the material within occluded central venules. Am J Pathol. 1987 Jun. 127(3):549-58. [QxMD MEDLINE Link]. [Full Text].
DeLeve LD, Shulman HM, McDonald GB. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis. 2002 Feb. 22(1):27-42. [QxMD MEDLINE Link].
Pihusch M, Wegner H, Goehring P, et al. Diagnosis of hepatic veno-occlusive disease by plasminogen activator inhibitor-1 plasma antigen levels: a prospective analysis in 350 allogeneic hematopoietic stem cell recipients. Transplantation. 2005 Nov 27. 80(10):1376-82. [QxMD MEDLINE Link].
Matsumoto M, Kawa K, Uemura M, Kato S, Ishizashi H, Isonishi A, et al. Prophylactic fresh frozen plasma may prevent development of hepatic VOD after stem cell transplantation via ADAMTS13-mediated restoration of von Willebrand factor plasma levels. Bone Marrow Transplant. 2007 Aug. 40(3):251-9. [QxMD MEDLINE Link].
Bazarbachi AH, Al Hamed R, Labopin M, et al. Underdiagnosed veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) as a major cause of multi-organ failure in acute leukemia transplant patients: an analysis from the EBMT Acute Leukemia Working Party. Bone Marrow Transplant. 2021 Apr. 56 (4):917-927. [QxMD MEDLINE Link]. [Full Text].
McDonald GB, Hinds MS, Fisher LD, 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 Feb 15. 118(4):255-67. [QxMD MEDLINE Link].
Strouse C, Zhang Y, Zhang MJ, DiGilio A, Pasquini M, Horowitz MM, et al. Risk Score for the Development of Veno-Occlusive Disease after Allogeneic Hematopoietic Cell Transplant. Biol Blood Marrow Transplant. 2018 Oct. 24 (10):2072-2080. [QxMD MEDLINE Link]. [Full Text].
Hasegawa S, Horibe K, Kawabe T, et al. Veno-occlusive disease of the liver after allogeneic bone marrow transplantation in children with hematologic malignancies: incidence, onset time and risk factors. Bone Marrow Transplant. 1998 Dec. 22(12):1191-7. [QxMD MEDLINE Link].
Corbacioglu S, Greil J, Peters C, 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 Jan. 33(2):189-95. [QxMD MEDLINE Link].
Mohty M, Malard F, Abecassis M, et al. Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2016 Jul. 51 (7):906-12. [QxMD MEDLINE Link]. [Full Text].
Yeager AM, Wagner JE Jr, Graham ML, et al. Optimization of busulfan dosage in children undergoing bone marrow transplantation: a pharmacokinetic study of dose escalation. Blood. 1992 Nov 1. 80(9):2425-8. [QxMD MEDLINE Link]. [Full Text].
Dix SP, Wingard JR, Mullins RE, et al. Association of busulfan area under the curve with veno-occlusive disease following BMT. Bone Marrow Transplant. 1996 Feb. 17(2):225-30. [QxMD MEDLINE Link].
Slattery JT, Clift RA, Buckner CD, et al. Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation. Blood. 1997 Apr 15. 89(8):3055-60. [QxMD MEDLINE Link]. [Full Text].
Lee JH, Choi SJ, Lee JH. 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 May. 84(5):321-30. [QxMD MEDLINE Link].
Nagler A, Labopin M, Berger R, Bunjes D, Campos A, Socié G, et al. Allogeneic hematopoietic SCT for adults AML using i.v. BU in the conditioning regimen: outcomes and risk factors for the occurrence of hepatic sinusoidal obstructive syndrome. Bone Marrow Transplant. 2014 May. 49(5):628-33. [QxMD MEDLINE Link].
Elbahlawan L, McArthur J, Quasney MW, Pei D, Srivastava K, Dahmer MK, et al. Association of IL-1ß -511 Polymorphism With Severe Veno-occlusive Disease in Pediatric-matched Allogeneic Hematopoietic Stem Cell Transplantation. J Pediatr Hematol Oncol. 2012 Apr. 34(3):175-9. [QxMD MEDLINE Link].
Carreras E, Granena A, Navasa M, et al. On the reliability of clinical criteria for the diagnosis of hepatic veno-occlusive disease. Ann Hematol. 1993 Feb. 66(2):77-80. [QxMD MEDLINE Link].
Corbacioglu S, Carreras E, Ansari M, et al. Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European society for blood and marrow transplantation. Bone Marrow Transplant. 2018 Feb. 53 (2):138-145. [QxMD MEDLINE Link]. [Full Text].
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 Jan 1. 107(1):132-4. [QxMD MEDLINE Link]. [Full Text].
Richardson PG, Elias AD, Krishnan A, 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 Aug 1. 92(3):737-44. [QxMD MEDLINE Link]. [Full Text].
Jiang S, Penack O, Terzer T, Schult D, Majer-Lauterbach J, Radujkovic A, et al. Predicting sinusoidal obstruction syndrome after allogeneic stem cell transplantation with the EASIX biomarker panel. Haematologica. 2021 Feb 1. 106 (2):446-453. [QxMD MEDLINE Link]. [Full Text].
Yakushijin K, Okamura A, Ono K, et al. [Defibrotide therapy for patients with sinusoidal obstruction syndrome after hematopoietic stem cell transplantation]. Rinsho Ketsueki. 2009 Jan. 50(1):3-8. [QxMD MEDLINE Link].
Guglielmelli T, Bringhen S, Palumbo A. Update on the use of defibrotide. Expert Opin Biol Ther. 2012 Mar. 12(3):353-61. [QxMD MEDLINE Link].
Richardson PG, Soiffer RJ, Antin JH, Uno H, Jin Z, Kurtzberg J, et al. Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial. Biol Blood Marrow Transplant. 2010 Jul. 16(7):1005-17. [QxMD MEDLINE Link]. [Full Text].
Richardson PG, Riches ML, Kernan NA, Brochstein JA, Mineishi S, Termuhlen AM, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016 Jan 29. [QxMD MEDLINE Link]. [Full Text].
Kulkarni S, Rodriguez M, Lafuente A, et al. Recombinant tissue plasminogen activator (rtPA) for the treatment of hepatic veno-occlusive disease (VOD). Bone Marrow Transplant. 1999 Apr. 23(8):803-7. [QxMD MEDLINE Link].
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 Mar 1. 89(5):1501-6. [QxMD MEDLINE Link]. [Full Text].
Bajwa RP, Cant AJ, Abinun M, et al. Recombinant tissue plasminogen activator for treatment of hepatic veno-occlusive disease following bone marrow transplantation in children: effectiveness and a scoring system for initiating treatment. Bone Marrow Transplant. 2003 Apr. 31(7):591-7. [QxMD MEDLINE Link].
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 Jun. 5(6):439-41. [QxMD MEDLINE Link].
Bearman SI, Hinds MS, Wolford JL, 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 Jun. 5(6):407-11. [QxMD MEDLINE Link].
Attal M, Huguet F, Rubie H, 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 Jun 1. 79(11):2834-40. [QxMD MEDLINE Link]. [Full Text].
Rosenthal J, Sender L, Secola R, 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 Jul. 18(1):185-91. [QxMD MEDLINE Link].
Song JS, Seo JJ, Moon HN, Ghim T, Im HJ. Prophylactic low-dose heparin or prostaglandin E1 may prevent severe veno-occlusive disease of the liver after allogeneic hematopoietic stem cell transplantation in Korean children. J Korean Med Sci. 2006 Oct. 21(5):897-903. [QxMD MEDLINE Link]. [Full Text].
Chueh HW, Sung KW, Lee SH, Yoo KH, Koo HH, Kim JY, et al. Iron chelation treatment with deferasirox prior to high-dose chemotherapy and autologous stem cell transplantation may reduce the risk of hepatic veno-occlusive disease in children with high-risk solid tumors. Pediatr Blood Cancer. 2012 Mar. 58(3):441-7. [QxMD MEDLINE Link].
Corbacioglu S, Cesaro S, Faraci M, et al. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet. 2012 Apr 7. 379 (9823):1301-9. [QxMD MEDLINE Link].
Park SH, Lee MH, Lee H, 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 Jan. 29(2):137-43. [QxMD MEDLINE Link].
Cheuk DK, Chiang AK, Ha SY, Chan GC. Interventions for prophylaxis of hepatic veno-occlusive disease in people undergoing haematopoietic stem cell transplantation. Cochrane Database Syst Rev. 2015 May 27. 5:CD009311. [QxMD MEDLINE Link].

Media Gallery

of 0

Author

James L Harper, MD Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Associate Clinical Professor, Department of Pediatrics, Creighton University School of Medicine; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center

James L Harper, MD is a member of the following medical societies: American Society of Pediatric Hematology/Oncology, American Federation for Clinical Research, Council on Medical Student Education in Pediatrics, Hemophilia and Thrombosis Research Society, American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology

Disclosure: Nothing to disclose.

Coauthor(s)

Selim Corbacioglu, MD Professor of Pediatrics, Chair of Pediatric Hematology, Oncology and Stem Cell Transplantation, Children's Hospital Regensburg, University of Regensburg, Germany

Selim Corbacioglu, MD is a member of the following medical societies: American Association for Cancer Research, American Society of Hematology, European Hematology Association, European Society for Blood and Marrow Transplantation

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Steven K Bergstrom, MD Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland

Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, Children's Oncology Group, American Society of Clinical Oncology, International Society for Experimental Hematology, American Society of Hematology, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Chief Editor

Jennifer Reikes Willert, MD Associate Clinical Professor, Department of Pediatrics, Division of Pediatric Hematology/Oncology, Section of Stem Cell Transplantation, Stanford University Medical Center, Lucile Packard Children's Hospital

Jennifer Reikes Willert, MD is a member of the following medical societies: American Academy of Pediatrics, American Society for Blood and Marrow Transplantation, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group

Disclosure: Nothing to disclose.

Additional Contributors

Stephan A Grupp, MD, PhD Director, Stem Cell Biology Program, Department of Pediatrics, Division of Oncology, Children's Hospital of Philadelphia; Associate Professor of Pediatrics, University of Pennsylvania School of Medicine

Stephan A Grupp, MD, PhD is a member of the following medical societies: American Association for Cancer Research, Society for Pediatric Research, American Society for Blood and Marrow Transplantation, American Society of Hematology, American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Sections Veno-occlusive Hepatic Disease (Sinusoidal Obstruction Syndrome)
Overview
Presentation
DDx
Workup
Treatment
Medication
Follow-up
Tables
References

Criteria	Mild	Moderate	Severe	Very Severe (Multi-Organ Dysfunction/Failure)
Time since first clinical manifestations	> 7 days	5-7 days	≤4 days	Any time
Bilirubin	2 to < 3 mg/dL 34 to < 51 μmol/L	3 to < 5 mg/dL 51 to < 85 μmol/L	5 to < 8 mg/dL 85 to < 136 μmol/L or doubling of bilirubin within 48 hr	≥8 mg/dL ≥136 μmol/L
Transaminases	≤2 x normal	> 2 to 5 x normal	> 5 to 8 x normal	> 8 x normal
Weight increase	< 5%	5% to < 10%	5% to < 10%	≥10%
Kidney function	< 1.2 x baseline	1.2 to < 1.5 x baseline at transplant	1.5 to < 2 x baseline at transplant	≥2 x baseline at transplant or other signs of multi-organ dysfunction/failure

Veno-occlusive Hepatic Disease (Sinusoidal Obstruction Syndrome) Differential Diagnoses

Diagnostic Considerations

Differential Diagnoses

References

Tables

Contributor Information and Disclosures

What would you like to print?