Sections

Veno-occlusive Hepatic Disease (Sinusoidal Obstruction Syndrome)

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

Medication

Medication Summary

In the United States, defibrotide is the only FDA-approved drug showing significant results for treating veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) compared with historical controls. The mechanism of action has not been fully elucidated, but defibrotide is thought to enhance the enzymatic activity of plasmin to hydrolyze fibrin clots. It elicits antithrombotic and fibrinolytic properties and may increase prostaglandin E2 and prostacyclin levels, alter platelet activity, and increase tissue plasminogen activator function while decreasing tissue plasminogen activator inhibitor activity.

Class Summary

Defibrotide is a single-stranded polydeoxyribonucleotide derived from porcine tissue that possesses antithrombotic, thrombolytic, anti-inflammatory, and anti-ischemic properties.

Defibrotide (Defitelio)

View full drug information

The mechanism of action has not been fully elucidated. It enhances the enzymatic activity of plasmin to hydrolyze fibrin clots. Studies evaluating the pharmacological effects of defibrotide on endothelial cells (ECs) were conducted primarily in the human microvascular endothelial cell line. In vitro, defibrotide increased tissue plasminogen activator (t-PA) and thrombomodulin expression and decreased von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) expression, thereby reducing EC activation and increasing EC-mediated fibrinolysis. It protects ECs from damage caused by chemotherapy, TNF-alpha, serum starvation, and perfusion.

It is indicated for adults and children with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem cell transplantation (HSCT).

Follow-up

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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].
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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].
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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].
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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) Medication

Medication Summary

Antifibrinolytic/Antithrombotic Agent

Class Summary

Defibrotide (Defitelio)

Defibrotide (Defitelio)

Veno-occlusive Hepatic Disease (Sinusoidal Obstruction Syndrome) Medication

Medication Summary

Antifibrinolytic/Antithrombotic Agent

Class Summary

Defibrotide (Defitelio)

Defibrotide (Defitelio)

References

Tables

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