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VOD is a complex cascade of events that can ultimately lead to death1-13

An in-depth look at the complex pathogenesis of VOD

VOD is a post-HSCT complication thought to be a consequence of conditioning regimen–induced damage to sinusoidal endothelial cells.4-6 This video provides an in-depth look at the pathogenesis of VOD

Video Transcript


VOD, also known as sinusoidal obstruction syndrome, is a potentially life-threatening complication of hematopoietic stem-cell transplantation and, in severe cases, is associated with a mortality rate of over 80%.

The pathophysiology of VOD is complex, involving both endothelial cell damage and development of a prothrombotic and hypofibrinolytic state.

It is thought that the initial trigger for the development of VOD is the damage to hepatocytes and activation of sinusoidal endothelial cells in the liver. This is caused by toxic metabolites generated during the conditioning regimen used prior to transplantation.

This endothelial cell injury leads to the expression of adhesion molecules and the release of cytokines and chemokines, which trigger inflammatory pathways that further damage the endothelium.

Activated endothelial cells also release heparanase, which breaks down the extracellular matrix resulting in the loss of cytoskeletal architecture.

Activated endothelial cells begin to round up and gaps form in the endothelial lining.

Red blood cells, leukocytes, and cellular debris pass through these gaps and accumulate in the space of Disse, leading to narrowing of the sinusoid.

The endothelial cells dissect off and embolize downstream, resulting in blockage of the sinusoid and ultimately to reduced hepatic venous outflow.

VOD is also characterized by a prothrombotic and hypofibrinolytic state, in which an increase in tissue factor and plasminogen activator inhibitor 1 contributes to increased fibrin deposition and clot formation. This eventually leads to obstruction of the sinusoids.

VOD can progress from endothelial cell damage to multi-organ dysfunction and death1-13

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Buildup of toxic metabolites from the conditioning regimen4-6

Endothelial cell damage
  • Expression of cytokines and adhesion molecules is triggered by endothelial cell activation
  • Activation of inflammatory pathways causes additional endothelial damage
  • Extracellular matrix degradation and disruption of cytoskeletal structure lead to the formation of gaps in the endothelium
Sinusoidal narrowing
  • Red blood cells, leukocytes, and cellular debris accumulate in the space of Disse
  • Endothelial cells dissect and embolize downstream
Sinusoidal blockage
  • Expression of factors that regulate coagulation and fibrinolysis contributes to a prothrombotic and hypofibrinolytic state
  • Fibrin deposition, clot formation, and sinusoidal narrowing lead to further sinusoidal obstruction
  • Hepatocyte cell death may occur
The cascade of events appears to start before clear pathological and clinical manifestations are evident5,6

Clinical signs and symptoms3,4,12

  • Weight gain
  • Hepatomegaly
  • Right upper quadrant pain
  • Elevated bilirubin (>2 mg/dL)
  • Elevated serum transaminase and alkaline phosphatase
  • Ascites
Cascade of Events Block: Desktop Cascade of Events Block: Mobile
  1. Based on a study conducted by Carreras et al that used 2 sets of diagnostic criteria to estimate the incidence of VOD after HSCT.
  2. Based on 19 studies from a meta-analysis of 135 studies.

HSCT=hematopoietic stem-cell transplantation; VOD=veno-occlusive disease (also known as sinusoidal obstruction syndrome, or SOS).

References: 1. Coppell JA, Richardson PG, Soiffer R, et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant. 2010;16(2):157-168. 2. Carreras E, Díaz-Beyá M, Rosiñol L, et al. The incidence of veno-occlusive disease following allogeneic hematopoietic stem cell transplantation has diminished and the outcome improved over the last decade. Biol Blood Marrow Transplant. 2011;17(11):1713-1720. 3. 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;118(4):255-267. 4. Carreras E. Early complications after HSCT. In: Apperley J, Carreras E, Gluckman E, et al, eds. The EBMT Handbook. 6th ed. Paris, France: European School of Haematology; 2012:176-195. 5. Richardson PG, Ho VT, Cutler C, et al. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: novel insights to pathogenesis, current status of treatment, and future directions. Biol Blood Marrow Transplant. 2013;19(suppl 1):S88-S90. 6. Richardson PG, Corbacioglu S, Ho VT, et al. Exper Opin Drug Saf. 2013;12(1):123-136. 7. Vion AC, Rautou PE, Durand F, et al. Interplay of inflammation and endothelial dysfunction in bone marrow transplantation: focus on hepatic veno-occlusive disease. Semin Thromb Hemost. 2015;41(6):629-643. 8. Coppell JA, Brown SA, Perry DJ. Veno-occlusive disease: cytokines, genetics, and haemostasis. Blood Rev. 2003;17(2):63-70. 9. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995;85(11):3005-3020. 10. 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;51(7):906-912. 11. 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;53(2): 138-145. 12. Bayraktar UD, Seren S, Bayraktar Y. Hepatic venous outflow obstruction: three similar syndromes. World J Gastroenterol. 2007;13(13):1912-1927. 13. Ng CK, Chan MH, Tai MH, et al. Hepatorenal syndrome. Clin Biochem Rev. 2007;28(1):11-17.