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Pathogenesis and Symptoms

VOD/SOS is a complex cascade of events that can ultimately lead to death1-4

An in-depth look at the complex pathogenesis of VOD/SOS

VOD/SOS is a post-HSCT complication primarily associated with conditioning regimens that affects the endothelial cells within the sinusoids of the liver1,5

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/SOS can progress from endothelial cell damage to multi-organ dysfunction and death1-4

Based on experimental models, buildup of toxic metabolites from conditioning regimens may trigger damage to sinusoidal endothelium1-4

Endothelial cell damage
  • Activation of pro-inflammatory mediators may lead to sinusoidal endothelial cell damage3,4
  • Heparanase contributes to degradation of the extracellular matrix and gap formation between sinusoidal endothelial cells2,4
  • Degradation of the extracellular matrix leads to detachment of endothelial cells from the sinusoidal lining6,7
Sinusoidal narrowing
  • Red blood cells, leukocytes, and cellular debris accumulate in the space of Disse2-4
  • This can lead to sinusoidal narrowing and dissection of endothelial cells, which may embolize downstream and contribute to sinusoidal blockage2-4
Sinusoidal blockage
  • Expression of factors that regulate coagulation and fibrinolysis contributes to a procoagulant and hypofibrinolytic state1,3,4
  • Fibrin deposition, clot formation, and embolization of dissected endothelial cells can cause blockage1,3,4
  • Hepatocyte cell death is a consequence of sinusoidal disruption2,3,5
  • May lead to a reduction in hepatic venous outflow and to post-sinusoidal hypertension2-4
The cascade of events appears to start before clear clinical and laboratory manifestations are evident3,4,8

Most common signs and symptoms2,8,11

  • Weight gain due to fluid retention
  • Hepatomegaly
  • Right upper quadrant pain
  • Elevated bilirubin
  • Elevated serum transaminase and alkaline phosphatase
  • Ascites
  • Excessive platelet transfusions consistent with refractory thrombocytopenia

As liver dysfunction worsens, patients with VOD/SOS are at risk of other complications1-4,6,8-10

Severe liver dysfunction can be the result of the cascade of events in VOD/SOS1-4,6,8-10

 

Endothelial damage

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Sinusoidal narrowing

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Sinusoidal blockage

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Reduction of hepatic venous outflow

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Post-sinusoidal portal hypertension

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Multi-organ dysfunction

Not all patients progress to multi-organ dysfunction and death

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Death

Most common signs and symptoms2,8,11

  • Weight gain due to fluid retention
  • Hepatomegaly
  • Right upper quadrant pain
  • Elevated bilirubin
  • Elevated serum transaminase and alkaline phosphatase
  • Ascites
  • Excessive platelet transfusions consistent with refractory thrombocytopenia
As liver dysfunction worsens, patients with VOD/SOS are at risk of other complications1-4,6,8-10
Approximately 30% to 50% of cases developed multi-organ dysfunction12,a 84% overall mortality in VOD/SOS with multi-organ dysfunction1,b 
Understand the diagnostic criteria for VOD/SOS 
  1. Based on a study conducted by Carreras et al that used 2 sets of diagnostic criteria to estimate the incidence of VOD/SOS after HSCT.12
  2. Based on 19 studies (235 patients) that specifically determined mortality from severe VOD/SOS, as reported within a meta-analysis of 135 studies performed between 1979 and 2007.1

HSCT=hematopoietic stem-cell transplantation; SOS=sinusoidal obstruction syndrome; VOD=veno-occlusive disease.

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. 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. 3. 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. 4. Richardson PG, Corbacioglu S, Ho VT, et al. Expert Opin Drug Saf. 2013;12(1):123-136. 5. Carreras E. How I manage sinusoidal obstruction syndrome after haematopoietic cell transplantation. Br J Haematol. 2015;168(4):481-491. 6. 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. 7. DeLeve LD, Shulman HM, McDonald GB. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis. 2002;22(1):27-41. 8. Cairo MS, Cooke KR, Lazarus HM, et al. Modified diagnostic criteria, grading classification and newly elucidated pathophysiology of hepatitis SOS/VOD after haematopoietic cell transplantation. Br J Haematol. 2020;190(6):822-836. 9. Coppell JA, Brown SA, Perry DJ. Veno-occlusive disease: cytokines, genetics, and haemostasis. Blood Rev. 2003;17(2):63-70. 10. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995;85(11):3005-3020. 11. Carreras E. How I manage sinusoidal obstruction syndrome after haematopoietic cell transplantation. Br J Haematol. 2015;168(4):481-491. 12. 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.