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
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
- 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
- Red blood cells, leukocytes, and cellular debris accumulate in the space of Disse
- Endothelial cells dissect and embolize downstream
- 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