English - European Group for Blood and Marrow Transplantation

Report
Module 2
Pathophysiology of
veno-occlusive disease
Learning objectives
• To understand the cause of VOD
• To understand the sequence of steps in the
pathophysiology of VOD
• To recognise the pathophysiological
endpoint of VOD
VOD, veno-occlusive disease
Early complications of HSCT:
vascular endothelial syndromes
• It is proposed that during HSCT, endothelial cells lining blood
vessels are activated by:
–
–
–
–
The conditioning regimen
Cytokines produced by injured tissues
Microbial products translocated through mucosal barriers
The process of engraftment
• Intense and sustained activation of endothelial cells leads to
cellular damage
• Alloreactivity has been postulated to play a role in this
damage and activation
– This explains the greater incidence of these complications after
allogeneic transplantation
Carreras E & Diaz-Ricart M. Bone Marrow Transplant 2011;46:1495–1502
Early complications of HSCT:
vascular endothelial syndromes
Multi-organ dysfunction syndrome
DAH
ES
IPS
VOD
TAM
TAM
CLS
ES
TAM
Organ
dysfunction
Endothelial
dysfunction
(pathologic)
Endothelial
activation
(physiologic)
Conditioning
Endothelial phenotype represents a net liability to the host
(capillary flow obstruction, fibrin-related aggregates,
platelet and leukocyte adhesion, endothelial apoptosis)
Pro-coagulant
status
G-CSF
CNI
Inflammatory
response
LPS/infections
Increased
permeability
Engraftment
Vasoconstriction
Alloreactivity
Haematopoietic stem cell transplantation
CNI, calcineurin inhibitors; CLS, capillary leak syndrome; DAH, diffuse alveolar haemorrhage; ES, engraftment syndrome; GCSF, granulocyte-colony
stimulating factor; HSCT; haematopoietic stem cell transplantation; IPS, idiopathic pneumonia syndrome; LPS, lipopolysaccharide; TAM, transplantassociated microangiopathy; VOD, veno-occlusive disease
Carreras E & Diaz-Ricart M. Bone Marrow Transplant 2011;46:1495–1502
Veno-occlusive disease
• VOD, also known as sinusoidal obstruction
syndrome, is a potentially life-threatening
complication of HSCT
• The conditioning regimens given before HSCT
result in the production of toxic metabolites by
the hepatocytes in the liver
• These metabolites trigger the activation,
damage and inflammation of the endothelial
cells that line the sinusoids
– Sinusoids are small capillary-like blood vessels
found in the liver
• This ultimately leads to VOD, which is
characterised by
– Increased thrombosis and decreased fibrinolysis
– Sinusoidal damage and narrowing
– Inflammation
Richardson PG et al. Expert Opin Drug Saf 2013;12:123–136
Histological section of the liver viewed through
a microscope. Blood vessels shown in red,
cell nuclei in blue, cytoplasm in pink
Cell toxicity resulting from chemotherapy damages
the lining of the liver sinusoids
Red blood cells
Toxic metabolites
Sinusoidal
endothelial cells
Platelets
Toxic metabolites resulting from the HSCT conditioning regimen
damage and activate the sinusoidal endothelial cells
Richardson PG et al. Expert Opin Drug Saf 2013;12:123–136
Activation of sinusoidal endothelial cells can trigger
multiple pathways, resulting in inflammation and
narrowing of the sinusoids
Red blood cells
Cytokines
Cytokines
Sinusoidal
endothelial cells
Heparanase
Adhesion
molecules
Platelets
The accumulation of cells and debris in the space of Disse, the perisinusoidal space
located between the endothelium and the hepatocyte, lead to narrowing of the sinusoids
Richardson PG et al. Expert Opin Drug Saf 2013;12:123–136
VOD is characterised by increased clot formation
and reduced clot breakdown
Red blood cells
Cytokines
Fibrin
Heparanase
Adhesion molecules
Tissue factor
PAI-1
Platelets
The narrowing of the sinusoids, embolised endothelial cells and increased clot
formation lead to the endpoint of VOD, namely obstruction of the sinusoids
PAI-1,plasminogen activator inhibitor-1; TF, tissue factor
Richardson PG et al. Expert Opin Drug Saf 2013;12:123–136
Pathophysiology of VOD
Endothelial cell and hepatocyte
damage
•
Activation and damage due to
conditioning regimen-mediated
injury. Damage is both directed and
mediated by cytokines such as:
- TNF-α, IL-1b, IL-6
•
Triggering of multiple pathways
Sinusoidal narrowing
•
Increased expression of adhesion
molecules ICAM-1 and VCAM-1 of
endothelial cell surface
Activation of leukocytes that release
additional inflammatory cytokines
Digestion of extracellular matrix
VOD
•
•
Portal vein hypotension
Hepatic venous outflow obstruction
Inflammation
Cytoskeletal structure
•
ICAM, intracellular adhesion molecule; IL, interleukin; TNF, tumour necrosis factor; VCAM, vascular cell adhesion protein
Richardson PG et al. Expert Opin Drug Saf 2013;12:123–136; Coppell JA et al. Blood Rev 2003;17:63–70
Summary of VOD pathophysiology
• The conditioning regimen given prior to HSCT
increases endothelial cell activation, resulting in
damage to the SECs and hepatocytes
• The accumulation of cells in the space of Disse
(the perisinusoidal space), increased
inflammation and formation of clots lead to
narrowing of the sinusoids
• This results in VOD, which is characterised by
blockage of the sinusoids, portal vein
hypotension and reduced hepatic venous outflow
SEC, sinusoidal endothelial cell
Self-assessment questions
1. VOD affects which major organ?
Self-assessment questions
2. What by-product of HSCT conditioning causes damage to
the sinusoidal endothelial cells and hepatocytes?
Self-assessment questions
3. Which of the following is not a characteristic of
VOD pathophysiology?
a) Increased clot formation
b) Decreased clot breakdown
c) Expansion of the sinusoids
d) Inflammation
Self-assessment questions
4. What causes obstruction of the sinusoids?

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