Table 2.

Proposed downstream effects of defibrotide.

Downstream effects	Preclinical and clinical evidence
Effects on thrombo-fibrinolytic balance	• Inhibits thrombin-induced platelet aggregation, thromboxane biosynthesis, and fibrin clot formation [21] • Prevents increased expression of vWF [33, 34] • Reduces reactivity of the endothelial cell matrix toward platelets induced by exposure to GvHD serum [34] • Reduces LPS-induced tissue factor expression, tissue factor procoagulant activity, and tissue factor antigen in microvascular endothelial cells [40] • Stimulates thrombomodulin expression in macrovascular endothelial cells [42] • Enhances the activity of plasmin to degrade fibrin clots formed by fibrinogen, plasminogen, and thrombin [39] • Prevents LPS-induced increase in PAI-1 expression and enhanced LPS-induced increase in t-PA antigen expression, resulting in a net increase in fibrinolytic activation [40]
Reduction of cell adhesion	• Inhibits leukocyte adhesion by interfering with LFA-1/ICAM-mediated leukocyte transmigration in vitro [45] and by suppressing P-selectin in rats [46] • Stimulates the production of PGI2 and PGE2 [38] • Suppresses acute GvHD serum-induced expression of VCAM-1, ICAM-1, and vascular-endothelial cadherin [34] • Inhibits mononuclear cells and CD3+ T cells while downregulating expression of the adhesion molecules E-selectin, P-selectin, VCAM-1, and ICAM-1 [48] • Blocks the increased expression of ICAM-1 in patients undergoing autologous HCT [33]
Anti-inflammatory/antioxidant properties	• Decreases the release of inflammatory mediators (IL-6, thromboxane A2, LTB4, TNF, and ROS) [3, 26] • Decreases levels of the pro-inflammatory cytokines (IFNγ, TNF-α, IL-6, and IL-12) [48] • Increases levels of the anti-inflammatory mediators (TGFβ and IL-10) [48] • Maintains vascular tone by antagonizing the vasoconstrictor activity of endothelin 1 and enhancing the production of NO and NOS [3]
Endothelial cell protection and anti-apoptotic effects	• Protects endothelial and epithelial cells from F-Ara–induced apoptosis [41] • Inhibit the activity and cell surface expression of heparanase, VEGF, ICAM-1, and E-selectin in multiple myeloma and mesothelioma cells [49]
Anti-angiogenic effects	• Binds and mobilizes bFGF, while protecting it from oxidative and protease degradation and potentiating its binding to FGFR1-IIIc [53] • Inhibits formation of new blood vessels and reduces tumor microvascular density [35] • Reduces acute GvHD-induced expression of VE-cadherin and suppresses endothelial cell proliferation and endothelial cell tube formation [34]

vWF von Willebrand factor, HCT hematopoietic cell transplantation, GvHD graft-versus-host disease, LPS lipopolysaccharide, PAI-1 plasminogen activator inhibitor-1, t-PA tissue plasminogen activator, LFA-1 lymphocyte function-associated antigen-1, ICAM intercellular adhesion molecule, PGI₂ prostaglandin I2, PGE₂ prostaglandin E2, VCAM vascular cell adhesion molecule, IL interleukin, LTB4 leukotriene B4, TNF tumor necrosis factor, ROS reactive oxygen species, IFNγ interferon-γ, TGFβ transforming growth factor-β, NO nitric oxide, NOS nitric oxide synthase, VEGF vascular endothelial growth factor, bFGF basic fibroblast growth factor, FGFR fibroblast growth factor receptor.