Defibrotide^®Reduces Monocyte PAI-2 and Procoagulant Activity

Abstract

Defibrotide is a polydeoxyribonucleotide-derived anti-ischemic drug with multiple sites of action involving both plasmatic and cellular targets. This agent has been demonstrated to produce profibrinolytic, cytoprotective, and vaso-facilatory actions. Since monocytes are increased in the mediation of some of the pathophysiologic responses seen in ischemic disorders, the functional properties of these cells were investigated in experimental conditions to evaluate their behavior during resting and stimulated states. Defibrotide was supplemented in these systems to determine its modulatory action. In this investigation Defibrotide was found to decrease the PAI-1 levels and may indicate that this may be the mechanism for its profibrinolytic actions. Defibrotide was also found to reduce the procoagulant activity of monocytes in these experimental settings. Both PAI and procoagulant factors play an important role in the pathophysiology of inflammation, DIC, and ischemia. Defibrotide induced reduction of these two factors represents the mechanism whereby this agent produces its therapeutic action.

Review article: updates in the pathogenesis and therapy of hepatic sinusoidal obstruction syndrome

“…Therefore, it has been used in the treatment of many vascular diseases, and is a promising treatment of HSOS. The suggested mechanisms of action of DT include: (i) stimulation of endothelial‐cell release of t‐PA; (ii) up‐regulation of the release of nitric oxide, prostacyclin (PG I2), prostaglandin E2, thrombomodulin and t‐PA both in vitro and in vivo ; (iii) decreased release of plasminogen activator inhibitor‐1; and (iv) stimulation of the adenosine receptor 145–152 . Moreover, DT has been shown to decrease thrombin generation, tissue factor expression and endothelin activity 153–157 …”

Defibrotide reduces procoagulant activity and increases fibrinolytic properties of endothelial cells

“…Only one study has shown an increase of fibrinolytic activity by HUVEC alone, as measured by the shortening of the euglobulin lysis time, a test measuring the overall fibrinolytic activity. 18 Other in vitro studies have focused on DF effects on platelet and leukocyte hemostatic properties, [34][35][36][37] or on thrombomodulin expression by HUVEC. 19 This is the first report on the impact of DF in vitro on endothelial procoagulant (TF) and fibrinolytic proteins (PAI-1 and t-PA).…”

Treatment of nonproliferative diabetic retinopathy with Defibrotide in noninsulindependent diabetes mellitus, A pilot study

“…DEF, thanks to its multiple-sites activity, seems to be an ideal drug. Particularly, it acts on: endothelial cells (stimulation, production and balance of PGI 2 , PGE 2 and thrombomodulin; stimulation and release of tPA; inhibition of PAI; modulation of Endothelin-1 release); platelets (reduced adhesion and aggregation due to AMPc increase; reduction of molecular markers of spontaneous microaggregation as thromboglobulin, BTC and plasmatic factor 4); red blood cells (increased deformability; increase of PO 2 and reduction of PCO 2 ); monocytes and polymorphonucleates (reduced production of free radicals; reduced formation of lymphocytes' macroaggregates) (O'Brien et al 1984;Schror et al 1989;Violi et al 1989;Berti et al 1994;Zhou et al 1994;Abbate et al 1995).…”