Inhibition of Tissue Plasminogen Activator Inhibitor by Defibrotide in Atherosclerotic Patients

Abstract

Defibrotide, an antithrombotic drug, was previously shown to activate fibrinolysis. In order to elucidate the relationship between defibrotide treatment and fibrinolysis, ten atherosclerotic patients were given 1200 mg/day defibrotide intravenously for 7 days and then 400 mg/day intramuscularly for another 20 days. t-PA antigen assessed before and after venous occlusion was not affected by the treatment. Tissue PAI activity significantly decreased and t-PA activity, measured after venous occlusion, increased after 8 and 28 days of treatment; both these changes disappeared after defibrotide was discontinued. No particular side effects were detected throughout the investigation. The study suggests that defibrotide increases t-PA activity by reducing PAI activity.

Defibrotide®Reduces Monocyte PAI-2 and Procoagulant Activity

“…plasminogen activator inhibitor in patients with periph eral vascular disease. 20 In the present study the drug concentrations able to reduce PAI release by monocytes in vitro are, in fact, of the same order of magnitude as those obtained after in vivo administration to patients.…”

Impact of thrombotic thrombocytopenic purpura on leukemic children undergoing bone marrow transplantation

“…With regard to the treatment of TTP in BMT patients, there are a few promising reports regarding the use of defibrotide, [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] which seems to have a considerable antithrombotic effect due to its profibrinolytic activity, 36,37 based on its ability to induce release of plasminogen activator factor from the vascular tissue 38 and to decrease blood concentration of plasminogen activator inhibitor. 39 These and other defibrotide-related effects, the most important of which concerns inhibition of platelet aggregation, have recently been acknowledged to be of benefit in post-BMT venoocclusive disease, 40 which, like TTP, can occur as a result of endothelial damage.…”

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).…”