Acute t-PA release by defibrotide

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: A Review of Its Use in Severe Hepatic Veno-Occlusive Disease Following Haematopoietic Stem Cell Transplantation

“…Increased t-PA antigen levels and t-PA activity in resting HMECs and HUVECs [21] Counteracted LPS-induced increases in PAI-1 antigen levels and reductions in t-PA activity in LPS-stimulated HMECs and HUVECs [21] Counteracted thalidomide-induced reductions in t-PA antigen levels in thalidomide-stimulated HMECs [26] Counteracted thalidomide-induced reduction in the ability of HMECs to degrade a fibrin clot [26] Increased plasma t-PA release [49], increased plasma t-PA activity [52] and decreased PAI-1 activity [49,53] in rats and/or mice Increased t-PA antigen levels and decreased PAI-1 antigen levels in primates [54] Stimulated TM expression and activity in HUVECs [55] Stimulated plasmin activity in a dose-dependent manner [56] Counteracted LPS-induced increases in TF antigen levels and TF procoagulant activity in LPS-stimulated HMECs [21] Inhibited PAF formation in a rabbit model of myocardial ischaemia [57] Inhibited thrombin-induced platelet aggregation [58] and protected mice against thrombin-induced thromboembolism [59] Inhibited platelet activation by cathepsin G derived from stimulated polymorphonuclear leukocytes [60] Attenuated increased reactivity (in response to sera from HSCT pts) of HMEC-and HUVEC-generated ECM to platelets [61] Attenuated increased reactivity (in response to ciclosporin) of HMEC-generated ECM to platelets [62] Weak/negligible anticoagulant activity in plasma and whole blood assays [22] Effects on prostanoids Induced PGE 2 release in a rabbit model of myocardial ischaemia [63] and increased urinary PGE 2 levels in rats and mice [52] Induced 6-keto-PGF 1a release in a rabbit model of myocardial ischaemia [57,63], in a rat model of myocardial ischaemia [64], in leukocyteperfused isolated rabbit hearts [23] and in human saphenous vein samples [65] Reduced plasma TXB 2 levels in a rat model of myocardial ischaemia [64] and inhibited thrombin-induced TXB 2 formation in platelets [58] Effects on inflammatory cytokines/mediators…”

“…Not all studies used the approved defibrotide preparation derived from porcine intestinal mucosal DNA (e.g. some studies specified using defibrotide derived from bovine lung DNA [49,50] or mammalian lung DNA [29, 51]) In terms of other effects, therapeutic or supratherapeutic (fourfold higher than the approved dose) doses of defibrotide had no significant or clinically relevant effects on the corrected QT interval in healthy volunteers [14].…”

Interplay of Inflammation and Endothelial Dysfunction in Bone Marrow Transplantation: Focus on Hepatic Veno-Occlusive Disease

“…Defibrotide, a single-stranded polydeoxyribonucleotide drug derived from pig intestines, has been investigated for antishock, anti-ischemic, and endothelium-protective activities. 103 A wide variety of actions have been suggested including an increased endothelial release of NO, 104 prostacyclin, 105 and tissue plasminogen activator, 106 and a reduced LPS-induced tissue factor expression and PAI-1 release. 107 Platelet and leucocyte adhesion to endothelium are also decreased by defibrotide.…”