title: The fibrinolytic mechanism of defibrotide: effect of defibrotide on plasmin activity.
abstract: Fibrinolytic activity has been shown to be reduced in many vascular diseases, including hepatic veno-occlusive disease after stem cell transplantation, a microangiopathy characterized by sinusoidal endothelial cell injury. Defibrotide is a polydisperse oligonucleotide with antithrombotic, profibrinolytic, anti-ischemic, and antiadhesive properties. Numerous clinical studies have shown promising activity of defibrotide in the treatment and prevention of veno-occlusive disease, with minimal toxicity. In corollary laboratory studies, defibrotide has been shown to decrease plasminogen activator inhibitor-1, increase tissue plasminogen activator levels, and increase overall plasma fibrinolytic activity in patients. Plasmin, a potent and nonspecific serine protease, plays a pivotal role in fibrinolysis by virtue of its ability to effectively degrade fibrin clots. In this study, defibrotide increases the activity of plasmin in hydrolyzing its substrate in a dose-dependent and length-dependent manner. Similar concentration-dependent effects of defibrotide were observed when plasmin was generated by tissue plasminogen activator or urokinase activation of plasminogen. In contrast, defibrotide had no direct effect on the activation of plasminogen to plasmin. Defibrotide was also able to enhance the activity of plasmin in degrading fibrin clot formed from fibrinogen, plasminogen, and thrombin. This effect was also concentration-dependent and directly correlated with the enzymatic activity of plasmin. This study therefore demonstrates that defibrotide is capable of enhancing the activity of plasmin and so contributes to its fibrinolytic activity. Taken together, these results support the effect of defibrotide in restoring the fibrinolytic vascular phenotype, in microangiopathic conditions such as veno-occlusive disease.
authors.affiliation: Gentium SpA, villa Guardia, Como, Italy. cechart@gentium.it
authors.forename: Cinara L
authors.initials: CL
authors.lastname: Echart
authors.forename: Barbara
authors.initials: B
authors.lastname: Graziadio
authors.forename: Simona
authors.initials: S
authors.lastname: Somaini
authors.forename: Laura I
authors.initials: LI
authors.lastname: Ferro
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Jawed
authors.initials: J
authors.lastname: Fareed
authors.forename: Massimo
authors.initials: M
authors.lastname: Iacobelli
mesh_terms: D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000378:metabolism; D005341:Fibrinolysin / Q000187:drug effects*; D005342:Fibrinolysis / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006504:Hepatic Veno-Occlusive Disease / Q000188:drug therapy*; D006801:Humans; D010958:Plasminogen / Q000378:metabolism; D011089:Polydeoxyribonucleotides / Q000494:pharmacology*; D013917:Thrombin / Q000378:metabolism
chemical_list: D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D005340:Fibrinogen; D010958:Plasminogen; D013917:Thrombin; D005341:Fibrinolysin