The effect of defibrotide on thromboembolism in the pulmonary vasculature of mice and rabbits and in the cerebral vasculature of rabbits

Abstract

Administration of bovine thrombin (100 u kg−1) into the carotid artery of rabbits induces a sustained accumulation of 111Indium‐labelled platelets within the cranial vasculature over the subsequent 3 h. Intracarotid (i.c.) administration of defibrotide (64 mg kg−1 bolus plus 64 mg kg−1 h−1 for 1 h) prior to i.c. thrombin (100 u kg−1) significantly reduces the ability of thrombin to induce cranial thromboembolism in rabbits. Intravenous (i.v.) administration of thrombin (20 u kg−1) in rabbits induces a reversible accumulation of radiolabelled platelets into the thoracic circulation which is significantly reduced by i.v. administration of defibrotide (64 mg kg−1 bolus plus 64 mg kg−1 h−1 for 1 h) prior to i.v. thrombin. In contrast, platelet accumulation in response to adenosine diphosphate (ADP; 20 μg kg−1, i.v.) or platelet activating factor (PAF; 50 ng kg−1, i.v.) is not significantly affected by this treatment. Intravenous administration of the nitric oxide (NO)‐synthase inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME; 10 mg kg−1) potentiates platelet accumulation induced by low dose thrombin (10 u kg−1, i.v.) within the pulmonary vasculature of rabbits. The potentiated response is significantly abrogated following pretreatment with defibrotide (64 mg kg−1 bolus plus 64 mg kg−1 h−1 for 1 h, i.v.). Intravenous injection of human thrombin (1250 u kg−1) to mice induces death within the majority of animals which is significantly reduced by pretreatment with defibrotide (150–175 mg kg−1, i.v.). In contrast, death induced by i.v. collagen (1.25 mg kg−1) plus adrenaline (75 μg kg−1) is not significantly affected by defibrotide pretreatment. The inhibitory effect of defibrotide in mice is abolished following concomitant treatment with the inhibitor of fribrinolysis, tranexamic acid (100 mg kg−1, i.v.), but is unaffected following treatment with the cyclo‐oxygenase inhibitor, aspirin (300 mg kg−1, i.p.). The protective effect of defibrotide against thrombin‐induced thromboembolism in the mouse is potentiated by recombinant tissue‐plasminogen activator (rt‐PA; 1 mg kg−1, i.v.) or unfractionated heparin (10 u kg−1, i.v.) administration. The results suggest that defibrotide may possess antithrombotic activity on thrombin‐induced thromboembolism which, at least in the mouse, may be partially mediated via induction of the fibrinolytic pathway.

Defibrotide: An endothelium protecting and stabilizing drug, has an anti-angiogenic potential in vitro and in vivo

“…In the present study, DF as a DNA-based drug is found to have anti-angiogenic activity, although it was originally described as an endothelium protective and anti-inflammatory compound 1,7,16 with life saving properties. 6 This newly found biological activity of DF might be explained with a tumor endothelium normalization activity, as it has been proposed as a valuable anti-angiogenic strategy.…”

“…DF is a polydisperse mixture of 90% single-stranded polydesoxyribonucleotides with anti-thrombotic, anti-ischemic, and pro-fibrinolytic functions. [1][2][3][4] This mixture is obtained by controlled depolymerization of porcine mucosal DNA and has a mean molecular weight of 16-20 KD. DF is well tolerated and the only therapeutic option in severe hepatic veno-occlusive disease in the course of allogeneic stem cell transplantation (SCT).…”

Defibrotide and Endothelial Cell Activation

“…DFT has antithrombotic-thrombolytic activity in several different experimental models (28,29,30,34,41,53,57,62,64,78). DFT increases thrombomodulin (TM) (82), protein C (4), t-PA (42,44,45), Tissue Factor Pathway Inhibitor (TFPI) (52), PGI 2 (8,9,35,48), PGI 2 receptors on the surface of platelets and their affinity for PGI 2 (49), production of NO (50) and NOS activity, and NOS protein (36).…”

Efecto aditivo de las células madre mesenquimales y del defibrótido en un modelo de trombosis arterial en ratas

“…16,17 Asimismo, el DFT posee diferentes propiedades (profibrinolíticas, antitrombóticas, trombolíticas, antiisquémicas, antichoque y antiateroscleróticas) que se complementan con la actividad relacionada con la activación de anticuerpos anticélulas endoteliales. 14,[18][19][20] Por lo tanto, el presente estudio se diseñó para investigar el efecto aditivo de las MSC derivadas de médula ósea humana (hBM) y el DFT en un modelo experimental de trombosis arterial en ratas. Planteamos como hipótesis que este protocolo aumentaría la frecuencia de los precursores endoteliales circulantes y estimularía la formación de vasos sanguíneos nuevos (neovascularización).…”