Morphometric and Ultrastructural Study of Experimental Venous Thrombosis

Fumagalli, Guido Francesco; Angelaccio, Erenia; Lombardo, Nunzio; Clementi, Francesco

doi:10.1159/000215771

Cited by 16 publications

(12 citation statements)

References 11 publications

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“…However, this may not be the only mechanism involved, considering that defibrotide also inhibits the activation of leucocytes in human blood in vitro (Di Perri & Laghi Pasini, 1988), as well as in rat and rabbit blood (Fumagalli et al, 1991) in vitro and ex vivo. Therefore, it is not surprising that defibrotide could reduce the fibrin network and the number of leucocytes trapped in clots adhering to a collagen-coated prosthesis inserted into a femoral vein in rabbits, both in fresh and in up to 7 day old thrombi (Fumagalli et al, 1987;. These properties may well also contribute to the clinical effects of this drug in peripheral thrombotic diseases (Strano et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

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

Paul

Gresele

Momi

et al. 1993

British J Pharmacology

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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.

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Section: Discussionmentioning

confidence: 99%

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

Paul

Gresele

Momi

et al. 1993

British J Pharmacology

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“…Leukocytosis and thrombocytosis are decreased by DFT (60). DFT decreases leukocyte and platelet aggregates in thrombi (28,29).…”

Section: Change In Phenotype From Antithrombotic To Prothromboticmentioning

confidence: 98%

“…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).…”

Section: Change In Phenotype From Antithrombotic To Prothromboticmentioning

confidence: 99%

Defibrotide and Endothelial Cell Activation

Pescador¹,

Porta²,

Ferro³

2000

Cardiovascular Drug Reviews

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Defibrotide has several activities [profibrinolytic, antithrombotic-thrombolytic, antiischemic (heart, liver, kidney, skin, brain), antishock, antiatherosclerotic, and antirejection]. This host of activities has puzzled several people accustomed to the concept: one drug -one activity. But, if you see defibrotide as an antiendothelial cell activation drug, each piece of the puzzle will neatly fit into its right place and the host of activities becomes an array of activities. In fact the polyhedric inflammatory process is the common background of seemingly different illnesses, both acute and chronic. So the old concept of one drug-one activity proves true; one drug: defibrotide -one activity; antiendothelial cell activation activity.

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“…and 12.5, 25, and 50 mgkg orally) induced a significant (95) from animals treated with defibrotide at doses of 200 mg/kg showed a marked decrease in the fibrin mass but especially in the number of adhering platelets and leukocytes (41) (Fig. 1).…”

Section: Venous Thrombosis Modelsmentioning

confidence: 98%

“…Since morphological studies indicate that defibrotide reduces leukocyte participation in experimental thrombogenesis (41), the substance has been tested in different in vitro models of leukocyte activation. The agent inhibited the ionophore A 23187 and formylmethionyl-leucyl-phenylalanine (FMLP)-dependent activation of human polymorphonu-S. COCCHERIAND G .…”

Section: Leukocytesmentioning

confidence: 99%