Effects of a Defibrotide—Heparin Combination on Some Measures of Haemostasis in Healthy Volunteers

Abstract

In an open-study design five healthy volunteers were first given 2500 IU sodium heparin intravenously and then, after 72 h, another injection of the same dosage of sodium heparin followed immediately by 400 mg defibrotide intravenously. In two separate experiments, prothrombin time, activated partial prothrombin time, antithrombin III, tissue plasminogen activator, its inhibitor and plasma heparin levels were measured at baseline and after 15 min in one experiment, and at baseline and after 2 h in the other experiment. The most important finding was that an interaction exists between heparin and defibrotide on haemostatic activity: activated partial prothrombin time was increased three-fold in volunteers given the defibrotide--heparin combination compared with volunteers given heparin alone. This statistically and clinically significant effect was evident 15 min after administration of defibrotide--heparin and was still present after 2 h. Possible explanations for this effect are discussed briefly.

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

“…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.…”

Defibrotide enhances fibrinolysis in human endotoxemia – a randomized, double blind, crossover trial in healthy volunteers

“…Furthermore, defibrotide reduced tumor necrosis factor (TNF)-α expression in lipopolysaccharide (LPS)-stimulated dendritic cells and it attenuated the prothrombinase activity, platelet and complement activation in in vitro malaria models 7 . In healthy volunteers, combined infusion of defibrotide and heparin significantly enhanced the effect of heparin alone and prolonged the activated partial thromboplastin time and increased antithrombin III levels 8 . Moreover, defibrotide inhibited factor Xa, increased tissue factor pathway inhibitor and decreased tissue factor in healthy volunteers 9 .…”

Defibrotide

“…and defibrotide (400 mg i.v. bolus) induced a striking prolongation of the aPlT but apparently not of anti-Xa activity, when compared with heparin alone (80). Although the mechanism by which defibrotide potentiates the anticoagulant effect of heparin needs further clarification, these data suggest caution in regard to combined clinical use of the two agents.…”