title: Recombinant activated factor VII does not reduce bleeding in rabbits treated with aspirin and clopidogrel.
abstract: Combined antiplatelet agents (cAPA), aspirin plus clopidogrel, increase the risk of bleeding. We hypothesised that recombinant activated FVIIa (rFVIIa), which normalises thrombin generation in platelet-rich plasma from patients treated with cAPA, could limit this bleeding risk. It was the objective of this study to investigate the efficacy and safety of rFVIIa compared to placebo, in a bleeding and thrombosis model in rabbits treated with aspirin and clopidogrel. New-Zealand rabbits, randomised into two groups (Placebo1, n=36 ; cAPA, n=34), were anaesthetised, ventilated and monitored for blood pressure, temperature and carotid blood flow. The Folts model was applied to a carotid artery. Cyclic flow reductions (CFR) were recorded over a first 20-min period (Obs1). Each rabbit was then randomly assigned into one of three subgroups (Placebo2, 40μg/kg rFVIIa, 160 μg/kg rFVIIa) and CFR were monitored for a second 20-min period (Obs2). Ear bleeding time (BT) was measured at the end of each period. Hepatosplenic (HS) section was performed at the end of the experiment and HS blood loss defines the primary endpoint. Secondary endpoints were thrombosis (CFR), prothrombin time, platelet aggregation, and thrombin generation. Non- parametric statistical tests were used (p<0.05). cAPA significantly increased HS blood loss, BT and suppressed CFR compared to Placebo1 (p<0.05). rFVIIa injection did not modify HS blood loss, BT or CFR rate in Placebo1 rabbits nor in cAPA animals. These effects were unaffected by either rFVIIa dose. rFVIIa accelerated thrombin generation but had no effect on platelet aggregation in citrated platelet-rich plasma. rFVIIa did not modify HS blood loss associated with cAPA in rabbits.
authors.affiliation: Inserm UMRS 765, Pharmaceutical Sciences University, Paris, France.
authors.forename: Clemence
authors.initials: C
authors.lastname: Hindy-François
authors.forename: Christilla
authors.initials: C
authors.lastname: Bachelot-Loza
authors.forename: Bernard
authors.initials: B
authors.lastname: Le Bonniec
authors.forename: Francoise
authors.initials: F
authors.lastname: Grelac
authors.forename: Blandine
authors.initials: B
authors.lastname: Dizier
authors.forename: Anne
authors.initials: A
authors.lastname: Godier
authors.forename: Joseph
authors.initials: J
authors.lastname: Emmerich
authors.forename: Pascale
authors.initials: P
authors.lastname: Gaussem
authors.forename: Charles-Marc
authors.initials: CM
authors.lastname: Samama
mesh_terms: D000818:Animals; D001241:Aspirin / Q000008:administration & dosage / Q000009:adverse effects; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000077144:Clopidogrel; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D015942:Factor VIIa / Q000008:administration & dosage* / Q000009:adverse effects; D006470:Hemorrhage / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000009:adverse effects; D012039:Regional Blood Flow / Q000187:drug effects*; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy*; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives
chemical_list: D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D000077144:Clopidogrel; D015942:Factor VIIa; D013988:Ticlopidine; D001241:Aspirin