title: Effects of increasing doses of activated recombinant factor VII on haemostatic parameters in swine.
abstract: This study examined dose-response relationships between activated recombinant factor VII (rFVIIa) and (1) in vivo haemostasis and (2) in vitro measures of coagulation and platelet function. Anesthetized swine were used. Ear bleeding time (BT) was measured and blood was sampled following increasing doses of rFVIIa (0, 90, 180, 360 and 720 microg/kg; n=6) or saline (n=6). BT was not altered by rFVIIa. Prothrombin time (PT) using standard or pig-specific methods was decreased by rFVIIa. Activated clotting time (ACT) was decreased by rFVIIa. Thromboelastography using collagen (COLL) or pig thromboplastin (p-ThP) as agonist demonstrated shorter reaction times, shortened time to reach maximum velocity of clot formation, and increased alpha-angle in the presence of rFVIIa. rFVIIa dosing increased maximum velocity of clot formation when p-ThP was used to initiate the reaction but not when COLL was used. rFVIIa at the highest concentration increased maximum amplitude when COLL was used to initiate the reaction. Platelet aggregation was not altered by rFVIIa. Following completion of the dose escalation phase, a severe liver injury was produced. rFVIIa altered neither blood loss nor survival time following injury but improved mean arterial pressure. A small increase in systemic thrombin-antithrombin III complex occurred after administration of rFVIIa at doses of 180 microg/kg and above. However, there was no histological evidence of intravascular coagulation after rFVIIa administration. In summary, rFVIIa activity was detectable in vitro but did not change haemostasis in normal swine.
authors.affiliation: U.S. Army Institute of Surgical Research, 3400 Rawley E. Chambers Avenue, Ft. Sam Houston, TX 78234-6315, USA. anthony.pusateri@amedd.army.mil
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Pusateri
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Ryan
authors.forename: Angel V
authors.initials: AV
authors.lastname: Delgado
authors.forename: Raul S
authors.initials: RS
authors.lastname: Martinez
authors.forename: John M
authors.initials: JM
authors.lastname: Uscilowicz
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Cortez
authors.forename: Uri
authors.initials: U
authors.lastname: Martinowitz
mesh_terms: D000818:Animals; D000990:Antithrombin III; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D001794:Blood Pressure / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005167:Factor VII / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D015942:Factor VIIa; D006487:Hemostasis / Q000187:drug effects*; D007700:Kinetics; D010447:Peptide Hydrolases / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects; D010979:Platelet Function Tests; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D013552:Swine; D013925:Thromboplastin / Q000494:pharmacology
chemical_list: D011994:Recombinant Proteins; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D005167:Factor VII; D003094:Collagen; D013925:Thromboplastin; C103587:recombinant FVIIa; D010447:Peptide Hydrolases; D015942:Factor VIIa