Long-lasting antithrombotic effects of a single dose of human recombinant, active site-blocked factor VII: insights into possible mechanism(s) of action.
Tissue factor (TF) is important in initiating intravascular thrombosis. We demonstrated that active-site blocked factor VII (FVIIai) inhibits intravascular thrombosis for at least 6 h following a single injection, despite FVIIai plasma half-life was approximately 45 min. The aims of the present study were: (a) to determine the duration of the antithrombotic effects of a single injection of FVIIai; and (b) to assess whether FVIIai prolonged effects can be explained by a slow dissociation rate from TF in the arterial wall. Cyclic flow variations (CFVs), obtained in stenotic rabbit carotid arteries with endothelial injury, were abolished by either FVIIai (100 micro g kg-1 min-1 for 10 min) or hirudin (1 mg kg-1). After CFVs were abolished, carotid blood flow velocity was recorded continuously for 24 h. CFVs restored in all hirudin-treated animals after 2.1 +/- 0.3 h, while they restored in only four of nine FVIIai-treated rabbits in 10.1 +/- 2.2 h. Five animals in this group did not show restoration of CFVs up to 24 h. Immunohistochemistry revealed that FVIIai was still bound to the arterial wall 24 h following its administration, despite at this time FVIIai plasma levels were undetectable. Prothrombin time and partial thromboplastin time did not change significantly. FVIIai exerts potent, long-lasting antithrombotic effects without affecting systemic hemostatic parameters; a possible mechanism is a slow dissociation rate of FVIIai from TF. These proprieties make FVIIai particularly attractive as an antithrombotic intervention.
Cirillo
P
P
Division of Cardiology, University of Naples 'Federico II', Naples, Italy.
Golino
P
P
Ragni
M
M
D'andrea
D
D
Calabró
P
P
Corcione
N
N
Vigorito
F
F
Ravera
M
M
Chiariello
M
M
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D001783:Blood Flow Velocity / Q000187:drug effects; D002339:Carotid Arteries / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology; D005167:Factor VII / Q000032:analysis / Q000493:pharmacokinetics* / Q000494:pharmacology; D015942:Factor VIIa; D005343:Fibrinolytic Agents / Q000032:analysis / Q000493:pharmacokinetics* / Q000494:pharmacology; D006629:Hirudins / Q000493:pharmacokinetics / Q000494:pharmacology; D007150:Immunohistochemistry; D011817:Rabbits; D011994:Recombinant Proteins / Q000032:analysis / Q000493:pharmacokinetics* / Q000494:pharmacology; D013927:Thrombosis / Q000188:drug therapy* / Q000517:prevention & control; D013997:Time Factors
D005343:Fibrinolytic Agents; D006629:Hirudins; D011994:Recombinant Proteins; D005167:Factor VII; C103587:recombinant FVIIa; D015942:Factor VIIa