Pharmacological intervention at disparate sites in the coagulation cascade: comparison of anti-thrombotic efficacy vs bleeding propensity in a rat model of acute arterial thrombosis.
The Tissue Factor/Factor VIIa (TF/FVIIa) complex is an attractive target for pharmacological interruption of thrombin generation and hence blood coagulation, as this complex is the initiation point of the extrinsic pathway of coagulation. TF is a cell membrane-associated protein that interacts with soluble FVIIa to activate factors IX and X resulting in a cascade of events that leads to thrombin generation and eventual fibrin deposition. The goal of this non-randomized study was to evaluate XK1, a specific protein inhibitor of TF/FVIIa, and compare antithrombotic efficacy and bleeding propensity to a previously described Factor Xa (FXa) inhibitor (SC-83157/SN429) and a direct-acting thrombin inhibitor (SC-79407/L-374087) in an acute rat model of arterial thrombosis. All saline-treated animals experienced occlusion of the carotid artery due to acute thrombus formation within 20 minutes. Rats treated with XK1 exhibited a dose-dependent inhibition of thrombus formation with full antithrombotic efficacy and no change in bleeding time or total blood loss at a dose of 4.5 mg/kg, i.v. administered over a 60 minute period. FXa inhibition with SC-83157 resulted in complete inhibition of thrombus formation at a dose of 1.2 mg/kg, i.v.; however, this effect was associated with substantial blood loss. Thrombin inhibition with SC-79407 also afforded complete protection from thrombus formation and occlusion at a dose of 2.58 mg/kg, i.v., and like SC-83157, was associated with substantial blood loss. These data imply that TF/FVIIa inhibition confers protection from acute thrombosis without concomitant changes in bleeding, indicating that this target (TF/FVIIa) may provide improved separation of efficacy vs. bleeding side-effects than interruption of coagulation by directly inhibiting either FXa or thrombin.
Szalony
James A
JA
Department of Cardiovascular Pharmacology, Pharmacia, 4901 Searle Parkway, Skokie, IL 60077-5300, USA. james.a.szalony@pharmacia.com
Taite
Beatrice B
BB
Girard
Thomas J
TJ
Nicholson
Nancy S
NS
LaChance
Rhonda M
RM
D000208:Acute Disease; D000818:Animals; D001760:Bleeding Time / Q000706:statistics & numerical data; D001779:Blood Coagulation Factors; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000188:drug therapy*; D017536:Carotid Artery, Common / Q000503:physiopathology; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000097:blood / Q000737:chemistry / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D001779:Blood Coagulation Factors; D005343:Fibrinolytic Agents