RGD Reference Report - 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. - Rat Genome Database

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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.

Authors: Szalony, JA  Taite, BB  Girard, TJ  Nicholson, NS  LaChance, RM 
Citation: Szalony JA, etal., J Thromb Thrombolysis. 2002 Oct;14(2):113-21.
RGD ID: 11041657
Pubmed: PMID:12714830   (View Abstract at PubMed)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
F7RatArterial Thrombosis treatmentIMP  RGD 
F7MouseArterial Thrombosis treatmentISOF7 (Rattus norvegicus) RGD 
F7HumanArterial Thrombosis treatmentISOF7 (Rattus norvegicus) RGD 

Objects Annotated

Genes (Rattus norvegicus)
F7  (coagulation factor VII)

Genes (Mus musculus)
F7  (coagulation factor VII)

Genes (Homo sapiens)
F7  (coagulation factor VII)


Additional Information