Assessment of bleeding propensity in non-human primates by combination of selective tissue factor/VIIa inhibition and aspirin compared to warfarin and aspirin treatment.
This study in non-human primates was designed to evaluate the bleeding propensity of a selective, small molecule inhibitor of tissue factor (TF)/VIIa in combination with acetylsalicylic acid (ASA) in comparison to the combination of ASA and warfarin. Bleeding time was increased by ASA but was not prolonged further by the addition of the TF/VIIa inhibitor, PHA-927, at doses that elevated the prothrombin time to 8-fold. In contrast, bleeding time was prolonged by warfarin alone and further exacerbated by the presence of ASA. Acute blood loss at the bleeding site, while not significantly increased by either warfarin or PHA-927, was increased substantially in several individuals treated with a combination of warfarin and ASA but not by the combination of TF/VIIa inhibitor and ASA. These data predict that TF/VIIa inhibition, in the presence of chronic aspirin therapy in patients with cardiovascular risk factors, will be a safe therapy for thrombotic disorders.
Salyers
Anita K
AK
Department of Cardiovascular Pharmacology, Pfizer Corporation, Skokie, Ill, USA.
Szalony
James A
JA
Suleymanov
Osman D
OD
Parlow
John J
JJ
Wood
Rhonda S
RS
South
Michael S
MS
Nicholson
Nancy S
NS
D062365:Aminobenzoates / Q000494:pharmacology*; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D001760:Bleeding Time; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D006470:Hemorrhage / Q000097:blood; D008252:Macaca fascicularis; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011517:Prothrombin Time; D011719:Pyrazines / Q000494:pharmacology*; D013925:Thromboplastin / Q000037:antagonists & inhibitors*; D014859:Warfarin / Q000494:pharmacology*; D014914:Whole Blood Coagulation Time
C477641:3-amino-5-(1-(2-((4-(amino(imino)methyl)benzyl)amino)-2-oxoethyl)-3-chloro-5-(isopropylamino)-6-oxo-1,6-dihydropyrazin-2-yl)benzoic acid; D062365:Aminobenzoates; D000925:Anticoagulants; D004338:Drug Combinations; D010975:Platelet Aggregation Inhibitors; D011719:Pyrazines; D014859:Warfarin; D013925:Thromboplastin; D015942:Factor VIIa; D001241:Aspirin