Mechanism of the anticoagulant effect of warfarin as evaluated in rabbits by selective depression of individual procoagulant vitamin K-dependent clotting factors.
We have evaluated the contribution of depression of individual procoagulant vitamin K-dependent clotting factors to the ability of warfarin to protect rabbits against tissue factor-induced coagulation. Mean activities of individual procoagulant factors were determined, in assays with rabbit substrates, for a group of rabbits achieving a protective degree of anticoagulation with warfarin. Values were: factor VII, 12%; factor IX, 7%; factor X, 14%, and prothrombin, 13%. The effect upon tissue factor-induced coagulation of selective immunodepletion of each factor to a comparable level was then evaluated. Immunodepletion of plasma factor X or prothrombin, but not of factor VII or factor IX, protected otherwise normal rabbits against tissue factor-induced coagulation. Next, we determined the effect upon the protection in warfarin-treated rabbits of selectively restoring factor X or prothrombin before infusing tissue factor. When either factor was selectively restored, warfarin's protective effect was abolished. Moreover, selective restoration of prothrombin sensitized warfarin-treated rabbits to coagulation more severe than observed in nontreated control rabbits. One may extrapolate from these data that depression of both factor X and prothrombin are required for warfarin's clinical antithrombotic efficacy and that depression of plasma prothrombin is particularly important.
Zivelin
A
A
Department of Medicine, University of California, San Diego 92093.
Rao
L V
LV
Rapaport
S I
SI
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001779:Blood Coagulation Factors / Q000378:metabolism*; D004211:Disseminated Intravascular Coagulation / Q000139:chemically induced*; D005164:Factor IX / Q000378:metabolism; D005167:Factor VII / Q000378:metabolism; D005170:Factor X / Q000378:metabolism; D005260:Female; D007262:Infusions, Intravenous; D011498:Protein Precursors / Q000378:metabolism; D011516:Prothrombin / Q000378:metabolism; D011817:Rabbits; D013925:Thromboplastin / Q000494:pharmacology*; D014812:Vitamin K / Q000378:metabolism; D014859:Warfarin / Q000494:pharmacology*
D000925:Anticoagulants; D001779:Blood Coagulation Factors; D011498:Protein Precursors; D014812:Vitamin K; D014859:Warfarin; D005167:Factor VII; D011516:Prothrombin; D005164:Factor IX; D005170:Factor X; D013925:Thromboplastin