Activation of factor VII bound to tissue factor: a key early step in the tissue factor pathway of blood coagulation.
Whether the factor VII/tissue factor complex that forms in tissue factor-dependent blood coagulation must be activated to factor VIIa/tissue factor before it can activate its substrates, factor X and factor IX, has been a difficult question to answer because the substrates, once activated, back-activate factor VII. Our earlier studies suggested that human factor VII/tissue factor cannot activate factor IX. Studies have now been extended to the activation of factor X. Reaction mixtures were made with purified factor VII, X, and tissue factor; in some experiments antithrombin III and heparin were added to prevent back-activation of factor VII. Factor X was activated at similar rates in reaction mixtures containing either factor VII or factor VIIa after an initial 30-sec lag with factor VII. In reaction mixtures with factor VII a linear activation of factor X was established several minutes before cleavage of 125I-labeled factor VII to the two-chain activated molecule was demonstrable on gel profiles. Adding antithrombin III and heparin blocked activation of factor X by factor VII/tissue factor but not by factor VIIa/tissue factor. When the antithrombin III and heparin were added 1 min after the other reagents, factor VII/tissue factor activation of factor X was not blocked. These data suggest that factor VII/tissue factor cannot activate measurable amounts of factor X over several minutes. Overall, our results support the hypothesis that a rapid preferential activation of factor VII bound to tissue factor by trace amounts of factor Xa is a key early step in tissue factor-dependent blood coagulation.
Rao
L V
LV
Department of Medicine, UCSD Medical Center, La Jolla 92093.
Rapaport
S I
SI
D000990:Antithrombin III / Q000494:pharmacology; D001777:Blood Coagulation; D001923:Brain Chemistry; D004591:Electrophoresis, Polyacrylamide Gel; D005167:Factor VII / Q000378:metabolism*; D015942:Factor VIIa; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D013925:Thromboplastin / Q000378:metabolism*
D000990:Antithrombin III; D005167:Factor VII; D006493:Heparin; D013925:Thromboplastin; D015942:Factor VIIa