Activation of Factor VII Bound to Tissue Factor: A Key Early Step in the Tissue Factor Pathway of Blood Coagulation

• Published in: Proceedings of the National Academy of Sciences - PNAS 1988-09, Vol.85 (18), p.6687-6691
• Main Authors: L. Vijaya Mohan Rao, Rapaport, Samuel I.
• Format: Article
• Language: English
• Subjects: 550201 - Biochemistry- Tracer Techniques; ALKALI METAL COMPOUNDS; Antithrombin III - pharmacology; Antithrombins; BASIC BIOLOGICAL SCIENCES; BETA DECAY RADIOISOTOPES; BIOCHEMISTRY; Blood; BLOOD COAGULATION; BLOOD COAGULATION FACTORS; BODY; BRAIN; Brain Chemistry; Calcium; CENTRAL NERVOUS SYSTEM; CHEMICAL ACTIVATION; CHEMISTRY; COAGULANTS; Coagulation; DAYS LIVING RADIOISOTOPES; DRUGS; ELECTRON CAPTURE RADIOISOTOPES; Electrophoresis, Polyacrylamide Gel; Factor VII - metabolism; Factor VIIa; HALIDES; HALOGEN COMPOUNDS; HEMATOLOGIC AGENTS; HEMOSTATICS; Heparin; Heparin - pharmacology; Humans; HYDRIDES; HYDROGEN COMPOUNDS; INORGANIC PHOSPHORS; INTERMEDIATE MASS NUCLEI; IODIDES; IODINE 125; IODINE COMPOUNDS; IODINE ISOTOPES; ISOTOPES; Low concentrations; Molecules; NERVOUS SYSTEM; NUCLEI; ODD-EVEN NUCLEI; ORGANIC COMPOUNDS; ORGANS; PHOSPHORS; PROTEINS; RADIOISOTOPES; SODIUM COMPOUNDS; SODIUM HYDRIDES; SODIUM IODIDES; Thromboplastin - metabolism; tissue factor; TRITIUM COMPOUNDS; Ungulates
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.85.18.6687

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.