The Mechanism of Activation of Factor X KINETIC COETROL OF ALTERNATIVE PATHWAYS LEADING TO THE FORMATION

The initial step in the activation of Factor X by a tissue factor-Factor VII complex has been shown to involve hydrolysis of the same peptide bond as is hydrolyzed by Russell’s viper venom. The product, designated a-X&, undergoes autocatalytic conversion to a lower molecular weight form of equal coagulant activity, P-X,. The rate of this conversion is markedly enhanced by phospholipid which is present as the lipid component of tissue factor. An alternative pathway of activation, initiated by X,, has been demonstrated. This involves the conversion of Factor X to an enzymically inactive intermediate, designated 11. This intermediate may then be activated directly to /3-X, at rates identical with the activation of Factor X, by either the tissue factor-Factor VII complex or Russell’s viper venom. A third, apparently minor, pathway of activation of Factor X to P-X, has been demonstrated that is catalyzed entirely by X,. This involves the conversion of Factor X to 11, which is then converted to /3-X,. A second intermediate appears during this reaction, but whether it is an obligatory intermediate is not known. NH&erminal amino acid sequence data suggest that the conversion by X, of Factor X to 11, and of oc-X, to P-X,, probably involve the release of COOH-terminal peptides. The forms of P-X, produced from I1 and a-X, are apparently identical. These pathways are under kinetic control; at high rates of activation the direct pathway to cu-X, and P-X, predominates, whereas at low rates the X, formed initially by the direct pathway feeds back and converts Factor X to 11, thus initiating an alternative set of reactions. The final yield of X, is also shown to be a function of the concentration of the tissue factor-Factor VII complex. It is shown that this complex is rapidly inactivated by its product, X,, and we propose this as a mechanism of control of the tissue factor pathway.