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The Mechanism of Activation of Factor X

1974; Elsevier BV; Volume: 249; Issue: 17 Linguagem: Inglês

10.1016/s0021-9258(20)79771-1

1083-351X

Jolyon Jesty, Allen K. Spencer, Yale Nemerson,

Hemophilia Treatment and Research

Abstract 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 α-Xa, undergoes autocatalytic conversion to a lower molecular weight form of equal coagulant activity, β-Xa. 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 Xa, has been demonstrated. This involves the conversion of Factor X to an enzymically inactive intermediate, designated I1. This intermediate may then be activated directly to β-Xa 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 β-Xa has been demonstrated that is catalyzed entirely by Xa. This involves the conversion of Factor X to I1, which is then converted to β-Xa. A second intermediate appears during this reaction, but whether it is an obligatory intermediate is not known. NH2-terminal amino acid sequence data suggest that the conversion by Xa of Factor X to I1, and of α-Xa to β-Xa, probably involve the release of COOH-terminal peptides. The forms of β-Xa produced from I1 and α-Xa are apparently identical. These pathways are under kinetic control; at high rates of activation the direct pathway to α-Xa and β-Xa predominates, whereas at low rates the Xa formed initially by the direct pathway feeds back and converts Factor X to I1, thus initiating an alternative set of reactions. The final yield of Xa 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, Xa, and we propose this as a mechanism of control of the tissue factor pathway.