TISSUE FACTOR-DEPENDENT ACTIVATION OF TRITIUM-LABELED FACTOR-IX AND FACTOR-X IN HUMAN-PLASMA

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  • 1 January 1984
    • journal article
    • research article
    • Vol. 63  (6) , 1338-1347
Abstract
The activation of factor IX by factor VII/tissue factor may be an important alternative route to the generation of factor Xa. The tissue factor-dependent activation of tritium-labeled factor IX and factor X were compared in a human plasma system and the role of proteases known to stimulate factor VII activity was studied. Plasma was defibrinated by heating and depleted of its factors IX and X by passing it through antibody columns. Addition of human brain thromboplastin, Ca2+, and purified 3H-labeled factor X to the plasma resulted, after a short lag, in burst-like activation of the factor X, measured as the release of radiolabeled activation peptide. The progress of activation was slowed by both heparin and a specific inhibitor of factor Xa, suggesting a feedback role for this enzyme, but factor X activation could not be completely abolished by such inhibitors. In the case of 3H-factor IX activation, the rate also increased for .apprx. 3 min after addition of thromboplastin, but was not subsequently curtailed. A survey of proteases implicated as activators of factor VII in other settings showed that both factor Xa and (to a much smaller extent) factor IXa could accelerate the activation of factor IX. Factor Xa was unique in obliterating activation when present at concentrations > .apprx. 1 nM. Heparin inhibited the tissue factor-dependent activation of factor IX almost completely, apparently through the effect of antithrombin on the feedback reactions of factors Xa and IXa on factor VII. A very tight, biphasic control of factor VII activity apparently exists in human plasma, which is modulated mainly by factor Xa. Variation of the factor IX or factor X concentrations permitted kinetic parameters for each activation to be derived. At saturation of factor VIIa/tissue factor, factor IX activation was significantly more rapid than was previously found in bovine plasma under similar conditions. The activation of factor X at saturation was slightly more rapid than in bovine plasma, despite the presence of heparin.