Tissue factor-dependent activation of tritium-labeled factor IX and factor
X in human plasma
SA Morrison and J Jesty
Recent investigations have suggested that the activation of factor IX by
factor VII/tissue factor may be an important alternative route to the
generation of factor Xa. Accordingly, we have compared the tissue
factor-dependent activation of tritium-labeled factor IX and factor X in a
human plasma system and have studied the role of proteases known to
stimulate factor VII activity. 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 approximately 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.
However, factor Xa was unique in obliterating activation when present at
concentrations greater than approximately 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. These results suggest that a very tight,
biphasic control of factor VII activity 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.
Volume 63,
Issue 6,
pp. 1338-1347,
06/01/1984
Copyright © 1984 by The American Society of Hematology
