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Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2169-2178
"Normal" Thrombin Generation
Saulius Butenas,
Cornelis van't Veer, and
Kenneth G. Mann
From the Department of Biochemistry, University of Vermont,
Burlington, VT.
We have investigated the influence of alterations in plasma
coagulation factor levels between 50% and 150% of their mean values for prothrombin, factor X, factor XI, factor IX, factor VII, factor VIII, factor V, protein C, protein S, antithrombin III (AT-III), and
tissue factor pathway inhibitor (TFPI) as well as combinations of
extremes, eg, 50% anticoagulants and 150% procoagulants or 50%
procoagulants and 150% anticoagulants in a synthetic "plasma" system. The reaction systems were constructed in vitro using purified, natural, and recombinant proteins and synthetic phospholipid vesicles or platelets with the reactions initiated by recombinant tissue factor
(TF)-factor VIIa complex (5 pmol/L). To investigate the influence of
the protein C system, soluble thrombomodulin (Tm) was also added to the
reaction mixture. For the most extreme situations in which the
essential plasma procoagulants (prothrombin, and factors X, IX, V, and
VIII) and the stoichiometric anticoagulants (AT-III and TFPI) were
collectively and inversely altered by 50%, a 28-fold difference in the
total available thrombin generated was observed. Variations of most of
these proteins 50% above and below the "normal" range, with the
remainder at 100%, had only modest influences on the peak and total
levels of thrombin generated. The dominant factors influencing thrombin
generation were prothrombin and AT-III. When these 2 components were
held at 100% and all other plasma procoagulants were reduced to 50%,
there was a 60% reduction in the available thrombin generated. No
increase in the thrombin generated was observed when the 150% level of
all plasma procoagulants other than prothrombin was evaluated. When only prothrombin was raised to 150%, and all other factors were maintained at 100%, the thrombin generated increased by 71% to 121%.
When AT-III was at 50% and all other constituents were at 100%,
thrombin production was increased by 104% to 196%. The additions of
protein C and protein S over the 50% to 150% ranges with Tm at 0.1 nmol/L concentration had limited influence on thrombin generation.
Individual variations in factors VII, XI, and X concentrations had
little effect on the duration of the initiation phase, the peak
thrombin level achieved, or the available thrombin generated. Paradoxically, increases in factor IX concentration to 150% led to
lowered thrombin generation, while decreases to 50% led to enhanced
thrombin generation, most likely a consequence of factor IX as a
competitive substrate with factor X for factor VIIa-TF. Reductions in
factor V or factor VIII concentration led to prolongations of the
initiation phase, while the reduction of TFPI to 50% led to shortening
of this phase. However, none of these alterations led to significant
changes in the available thrombin generated. Based on these data, one
might surmise that increases in prothrombin and reductions in AT-III,
within the normal range, would be potential risk factors for thrombosis
and that algorithms that combine normal factor levels may be required
to develop predictive tests for thrombosis.
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