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Low-affinity heparin stimulates the inactivation of plasminogen activator
inhibitor-1 by thrombin
PA Patston and M Schapira
Department of Medicine, Vanderbilt University, Nashville, TN 37232-2287.
The influence of heparin on the reaction between thrombin and plasminogen
activator inhibitor-1 (PAI-1) has been examined. With a 50- fold excess of
PAI-1, the rate constant for the inhibition of thrombin was 458 mol/L-1s-1,
which increased to 5,000 mol/L-1s-1 in the presence of 25 micrograms/mL
unfractionated heparin or heparin with low affinity for antithrombin. The
effect of low affinity heparin was then examined by sodium dodecyl
sulfate-polyacrylamide gel electrophoresis, using close to equimolar
concentrations of reactants. Thrombin and PAI-1 formed a stable
stoichiometric complex in the absence of heparin, which did not dissociate
after the addition of 25 micrograms/mL low-affinity heparin. In contrast,
when low-affinity heparin was added at the beginning of the reaction, there
was an initial increase in PAI-1- thrombin complex formation, but this was
rapidly followed by substantial proteolytic cleavage of unreacted PAI-1 and
of the thrombin- PAI-1 complex. The idea that the relative concentrations
of thrombin and PAI-1, and the presence of low affinity heparin, could
influence the products of the reaction was examined in detail. Quantitative
zymographic analysis of tissue plasminogen activator and PAI-1 activities
and chromogenic substrate assay of thrombin activity showed that
low-affinity heparin stimulated the inactivation of PAI-1 by an equimolar
amount of thrombin, but caused only a minimal stimulation of thrombin
inhibition. It is concluded that low-affinity heparin stimulates thrombin
inhibition when PAI-1 is in excess, but, unexpectedly, that low-affinity
heparin enhances PAI-1 inactivation when thrombin is equimolar to PAI-1.
Volume 84,
Issue 4,
pp. 1164-1172,
08/15/1994
Copyright © 1994 by The American Society of Hematology
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