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Increased prothrombin activation in protein S-deficient plasma under flow
conditions on endothelial cell matrix: an independent anticoagulant
function of protein S in plasma
C van't Veer, TM Hackeng, D Biesbroeck, JJ Sixma and BN Bouma
Department of Haematology, University Hospital Utrecht, The Netherlands.
Protein S is a vitamin K-dependent nonenzymatic coagulation factor involved
in the regulation of activated protein C (aPC). In this study, we report an
aPC-independent anticoagulant function of protein S in plasma under flow
conditions. Plasma, anticoagulated with low-molecular- weight heparin
allowing tissue factor-dependent prothrombin activation, was perfused at a
wall shear rate of 100 s-1 over tissue factor containing matrices of
stimulated endothelial cells placed in a perfusion chamber. Fractions were
collected in time at the outlet and prothrombin activation was determined
by measuring the activation fragment F1+2 of prothrombin. In normal plasma,
a time-dependent prothrombin activation was detected by the generation of
fragment1+2. Prothrombin activation had ceased after 12 minutes perfusion,
independent of the amount of tissue factor present in the matrix. Depletion
of protein S from plasma or inhibition of protein S in plasma by monoclonal
antibodies induced a 5- to 25-fold increase of prothrombin activation on
the procoagulant endothelial cell matrix. A prolonged prothrombin
activation was detected in protein S-depleted plasma up to 20 minutes after
onset of the thrombin generation. The increased prothrombin activation in
protein S-depleted plasma could not be explained by the absence of the
cofactor function of protein S for aPC because depletion of protein C from
plasma did not result in increased prothrombin activation. These data
provide further evidence for a strong anticoagulant function of protein S
in plasma independent from activated protein C.
Volume 85,
Issue 7,
pp. 1815-1821,
04/01/1995
Copyright © 1995 by The American Society of Hematology
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