Protein C Inhibitor Acts as a Procoagulant by
Inhibiting the Thrombomodulin-Induced Activation of Protein C in
Human Plasma
Marc G.L.M. Elisen,
Peter A.Kr. von dem Borne,
Bonno N. Bouma, and
Joost C.M. Meijers
From the Department of Haematology, University Hospital and Institute
of Biomembranes, Utrecht University, Utrecht, The Netherlands.
Protein C inhibitor (PCI), which was originally identified as an
inhibitor of activated protein C, also efficiently inhibits coagulation
factors such as factor Xa and thrombin. Recently it was found, using
purified proteins, that the anticoagulant thrombin-thrombomodulin complex was also inhibited by PCI. The paradoxical inhibitory effect of
PCI on both coagulant and anticoagulant proteases raised questions
about the role of PCI in plasma. We studied the role of thrombomodulin
(TM)-dependent inhibition of thrombin by PCI in a plasma system.
Clotting was induced by addition of tissue factor to recalcified plasma
in the absence or presence of TM, and clot formation was monitored
using turbidimetry. In the absence of TM, PCI-deficient plasma showed a
slightly shorter coagulation time compared with normal plasma.
Reconstitution with a physiologic amount of PCI gave normal clotting
times. Addition of PCI to normal plasma and protein C-deficient plasma
resulted in a minor prolongation of the clotting time. This suggested
that PCI can act as a weak coagulation inhibitor in the absence of TM.
TM caused a strong anticoagulant effect in normal plasma due to
thrombin scavenging and activation of the protein C anticoagulant
pathway. This effect was less pronounced when protein C-deficient
plasma was used, but could be restored by reconstitution with protein
C. When PCI was added to protein C-deficient plasma in the presence of
TM, a strong anticoagulant effect of PCI was observed. This
anticoagulant effect was most likely caused by the TM-dependent
thrombin inhibition by PCI. However, when PCI was added to normal
plasma containing TM, a strong procoagulant effect of PCI was observed,
due to the inhibition of protein C activation. PCI-deficient plasma was
less coagulant in the presence of TM. A concentration-dependent
increase in clotting time was observed when PCI-deficient plasma was
reconstituted with PCI. The combination of these results suggest that
the major function of PCI in plasma during coagulation is the
inhibition of thrombin. A decreased generation of activated protein C
is a procoagulant consequence of the TM-dependent thrombin
inhibition by PCI. We conclude that TM alters PCI from an anticoagulant
into a procoagulant during tissue factor-induced coagulation.
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1542-1547
© 1998 by The American Society of Hematology.
