Thrombin activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase B-like proenzyme
that after activation by thrombin downregulates fibrinolysis. Thrombomodulin stimulates
the activation of both TAFI and protein C whereas activated protein C inhibits the
activation of TAFI by downregulation of thrombin formation, a process in which protein
S acts as a cofactor. Here we determined the role of protein S in the activation of
TAFI and regulation of fibrinolysis. Depletion of protein S from plasma or inhibition
of protein S by specific antibodies resulted in an increased rate of TAFI activation
and in an increased maximum of TAFIa activity generated. The effect on the rate of
TAFI activation could be attributed to the APC-independent anticoagulant function
of protein S whereas the effect on the maximum activity could be attributed to the
APC cofactor function of protein S. Therefore it is concluded that protein S inhibits
TAFI activation in two ways. On one hand, protein S functions as a cofactor for APC
which results in a reduction of the maximum induced TAFI activity and on the other
hand protein S inhibits the initial thrombin formation independently of APC which
results in a decreased rate of TAFI activation. The effect of the APC-independent
anticoagulant activity of protein S on the activation of TAFI provides a new mechanism
for the regulation of fibrinolysis in the early stages of clot formation.
Keywords
TAFI - carboxypeptidase U - protein C - protein S - fibrinolysis
