Coagulation and fibrinolysis are processes that form and dissolve fibrin, r
espectively. These processes are exquisitely regulated and protect the orga
nism from excessive blood loss or excessive fibrin deposition. Regulation o
f these cascades is accomplished by a variety of mechanisms involving cellu
lar responses, flow, and protein-protein interactions. With respect to regu
lation mediated by protein-protein interaction, the coagulation cascade app
ears to be more complex than the fibrinolytic cascade because it has more c
omponents. Yet each cascade is regulated by initiators, cofactors, feedback
reactions, and inhibitors. Coagulation is also controlled by an anticoagul
ant pathway composed of (minimally) thrombin, thrombomodulin, and protein C
.(1) Protein C is converted by the thrombin/thrombomodulin complex to activ
ated protein C (APC), which catalyzes the proteolytic inactivation of the e
ssential cofactors required for thrombin formation, factors Va and VIIIa. A
n analogous antifibrinolytic pathway has been identified recently. This pat
hway provides an apparent symmetry between coagulation and fibrinolysis and
is also composed of thrombin, thrombomodulin, and a zymogen that is activa
ted to an enzyme. The enzyme proteolytically inactivates a cofactor to atte
nuate fibrinolysis. However, unlike APC, which is a serine protease, the an
tifibrinolytic enzyme is a metalloprotease that exhibits carboxypeptidase B
-like activity. Within a few years of each other, 5 groups independently de
scribed a molecule that accounts for this antifibrinolytic activity. We ref
er to this molecule as thrombin activatable fibrinolysis inhibitor (TAFI),
a name that is based on functional properties by which it was identified, a
ssayed, and purified. (Because of the preferences of some journals "activat
able" is occasionally referred to as "activable.") This review will encompa
ss a historical account of efforts to isolate TAFI and characterize it with
respect to its activation, activity, regulation, and potential function in
vivo.