TAFI: a promising drug target?

420 Thrombin-activatable fibrinolysis inhibitor (TAFI) is a 60kDa metallocarboxypeptidase produced by the liver and present in plasma. Independently discovered by several groups, the enzyme is also known as plasma procarboxypeptidase B, procarboxypeptidase R, or procarboxypeptidase U (1-5). TAFI as nomenclature was introduced by Bajar et al. (5). TAFI is expressed as a latent precursor requiring maturation via proteolytic cleavage of a 92 amino acid-long activation peptide to achieve biological activity. The activation of TAFI is known to be catalysed by plasmin, trypsin, or thrombin. Indeed, it is the thrombin-dependent activation of TAFI that represents an interesting link between coagulation and fibrinolysis, which is further supported by the marked enhancement of TAFI-activation via the endothelial receptor thrombomodulin (6). In this context, upon activation, TAFI cleaves carboxy-terminal lysine residues from partially degraded fibrin. These lysine residues can function as high affinity binding sites for tissue-type-plasminogen activator (t-PA) and plasminogen. By removing these lysine residues TAFI dampens the cofactor activity of fibrin in the activation of plasminogen resulting in a decrease of fibrinolysis (7). The burst of thrombin during the propagation phase of coagulation has been suggested to be sufficient to activate TAFI, thereby suppressing fibrinolysis and prolonging clot lysis time (8, 9). In this issue of Thrombosis and Haemostasis, Guimaraes and Rijken (10) investigate the role TAFI might have on plasma clot lysis. Employing a choice of t-PA(t-PA, tenecteplase, DSPA), bacterial(staphylokinase, APSAC), and urokinase-related plasminogen activators (tcu-PA, amediplase) they demonstrate that (i) TAFI delays plasma clot lysis mediated by the plasminogen activators tested, (ii) the delay of clot lysis is dependent on the concentration of the plasminogen activators, but is independent of the fibrin selectivity of the plasminogen activators, and (iii) that α2-plasmin inhibitor does not significantly interfere with the inhibition of clot lysis by TAFI. Thus, the paper highlights the potential pivotal role of TAFI inhibition in clinical thrombolysis, since most of the plasminogen activators tested are in clinical use or evaluation for thrombolytic therapy and existing knowledge is mostly based on experiments employing t-PA. Several investigators have shown this antifibrinolytic effect of TAFI in vitro and in vivo by using clot models generated from plasma or whole blood (mimicking endogenous fibrinolysis) or thrombolytic therapy (mimicking exogenous clot lysis), respectively (5-7, 11, 12). Applying Carboxypeptidase inhibitor from potato (CPI) has been demonstrated to be a specific inhibitor of TAFI (13). Incorporation of CPI into plasma clots or the clot surrounding plasma shortened t-PA-mediated clot lysis time by several fold on average, again suggesting that TAFI can markedly prolong clot lysis time (11). Guimarraes and Rijken also employed CPI in the present study (10): They created plasmaderived thrombi by adding thrombin to pooled blood bank plasma. Before clotting, plasminogen activators such as t-PA were added with or without CPI. Subsequently, internal clot lysis was monitored and a retardation factor was determined. For all plasminogen activators employed a relevant retardation factor could be observed demonstrating that retardation of clot lysis is not limited to t-PA mediated clot lysis. Furthermore, no correlation between the magnitude of the retardation factors and the fibrin specificity of the plasminogen activators was apparent. These data are in agreement with the recent report by Mutch et al. (14) on TAFI regulated thrombus lysis by urokinase plasminogen activator (uPA), single chain plasminogen activator (scuPA), and tPA. In a similar model employing whole blood thrombi, Mutch et al. showed that uPA mediated thrombus lysis is susceptible to TAFI: a promising drug target?