New direction for WE thrombin.

An appealing strategy for developing therapeutic agents is to modify the design of human proteins, thereby taking advantage of target-specificity, multifunctionality of many proteins, and human compatibility—that is, provided any undesirable functional effects of the parent molecule can be selectively engineered away. In 2000, Cantwell & Di Cera1 reported a mutant form of the human serine protease, -thrombin, a multifunctional enzyme involved in both proand antithrombotic pathways. This mutant, termed WE thrombin, containing Trp215Ala and Glu217Ala substitutions, still promoted formation of activated protein C (APC) that inhibits coagulation factors Va and VIIIa (antithrombotic), but inefficiently converted fibrinogen to fibrin (prothrombotic), and was an effective antithrombotic agent in primate models of thrombosis.2,3 But a number of observations suggested this was not the full story. For instance, at low WE thrombin concentrations, there was a greater antithrombotic effect than expected based on circulating APC levels and minimal systemic anticoagulation, and in addition, labeled WE thrombin was incorporated into a developing thrombus, suggesting it might be interacting with platelets. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Berny and colleagues4 have provided further information (see Figure), revealing an unanticipated additional antithrombotic effect of WE thrombin, that is, binding to platelet glycoprotein (GP)Ib (the major ligand-binding subunit of the GPIb-IX-V complex),5–7 and inhibiting platelet adhesion to von Willebrand factor (vWF) under hydrodynamic flow and thrombus formation on a collagen matrix. The interaction of both wild-type and WE thrombin with GPIb involves the N-terminal ligand-binding region of GPIb (residues 1 to 282), but with profoundly different functional consequences.