Thrombin as an anticoagulant

Thrombosis is the most prevalent cause of fatal diseases in developed countries. An antithrombotic agent that can be administered to patients with severe acute thrombotic diseases without the risk of causing hemorrhage, as experienced with antithrombotic/thrombolytic therapy in the treatment of acute ischemic stroke or systemic anticoagulants like heparin, would likely revolutionize the treatment of cardiovascular and cerebrovascular diseases. Thrombin remains at the forefront of cardiovascular medicine and a major target of antithrombotic and anticoagulant therapies, due to its involvement in thrombotic deaths. Heparins and direct thrombin inhibitors currently used in the treatment of acute thrombotic complications, especially in the venous circulation, are plagued by complications related to dosage and bleeding. A new strategy of intervention has been proposed in recent years aiming at modulating, rather than inhibiting, thrombin function. Specifically, efforts have been directed toward finding ways of exploiting the anticoagulant function of thrombin unleashed by the activation of protein C, either using small modulators or protein engineering. The ability of thrombin to activate protein C coexists with its procoagulant and prothrombotic functions, mediated respectively by cleavage of fibrinogen and the protease-activated receptor 1 (PAR1). A strategy that inhibits thrombin at the active site abrogates the procoagulant and prothrombotic functions, but also shuts down activity toward the anticoagulant protein C. On the other hand, a strategy that selectively compromises fibrinogen and PAR1 recognition may take advantage of the anticoagulant and cytoprotective functions of activated protein C and prove of interest for in vivo applications. This chapter summarizes current protein engineering efforts to convert thrombin into a potent and safe anticoagulant for in vivo applications.