Mechanisms of platelet activation by thrombin: A short history

Platelet activation by thrombin is relevant to arterial thrombosis, therefore it is an attractive target for the development of new antithrombotic drugs. In the 1970s the platelet membrane complex glycoprotein (GP) Ib-V-IX was shown to have a high affinity binding site for thrombin on GPIb alpha and a substrate cleaved by thrombin, GPV. For several years it was considered to be involved in platelet activation by thrombin. The discovery of the protease activated receptors (PARs) in 1991 was a major breakthrough in the field. The first member of this family of receptors to be discovered was PAR1, a seven transmembrane G-protein coupled receptor which, upon cleavage by thrombin, unmasks a new amino-terminus able to bind intramolecularly to PAR1 itself thus inducing signaling. On human platelets PAR1 and, later PAR4, were demonstrated to mediate most of the platelet responses to thrombin. However, after the discovery of PARs, different groups demonstrated that GPIb alpha is required to stimulate a full platelet activation by thrombin. A model where thrombin binds to the GPIb receptor prior to proteolysis of the PAR receptors was supported by several lines of evidence. A role for GPV as inhibitor of GPIb alpha signaling has been shown by using GPV knock-out mice. Crystallographic data suggested that thrombin bound to GPIb alpha might be able to interact with other GPIb alpha molecules on the same or other platelets, shedding light on a new role for thrombin binding to GPIb alpha. Finally, anti-PAR1 molecules were developed which are now in phase II and III clinical studies as antithrombotic drugs. (C) 2011 Elsevier Ltd. All rights reserved.