New developments in antiplatelet and antithrombotic therapy

Several agents which inhibit platelet aggregation (aspirin, ticlopidine, dipyridamole), and anticoagulants (vitamin K antagonists, unfractionated heparin, low molecular weight heparins and heparinoids) are in clinical use. The search for more effective antiaggregating agents has resulted in the development of clopidogrel, a chemical analogue of ticlopidine with minimal bone-marrow suppressing effects, thromboxane synthase inhibitors and receptor blockers, and antagonists of platelet receptor glycoproteins Ib and IIb/IIIa. In addition there is increasing therapeutic experience with chimeric monoclonal antibodies against the platelet receptors, glycoprotein IIb/IIIa, and, to a minor extent, with synthetic peptides or non-peptide inhibitors against the same receptors. Although new anticoagulants have become available, their efficacy has only been tested in animal models of thrombosis: tissue factor pathway inhibitor, factor Xa inhibitors (recombinant tick anticoagulant peptide, antistasin, natural pentasaccharide and DX-9065), recombinant thrombomodulin and recombinant protein C have been tested in this manner. Considerable clinical progress has been made with direct thrombin inhibitors, such as recombinant hirudin and hirulog which appear to be effective antithrombotic agents in patients. There is also clinical experience with argatroban, an arginine derivative which is a competitive antagonist to thrombin. However, PPACK, a tripeptide synthetic compound which irreversibly blocks the active catalytic site of thrombin, has not been investigated in the clinical setting.