The therapeutic potential of novel anticoagulants

Abstract

For several decades, conventional anticoagulant therapy has been based on indirect inhibition of coagulation factors with heparin and warfarin (coumadin). Although used widely and effectively, heparin and warfarin display liabilities which have prompted the development of new anticoagulants over the last two decades. The first to be developed was a series of low molecular weight heparins (LMWHs). Their favourable pharmacokinetic profiles and risk/benefit ratios led to widespread use in Europe and more recently, approval for their use in the USA. Paralleling the development of LMWHs, but lagging behind in terms of clinical development, has been the pursuit of a different strategy focused on direct rather than indirect inhibition of enzymes in the coagulation cascade. In contrast to heparin, LMWHs, or other glycosaminoglycans, direct inhibitors, exert their effects independent of either antithrombin III (ATIII) or heparin co-factor II (HCII) and more effectively inhibit clot-bound thrombin or FXa. Highly potent, selective (versus other serine proteases), direct thrombin and FXa inhibitors have been identified and isolated from natural sources, such as leeches, ticks and hookworms. The recombinant forms and analogues of these natural proteins have been produced using molecular biology techniques, i.e., rHirudin, Hirulogs, recombinant tick anticoagulant peptide (rTAP), recombinant antistasin (rATS) and recombinant nematode anticoagulant factor (rNAP-5). The design of novel structures or the modification of existing chemicals has led to the synthesis of many non-peptide, low molecular weight inhibitors of thrombin and FXa. Some of them are orally active and may be suitable for long-term clinical use. In addition, considerable progress has been made in developing specific TF/VIIa complex inhibitors. The anticoagulation properties of the new agents have been and are being characterised in experimental studies. Some of them have been advanced to large scale clinical trials and their effectiveness (and sometimes relative ineffectiveness compared with conventional therapy) in arterial and venous thromboembolic disorders has been demonstrated. These novel anticoagulents are curently being tested or will for their validity and potential as new antithrombotic agents acting via direct enzyme inhibition. In doing so, it is hoped that the clinician will in future be able to turn to proven specific anticoagulant interventions, targeted at each respective thrombotic state.

• anticoagulants
• antithrombotic agents
• thrombosis