Antithrombotic agents

Abstract

The morbidity and mortality associated with thromboembolic diseases are a worldwide problem. Deep venous thrombosis (DVT) and pulmonary embolism (PE) were estimated, some years ago, to be responsible for between 300,000 and 600,000 hospitalisations annually in the US. Arterial thrombosis is a major cause of myocardial infarction (MI), cerebral infarction and peripheral arterial diseases. Currently available antithrombotic drugs can be divided into three classes: anticoagulants (including vitamin K antagonists, unfractionated heparin and low molecular weight heparins [LMWHs]), antiplatelet agents (platelet aggregation inhibitors such as aspirin, ticlopidine and dipyridamole) and thrombolytics (streptokinase, urokinase and tissue plasminogen activator [t-PA]). All these drugs have demonstrated efficacy in the clinic, but each has its limitations. The risk of haemorrhage persists (though to varying degrees), and efficacy in the prevention, in addition to the treatment, of thromboembolic diseases needs to be improved. In addition, reocclusion following thrombolytic therapy remains a far from negligible risk. Current research goals are focused on identifying more potent and specific inhibitors of targets playing a crucial role in the coagulation pathway, such as thrombin and Factor Xa. Long-term goals are to develop thrombin receptor antagonists or analogues of natural occurring anticoagulants (e.g., tissue factor pathway inhibitor [TFPI] and protein C). The search for more effective anti-aggregating agents has resulted in the ongoing development of clopidogrel (a chemical analogue of ticlopidine), and thromboxane synthase inhibitors and receptor blockers. However, the main efforts have been focused on developing antagonists of the platelet receptor glycoprotein, Gp IIb/IIIa.Much work has been performed to improve the fibrin specificity of thrombolytic agents. In all these areas, new promising chemical structures have been identified, and a number of new antithrombotic agents are in development. The potential development issues remain the risk of bleeding at therapeutic doses, the possible lack of efficacy in sub-groups of treated patients, as well as dose adjustment and treatment duration.The considerable clinical progress in interventional cardiology (e.g., percutaneous transluminal coronary angioplasty [PTCA] and stent implantation) has increased the need for antithrombotic drugs with high local efficacy at the site of arterial injury. Recent progress in the knowledge of plaque rupture-induced disorders, particularly the major role of tissue factor, is suggesting new concepts for antithrombotic therapy. The experience from clinical trials with antithrombotic agents, the validation of biological parameters predictive of a prethrombotic state, and the improvement in non-invasive methods to control drug efficacy are likely to contribute to significant therapeutic progress in the prevention and treatment of venous and arterial thrombosis.