For many decades, heparin and oral anticoagulants have been the antithrombotic drugs of choice in the prevention and treatment of both venous and arterial thromboembolism. The efficacy and the relative safety of these compounds have been consistently proven by a large number of clinical studies that have also progressively contributed to improve their management. However, these drugs have limitations. Unfractionated heparin (UFH) acts by catalyzing the effect of antithrombin III, a natural anticoagulant able to inactivate factors IIa, IXa, and Xa, and also by inhibiting the activation of factors V and VIII by thrombin. The anticoagulant effect of UFH is unpredictable and varies considerably among patients, depending upon age, gender, body weight, smoking status, and renal function. This wide variability is caused by heparin binding to phase reactant proteins; the level of which varies among normal individuals and among disease states. Before therapeutic plasma levels are achieved, the binding to plasma proteins as well as to receptor sites on endothelium must be saturated. Unfractionated heparin must be given parenterally and it requires careful laboratory monitoring to ensure the anticoagulant response is therapeutic.1 Low molecular weight heparin (LMWH) also acts by catalyzing antithrombin III, but because of the reduced number of saccharide units, its antithrombotic activity is more selective and it is mainly based on inactivation of factor Xa because of a reduced ability to inactivate factor IIa. Low molecular weight heparin does not bind to the endothelium and have a lower affinity for plasma proteins. This results in a more predictable bioavailability, in a substantially longer half-life, and in a stable dose response when injected subcutaneously. Therefore, LMWH has a more predictable anticoagulant response that has overcome the need for laboratory monitoring. However, it also needs to be administered parenterally and thus has limited indications for long-term use.2 Characteristics and pharmacokinetics of UFH and LMWH are summarized in T1 and T2. In the last years, new antithrombotic agents have been developed to overcome some of heparin and warfarin limitations. One of the main goals was the search for a greater selectivity in the pharmacologic action of the new compounds. Direct factor Xa inhibitors (DTI) and direct thrombin inhibitors recently underwent extensive evaluation in the prevention and treatment of both venous and arterial thromboembolism. science [coagulation and hematology] New Antithrombotic Drugs Walter Ageno,1 Alexander G.G. Turpie2 1Department of Internal Medicine, University of Insubria, Varese, Italy, 2Department of Internal Medicine, McMaster University, Hamilton, Canada