especially in the elderly. A distinctive characteristic of the newer anticoagulants is their targeted action on a single factor of the coagulation cascade, while older anticoagulant agents such as heparins and VKAs inhibit multiple targets.
Essential characteristics of the newer agents We have highlighted the main characteristics of these newer anticoagulant molecules in Table 1. Their site of action in the blood coagulation process, in which, according to the modern concept, tissue factor/FVIIa complex induces FXa generation leading to the formation of the first traces of thrombin, makes it possible to differentiate the active anticoagulant agents on the initiation phase from the coagulation phase (governed mainly by TF/FVIIafactor tissue, free FXa, and TFPI etc.), as well as on that of the coagulation amplification phase or propagation phase related to the formation of the prothrombinase complex containing the FXa bound to FVa, which then provokes the burst of thrombin formation in the final coagulation phase. This leads to one question which divides the specialists: ‘‘Should we prefer the anticoagulant agents inhibiting FXa to those inhibiting FIIa keeping in mind, that in the animal model, a small number of studies grants a less hemorrhagic activity to the FXa inhibitors than those of the FIIa’’. However the dilemma could be posed from another point of view: which is the intensity of inhibition of each phase of thrombin generation process that warrants optimal benefit / risk ratio? Moreover, timing and dosing of the antithrombotic prophylaxis are crucial parameters for the efficacy and safety of the treatment at least in major orthopedic surgery. Additionally to the single clotting factor target, once defined, it is critical to demonstrate the specificity of the anticoagulant activity of the new agent, its affinity for the target as well as the reversible or non reversible characteristics of its binding to the target. It is also necessary to seek a potential antigenicity effect (given the example of hirudin). The clinical development, after pharmacokinetic and pharmacodynamic studies, requires the demonstration of the efficacy of the product in animal models of venous or arterial thrombosis and safety studies to evaluate the potential risk of bleedings and other adverse effects. In clinical studies in healthy volunteers, a difficulty appears in monitoring the efficacy and the tolerability of escalating doses of these newer anticoagulant agents. As a matter of fact, the usual laboratory tests of coagulation which could evaluate the risk of bleeding are not quite sensitive to these new anticoagulant agents. Thus, Fondaparinux and Idraparinux, two 72