Targeting at the level of factor Xa and/or prothrombinase complex by synthetic anti-Xa agents such as JTV-803 (Akros Pharma, Princeton, NJ), DX-9065a (Daiichi Pharmaceuticals, Tokyo, Japan), and Fondaparinux (Sanofi-Synthelabo, Toulouse, France) represents an important approach in anticoagulant therapy. Factor Xa is an essential component of the prothrombinase complex and leads to the generation of thrombin. Synthetic heparin pentasaccharide, Fondaparinux (Arixtra®) has been approved by the United States Food and Drug Administration for the prophylaxis of deep vein thrombosis in patients undergoing hip and knee replacement surgeries. There is a rapid stride in the development of newer synthetic inhibitors of factor Xa such as DX-9065a, and JTV-803 in various thrombotic indications. In order to evaluate the parenteral anticoagulant potential of these synthetic factor Xa inhibitors, we used the Hemochron (celite) activated clotting time (ACT) assay. DX-9065a at a final concentration of 5 and 10 μg/ml increased the ACTs to 250 and 300 seconds, respectively. Similar anticoagulant potential was noticed with JTV-803. These findings suggest that these agents may be useful as parenteral anticoagulants during interventional cardiologic procedures, surgical anticoagulation and for the prevention of vascular access occlusion. Fondaparinux requiring antithrombin (AT) for its anticoagulant effect does not increase the celite ACT to the extent as other synthetic factor Xa inhibitors. Fondaparinux even at a final concentration of 100 μg/ml increase the ACT to about 200 seconds and hence are not suitable to be used as parenteral anticoagulants. The concentrations of JTV-803, DX-9065a and fondaparinux required to increase the ACT to near 250 seconds are 6.2, 5 and 125 μg/ml, respectively. While fondaparinux is AT-dependent, the synthetic anti-Xa agents are AT-independent in their actions. The antithrombin sparing effect of direct anti-Xa agents may contribute to an additional anticoagulant effect as reflected by increased ACT levels. Furthermore, there are some other advantages of direct anti-Xa agents when compared to fondaparinux. While direct anti-Xa agents may be used for patients with AT deficiency, fondaparinux being AT-dependent, may not. The inhibition of the clot-bound and prothrombinase-bound factor Xa are additional advantages of direct Xa inhibitors when compared to fondaparinux. Fondaparinux being AT-dependent and upon complexation with AT is not capable of inhibiting the clot-bound factor Xa. Oral Xa inhibitors are being developed and when available patients may have an ideal transition from a parenteral anti-Xa agent to an oral Xa inhibitor. The results clearly suggest that synthetic factor Xa inhibitors except fondaparinux may be used as parenteral anticoagulants. Large-scale clinical studies are warranted to evaluate these findings.