Neutralization of the Anticoagulant and Anti‐Xa Effects of Fondaparinux and Idraparinux by a Novel Synthetic Antagonist. Pharmacologic Implications

Abstract

Synthetic analogues of the oligosaccharide sequence mimicking the antithrombin binding sites of heparin (UFH) have been developed as antithrombotic agents. Arixtra (Fondaparinux) (F) is currently approved for the management of post surgical DVT and ACS, while its methylated derivative, namely Idraparinux (I) is in clinical development for different clinical indications. Despite their clinical efficacy, bleeding complications have been reported with the use of these agents. Currently, there is no pharmacologic antagonist available to neutralize these agents. Recently, a series of synthetic salicylamide derived antagonists for (UFH) and low molecular weight heparins are developed (Polymedix, Radnor, PA). To further investigate the relative neutralization of F and I, each of these agents were added to citrated whole blood and citrated plasma at a concentration range of 0–10 ug/ml. PS and PMX 60056 were added at fixed concentrations of 6.2, 12.5 and 25 ug/ml. Heptest was used to measure the anticoagulant effects of these agents. In addition, FPA and thrombin generation was also measured. PMX 60056 effectively neutralized the heptest prolongation by both the F and I. However, PS did not produce any antagonism of the anticoagulant effects of these two agents. In the anti‐Xa assay as measured by using the amidolytic assays, neither the PMX 60056 nor the PS produced any neutralization of these effects at any concentrations. In the whole blood assays, PMX 60056 was effective in the neutralization of the fibrinopeptide A generation inhibition, however PS did not produce any inhibition. These results suggest that PMX 60056 is effective in neutralizing the anticoagulant effects of Fand I and warrant additional in vivo validation of these studies.