The Synthetic Pentasaccharide Fondaparinux: First in the Class of Antithrombotic Agents that Selectively Inhibit Coagulation Factor Xa

Abstract

Fondaparinux (Arixtra), a synthetic pentasaccharide, is the first in a new class of antithrombotic agents that selectively inhibit coagulation factor Xa. In vitro experiments demonstrated that it is a selective inhibitor of factor Xa. In plasma, fondaparinux selectively binds to antithrombin, catalyzes factor Xa inhibition, and thereby inhibits thrombin generation. Its antithrombotic efficacy has been demonstrated in various animal models mimicking venous and arterial thrombosis. In humans, its pharmacokinetic profile is favorable, with a rapid onset of antithrombotic activity and an elimination half-life allowing a convenient once-daily dosing regimen. In several clinical trials, fondaparinux was more effective than the reference drug, enoxaparin, in preventing venous thromboembolism after hip fracture, major knee, and elective hip replacement surgeries. The overall reduction in the risk of venous thromboembolism ranged between 26.3 and 56.4%, depending on the trial. This superior efficacy was achieved without increasing the risk of clinically relevant bleeding. Fondaparinux also showed promising results in the treatment of patients with venous thromboembolism and acute coronary syndromes. Thus, it is now established that selective factor Xa inhibition is an efficient way to prevent venous thrombosis. The advent of fondaparinux offers an opportunity to improve substantially the management of venous thromboembolism.

Differential Metastasis Inhibition by Clinically Relevant Levels of Heparins—Correlation with Selectin Inhibition, Not Antithrombotic Activity

“…Taken together with a similar efficacy in clinical anticoagulation (via anti-Xa activity) and a lower incidence of side effects, such as heparininduced thrombocytopenia, they have become favored in clinical practice (35,46). Further benefits are claimed for Fondaparinux, a synthetic heparinoid pentasaccharide of defined structure (33) that specifically binds to antithrombin (47,48).…”

Heparin as an Inhibitor of Cancer Progression

“…The identification of a pentasaccharide reponsible for the antithrombin inhibitory activity in the heparin sequence enabled to evaluate the anti-cancer activity of heparin [47]. While the synthetic pentasaccharide -fondaparinux did not affect cancer progression, LMWH effectively attenuated metastasis at clinically tolerable levels [25,26] However, the antimetastatic activity of LMWH has been found to vary among different preparations.…”

EP42675, a synthetic parenteral dual‐action anticoagulant: pharmacokinetics, pharmacodynamics, and absence of interactions with antiplatelet drugs

“…1) combines in a single molecule an active site reversible DTI, a peptidomimetic moiety (a-N-(2-naphtalenesulfonyl)-glycyl-D-4-aminophenylalanyl-piperidine) [a-NAPAP] analog), and an indirect FXa inhibitor, an antithrombin-binding pentasaccharide moiety (fondaparinux analog). Its synthesis [4] and antithrombotic properties in vitro [5][6][7] and in animals [5,6] were previously described. Thus, the predictable pharmacokinetic properties of the fondaparinux analog moiety could be transferred to the DTI moiety, making EP42675 a unique anticoagulant with a low interindividual variability.…”