Selective Factor Xa Inhibition Improves Efficacy of Venous Thromboembolism Prophylaxis in Orthopedic Surgery

Philip C. Comp, M.D., Ph.D.

Disclosures

Pharmacotherapy. 2003;23(6) 

In This Article

Factor Xa Inhibitors

This group of novel antithrombotic agents binds to and inhibits factor Xa directly without a requirement for antithrombin III. Antithrombotic activity is specific for factor Xa with no effect on other components of the coagulation cascade. Several direct factor Xa inhibitors are under development, including the synthetic molecules YM-60828[51] and DX-9065a[52] and recombinant forms of natural inhibitors such as tick anticoagulant peptide[53] and the nematode protein NAP-5.[54]

As a class of antithrombotic agents, the major advantage of direct factor Xa inhibitors lies in their small size and resultant ability to inactivate circulating, as well as bound, forms of factor Xa. The inhibition is produced in a stoichiometric manner: one molecule of direct factor Xa inhibitor inactivates one molecule of Xa. In theory, the capacity to inhibit factor Xa within the prothrombinase complex, as well as clot-bound factor Xa, suggests more powerful control over thrombus formation and progression and, therefore, potentially greater clinical efficacy. To date, however, most of the direct factor Xa inhibitors are either in preclinical stages of development or have been withdrawn from investigation.[55] The exception is DX-9065a, which appears to hold considerable promise as an antithrombotic agent for arterial disease indications.[56,57]

Fondaparinux sodium (Arixtra; Organon Sanofi-Synthelabo LLC, West Orange, NJ) is the first in a new class of antithrombotic agents that selectively inhibit factor Xa. It is a small, totally synthetic molecule, developed based on the native pentasaccharide sequence (in heparin) that binds to antithrombin III and potentiates its antifactor Xa activity.[58,59,60] Because fondaparinux is produced by total chemical synthesis, it has batch-to-batch consistency and eliminates the risk of pathogen contamination associated with animal-sourced agents such as the heparins.

Unlike the direct factor Xa inhibitors that inactivate factor Xa by binding to its catalytic site, fondaparinux inhibits factor Xa activity indirectly through antithrombin III. Also, in contrast to the heparin family of antithrombotic agents, which contain antifactor IIa activity to varying degrees, fondaparinux has no effect whatsoever on thrombin activity. Rather, by specifically targeting factor Xa, fondaparinux exerts its antithrombotic effect by inhibiting thrombin generation and, therefore, fibrin formation (Figure 1).

As an inhibitor that acts through antithrombin III to limit thrombin generation, the selective antifactor Xa activity (without antifactor IIa activity) of fondaparinux is defined by its characteristic pentasaccharide structure and the absence of additional structural elements required for antithrombin-mediated thrombin inhibition.[61,62,63] The mechanism of action of fondaparinux involves high-affinity (but reversible) binding to antithrombin III and a resultant conformational change in the serpin's reactive loop that greatly enhances antithrombin III's basal rate of factor Xa inactivation.[22] Fondaparinux is not consumed in this reaction but instead is released from the inhibitory complex once binding of antithrombin III to factor Xa has occurred. This feature and the potentiating effect of fondaparinux's basic mechanism of action contrast sharply with the mechanism of action of the direct factor Xa inhibitors. Fondaparinux sodium acts as an antithrombin III catalyst, with one molecule of fondaparinux leading to the inhibition of many factor Xa molecules (Figure 2).[64]

The synthetic pentasaccharide fondaparinux sodium represents a new class of antithrombotic agents with a distinct mechanism of action that imparts selective and specific antifactor Xa activity. Fondaparinux binding to antithrombin III (AT III) potentiates antithrombin III-mediated factor Xa inhibition exclusively. (See text for details.) From reference 64 with permission.

Fondaparinux binds specifically to antithrombin III and not to irrelevant plasma proteins,[65] exhibits no inhibitory effect on platelet aggregation,[37] and is unlikely to be associated with clinical heparin-induced thrombocytopenia, according to the results of studies conducted to date.[37,66,67,68] Fondaparinux has a favorable pharmacokinetic profile after subcutaneous administration, including rapid and complete (100%) absorption into plasma (reaching maximal concentration by approximately 2 hrs), a relatively long half-life (approximately 17 hrs), and a predictable dose response that is independent of age or sex.[69,70] These features allow for subcutaneous once-daily fixed dosing without the need to monitor the drug's anticoagulant effect -- distinct advantages over unfractionated heparin regimens, and to a lesser extent, LMWH, in terms of ease of clinical use ( Table 1 ). As is the case for LMWH, fondaparinux is renally cleared, and caution therefore is required when administering either of these agents to patients with impaired kidney function because bleeding risk is increased under these circumstances. Fondaparinux is contraindicated in patients with severe renal impairment as defined by a creatinine clearance of less than 30 ml/minute, whereas adjustment of LMWH dosage is recommended in these patients.

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