UFH readily binds to plasma proteins, which contributes to its variable anticoagulant response after parenteral administration. When given via subcutaneous injection for therapeutic anticoagulation, doses need to be large enough (>30,000 U/day) to overcome UFHs low bioavailability. Intravenous (IV) infusion or subcutaneous injections are the available routes for UFH administration and IV is preferred. This results in neutralization of factor Xa, which ultimately inhibits thrombin formation and thrombus development. Fondaparinux selectively and irreversibly binds to AT. Fondaparinux is a synthetic analog of the naturally occurring pentasaccharide found in heparins. The active pentasaccharide sequence responsible for catalyzing AT is found on one-third and one-fifth of the chains of UFH and LMWH, respectively. This binding produces a conformational change, accelerating AT binding and inactivation of coagulation factors XIIa, IXa, XIa, Xa and thrombin. Once heparin binds and activates AT, it can readily dissociate and bind to additional AT, providing a continuous anticoagulant effect. Heparins contain an active pentasaccharide sequence that binds to AT. Heparins have no fibrinolytic activity and will not lyse existing thrombi.

Since heparins are dependent on the presence of AT for clotting factor inhibition, they are considered indirect anticoagulants (Table 1). Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are the anticoagulants of choice in acute thrombosis due to their rapid onset of antithrombotic activity. Indirect inhibitors, however, target and bind to naturally occurring plasma cofactors, such as antithrombin (AT), catalyzing their interaction with clotting enzymes. Anticoagulant agents can inhibit thrombogenesis by altering various pathways within the clotting cascade or by targeting thrombin directly, attenuating thrombin generation. Thrombin may also potentiate clot formation by fibrin polymerization, platelet receptor activation, endothelium activation, and activation of factors V, VIII, XI, and XIII.

Thrombin is one of the most potent activators of primary (platelet-mediated) and secondary (clotting factor-mediated) hemostasis. The prothrombinase complex is then assembled on a phospholipid membrane and cleaves prothrombin (factor II) to factor IIa (thrombin). Tissue factor forms a complex with factor VIIa in the presence of calcium and cleaves clotting factors X and IX to their activated forms (factors Xa and IXa). The coagulation cascade is triggered by tissue factor release from tissue trauma or vascular injury (Fig.

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