Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

Abstract

This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid, as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin, factor Xa, and other clotting enzymes. Heparin also binds to cells and plasma proteins other than antithrombin causing unpredictable pharmacokinetic and pharmacodynamic properties and triggering nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and plasma proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and are associated with a lower risk of nonhemorrhagic side effects. LMWHs can be administered once daily or bid by subcutaneous injection, without coagulation monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin. Therefore, fondaparinux-associated HIT or osteoporosis is unlikely to occur. Fondaparinux exhibits complete bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without coagulation monitoring. Three additional parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in patients with HIT.

Figure 1.

Inactivation of clotting enzymes by heparin. Top, ATIII is a slow inhibitor without heparin. Middle, Heparin binds to ATIII through a high-affinity pentasaccharide and induces a conformational change in ATIII, thereby converting ATIII from a slow inhibitor to a very rapid inhibitor. Bottom, ATIII binds covalently to the clotting enzyme, and the heparin dissociates from the complex and can be reused. AT = antithrombin. (Reprinted with permission from Hirsh et al.)

Figure 2.

Molecular weight distribution of LMWHs and heparin. LMWH = low-molecular-weight heparin. (Reprinted with permission from CHEST.)

Figure 3.

Low doses of heparin clear rapidly from plasma through a saturable (cellular) mechanism and the slower, nonsaturable, dose-independent mechanism of renal clearance. Very high doses of heparin are cleared predominantly through the slower nonsaturable mechanism of clearance. t1/2 = half-life. (Reprinted with permission from CHEST.)

Figure 4.

As heparin enters the circulation, it binds to heparin-binding proteins (ie, other plasma proteins), endothelial cells, macrophages, and ATIII. Only heparin with the high-affinity pentasaccharide binds to ATIII, but binding to other proteins and to cells is nonspecific and occurs independently of the ATIII binding site. See Figure 1 legend for expansion of abbreviation. (Reprinted with permission from CHEST.)