Parenteral Anticoagulants

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.

The use of anticoagulants in morbidly obese patients

“…Similar correlations were demonstrated for nadroparin [9]. As shown by these studies, higher prophylactic doses of low molecular weight heparins should be used in patients with obesity [10]. However, it seems justified to measure anti-Xa activity in extremely obese patients.…”

“…Studies on clinical use of anticoagulants provide no basis for any adjustment of doses in obese patients as compared to patients with normal body weight [10,16]. In our opinion, however, further studies are required in this specific population.…”

A Prospective Study of Adequacy of Anticoagulation with Fixed Dose Weight Adjusted Unfractionated Heparin in Patients with Deep Vein Thrombosis

“…Variation in aPTT values occur depending on the reagents and instruments used [10]. But the values were consistently lower here.…”

“…Prolonged aPTT does not correlate with the risk of bleeding and similarly subtherapeutic aPTT does not correlate with recurrent thromboembolism [7]. Estimating heparin levels using anti-Xa assay has been studied as an alternative monitoring method but it too has its limitations [10].…”

Thrombo-Embolic Events in Cancer Patients with Impaired Renal Function

“…For very old patients, it should be common clinical practice to accurately adjust the dose to body weight, to regularly monitor platelet counts in a surgical context, to determine anti-Xa levels, and to correctly manage any interaction with other antithrombotic drugs. In their literature overview these guidelines further state that when used in full therapeutic doses, nadroparin clearance, but not tinzaparin clearance, was correlated with creatinine clearance (R=0.49; p<0.002), even when creatinine clearance was as low as 20 mL/min [25]. Guidelines report that enoxaparin (40 mg once daily), but not tinzaparin (4500 Units once daily), bio accumulate over 8 days of exposure [25].…”