The currently available anticoagulants include unfractionated heparin, LMWHs, fondaparinux, vitamin K antagonists (ie, warfarin), and direct-acting oral anticoagulants (DOACs) (ie, dabigatran, rivaroxaban, apixaban, edoxaban, betrixaban). (For a discussion of the injectable DTIs, see section Heparin-Induced Thrombocytopenia above.)
CLASSES OF ANTICOAGULANTS
A. Unfractionated Heparin and LMWHs
Unfractionated heparin is a biologic product most commonly derived from porcine intestinal tissue rich in heparin-bearing mast cells. It is heterogeneous with respect to sulfation and polymer length; individual molecules may range from 3000 to 30,000. Only about one-third of the molecules in a given preparation of unfractionated heparin contain the crucial pentasaccharide sequence necessary for binding of antithrombin and exerting its anticoagulant effect upon thrombin. Heparin is highly negatively charged, and upon intravenous infusion, it binds to a large array of blood components, such as endothelial cells, platelets, mast cells, and plasma proteins. The degree of anticoagulation with unfractionated heparin is typically monitored by aPTT or anti-Xa level in patients who are receiving the drug in therapeutic doses, although the pharmacokinetics of unfractionated heparin are poorly predictable. Only a fraction of an infused dose of heparin is metabolized by the kidneys, making it safe to use in most patients with significant kidney disease.
The LMWHs are produced from chemical depolymerization of unfractionated heparin, resulting in products of lower molecular weight (mean molecular weight, 4500–6500d, depending on the LMWH). Due to less protein and cellular binding, the pharmacokinetics of the LMWHs are much more predictable than those of unfractionated heparin, allowing for fixed weight-based dosing. All LMWHs are principally renally cleared and must be avoided or used with extreme caution in individuals with creatinine clearance less than 30 mL/min. A longer half-life permits once- or twice-daily subcutaneous dosing, allowing for greater convenience and outpatient therapy in selected cases. Most patients do not require monitoring, although monitoring using the anti-Xa activity level is appropriate for patients with moderate kidney disease, those with elevated body mass index or low weight, and selected pregnant patients. LMWHs are associated with a lower frequency of heparin-induced thrombocytopenia and thrombosis (approximately 0.6%) than unfractionated heparin (3%).
Fondaparinux is a synthetic molecule consisting of the highly active pentasaccharide sequence found in LMWHs. As such, it exerts almost no thrombin inhibition and works to indirectly inhibit factor Xa through binding to antithrombin. Fondaparinux, like the LMWHs, is almost exclusively metabolized by the kidneys, and should be avoided in patients with creatinine clearance less than 30 mL/min. Predictable pharmacokinetics allow for weight-based dosing.
C. Vitamin K Antagonist (Warfarin)
The vitamin K antagonist warfarin inhibits the activity of the vitamin K–dependent carboxylase that is important for the posttranslational modification of coagulation factors II, VII, IX, and X. Although warfarin is taken orally, leading to a significant advantage over the heparins and heparin derivatives, interindividual differences in nutritional status, ...