The currently available anticoagulants include unfractionated heparin, LMWHs, fondaparinux, vitamin K antagonist (ie, warfarin), and DOACs (ie, dabigatran, rivaroxaban, apixaban, edoxaban). (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 repeating polymer of sulfated glycosaminoglycans that is most commonly derived from porcine intestinal tissue, which is rich in heparin-bearing mast cells. A biologic product, it is extremely 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 that is necessary for binding of antithrombin and exerting its anticoagulant effect by converting thrombin from a slow inhibitor of coagulation factor activity to a rapid inhibitor. 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, however, making it safe to use in most patients with significant kidney disease. Heparin should be discontinued in patients who have bleeding, and in some cases, protamine sulfate should be administered; 1 mg of protamine neutralizes approximately 100 units of heparin sulfate, and the maximum dose is 50 mg intravenously.
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. About 30% of the molecules in a dose of LMWH are long enough (ie, sufficiently negatively charged) to bind protamine sulfate, allowing for some neutralization of anticoagulant effect. LMWHs are associated with a lower frequency of HIT (approximately 0.6%) than unfractionated heparin.
Fondaparinux, which is chemically related to LMWHs, is a synthetic molecule consisting of the highly active pentasaccharide sequence. 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 ...