Chapter 7: Unfractionated Heparin and Low-Molecular Heparins

UNFRACTIONATED HEPARIN

OVERVIEW

Unfractionated heparin (UFH) is considered an indirect parenteral anticoagulant, as it has little or no intrinsic anticoagulant activity and works by potentiating the effect of antithrombin (AT), by UFH binding to it, and thereby inhibiting various activated clotting factors.¹

UFH is a glycosaminoglycan found in the secretory granules of mast cells.² UFH is a heterogeneous mixture of various lengths and properties. Each heparin molecule is made up of alternating D-glucuronic acid and N-acetyl-D-glucosamine residues with varying molecular size from 5,000 to 30,000 daltons (mean 15,000 daltons).^{3, 4, and 5} The anticoagulant effect of UFH is mediated through a specific pentasaccharide sequence on the heparin molecule that binds to AT, which causes a conformational change to antithrombin.³ This UFH-AT complex inhibits the activity of factors IXa, Xa, XIIa, and thrombin (IIa). Only one-third of the heparin molecule possesses this unique pentasaccharide sequence with affinity to antithrombin. This complex is 100 to 1,000 times more potent as an anticoagulant compared to antithrombin alone.⁶ Through its action on thrombin, this UFH-AT complex also inhibits factors V and VIII. Not only does UFH prevent the growth of formed thrombus, it may also have effects on the patient's own thrombolytic system.⁷ The factors that are most sensitive to this complex are IIa and Xa. Only molecules that contain >18 pentasaccharides can bind to both antithrombin and thrombin simultaneous. Conversely, molecules with as few as 5 pentasaccharides can inhibit factor Xa.⁸ In addition, heparin binds to platelets, thereby inhibiting platelet function by either inducing or inhibiting platelet aggregation, which may contribute to the bleeding effects of heparin by a mechanism independent of its anticoagulation effect.

Commercially available UFH preparations are derived from porcine intestinal mucosa.⁹

PHARMACOKINETICS

Due to its large molecular size and anionic structure, UFH is not absorbed reliably from the gastrointestinal tract when taken orally.2 Intramuscular (IM) injection is discouraged, given its erratic absorption. In addition, IM administration may result in hematomas. Therefore, the preferred route of UFH administration is either by a continuous intravenous (IV) infusion or by subcutaneous injection. It is recommended to give UFH as an IV bolus if an immediate anticoagulant effect is required rather than via a subcutaneous route, because its anticoagulant effect is seen in one to two hours.¹⁰

The bioavailability of UFH is dose dependant, which ranges from 30 percent at lower doses to as high as 70 percent at the higher doses. Therefore, if the subcutaneous route is chosen to deliver a dose, this dose should be higher than the usual intravenous dose.^11,12 The bioavailability and anticoagulant activity of UFH is limited by the binding of UFH to a number of circulating plasma proteins such as platelet factor-4, macrophages, fibrinogen, lipoprotein, and endothelial cells, which may account for ...