Unfractionated and Low-Molecular-Weight Heparins, Basic Mechanism of Action and Pharmacology

Abstract

Unfractionated heparin has enjoyed sole anticoagulant status for nearly 50 years. Despite a dramatic growth in the development and the introduction of many newer anticoagulant and antithrombotic drugs and polytherapeutic approaches during the past decade, unfractionated and low-molecular-weight heparins remain the drugs of choice for many indications, including surgical anticoagulation, interventional cardiology, and in several additional considerations. Unfractionated heparin has a major role in the areas of vascular medicine and surgery, and it is the only parenteral anticoagulant drug that can be empirically neutralized by such agents as protamine sulfate. The development of low and ultra low-molecularweight heparins, which are a class of depolymerized heparin derivatives with distinct pharmacologic profiles that are largely determined by their composition, represents a refinement for the use of heparin. These drugs produce their major effects by combining with antithrombin Ill and exerting antithrombin and anti-Xa inhibition. The low-molecular-weight heparins also increase non-antithrombin III-dependent effects, such as tissue factor pathway inhibitor release, modulation of adhesion molecules, and the release of profibrinolytic and antithrombotic mediators from the blood vessels. Each of the low-molecular-weight heparins has different cumulative effects, and each product exhibits a distinct profile. Initially developed for the prophylaxis of postsurgical deep vein thrombosis, these drugs are now also used for the treatment of both venous and arterial thrombotic disorders. To a large extent, the low-molecular-weight heparins have replaced unfractionated heparin in most of the subcutaneous indications. This has resulted in a dramatic evolution in anticoagulant management that allows patients with thrombotic disorders to be treated in an outpatient setting. Thus, the introduction of low-molecular-weight heparins represents a major advance in improving the use of heparin. Generic versions of these drugs are likely to be developed as their patents expire. Currently, there are no clear guidelines for the acceptance of the generic versions of branded products. To avoid safety and efficacy-related problems, a generic drug must meet both the chemical and biologic equivalence criterion. Synthetically and biosynthetically derived agents such, as pentasaccharide, will also be introduced for clinical use; however, these drugs will have a narrower therapeutic spectrum due to their monotherapeutic nature. Heparin and its derivatives will continue to have a crucial role in the management of thrombotic and cardiovascular disorders in years to come.