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Chest

Volume 126, Issue 3, Supplement, September 2004, Pages 188S-203S
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Heparin and Low-Molecular-Weight Heparin: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy

https://doi.org/10.1378/chest.126.3_suppl.188SGet rights and content

This article about unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) is part of the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a pentasaccharide, catalyzing the inactivation of thrombin and other clotting factors. UFH also binds endothelial cells, platelet factor 4, and platelets, leading to rather unpredictable pharmacokinetic and pharmacodynamic properties. Variability in activated partial thromboplastin time (aPTT) reagents necessitates site-specific validation of the aPTT therapeutic range in order to properly monitor UFH therapy. Lack of validation has been an oversight in many clinical trials comparing UFH to LMWH. In patients with apparent heparin resistance, anti-factor Xa monitoring may be superior to measurement of aPTT. LMWHs lack the nonspecific binding affinities of UFH, and, as a result, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties. LMWHs have replaced UFH for most clinical indications for the following reasons: (1) these properties allow LMWHs to be administered subcutaneously, once daily without laboratory monitoring; and (2) the evidence from clinical trials that LMWH is as least as effective as and is safer than UFH. Several clinical issues regarding the use of LMWHs remain unanswered. These relate to the need for monitoring with an anti-factor Xa assay in patients with severe obesity or renal insufficiency. The therapeutic range for anti-factor Xa activity depends on the dosing interval. Anti-factor Xa monitoring is prudent when administering weight-based doses of LMWH to patients who weigh > 150 kg. It has been determined that UFH infusion is preferable to LMWH injection in patients with creatinine clearance of < 25 mL/min, until further data on therapeutic dosing of LMWHs in renal failure have been published. However, when administered in low doses prophylactically, LMWH is safe for therapy in patients with renal failure. Protamine may help to reverse bleeding related to LWMH, although anti-factor Xa activity is not fully normalized by protamine. The synthetic pentasaccharide fondaparinux is a promising new antithrombotic agent for the prevention and treatment of venous thromboembolism.

Section snippets

1.0 Heparin: Historical Perspective, Chemical Structure, and Mechanism of Action

Heparin, a heterogeneous mixture of branched glycosaminoglycans, was discovered to have antithrombotic properties by McLean almost 90 years ago.1 Brinkhous and associates2 then demonstrated that heparin is an indirect anticoagulant, requiring a plasma cofactor. This cofactor was subsequently named antithrombin (AT) III by Abildgaard in 19683 and now is referred to simply as AT. The main anticoagulant action of heparin is mediated by the heparin/AT interaction. The mechanism of this interaction

2.0 LMWHs: Historical Perspective and Overview

LMWHs are derived from UFH by chemical or enzymatic depolymerization. The development of LMWHs for clinical use was stimulated by the following three main observations: (1) LMWHs have reduced anti-factor IIa activity relative to anti-factor Xa activity15141; (2) LMWHs have a more favorable benefit/risk ratio142143 in animal studies; and (3) LMWHs have superior pharmacokinetic properties.144145146147148149 Of these potential advantages, only the superior pharmacokinetic properties are of clear

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    Copyright © 2004 The American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.