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Volume 141, Issue 2, Supplement, February 2012, Pages e24S-e43S
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Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physician Evidence-Based Clinical Practice Guidelines Online Only Articles
Parenteral Anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

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This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid, as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin, factor Xa, and other clotting enzymes. Heparin also binds to cells and plasma proteins other than antithrombin causing unpredictable pharmacokinetic and pharmacodynamic properties and triggering nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and plasma proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and are associated with a lower risk of nonhemorrhagic side effects. LMWHs can be administered once daily or bid by subcutaneous injection, without coagulation monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin. Therefore, fondaparinux-associated HIT or osteoporosis is unlikely to occur. Fondaparinux exhibits complete bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without coagulation monitoring. Three additional parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in patients with HIT.

Section snippets

Heparin

More than 90 years ago, McLean1 discovered that heparin has anticoagulant properties. Brinkhous and associates2 then demonstrated that heparin requires a plasma cofactor to express its anticoagulant activity. In 1968, Abildgaard identified this cofactor as antithrombin III,3 which is now referred to as antithrombin. The major anticoagulant action of heparin is mediated by the heparin/AT interaction. The mechanism of this interaction was demonstrated in the 1970s.4, 5, 6 Heparin binds to

Direct Thrombin Inhibitors

In contrast to indirect anticoagulants, which require a plasma cofactor to exert their activity, direct thrombin inhibitors have intrinsic activity because they bind to thrombin and block its enzymatic activity. The currently approved direct thrombin inhibitors are hirudin, bivalirudin, and argatroban.

Acknowledgments

Author Contributions: As Topic Editor, Dr Garcia oversaw the development of this article, including any analysis and subsequent development of the information contained herein.

Dr Garcia: contributed as a Topic Editor.

Dr Baglin: contributed as a panelist.

Dr Weitz: contributed as a panelist.

Dr Samama: contributed as a panelist.

Financial/nonfinancial disclosures: In summary, the authors have reported to CHEST the following conflicts of interest: Drs Weitz and Garcia have served as consultants for

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    Funding/Support: The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758] and Bayer Schering Pharma AG. Support in the form of educational grants was also provided by Bristol-Myers Squibb; Pfizer, Inc; Canyon Pharmaceuticals; and sanofi-aventis US.

    Disclaimer: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://chestjournal.chestpubs.org/content/141/2_suppl/1S.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

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