Chest

Chest

Volume 133, Issue 6, Supplement, June 2008, Pages 141S-159S
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Antithrombotic and Thrombolytic Therapy, 8th ED: ACCP Guidelines
Parenteral Anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)

https://doi.org/10.1378/chest.08-0689Get rights and content

This chapter describes the pharmacology of approved parenteral anticoagulants, including 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 factors. Heparin also binds to cells and other plasma proteins, endowing it with unpredictable pharmacokinetic and pharmacodynamic properties, and can lead to 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 proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and have a lower risk of nonhemorrhagic side effects. LMWHs can be administered once or twice daily by subcutaneous injection, without anticoagulant 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, HIT and osteoporosis are unlikely to occur. Fondaparinux has excellent bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without anticoagulant monitoring. Three parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in HIT patients.

Section snippets

Monitoring Antithrombotic Effect

2.2.3 In patients treated with LMWH, we recommend against routine coagulation monitoring (Grade 1C). In pregnant women treated with therapeutic doses of LMWH, we recommend monitoring of anti-Xa levels (Grade 1C).

Dosing and Monitoring in Special Situations

2.2.4 In obese patients given LMWH prophylaxis or treatment, we suggest weight-based dosing (Grade 2C). In patients with severe renal insufficiency (creatinine clearance [CrCl] < 30 mL/min) who require therapeutic anticoagulation, we suggest the use of UFH instead of LMWH (Grade 2C). If

Heparin

About 90 years ago, McLean1 discovered that heparin has antithrombotic properties. Brinkhous et al2 then demonstrated that heparin is an indirect anticoagulant and requires a plasma cofactor to express its anticoagulant activity. Abildgaard3 subsequently identified this cofactor as ATIII in 1968, but it is now referred to as AT. The major anticoagulant action of heparin is mediated by the heparin/AT interaction. The mechanism of this interaction was elucidated in 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.

CONLICT OF INTEREST DISCLOSURES

Dr. Hirshdiscloses that he has received partial support for writing two books, one on Fondaparinux and one on low-molecular-weight heparin.

Dr. Bauerdiscloses that he received consultant fees from GlaxoSmithKline, Bayer Healthcare, Pfizer, Eisai, and Bristol-Myers Squibb. He is on the speakers bureau for GlaxoSmithKline and Sanofi-Aventis, and has assisted the advisory committees of Bayer Healthcare and Bristol-Myers Squibb. Dr. Bauer is also in a fiduciary position for the International Society

ADDENDUM

On page 153S, first column, second paragraph under Argatroban, the authors wish to add the following clarifying language:

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