Fondaparinux is nearly completely dependent on renal clearance; thus, it is contraindicated in patients with renal insuf- ciency (CrCl,30 mL/min). 1.3.3 Dosing and Monitoring: Fondaparinux is given at a xed dose of 2.5 mg daily for thrombopro- phylaxis and for the treatment of acute coronary syndromes. For treatment of DVT or pulmonary embolism, the drug is given at a dose of 7.5 mg for patients with a body weight of 50 to 100 kg; the dose is decreased to 5 mg for patients weighing,50 kg and increased to 10 mg in those weighing.100 kg. Fondaparinux has not been monitored in clinical studies. Therefore, routine coagulation monitoring is not recommended. In patients with moderate renal insuf ciency (ie, CrCl 30-50 mL/min) who require thromboprophylaxis, the dose of fondaparinux should be reduced by 50% or low-dose heparin should be used in place of fondaparinux. Although coagulation monitoring is not recom- mended on a routine basis, there may be circum- stances in which it is useful to determine the anticoagulant activity of fondaparinux. This can be measured using fondaparinux-speci c anti-Xa assays. The therapeutic anti-Xa range for fondaparinux has not been established. However, when given at the 2.5 mg daily dose, the peak steady-state plasma con- centration is, on average, 0.39 to 0.50 mg/L and is reached approximately 3 h post dose. For patients receiving therapeutic doses of fondaparinux (eg, 7.5 mg daily for an individual of average body weight), the mean peak steady-state plasma concentration can be expected to be 1.20 to 1.26 mg/L 3 h post dose. Fondaparinux does not bind to protamine sulfate, the antidote for heparin. If uncontrollable bleeding occurs with fondaparinux, recombinant factor VIIa may be effective.202 1.3.4 Nonhemorrhagic Side Effects: Fondaparinux has low af nity for PF4 and does not cross-react with HIT antibodies.203 Although there have been isolated case reports of HIT associated with the use of fonda- parinux204,205 and reports of HIT antibodies without thrombocytopenia in patients given prophylaxis with fondaparinux,206 numerous case reports and case series suggest that this agent can be used to treat patients with HIT.207 This issue is further discussed in the article on HIT by Linkins et al32 in this supple- ment and has been summarized by Blackmer et al.208 2012 American College of Chest Physicians by Kimberly Henricks on February 10, 2012 chestjournal.chestpubs.org Downloaded from www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e35S drug accumulates rapidly in patients with renal insuf- ciency. The dose of hirudin must be reduced when the CrCL is,60 mL/min, and the drug is contraindi- cated in patients with renal failure.216 In a retro- spective observational analysis of 181 patients with con rmed HIT who were treated with lepirudin at a mean dose of 0.06 mg/kg/h for a median treatment duration of 7.7 days, 13.8% suffered a thrombotic event and 20.4% suffered major hemorrhage. The Antibodies against hirudin develop in up to 40% of patients treated with lepirudin. Although most of these antibodies have no clinical impact, some can prolong the plasma half-life of lepirudin, resulting in drug accumulation. In addition, anaphylaxis can occur if patients with antibodies are re-exposed to hirudin. Consequently, an alternative anticoagulant should be considered in patients with HIT who have previously been treated with hirudin. Bivalirudin A 20-amino acid synthetic polypeptide, bivalirudin is an analog of hirudin.218 The amino terminal D-Phe- Pro-Arg-Pro sequence, which binds to the active site of thrombin, is connected via four Gly residues to a carboxy-terminal dodecapeptide that interacts with exosite 1 on thrombin.219 Like hirudin, bivalirudin forms a 1:1 stoichiometric complex with thrombin. However, once bound, thrombin cleaves the Pro-Arg bond within the amino terminal of bivalirudin, thereby allowing recovery of thrombin activity.220 Bivalirudin has a plasma half-life of 25 min after IV injection,221 and only 20% is excreted via the Bivalirudin is licensed as an alternative to hep- arin in patients undergoing percutaneous interven- tions for unstable angina or non-ST-elevation or ST-elevation myocardial infarction and in patients with HIT (with or without thrombosis) who require per- cutaneous coronary interventions.223 The currently recommended dose is a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/h for the duration of the procedure. Dose reduction should be considered in patients with moderate to severe renal impairment. The drug has also been explored as an alternative to heparin in patients undergoing cardiopulmonary bypass surgery. In contrast to hirudin, bivalirudin is not immunogenic. However, antibodies against hiru- din can cross-react with bivalirudin in vitro. The clinical consequences of this cross-reactivity are uncertain. Argatroban Argatroban is a small molecule competitive inhib- itor of thrombin (molecular weight, 500 kDa). It HIT from danaparoid to vitamin K antagonists. The long half-life of danaparoid is a disadvantage if patients require urgent surgery or invasive procedures. It also is problematic if patients have serious bleeding because there is no antidote for danaparoid. 2.0 Direct Thrombin Inhibitors In contrast to indirect anticoagulants, which require a plasma cofactor to exert their activity, direct throm- bin inhibitors have intrinsic activity because they bind to thrombin and block its enzymatic activity. The cur- rently approved direct thrombin inhibitors are hiru- din, bivalirudin, and argatroban. Hirudin A 65-amino acid polypeptide originally isolated from the salivary glands of the medicinal leech, Hirudo medicinalis,214,215 hirudin is now available in recombinant forms. Expressed in yeast, recombinant hirudins differ from native hirudin in that the Tyr residue at position 63 is not sulfated. Two recombi- nant forms of hirudin, known as lepirudin and desiru- din, are currently approved for clinical use in North America and in Europe, respectively. Lepirudin is licensed for treatment of thrombosis complicating HIT, whereas desirudin is approved in Europe and the United States for postoperative thromboprophy- laxis in patients undergoing elective hip arthroplasty. Although there are minor differences in the amino- terminal composition of the two forms of recombinant hirudin, their mechanism of action and pharmaco- kinetic properties are identical. Both inhibit thrombin in a bivalent fashion. Thus, their globular amino- terminal domains interact with the active site of thrombin, whereas the anionic carboxy-terminal tails bind to exosite 1 on thrombin, the substrate-binding site.215 Both lepirudin and desirudin form high-af nity 1:1 stoichiometric complexes with thrombin that are essentially irreversible. Dosing and Monitoring: The recommended dose of IV lepirudin for HIT is 0.15 mg/kg/h with or with- out an initial bolus of 0.4 mg/kg. The anticoagulant effect of lepirudin in this setting is monitored by using the aPTT, and the dose is adjusted to achieve a target aPTT ratio of 1.5 to 2.5 times control (Linkins et al).32 When given for thromboprophylaxis after elective hip replacement surgery, desirudin is given subcutaneously at a dose of 15 mg twice daily with- out monitoring. The plasma half-life of the hirudins is 60 min after IV injection and 120 min after subcutaneous injec- tion.216 Hirudin is cleared via the kidneys, and the 2012 American College of Chest Physicians by Kimberly Henricks on February 10, 2012 chestjournal.chestpubs.org Downloaded from e36S Parenteral Anticoagulants Hemodialysis or hemoperfusion can remove bivalirudin or argatroban. Dialysis using high-flux dialysis membranes can clear hirudin. 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 Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Daiichi-Sankyo, Bayer, and Johnson & Johnson. Dr Samama has received honoraria for lectures or consulting from Bayer Healthcare, Johnson & Johnson, Bristol- Myers Squibb, Boehringer Ingelheim, sanofi-aventis, and Rovi, and has served on a steering committee for Daiichi-Sankyo. Dr Baglin has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be dis- cussed in this article. Role of sponsors: The sponsors played no role in the development of these guidelines. Sponsoring organizations cannot recommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Conflict of Interest Policy are available online at http://chestnet.org. Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clin- ical Pharmacy, the American Society of Health-System Pharma- cists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis. References 1. McLean J. The thromboplastic action of cephalin. Am J Physiol. 1916;41:250-257. 2. Brinkhous K, Smith H, Warner E, et al. The inhibition of blood clotting: an unidentified substance which acts in conjunction with heparin to prevent the conversion of pro- thrombin into thrombin. Am J Physiol. 1939;125:683-687. 3. Abildgaard U. Highly purified antithrombin 3 with heparin cofactor activity prepared by disc electrophoresis. 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