CHEST Supplement Parenteral Anticoagulants ANTITHROMBOTICTHERAPY AND PREVENTION OFTHROMBOSIS, 9TH ED: ACCP GUIDELINES This article focuses on parenteral anticoagulants in current use. These agents can be divided into indirect anticoagulants whose activity is mediated by plasma cofactors and direct anticoagulants that do not require plasma cofactors to express their activity. The indirect parenteral anticoagulants in current use include heparin, low-molecular-weight-heparins (LMWHs), fondaparinux, and danaparoid. These drugs have little or no intrinsic anticoagulant activity, and exert their anticoagulant activity by potentiating antithrombin (AT), an endogenous inhibitor of var- ious activated clotting factors. The parenteral direct anticoagulants in current use all target thrombin. These agents include recombinant hirudins, bivaliru- din, and argatroban. 1.0 Indirect Parenteral Anticoagulants 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. 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, biva- lirudin, 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 trig- gering nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteo- porosis. 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. Fonda- parinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin. Therefore, fonda- parinux-associated HIT or osteoporosis is unlikely to occur. Fondaparinux exhibits complete bio- availability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in xed doses, without coagulation monitoring. Three addi- tional parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to hep- arin in patients with HIT. CHEST 2012; 141(2)(Suppl):e24S e43S Abbreviations: aPTT 5 activated partial thromboplastin time; AT 5 antithrombin; CrCl 5 creatinine clearance; HCII 5 heparin cofactor II; HIT 5 heparin-induced thrombocytopenia; INR 5 international normalized ratio; Parenteral Anticoagulants Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines David A. Garcia, MD; Trevor P. Baglin, MBChB, PhD; Jeffrey I. Weitz, MD, FCCP; and Meyer Michel Samama, MD 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 e25S At even higher concentrations, low-af nity heparin impairs factor Xa generation through AT- and HCII- independent mechanisms13 (Table 2). The heparin/AT complex inactivates thrombin (factor IIa) and factors Xa, IXa, XIa, and XIIa.5 Hep- arin catalyzes AT-mediated thrombin inhibition in a nonspeci c charge-dependent fashion to form a ter- nary heparin/AT/thrombin complex. In contrast, to catalyze factor Xa inhibition by AT, heparin needs only to bind to AT.14 In both cases binding occurs at the unique pentasaccharide sequence found within some heparin molecules. Heparin chains consisting of ,18 saccharide units are too short to bridge AT to thrombin. Consequently, these chains are unable to catalyze thrombin inhibition. However, short heparin chains can catalyze inhibition of factor Xa by AT.15-18 By inactivating thrombin or attenuating its genera- tion, heparin not only prevents brin formation but also inhibits thrombin-induced activation of platelets and factors V, VIII, and XI.19-21 The interaction of heparin with HCII is charge dependent, but pentasaccharide independent. Catalysis In 1968, Abildgaard identi ed this cofactor as anti- thrombin III,3 which is now referred to as anti- thrombin. The major anticoagulant action of heparin is mediated by the heparin/AT interaction. The mech- anism of this interaction was demonstrated in the 1970s.4-6 Heparin binds to positively charged residues on AT, producing a conformational change at the AT arginine reactive center that converts AT from a slow to a rapid inhibitor of serine proteases. The arginine reactive center on AT binds covalently to the active center serine of thrombin and other coagulation enzymes, thereby irreversibly inhibiting their proco- agulant activity.5 Heparin then dissociates from AT and is reused (Fig 1).7 1.1.1 Structure and Mechanism of Action: Heparin is a highly sulfated mucopolysaccharide. It is hetero- geneous with respect to molecular size, anticoagulant activity, and pharmacokinetic properties (Table 1). Heparin molecules range in molecular weight from 3,000 to 30,000 kDa with a mean of 15,000, which corresponds to approximately 45 saccharide units (Fig 2).8-10 Only about one-third of the heparin mole- cules possess the unique pentasaccharide sequence and it is this fraction that is responsible for most of the anticoagulant effect of heparin.8,11 Heparin chains that lack the pentasaccharide sequence have minimal anticoagulant activity when heparin is given in thera- peutic concentrations. However, at concentrations higher than those usually administered clinically, heparin chains with or without the pentasaccharide sequence can catalyze thrombin inhibition by hep- arin cofactor II (HCII), a second plasma cofactor.12 Figure 1. Inactivation of clotting enzymes by heparin. Top, ATIII is a slow inhibitor without heparin. Middle, Heparin binds to ATIII through a high-af nity pentasaccharide and induces a con- formational change in ATIII, thereby converting ATIII from a slow inhibitor to a very rapid inhibitor. Bottom, ATIII binds cova- lently to the clotting enzyme, and the heparin dissociates from the complex and can be reused. AT5antithrombin. (Reprinted with permission from Hirsh et al.7) Table 1 Molecular Size, Anticoagulant Activity, and Pharmacokinetic Properties of Heparin Attribute Characteristics Molecular size Mean molecular weight, 15,000 kDa Anticoagulant activity Only one-third of heparin molecules contain the high-af nity pentasaccharide required for anticoagulant activity Clearance High-molecular-weight moieties are cleared more rapidly than lower-molecular-weight moieties Revision accepted August 31, 2011. Af liations: From the University of New Mexico (Dr Garcia), Albuquerque, NM; the Cambridge University Hospitals NHS Trust (Dr Baglin), Addenbrooke s Hospital, Cambridge, England; the Thrombosis and Atherosclerosis Research Institute and McMaster University (Dr Weitz), Hamilton, ON, Canada; and the Hotel Dieu University Hospital (Dr Samama), Place du Parvis Notre Dame, Paris, France. 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; P zer, Inc; Canyon Pharmaceuticals; and sano -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 condi- tion. The complete disclaimer for this guideline can be accessed at http://chestjournal.chestpubs.org/content/141/2_suppl/1S. Correspondence to: David A. Garcia, MD, 1 University of New Mexico, MSC07-4025, Albuquerque, NM 87131; e-mail: davgarcia@ salud.unm.edu 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/ site/misc/reprints.xhtml). 2012 American College of Chest Physicians by Kimberly Henricks on February 10, 2012 chestjournal.chestpubs.org Downloaded from e26S Parenteral Anticoagulants 1.1.2 Pharmacokinetics: Heparin is not absorbed orally and therefore must be administered parenter- ally. The two preferred routes of administration are by continuous IV infusion or subcutaneous injection. When the subcutaneous route is selected for delivery of treatment doses of heparin, the dose of heparin should be higher than the usual IV dose because sub- cutaneous administration is associated with reduced bioavailability.33,34 If an immediate anticoagulant effect is required, a higher initial subcutaneous dose of heparin can be administered.35 Alternatively, an IV bolus of heparin can be given in conjunction with the rst subcutaneous dose. Administration by subcutaneous injection in low doses36 (eg, 5,000 units q12h), moderate doses of plasma recovery of heparin.33 However, at high ther- apeutic doses (.35,000 units q24h) plasma recovery is almost complete.34 After entering the bloodstream, heparin binds to a number of plasma proteins other than AT, reducing its anticoagulant activity. This phenomenon contrib- utes to the variability of the anticoagulant response to heparin among patients with thromboembolic disor- ders38 and to the laboratory phenomenon of heparin resistance.39 Heparin also binds to endothelial cells40 and macrophages, a property that further complicates its pharmacokinetics. Binding of heparin to von Willebrand factor also inhibits von Willebrand factor- dependent platelet function.41 Heparin is cleared through a combination of a rapid saturable and a much slower rst-order mecha- nism (Fig 3).42-44 The saturable phase of heparin clearance is believed to be due to binding to endothe- lial cell receptors45 and macrophages.46 Bound hep- arin is internalized and depolymerized (Fig 4).47,48 The slower nonsaturable mechanism of clearance is largely renal. At therapeutic doses, a large proportion of heparin is cleared through the rapid saturable, dose-dependent mechanism. The complex kinetics of clearance render the anticoagulant response to hep- arin nonlinear at therapeutic doses, with both the intensity and duration of effect rising disproportion- ately with increasing dose. Thus, the apparent bio- logic half-life of heparin increases from approximately 30 min after an IV bolus of 25 units/kg, to 60 min with an IV bolus of 100 units/kg, to 150 min with a 1.1.3 Initial Dosing: The ef cacy of heparin in the initial treatment of VTE is critically dependent on patients assigned to lower starting doses of heparin had higher recurrence rates than those treated with higher doses. In the randomized study by Hull and associates,33 patients with venous thrombosis were of HCII requires a higher concentration of heparin than that needed to promote thrombin inhibition by AT. Heparin s capacity to activate HCII is also chain length-dependent, with maximum catalysis requiring heparin chains composed of a minimum of 24 sac- charide units.12 Consequently, LMWHs are less effec- tive at activating HCII than is heparin. In vitro, heparin binds to platelets and, depending on the experimental conditions, can either induce or inhibit platelet aggregation.22,23 High-molecular- weight heparin fractions with low af nity for AT have a greater effect on platelet function than low- molecular-weight fractions with high AT af nity.24 Heparin can prolong the bleeding time in humans,25 and it enhances blood loss from the microvasculature in rabbits.20,26,27 The interaction of heparin with platelets26 and endothelial cells20 may contribute to heparin-induced bleeding by mechanisms indepen- dent of its anticoagulant effect.27 In addition to its anticoagulant effects, heparin attenuates the proliferation of vascular smooth muscle cells,28,29 inhibits osteoblast formation, and activates osteoclasts; these last two effects promote bone loss.30,31 Heparin-induced thrombocytopenia (HIT) is the most important nonhemorrhagic side effect of heparin. This is discussed by Linkins et al32 in this supplement. Figure 2. Molecular weight distribution of LMWHs and hep- arin. LMWH 5 low-molecular-weight heparin. (Reprinted with permission from CHEST.7) Table 2 Anticoagulant Effects of Heparin Effect Comment Binds to AT and catalyzes the inactivation of thrombin and factors IIa, Xa, IXa, XIa and XIIa Major mechanism for anticoagulant effect, produced by only one-third of heparin molecules (those containing the unique AT-binding pentasaccharide) Binds to HCII and catalyzes inactivation of factor IIa Requires high concentrations of heparin and is independent of the pentasaccharide Binds to factor IXa and inhibits factor X Activation Requires very high concentration of heparin and is AT- and HCII-independent AT5antithrombin; HCII5heparin cofactor II. 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 e27S weight-based nomogram (starting dose, 80 units/kg bolus followed by 18 units/kg/h by infusion). Patients whose heparin was weight-adjusted received higher doses within the rst 24 h than those given xed doses of heparin. The rate of recurrent thromboem- bolism was significantly lower with the weight- adjusted heparin regimen. Initial dosing of IV heparin for VTE is either weight-based (80 units/kg bolus and 18 units/kg/h infusion49) or administered as a bolus of 5,000 units followed by an infusion of at least 32,000 units/d.51 If heparin is given subcutaneously for treatment of VTE, there are at least two options: (1) an initial IV bolus of 5,000 units followed by 250 units/kg twice daily52; or (2) an initial subcutaneous dose of 333 units/kg followed by 250 units/kg twice daily The doses of heparin recommended for treatment of acute coronary syndromes are lower than those used to treat VTE. The American College of Cardi- ology recommends a heparin bolus of 60 to 70 units/kg (maximum 5,000 units) followed by an infusion of 12 to 15 units/kg/h (maximum 1,000 units/h) for unsta- ble angina and non-ST-segment elevation myocardial infarction.53 Even lower doses of heparin are recom- mended when heparin is given in conjunction with brinolytic agents for treatment of ST-segment ele- vation myocardial infarction. Here, the bolus is about 60 units/kg (maximum 4,000 units) and the infusion is 1.1.4 Monitoring: The risk of heparin-associated bleeding increases with heparin dose55,56 and with concomitant administration of brinolytic agents57-60 or glycoprotein IIb/IIIa inhibitors.61,62 The risk of bleeding is also increased by recent surgery, trauma, invasive procedures, or concomitant hemo- static defects.63 In hospitalized patients, increasing number of comorbidities, age . 60 y, suprathera- peutic clotting times, and worsening hepatic dysfunc- tion increase the risk of anticoagulant-associated Investigators have reported a relationship between the dose of heparin administered and both its ef - cacy33,47,65 and safety.61,62 Because the anticoagulant response to heparin varies among patients, it is stan- dard practice to monitor heparin and to adjust the dose based on the results of coagulation tests. The evidence for adjusting the dose of heparin to main- tain a therapeutic range is weak and is based on a post hoc subgroup analysis of a descriptive study.66 In contrast, the evidence for maintaining the interna- tional normalized ratio (INR) within a therapeutic range in patients who are treated with vitamin K antagonists is strong because it is based on consistent results of randomized trials and case control studies. assigned to receive identical doses of heparin (an IV bolus of 5,000 units and 30,000 units per day), but one group received 15,000 units of heparin every 12 h by subcutaneous injection and the other 30,000 units of heparin per day by continuous IV infusion. Patients assigned to IV heparin had a signi cantly lower rate of recurrence than those given subcutaneous heparin, presumably as a result of reduced availability of the subcutaneously admin- istered heparin. A study of 400 consecutive patients with acute pulmonary embolism further highlights the importance of early, aggressive therapy: Patients who achieved a therapeutic aPTT in,24 h also had lower in-hospital and 30-day mortality rates compared with those who did not.50 Raschke et al49 randomized patients to receive heparin in xed doses (5,000-unit bolus followed by 1,000 units/h by infusion) or adjusted doses using a Figure 3. Low doses of heparin clear rapidly from plasma through a saturable (cellular) mechanism and the slower, nonsaturable, dose-independent mechanism of renal clearance. Very high doses of heparin are cleared predominantly through the slower nonsatu- rable mechanism of clearance. t1/25half-life. (Reprinted with permission from CHEST.7) Figure 4. As heparin enters the circulation, it binds to heparin- binding proteins (ie, other plasma proteins), endothelial cells, macrophages, and ATIII. Only heparin with the high-af nity pentasaccharide binds to ATIII, but binding to other proteins and to cells is nonspeci c and occurs independently of the ATIII binding site. See Figure 1 legend for expansion of abbreviation. (Reprinted with permission from CHEST.7) 2012 American College of Chest Physicians by Kimberly Henricks on February 10, 2012 chestjournal.chestpubs.org Downloaded from e28S Parenteral Anticoagulants least in part, greater variation in the results of anti-Xa assays than in the aPTT results.84 Therefore, more research is needed to identify the optimal approach for monitoring unfractionated heparin (UFH) therapy. The therapeutic range of heparin for coronary indica- tions is unknown, but is likely to correspond to heparin levels that are about 10% lower than those used for treatment of patients with VTE. The results of a ran- domized trial in patients with VTE that showed that unmonitored weight-adjusted subcutaneous heparin given twice daily in high doses was as safe and effec- tive as unmonitored, weight-adjusted LMWH chal- lenge the requirement for aPTT monitoring of heparin 1.1.5 Heparin Resistance: Heparin resistance is a term used to describe the situation wherein patients require unusually high doses of heparin to achieve a therapeutic aPTT.86-88 Several mechanisms explain heparin resistance, including AT de ciency,73 increased heparin clearance,38,87 elevations in the levels of heparin-binding proteins,39,89 and high levels of factor VIII88,90 and/or brinogen.90 Aprotinin and nitroglycerin may cause drug-induced heparin resis- tance,91,92 although the association with nitroglycerin In patients with VTE who required large doses of heparin (.35,000 units/d), patients randomized to heparin dosing based on anti-Xa levels (target range between 0.35-0.7 units/mL) had similar clinical outcomes and received lower doses of heparin than those randomized to dose adjustment based on aPTT values.88 Given these results, it is reasonable to adjust heparin doses based on anti-Xa levels in patients with VTE who require very high doses of heparin to achieve a therapeutic aPTT. 1.1.6 Limitations of Heparin: In addition to hemor- rhagic complications, heparin has limitations based on its pharmacokinetic properties; its ability to induce immune-mediated platelet activation, which can lead to HIT32; and its effect on bone metabolism, which can lead to osteoporosis. Other nonhemorrhagic side effects are very uncommon and include skin reactions that can progress to necrosis, alopecia, and hypersen- to heparin are uncommon, an unusually high number of adverse events with heparin were reported in North America in 2007. Typically, these events con- sisted of hypotension, nausea, and shortness of breath within 30 min of heparin administration. An investi- gation into this problem conducted by the US Cen- ters for Disease Control identi ed the cause of these reactions to be a contaminant in heparin manufac- tured in China. The contaminant was an oversul- fated chondroitin sulfate.94 It is postulated that When given in therapeutic doses, the anticoagulant effect of heparin is usually monitored using the aPTT. The activated clotting time is used to monitor the higher heparin doses given to patients undergoing percutaneous coronary interventions or cardiopul- monary bypass surgery. A retrospective study done in the 1970s suggested that an aPTT ratio between 1.5 and 2.5 was associ- ated with a reduced risk of recurrent VTE.66 Based on this study, a therapeutic aPTT range of 1.5 to 2.5 times control gained wide acceptance. The clinical relevance of this therapeutic range is uncertain because it has not been con rmed by randomized trials. Further, the measured response to the aPTT varies between reagents and instruments used to measure the aPTT.67-76 Depending on reagent and coagulometer, aPTT results ranging from 48 to 108 s can be measured in samples with a heparin concen- tration of 0.3 units/mL, as determined using an anti-Xa assay.69,71 With heparin levels of 0.3 to 0.7 anti-Xa units/mL, modern aPTT reagents and coagulometers produce aPTT ratios that range from ious heparin dose-adjustment nomograms have been developed (Table 365), none is applicable to all aPTT reagents.71 For these reasons, the therapeutic aPTT range at a particular institution should be adapted to the responsiveness of the reagent and coagulometer used.67,70,72,73,75,76,78,80-83 In the study that established a therapeutic range for the aPTT,66 an aPTT ratio of 1.5 to 2.5 corresponded to a heparin level of 0.2 to 0.4 units by protamine titration and a heparin level of 0.3 to 0.7 units measured by an anti-Xa assay. Like aPTT assays, anti-Xa assays vary in their responsive- ness to heparin; therefore, standardization of aPTT ratios by reference to anti-Xa levels is also problematic. Studies evaluating interlaboratory agreement in the monitoring of heparin have failed to show that corre- lating the aPTT with anti-Xa assays improves agree- ment between hospital laboratories,84,85 re ecting, at Table 3 Example of a Heparin Dose Adjustment Nomogram Initial dose 80 units/kg bolus, then 18 units/kg/h aPTT,,35 s 80 units/kg bolus, then increase 4 units/kg/h aPTT, 35-45 s 40 units/kg bolus, then increase 2 units/kg/h aPTT, 46-70 sa No change aPTT, 71-90 s Decrease infusion rate by 2 units/kg/h aPTT,.90 s Hold infusion 1 h, then decrease infusion rate by 3 units/kg/h aPTT5activated partial thromboplastin time. (Adapted with permis- sion from Raschke et al.65) aTherapeutic aPTT range of 46-70 s corresponded to anti-Xa activity of 0.3-0.7 units/mL. The target aPTT range in a particular institution should re ect what is known about the local reagents and equipment used to perform the assay. 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 e29S Patients who have previously received protamine sulfate-containing insulin, have undergone vasec- tomy, or have known sensitivity to sh are at increased risk to have preformed antibodies against protamine sulfate and to suffer from allergic reactions, including anaphylaxis.100,101 Such reactions are uncommon, but if there is concern about a potential protamine sulfate allergy, patients can be pretreated with corticoste- roids and antihistamines. A number of other substances or devices have been shown to neutralize the anticoagulant effects of UFH. These include hexadimethrine (Polybrene),102,103 heparin removal devices,107 and synthetic protamine variants.108 None of these is approved for clinical use. 1.2 Low-Molecular-Weight Heparins LMWHs are derived from UFH by chemical or enzymatic depolymerization. LMWHs have reduced inhibitory activity against thrombin relative to factor Xa,9,10,109-111 have a more favorable bene t-to-risk ratio than heparin in animal models112,113 and when used to treat VTE,114 and have superior pharmacokinetic 1.2.1 Structure and Mechanism of Action: LMWHs are about one-third the molecular weight of UFH. LMWHs have a mean molecular weight of 4,000 to 5,000 which corresponds to about 15 saccharide units and a range of 2,000 to 9,000. Table 4 shows the various LMWHs approved for use in Europe, Canada, and the United States. Because they are pre- pared using different methods of depolymerization, the various LMWHs differ, at least to some extent, in their pharmacokinetic properties and anticoagulant pro les and in their recommended dosing regimens. Therefore, these drugs are not interchangeable on a unit-for-unit basis. oversulfated chondroitin sulfate induces hypotension by promoting the activation of factor XII and the sub- sequent generation of bradykinin.95 Heparin therapy can also cause elevations of serum transaminases. The increase in transaminases is usually transient and is not associated with an increase in bilirubin; it is presumed to have no clinical The main nonhemorrhagic side effects of heparin are HIT and osteoporosis. HIT (discussed further by Linkins et al32 in this supplement) is caused by IgG subclass, heparin-dependent antibodies. These anti- bodies bind to a conformationally modi ed epitope on platelet factor 4 (PF4). Simultaneous binding of these antibodies to Fc receptors on the platelet sur- face causes platelet activation. Activated platelets shed highly prothrombotic microparticles and are then removed from the circulation causing thrombo- cytopenia. In addition, these activated platelets and microparticles provide a surface onto which coagula- tion factor complexes can assemble to promote thrombin generation. This phenomenon can then trigger venous or arterial thrombosis with venous thrombosis being more common.97 Osteoporosis is caused by binding of heparin to osteoblasts,32 which then release factors that activate osteoclasts in an 1.1.7 Reversing the Anticoagulant Effect of Heparin: One advantage of heparin is that IV protamine sulfate can rapidly reverse its anticoagulant effects. Protamine sulfate is a basic protein derived from sh sperm that binds to heparin to form a stable salt. One milligram of protamine sulfate will neutralize approx- imately 100 units of heparin. Therefore, a patient who bleeds immediately after receiving an IV bolus of 5,000 units of heparin should receive about 50 mg of protamine sulfate. Protamine sulfate is cleared from the circulation with a half-life of about 7 min. Because the half-life of IV heparin is 60 to 90 min when heparin is given as an IV infusion, only heparin given during the preceding several hours needs to be considered when calculating the dose of protamine sulfate that needs to be administered. Therefore, a patient receiving a continuous IV infusion of heparin at 1,250 units/h requires approximately 30 mg of protamine sulfate to neutralize the heparin that was given in the past 2 to 2.5 h. Neutralization of subcu- taneously administered heparin may require a pro- longed infusion of protamine sulfate. The aPTT can be used to assess the effectiveness of protamine sul- fate neutralization of the anticoagulant effects of The risk of severe adverse reactions to protamine sulfate, such as hypotension or bradycardia, can be minimized by administering the protamine slowly. Table 4 Methods for Preparation of LMWH and Danaparoid Agent Method of Preparation Bemiparin Alkaline degradation Dalteparin (Fragmin) Nitrous acid depolymerization Danaparoid sodium (Orgaran) Prepared from animal gut mucosa; contains heparan sulfate (84%), dermatan sulfate (12%), and chondroitin sulfate (4%) Enoxaparin sodium (Lovenox/Clexane) Benzylation followed by alkaline depolymerization Nadroparin calcium (Fraxiparine) Nitrous acid depolymerization Tinzaparin (Innohep) Enzymatic depolymerization with heparinase LMWH5low-molecular-weight heparin. 2012 American College of Chest Physicians by Kimberly Henricks on February 10, 2012 chestjournal.chestpubs.org Downloaded from e30S Parenteral Anticoagulants trials have shown that LMWHs are safe and effective for the prevention and treatment of VTE and for the treatment of non-ST-elevation acute coronary syndromes. 1.2.2 Pharmacokinetics: LMWHs have pharmaco- kinetic advantages over heparin;115,116,121 after subcu- taneous injection, the bioavailability of LMWHs is about 90% and LMWHs produce a more predictable anticoagulant response than heparin.126 The elimina- tion half-life of LMWHs, which is 3 to 6 h after sub- cutaneous injection, is dose independent, and anti-Xa levels peak 3 to 5 h after dosing. One limitation of LMWHs is that they are predominately cleared by the kidneys so their biologic half-life may be pro- longed in patients with renal failure.127,128 1.2.3 Monitoring Antithrombotic Effect: LMWHs are typically administered in xed or weight-adjusted doses for thromboprophylaxis and in weight-adjusted doses for therapeutic purposes. Coagulation moni- toring is not generally necessary, but some authorities suggest that monitoring be done in obese patients and in those with renal insuf ciency.129-131 Monitoring may also be advisable when treatment doses of LMWH are given during pregnancy.132 Although some studies reported that high anti-Xa levels were associated with an increased bleeding risk,55,133 several other studies failed to show a rela- tionship between anti-Xa levels and bleeding.134-136 A randomized controlled trial comparing monitored and unmonitored dalteparin therapy for treatment of VTE showed no bene t of monitoring.137 Monitoring is thus not recommended for the majority of patients; if monitoring is required, the anti-Xa level is the rec- For treatment of VTE, a conservative peak anti-Xa level with twice-daily enoxaparin or nadroparin is 0.6 to 1.0 units/mL.132,138-140 The target range for peak anti-Xa levels (measured 4 h after dosing) with once- daily enoxaparin is likely to be above 1.0 units/mL,138 whereas it is 0.85 units/mL with tinzaparin and 1.3 units/mL and 1.05 units/mL with nadroparin and dalteparin, respectively.140 The suggested peak target ranges for several LMWHs are shown in Table 6. 1.2.4 Dosing and Monitoring in Special Situations: With enoxaparin, anti-Xa activity is increased to appropriate levels when the drug is administered to obese patients in doses based on total body weight up to a weight of 144 kg.141 The same is true for dalteparin142,143 and tinzaparin144 in patients weighing up to 190 and 165 kg, respectively. In a meta-analysis that included data on 921 patients with a BMI30, there was no excess in the rate of major bleeding over that observed in nonobese patients who received Depolymerization of heparin yields low-molecular weight fragments that exhibit reduced binding to proteins and cells (Table 5). The reduced af nity for proteins and cells explains the anticoagulant, phar- macokinetic, and other biologic differences between heparin and LMWH. Thus, compared with heparin, LMWHs have reduced ability to inactivate thrombin because the smaller fragments cannot bind simulta- neously to AT and thrombin. Reduced binding to plasma proteins other than AT is responsible for the more predictable dose-response relationship of LMWHs.122 Decreased binding to macrophages and endothelial cells explains the longer plasma half-life of LMWH relative to UFH, whereas reduced binding to platelets and PF4 explains the lower incidence of HIT.123,124 Finally, the decreased binding of LMWH to osteoblasts results in less activation of osteoclasts and less bone loss.30,31 Like heparin, LMWHs produce their major anti- coagulant effect by catalyzing AT-mediated inhi- bition of coagulation factors. The pentasaccharide sequence required for binding is found on fewer than one-third of LMWH molecules.14,125 Because only pentasaccharide-containing heparin chains composed of at least 18 saccharide units are of suf cient length to bridge AT to thrombin, 50% to 75% of LMWH chains are too short to catalyze thrombin inhibition. However, these chains are capable of promoting factor Xa inactivation by AT because this reaction does not require bridging. Because virtually all mole- cules of UFH contain at least 18 saccharide units, heparin has, by de nition, an anti-Xa to anti-IIa ratio of 1:1. In contrast, commercial LMWHs have anti-Xa to anti-IIa ratios between 2:1 and 4:1 depending on their molecular size distribution. At present, there is no evidence that the differences in anti-Xa to anti-IIa ratio among the LMWHs in uence clinical outcomes such as recurrent thrombosis or bleed- ing complications. Numerous randomized clinical Table 5 Biologic Consequences of Reduced Binding of LMWH to Plasma Proteins and Cells Binding Target Biologic Effects Clinical Consequence Thrombin Reduced anti-IIa activity relative to anti-Xa activity Unknown Proteins More predictable anticoagulant response Coagulation monitoring unnecessary Macrophages Cleared through renal mechanism Longer plasma half-life permits once-daily administration Platelets Reduced formation of HIT antibodies Reduced incidence of HIT Osteoblasts Reduced activation of osteoclasts Lower risk of osteopenia HIT5heparin-induced thrombocytopenia. See Table 4 legend for expansion of other abbreviation. 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 e31S low as 20 mL/min.159 The apparent difference in tinzaparin clearance in patients with severe renal insuf ciency may re ect metabolism by hepatic mechanisms, possibly due to the higher molecular weight of tinzaparin compared with other LMWHs. Decreased LMWH clearance has been associated with increased bleeding risks in patients with severe renal insuf ciency. Lim and associates160 compared the risk of major bleeding and anti-Xa levels in patients receiving LMWH who had severe renal insuf- ciency (CrCl30 mL/min) with those in patients without renal impairment (CrCl . 30 mL/min). In 12 studies involving 4,971 patients given LMWH, the OR for major bleeding was 2.25 (95% CI, 1.19-4.27) in patients with a CrCl  30 mL/min compared with that in those with a CrCl . 30 mL/min. Enox- aparin at a therapeutic dose was associated with a further increase in major bleeding in patients 95% CI, 1.78-8.45), but this was not observed when enoxaparin was empirically dose reduced (0.9% these data, nondialysis-dependent patients with CrCl30 mL/min who are treated with standard ther- apeutic doses of enoxaparin have an increased risk of major bleeding, and empirical dose reduction appears to reduce this risk. No conclusions could be made regarding other LMWHs because of limited data. Increased bleeding was also found in a post hoc analysis of data from the Ef cacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coro- nary Events (ESSENCE) and Thrombolysis in Myo- cardial Infarction (TIMI) 11B trials, in which CrCl  30 mL/min was associated with an increased risk for major hemorrhage in patients receiving ther- apeutic doses of enoxaparin (relative risk [RR]5 6.1; patients with either VTE or acute coronary ischemia treated with therapeutic doses of enoxaparin or tinza- parin, a CrCl , 20 mL/min was associated with a RR of 2.8 (95% CI, 1.0-7.8) for bleeding complica- tions.162 Finally, in a retrospective study of patients receiving multiple doses of enoxaparin, patients with renal insuf ciency had an RR for any bleeding com- plication of 2.3 (P,.01) and an RR for major hemor- In the setting of severe renal insuf ciency in which therapeutic anticoagulation is required, use of UFH avoids the problems associated with impaired clear- ance of LMWH preparations. Although there is no speci c CrCl threshold at which the risk for LMWH accumulation becomes clinically signi cant, an esti- mated CrCl of about 30 mL/min is a reasonable cutoff value based on the available literature. If LMWH is chosen for patients with an estimated cre- atinine clearance of,30 mL/min, anti-Xa monitoring LMWH in doses adjusted by total body weight.145 For thromboprophylaxis with xed-dose enoxaparin and nadroparin, there is a strong negative correlation between total body weight and anti-Xa levels in obese patients.146-148 Several small prospective trials have examined this issue in patients undergoing bariatric surgery, with inconclusive ndings.149-152 Appropriate dosing of LMWH in patients with severe renal insuf ciency is uncertain. Contempo- rary randomized controlled trials evaluating LMWH ef cacy and safety have generally excluded patients with severe renal insuf ciency, de ned in most studies as a creatinine clearance (CrCl)30 mL/min. With few exceptions,153 pharmacokinetic studies have demonstrated that clearance of the anti-Xa effect of LMWH is highly correlated with CrCl.154 This was also observed in a large study of patients receiving therapeutic-dose enoxaparin for coronary indications, in which a strong linear relationship was reported between CrCl and enoxaparin clearance (R5 0.85, P,.001).141 Of particular concern is the potential for accumulation of anti-Xa activity after multiple therapeutic doses. A linear correlation was shown between CrCl and anti-Xa levels (P,.0005) after multiple therapeutic doses of enoxaparin, with sig- ni cantly increased anti-Xa levels in patients with a CrCl,30 mL/min.155 Accumulation after multiple prophylactic doses appears to occur less frequently, but it is still observed. Thus, after multiple prophy- lactic doses of enoxaparin, anti-Xa clearance was reduced by 39% and drug exposure (area under the curve of anti-Xa activity vs time) was 35% higher in patients with a CrCl,30 mL/min compared with that in patients with a CrCl  30 mL/min.156 The data on accumulation with LMWHs other than enoxaparin is limited. Although the amount of pub- lished evidence is limited, bioaccumulation of dalteparin has been reported in patients with signi - cant renal insuf ciency who receive therapeutic doses of dalteparin.157 When used in full therapeutic doses, nadroparin clearance, but not tinzaparin clearance, was shown to be correlated with CrCl (R5 0.49, P , .002),158 even when the CrCl was as Table 6 LMWH Target Ranges for the Treatment of VTE LMWH and Frequency of Administration Target Rangea (Anti-Xa units/mL) Twice daily enoxaparin 0.6-1.0 Twice daily nadroparin 0.6-1.0 Once daily dalteparin 1.05 Once daily enoxaparin .1.0 Once daily nadroparin 1.3 Once daily tinzaparin 0.85 See Table 4 legend for expansion of abbreviation. aMeasured 4 h after LMWH administration. 2012 American College of Chest Physicians by Kimberly Henricks on February 10, 2012 chestjournal.chestpubs.org Downloaded from e32S Parenteral Anticoagulants bleeding associated with the use of LMWH. One animal study reported a reduction in bleeding with protamine sulfate in a microvascular bleeding model, despite persistent anti-Xa activity.175 Another study demonstrated incomplete attenuation of LMWH- A single case report describes the successful use of recombinant activated factor VII to control bleeding in a postoperative patient with renal failure who was receiving LMWH.177 In animal studies, synthetic protamine variants have been shown to be highly effective in neutralizing the anticoagulant effects of LMWH (including anti-Xa activity) and appear to be less toxic than protamine sulfate.109,178-180 Adenosine triphosphate completely reversed LMWH-induced bleeding related to LMWH in a rat model,181 as did PMX 60056, a salicylamide-derived heparin antago- nist.182 In vitro experiments suggest that an anti- thrombin variant (AT-N135Q-Pro394) may neutralize the anticoagulant effects of heparin derivatives, including LMWH and fondaparinux. These agents are not approved for clinical use. The following approach is recommended in clin- ical situations in which the anticoagulant effect of LMWH needs to be neutralized. If LMWH was given within 8 h, protamine sulfate should be administered in a dose of 1 mg per 100 anti-Xa units of LMWH up to a maximum single dose of 50 mg (1 mg enoxaparin equals approximately 100 anti-Xa units). A second dose of 0.5 mg protamine sulfate per 100 anti-Xa units should be administered if bleeding continues. Smaller doses of protamine sulfate can be given if the time since LMWH administration is longer than 8 h. 1.2.6 Nonhemorrhagic Complications: The fre- quency of HIT is threefold lower with LMWHs than with heparin.124 This re ects the fact that the interac- tion of heparin with PF4 is chain length-dependent. Although binding to PF4 is reduced, LMWHs can form complexes with PF4 that are capable of binding HIT antibodies. Consequently, in patients with HIT antibodies, there is cross-reactivity with LMWH (Linkins et al).32 The risk of osteoporosis is lower with LMWH than with heparin. Likely, this re ects the lower af nity of LMWH for osteoclasts and osteoblasts. Monreal and associates183 compared the effects of heparin and LMWH on bone loss in rats and demonstrated that although both produced bone loss, the osteopenic effect was greater with heparin than LMWH. In con- trast, using different measures of bone loss, M tzsch and associates184 reported that, at similar anti-factor Xa activities, the effects of LMWH and UFH on exper- imental bone loss were similar. Shaughnessy and col- leagues reported that heparin and LMWH both and/or dose reduction should be considered to ensure that there is no accumulation. In the case of enox- aparin, dose reduction may be used in patients with CrCl,30 mL/min. The recommended treatment dose of enoxaparin for patients with a CrCl,30 mL/min who have acute coronary syndromes or VTE is 50% of the usual dose (ie, 1 mg/kg once daily). No speci c recommendations have been made for other LMWH preparations. When given in prophylactic doses, LMWH has not been shown to increase the risk of bleeding complica- tions, irrespective of the degree of impairment of renal function. Although higher anti-Xa levels were found in patients with renal failure who received repeated once-daily prophylactic doses of enoxaparin, the mean peak anti-Xa level was only 0.6 units/mL, the trough was,0.2 units/mL, and no increased bleeding was observed.156,164 In a prospective cohort study of critically ill patients with a wide range of renal function, including some with acute renal fail- ure who required hemodialysis, dalteparin bioaccu- mulation was not observed despite repeated dosing.165 In a more recent study, subcutaneous dalteparin (5,000 International Units) was given daily to consec- utive ICU patients who had an estimated creatinine clearance,30 mL/min. There was no evidence of drug accumulation nor was the risk of bleeding increased.166 For patients with a CrCl,30 mL/min who require pharmacologic VTE prophylaxis, manu- facturer of enoxaparin recommends that 30 mg once daily be used. In a small comparative study of enox- aparin (40 mg once daily) or tinzaparin (4,500 units once daily), bioaccumulation of enoxaparin, but not tinzaparin, was seen over 8 days of exposure.167 For other LMWHs, dosing recommendations cannot be made in the setting of renal insuf ciency. 1.2.5 Reversing the Anticoagulant Effects of LMWH: There is no proven method for neutralizing LMWH. Studies in vitro and in animals have demon- strated that protamine sulfate neutralizes the anti-IIa activity of LMWH, thereby normalizing the aPTT and the thrombin time. However, protamine sulfate neutralizes a variable portion of the anti-Xa activity of LMWH.168-172 It is likely that incomplete neutraliza- tion of anti-Xa activity re ects the fact that prot- amine does not bind to LMWH fragments within the LMWH preparations that have low sulfate charge The clinical signi cance of incomplete anti-Xa neutralization of LMWH by protamine sulfate is unclear. In a small case series, protamine sulfate failed to correct clinical bleeding associated with LMWH in two of three patients,169 but there are no human studies that convincingly demonstrate or refute a bene cial effect of protamine sulfate on 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 e33S 1.3.1 Discovery of the Natural High-Af nity Pen- tasaccharide: Building on the discovery of Lindahl and associates, who isolated heparin fragments with high af nity for AT, Choay and colleagues192 and Thunberg et al193 demonstrated that the minimum heparin fragment necessary for high-af nity binding to AT consisted of a pentasaccharide. Choay and associates125,194 then isolated this high-af nity pen- tasaccharide and demonstrated that it formed an equimolar complex with AT and enhanced AT- mediated inhibition of factor Xa. In 1987, Atha and associates195 reported that both the 3-O- and 6-O- sulfated glucosamine residues within the pentasac- charide sequence were critical for its activity. These observations paved the way for the development of fondaparinux. 1.3.2 Pharmacology: A synthetic analog of the AT-binding pentasaccharide found in heparin and LMWH was prepared and its structure modi ed so as to increase its af nity for AT, thereby increasing its speci c activity and its half-life. The resulting syn- thetic pentasaccharide, fondaparinux, has a molec- ular weight of 1,728. Its speci c anti-Xa activity is higher than that of LMWH (about 700 units/mg and 100 units/mg, respectively), and its half-life after sub- cutaneous injection is longer than that of LMWH (17 h and about 4 h, respectively). The use of LMWH as the reference preparation for determining the measured anti-Xa activity of fondaparinux is prob- lematic.196,197 As a result, fondaparinux levels should only be determined using assays that use known fondaparinux concentrations to generate their stan- dard curve. Fondaparinux binds to AT and produces a confor- mational change at the reactive site of AT that enhances its reactivity with factor Xa.198 AT then forms a covalent complex with factor Xa. Fonda- parinux is released from AT and is available to acti- vate additional AT molecules. Because it is too short to bridge AT to thrombin, fondaparinux does not increase the rate of thrombin inhibition by AT. The pharmacokinetic properties and metabolism of fondaparinux have been studied in healthy volun- teers.199,200 After subcutaneous injection, fondaparinux is rapidly and completely absorbed. A steady state is reached after the third or fourth once-daily dose, and fondaparinux is excreted unchanged in the urine. The terminal half-life is 17 h in young subjects and 21 h in elderly volunteers. Fondaparinux produces a predict- able anticoagulant response and exhibits linear phar- macokinetics when given in subcutaneous doses of 2 to 8 mg or in IV doses ranging from 2 to 20 mg.200 There is minimal nonspeci c binding of fondaparinux produced a dose-dependent decrease in cancellous bone volume in rats. However, the effects were greater with UFH than with LMWH.185 These inves- tigators also showed that although both anticoagu- lants inhibited bone nodule formation and increased alkaline phosphatase in a dose-dependent manner, UFH had a sixfold greater effect than LMWH.30 Other investigators also reported that LMWH causes signi cant inhibition of osteoblast growth186 and pro- duces osteopenic changes in rats.187 Three small prospective clinical studies have reported on the effects of prophylactic doses of LMWH on bone density. The rst was a cohort study in which 16 women receiving enoxaparin (40 mg daily) during pregnancy had serial bone density measurements of the proximal femur. Baseline mea- surements were taken within 2 weeks of starting therapy and then at 6 to 8 weeks and 6 months post- partum. Patients received enoxaparin for a mean duration of 25 weeks (range, 19-32 weeks). Com- pared with baseline values, there was no signi cant change in mean bone density at 6 weeks postpartum and no patient experienced a . 10% decrease in bone mass. At 6 months postpartum, there was a sig- ni cant reduction in mean bone density (P 5 .02) and two of the 14 patients evaluated (14%) had The second study was an open randomized trial that included 44 pregnant women with VTE. Patients were assigned to either prophylactic doses of LMWH (dalteparin; n 5 21) once daily subcuta- neously or UFH (n 5 23) twice daily subcutane- ously during pregnancy and the puerperium. Dual x-ray absorptiometry of the lumbosacral spine was performed at 1, 6, 16, and 52 weeks. A healthy untreated control group was included for compar- ison. Mean bone density of the lumbar spine was signi cantly lower in the UFH group than in the dalteparin or control groups. Bone density measure- ments did not differ between the dalteparin and The third clinical trial compared the effects of long-term treatment with LMWH (enoxaparin) and acenocoumarol on bone mineral density in 86 patients with VTE. Treatment was given for 3 to 24 months. At 1 and 2 years of follow-up, the mean decrease in bone density of the femur was 1.8% and 2.6% in patients given acenocoumarol and 3.1% and 4.8% in patients given enoxaparin, respectively. These differences were not statistically signi cant.190 A recent review con rms that the strength of the association between LMWH and osteoporosis In summary, both UFH and LMWH preparations have the potential to produce osteopenia. The risk is lower with LMWH. 2012 American College of Chest Physicians by Kimberly Henricks on February 10, 2012 chestjournal.chestpubs.org Downloaded from e34S Parenteral Anticoagulants Heparin and LMWH can cause urticarial skin reac- tions. Rarely, skin necrosis can occur at sites of injec- tion. In these cases, HIT should be suspected. In a single case report, fondaparinux was used success- fully in a patient who developed skin reactions to three different LMWH preparations.209 To date, studies on the effects of fondaparinux on bone metabolism have been limited to in vitro exper- iments using cultured osteoblasts. In one study, fondaparinux was compared with heparin, dalteparin, or enoxaparin. Osteoblasts exposed to fondaparinux showed signi cantly higher mitochondrial activity and protein synthesis than unexposed osteoblasts. In contrast, therapeutically relevant concentrations of heparin, dalteparin, or enoxaparin decreased matrix collagen type 2 content and calcification; fonda- parinux had no effect on these measures of osteo- blastic activity.210 A second study compared the effects of fondaparinux and dalteparin on human osteoblasts in culture. Dalteparin inhibited osteoblast prolifera- tion, protein synthesis, and the decreased levels of osteocalcin and alkaline phosphatase. In contrast, fondaparinux had no effect.211 Because of insuf cient safety data, fondaparinux is not widely used in pregnancy. Although one pharma- cologic study showed that there was no placental transfer of the pentasacccharide,212 low levels of anti-Xa activity were detected in the umbilical cord blood in newborns of mothers treated with 1.4 Danaparoid Sodium Although it is a mixture of glycosaminoglycans (heparan sulfate, dermatan sulfate, and chondroitin sulfate), danaparoid acts as an anticoagulant primarily by catalyzing the inhibition of factor Xa in an AT-dependent fashion. The drug has low speci c anti-Xa activity. Based on anti-Xa levels, danaparoid has a half-life of approximately 25 h. Although danaparoid was shown to be effective for the prevention of venous thrombosis in high-risk patients, it is no longer marketed for this indication. Currently, its use is limited to the management of patients with HIT; it is discussed in greater detail in the article on HIT in this supplement.32 Danaparoid is the only agent that has been evaluated for HIT in a randomized clinical trial, wherein it was reported to be signi cantly better than dextran. High success rates in the treatment of HIT have also been observed in retrospective studies. Danaparoid is approved for the treatment of HIT in some countries (eg, The Netherlands, Belgium, New Zealand) but not in the United States. Danaparoid does not prolong the INR. This facili- tates monitoring when transitioning patients with to plasma proteins other than AT, and most of the compound is bound to AT.201 Based on its almost complete bioavailability after subcutaneous injection, lack of variability in anticoag- ulant response, and long half-life, fondaparinux can be administered subcutaneously once daily in xed doses without coagulation monitoring. 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. Scand J Clin Lab Invest. 1968;21(1):89-91. 4. Lindahl U, B ckstr m G, H k M, Thunberg L, Fransson LA, Linker A. Structure of the antithrombin-binding site in hep- arin. Proc Natl Acad Sci U S A. 1979;76(7):3198-3202. 5. Merlini PA, Bauer KA, Oltrona L, et al. Persistent activation of coagulation mechanism in unstable angina and myocar- dial infarction. Circulation. 1994;90(1):61-68. 6. Rosenberg RD, Lam L. Correlation between structure and function of heparin. Proc Natl Acad Sci U S A. 1979;76(3): 1218-1222. 7. Hirsh J, Bauer KA, Donati MB, et al. Parenteral anticoagu- lants: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6 suppl):141S-159S. 8. Andersson LO, Barrowcliffe TW, Holmer E, Johnson EA, Sims GE. Anticoagulant properties of heparin fractionated by affinity chromatography on matrix-bound antithrombin iii and by gel filtration. Thromb Res. 1976;9(6):575-583. 9. Harenberg J. Pharmacology of low molecular weight hepa- rins. Semin Thromb Hemost. 1990;16(suppl):12-18. 10. Johnson EA, Kirkwood TB, Stirling Y, et al. Four heparin preparations: anti-Xa potentiating effect of heparin after sub- cutaneous injection. Thromb Haemost. 1976;35(3):586-591. binds noncovalently to the active site of thrombin to form a reversible complex.224-226 The plasma half-life of argatroban is 45 min. It is metabolized in the liver226 via the cytochrome P450 3A4/5 enzyme system. Con- sequently, argatroban must be used with caution in patients with hepatic dysfunction. Because it is not renally excreted, however, argatroban is particu- larly useful in patients with HIT with severe renal impairment. Argatroban is licensed for treatment and preven- tion of HIT-associated thrombosis and for antico- agulation during percutaneous coronary interventions when heparin is contraindicated because of a recent history of HIT. Argatroban is given as a continuous IV infusion with an initial dose of 1 to 2 mg/kg/min and the dose is adjusted to maintain the aPTT ratio in the 1.5 to 2.5 range (Linkins et al).32 2.1 Monitoring of Direct Thrombin Inhibitors Although the aPTT is used to monitor therapy with direct thrombin inhibitors, this test is not ideal. The dose-response is not linear and the aPTT reaches a plateau with higher doses of the various drugs. In addition, aPTT reagents vary in their sensitivities to direct thrombin inhibitors. The ecarin clotting time yields a more linear dose-response, but this test is not widely available and has not been standardized. All of the direct thrombin inhibitors increase the INR, albeit to a variable extent. When given in thera- peutic doses, argatroban has the greatest effect on the INR.227 This phenomenon complicates transition- ing from argatroban to vitamin K antagonists. To overcome this problem, the INR can be measured after stopping the argatroban infusion for several hours. Because holding argatroban may expose patients to a risk of thrombosis, another option is to monitor the vitamin K antagonist with a chromogenic factor X assay. In this setting, factor X levels,45% have been associated with INR values.2 when the effect of argatroban has been eliminated.228 Moni- toring factor X levels may be safer than aiming for an INR 4 when vitamin K antagonists are given in conjunction with argatroban.229,230 2.2 Reversal of Anticoagulant Effects There are no specific antidotes for direct thrombin inhibitors. 