Inpatient Anticoagulation E-Book

Margaret C. Fang

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Serie: Hospital Medicine - Current Concepts
• Sprache: Englisch

Seitenzahl: 730

Veröffentlichungsjahr: 2011

Beschreibung

The first practical guide for hospitalists on the use ofanticoagulants in hospitalized patients This edited volume provides a comprehensive overview of thevital topic of anticoagulation in the hospital setting. Designedspecifically for use by hospital-based clinicians and associatedhospital-based staff, this fully evidence-based book addresses themost commonly used anticoagulant agents, the latest advances inanticoagulation drugs, and primary indications for their use attherapeutic levels. This thorough, easy-to-use reference summarizes the mostimportant guidelines and medical literature on anticoagulation. Itfeatures a careful review of the epidemiology and treatment ofcomplications associated with anticoagulants. Unique topics includetransition of care and practical strategies for developing andimplementing quality improvement programs to enhance theadministration and safety of anticoagulants. This concise resource also covers: * Antiplatelet medications * The treatment and prevention of venous thromboembolism inmedical patients * Venous thromboembolism prophylaxis in surgical patients * Peri-operative management of oral anticoagulants andantiplatelet agents * Prevention of cardioembolic stroke * Antithrombotics for ischemic stroke * Antithrombotic therapy for non-ST elevation acute coronarysyndrome * Hemorrhagic complications of anticoagulants in hospitalizedpatients * Heparin-induced thrombocytopenia Hospitalists and other members of the patient care team willfind that Inpatient Anticoagulation answers their questions withdependable and timely information.

Leseprobe

Table of Contents

Series Page

Title Page

Copyright

Preface

Contributors

Chapter 1: Pharmacology of Parenteral Anticoagulants

1.1 Introduction

1.2 Unfractionated Heparin

1.3 Low-Molecular-Weight Heparin (LMWH)

1.4 Fondaparinux

1.5 Idraparinux

1.6 Drug–Drug Interactions

1.7 Adverse Events

1.8 Special Populations

1.9 Conclusion

References

Chapter 2: Pharmacology of Vitamin K Antagonists

2.1 Introduction

2.2 Pharmacodynamics

2.3 Pharmacokinetics

2.4 Adverse Reactions

2.5 Monitoring Warfarin Therapy

2.6 Relationship Between INR and Blood Reserve of Coagulation Factors

2.7 Dosing

References

Chapter 3: Antiplatelet Medications

3.1 Aspirin

3.2 Clopidogrel and Other P2Y12 Receptor Antagonists

3.3 Glycoprotein IIb/IIIa Antagonists

3.4 Dipyridamole

3.5 Cilostazol

References

Chapter 4: Newer Oral Anticoagulants

4.1 Introduction

4.2 Pharmacology

4.3 Clinical Trials

4.4 Conclusion and Clinical Considerations

References

Chapter 5: Prevention of Venous Thromboembolism in Medical Patients

5.1 The Epidemiology of Venous Thromboembolism in Hospitalized Acutely Ill Medical Patients

5.2 Risk Factors for Venous Thromboembolism and Risk Assessment Models in Hospitalized Medical Patients

5.3 Clinical Data

5.4 Overview of Guideline Recommendations for Thromboprophylaxis in Hospitalized Acutely Ill Medical Patients

5.5 Underutilization of Thromboprophylaxis in Hospitalized Medical Patients

5.6 Current Controversies

5.7 National Quality Measures

5.8 Future Direction and Perspectives

5.9 Conclusion

5.10 Acknowledgment

References

Chapter 6: Prevention of Venous Thromboembolism in Surgical Patients

6.1 Introduction

6.2 Prevalence of Venous Thromboembolism in the Surgical Population

6.3 Pathophysiology

6.4 Risk Factors for Venous Thromboembolism in Surgical Patients

6.5 DVT Prophylaxis in the Perioperative Setting Based on Risk Stratification

6.6 Venous Thromboembolism Prophylactic Therapies

6.7 Recommendations from Professional Societies for VTE Prophylaxis in the Surgical Patient

6.8 VTE Prophylaxis for Patients Undergoing Orthopedic Surgery

6.9 VTE Prophylaxis in Patients Undergoing Neurosurgery

6.10 Initiation and Duration of Venous Thromboembolism Prophylaxis

6.11 Contraindications to Venous Thromboembolism Prophylaxis

6.12 Emerging Therapies in Prevention of Venous Thromboembolism

6.13 Conclusions

References

Chapter 7: Treatment of Acute Venous Thromboembolism in Hospitalized Patients

7.1 Goals of Therapy

7.2 Before Initiating Treatment

7.3 Initiation of Anticoagulation

7.4 Triaging the Patient

7.5 Identifying Candidates for Thrombolysis

7.6 Catheter-Related Thrombosis

7.7 Postoperative VTE

7.8 The Role of the IVC Filter

7.9 Classifying the Event: A Search for the Cause

7.10 Testing for Laboratory Thrombophilia

7.11 Duration of Anticoagulation for VTE

7.12 Additional Measures

References

Chapter 8: Perioperative Management of Oral Anticoagulants and Antiplatelet Agents

8.1 Introduction and Basic Principles

8.2 Oral Anticoagulants

8.3 Antiplatelet Therapy

8.4 Conclusions

References

Chapter 9: Prevention of Cardioembolic Stroke

9.1 Introduction

9.2 Atrial Fibrillation

9.3 Valvular Heart Disease

9.4 Post–Myocardial Infarction

9.5 Heart Failure

References

Chapter 10: Antithrombotics for Ischemic Stroke

10.1 Introduction

10.2 Antithrombotic Therapy in the Primary Prevention of Ischemic Stroke

10.3 Acute Ischemic Stroke Management

10.4 Antithrombotic Therapy in Secondary Prevention of Ischemic Stroke

10.5 Conclusion

References

Chapter 11: Antithrombotic Therapy for Non-ST-Elevation Acute Coronary Syndrome

11.1 Introduction and Background

11.2 Definition

11.3 Early-Stage NSTEACS

11.4 Antiplatelet Therapies

11.5 Antithrombins and Anticoagulation

11.6 Timing of Early Invasive Approach

11.7 Special Circumstances

11.8 Discharge Medications

11.9 Future Therapies

11.10 Summary

References

Chapter 12: Parenteral Anticoagulants: Special Considerations in Patients with Chronic Kidney Disease and Obesity

12.1 Introduction

12.2 Anticoagulation in Patients with Chronic Kidney Disease

12.3 Anticoagulation in Obese Patients

References

Chapter 13: Hemorrhagic Complications of Anticoagulants in Hospitalized Patients

13.1 Introduction

13.2 General Management of Anticoagulation-Associated Hemorrhage

13.3 Warfarin

13.4 Heparin

13.5 Fondaparinux

13.6 Direct Thrombin Inhibitors (DTIs)

13.7 Novel Anticoagulants

13.8 Summary

References

Chapter 14: Heparin-Induced Thrombocytopenia

14.1 Introduction

14.2 Pathophysiology

14.3 Prevalence of Heparin-Induced Thrombocytopenia (HIT)

14.4 Clinical Features of HIT

14.5 Diagnosis of HIT

14.6 Treatment of HIT

14.7 Conclusion

References

Chapter 15: Transitions in Care: Inpatient Anticoagulation

15.1 Introduction

15.2 Strategies for Optimization of Health Systems

15.3 Interventions for Improving Follow-Up After Discharge

15.4 Strategies for Improving Patient Education

15.5 Facilitating Inpatient–Outpatient Communication

15.6 Summary

References

Chapter 16: Optimizing Inpatient Anticoagulation: Strategies for Quality Improvement

16.1 Introduction

16.2 Overview: Improving Anticoagulation

16.3 Warfarin Initiation and Maintenance

16.4 Management of Venous Thromboembolism (VTE)

16.5 VTE Prevention

16.6 Looking Forward

References

Index

Copyright © 2011 by John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.

Published simultaneously in Canada.

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Library of Congress Cataloging-in-Publication Data:

Inpatient anticoagulation / [edited by] Margaret C. Fang, MD, MPH, University of California at San Francisco.

p. ; cm.

ISBN 978-0-470-60211-9 (cloth)

Anticoagulants (Medicine)–Administration. I. Fang, Margaret C., editor.

[DNLM: 1. Anticoagulants–therapeutic use. 2. Blood Coagulation–drug effects. 3. Inpatients.]

4. Patient Care Planning. 5. Pharmacy Service, Hospital–methods. 6. Thrombosis–drug therapy. QV 193]

RM340.I535 2011

615'.718–dc22

2011008300

Preface

This is an exciting time in the world of anticoagulation. Not only may potentially viable alternatives to warfarin, but unprecedented attention is being paid towards quality measurement and improvement strategies related to anticoagulation.

The inpatient setting is often where clinicians decide whether to start, stop, or continue anticoagulant therapy. Familiarity with when and how to use these high-risk agents is an integral part of hospital medicine. The ongoing tensions between the therapeutic benefits of anticoagulants and their contribution to bleeding risk are issues that hospital-based clinicians face on a daily basis; one moment, a person after hip surgery has a sudden pulmonary embolism; the next moment, a person on heparin suffers a devastating intracranial hemorrhage. This book attempts to summarize current guidelines and recent medical literature to help busy clinicians apply evidence to practice.

We review common situations faced by clinicians in the hospital setting, and review when and how to use antithrombotic medications. We provide guidance on how to balance the risks of therapy with the benefits of anticoagulants, across different clinical indications. Finally, we cover strategies on how to improve transitions in care and discuss how to measure and improve the quality of anticoagulant care, issues highly relevant to today's clinicians.

As this field continues to evolve and as newer anticoagulants become available, we hope that this book can serve as a framework on how to approach the often difficult decisions that need to be made with regards to anticoagulant management.

Happy reading!

Margaret C. Fang

San Francisco, California

March 2011

Contributors

Julie K. Atay, Pharm.D., M.B.A., Department of Pharmacy, Brigham and Women's Hospital, Boston, Massachusetts, USA

Andrew Boyle, M.D., University of California, San Francisco, California, USA

Allison Burnett, Pharm.D., Department of Pharmacy, University of New Mexico Hospital Albuquerque, New Mexico, USA

Brian Clay, M.D., Division of Hospital Medicine, University of California, San Diego, California, USA

Jason Cohen, M.D., Health Sciences Center, University of New Mexico, Albuquerque, New Mexico, USA

Lauren Doctoroff, M.D., Hospital Medicine Program, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

Andrew Dunn, M.D., Mt. Sinai Medical Center, New York, New York, USA

Margaret C. Fang, M.D., University of California, San Francisco, California, USA

John Fanikos, M.B.A., Department of Pharmacy, Brigham and Women's Hospital, Boston, Massachusetts, USA

Elizabeth A. Farrell, M.D., Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

David Feinbloom, M.D., Hospital Medicine Program, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

Nancy Torres Finnerty, M.D., Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

Taki Galanis, M.D., Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA

David A. Garcia, M.D., Health Sciences Center, University of New Mexico, Albuquerque, New Mexico, USA

Neil Gupta, M.D., Centers for Disease Control and Prevention, Atlanta, Georgia, USA

Doug Humber, Pharm.D., Department of Pharmacy, University of California San Diego Medical Center, San Diego, California, USA

Ian Jenkins, M.D., Division of Hospital Medicine, University of California, San Diego, California, USA

Ramiro Jervis, M.D., Mt. Sinai Medical Center, New York, New York, USA

Steven R. Kayser, Pharm.D., Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, California, USA

Michael Kornfeld, M.D., Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

David Lao, M.D., University of California, San Francisco, California, USA

Charles E. Mahan, Pharm.D., Department of Pharmacy, Lovelace Medical Center, Albuquerque, New Mexico, USA

Ali Mahajerin, M.D., West Michigan Heart, Spectrum Health System, Grand Rapids, Michigan, USA

Warren J. Manning, M.D., Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

Greg Maynard, M.D., Division of Hospital Medicine, University of California, San Diego, California, USA

Kathleen H. McCool, Pharm.D., Kaiser Permanente, Aurora, Colorado, USA

Geno Merli, M.D., Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, USA

Franklin Michota, M.D., Department of Hospital Medicine, Cleveland Clinic, Cleveland, Ohio, USA

Tracy Minichiello, M.D., Division of Hematology, University of California, San Francisco, California, USA

Michael Montazeri, M.D., Division of Hospital Medicine, University of California, San Diego, California, USA

Joseph R. Munsayac, M.D., Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

Fadi B. Nahab, M.D., Department of Neurology, Emory University, Atlanta, Georgia, USA

Sakib Qureshi, M.D., Emory University, Atlanta Georgia, USA

Millie Rajyaguru, Pharm.D., Philadelphia College of Pharmacy, Philadelphia, Pennsylvania, USA

Jaekyu Shin, Pharm.D., Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, California, USA

Diane Sliwka, M.D., University of California, San Francisco, California, USA

Sarah Spinler, Pharm.D., Philadelphia College of Pharmacy, Philadelphia, Pennsylvania

Alex C. Spyropoulos, M.D., McMaster University, Hamilton, Ontario, Canada

John Fani Srour, M.D., Hospital Medicine Program, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

Daniel M. Witt, Pharm.D., Kaiser Permanente Colorado, Aurora, Colorado, USA

Chapter 1

Pharmacology of Parenteral Anticoagulants

Kathleen H. McCool and Daniel M. Witt

1.1 Introduction

Many hospitalized patients require parenteral anticoagulant medications for prevention or treatment of thrombosis. The majority of hospitalized patients have at least one risk factor for venous thromboembolism (VTE), a severe problem that causes mortality, morbidity, and considerable challenges for healthcare systems (1). Many common admitting diagnoses such as myocardial infarction, stroke, and VTE also require the use of parenteral anticoagulants (2). Because the delicate balance of hemostasis is altered, the risk of bleeding is unavoidably linked to the use of anticoagulant medications (3). Therefore, familiarity with pharmacologic, pharmacokinetic, and pharmacodynamic properties of these agents as well as nuances associated with their clinical application is important for those caring for hospitalized patients. This chapter provides an overview of the most commonly used parenteral anticoagulants, namely, unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and fondaparinux. Other parenteral anticoagulants, such as the direct thrombin inhibitors and glycoprotein IIb/IIIa inhibitors, which are used less frequently and in more specialized practice settings, are not addressed here.

1.2 Unfractionated Heparin

The antithrombotic effect of UFH has been known for almost a century. To this day it continues to be used in various circumstances to prevent and treat thrombosis (2). Commercially available UFH preparations are derived from bovine lung or porcine intestinal mucosa. However, bovine derived UFH is unavailable in the United States. Although some differences exist between the two sources, no differences in antithrombotic activity have been demonstrated (4).

1.2.1 Pharmacology

Unfractionated heparin is a heterogeneous mixture of sulfated mucopolysaccharides of variable lengths and pharmacologic properties (2). The weight of UFH molecules ranges from 3000 to 30,000 daltons (Da), with a mean of 15,000 Da. The average UFH molecule is about 45 saccharide units in length (2). The anticoagulant profile and clearance of each UFH molecule varies according to its length. Smaller chains are cleared less rapidly than are their longer counterparts (2). The anticoagulant effect of UFH is mediated through a specific pentasaccharide sequence that binds to antithrombin in a reversible manner, provoking a conformational change (Fig. 1.1). Antithrombin inhibits the activity of several clotting factors, including IXa, Xa, XIIa, and thrombin (IIa). The UFH–antithrombin complex is 100–1000 times more potent an anticoagulant than is antithrombin alone. Factors IIa and Xa are most sensitive to inhibition by the UFH–antithrombin complex (2). Ultimately, inactivation of thrombin and factor Xa by the UFH–antithrombin complex prevents clot propagation by allowing the native thrombolytic system to break down clots. Because of its large size, the UFH–antithrombin complex is unable to inactivate thrombin or factor Xa bound to surfaces or within formed clots (4).

Figure 1.1 Action mechanisms of unfractionated heparin, low-molecular-weight heparin, and fondaparinux.

To inactivate thrombin, the heparin molecule must bind to antithrombin and thrombin simultaneously, forming a ternary complex (see Fig. 1.1). This occurs only with heparin molecules with a length of more than 18 saccharide units. Smaller heparin molecules cannot inactivate thrombin (5). At high doses UFH also binds heparin cofactor II, further inhibiting thrombin (2). Through its action on thrombin, the UFH–antithrombin complex also inhibits thrombin-induced activation of factors V and VIII (2).

In contrast, the inactivation of factor Xa does not require ternary complex formation, but only that UFH bind to antithrombin via the specific pentasaccharide sequence (5). Therefore, heparin molecules with as few as five saccharide units are able to catalyze the inhibition of factor Xa, but only one-third of UFH molecules possess this unique pentasaccharide sequence (2). The inhibitory effect of UFH on factor Xa is augmented through the release of tissue factor pathway inhibitor from vascular endothelium (6).

1.2.2 Pharmacokinetics

Unfractionated heparin is not reliably absorbed orally as a consequence of its large molecular size and anionic structure. The subcutaneous bioavailability of UFH is dose-dependent and ranges from 30% at low doses to as much as 70% at high doses. The onset of anticoagulant effect is usually evident 1–2 h after subcutaneous injection peaking at 3 h (5). Continuous intravenous infusion is preferable as intermittent intravenous boluses produce relatively high peaks in anticoagulation activity and have been associated with a greater risk of major bleeding (7). Intramuscular administration is discouraged because of erratic absorption and potential for large hematoma formation.

With the usual therapeutic doses, UFH has a dose-dependent half-life of approximately 30–90 min (2). Unfractionated heparin is eliminated by a rapid, saturable process involving binding to endothelial cells and macrophages followed by subsequent enzymatic inactivation, and slower, nonsaturable renal elimination (2). Therapeutic doses of UFH are cleared principally by the saturable mechanism, whereas the renal route predominates at very high doses (2). Renal and hepatic dysfunction can reduce the rate of UFH clearance, while patients with active thrombosis may eliminate UFH more quickly, potentially because of increased binding to acute-phase reactants (2).

1.2.3 Dosing

The dose and route of administration for UFH are based on the indication, the therapeutic goals, and the patient's individual response to therapy (see Table 1.1). The dose of UFH is expressed in units of activity. The number of units per milligram varies depending on the manufacturing process.

Table 1.1 Unfractionated Heparin Dosing

1.2.4 Monitoring

Administration of UFH requires close monitoring of anticoagulant effect, due to unpredictable patient response. A complete blood count with platelets should be obtained prior to initiation of UFH and periodically during treatment to assist in monitoring for adverse events (see Section 1.7). For UFH dosing titration, multiple tests may be used including whole-blood clotting time, activated partial thromboplastin time (aPTT), activated clotting time (ACT), anti–factor Xa activity, and plasma heparin concentrations (see Table 1.2). The most frequently used test for monitoring heparin is the aPTT, which traditionally is considered to be within therapeutic range at values 1.5–2.5 times the mean normal control (2). Unfortunately, few currently available reagents are able to accurately measure the response to heparin within this range, and as a result a fixed aPTT therapeutic range of 1.5–2.5 times control may represent a subtherapeutic dose of UFH (2). Consequently, an institution-specific aPTT therapeutic range that correlates with a plasma heparin concentration of 0.3–0.7 international units per milliliter (IU/mL) by an amidolytic antifactor Xa assay should be established (2). The baseline aPTT should be established prior to initiation of UFH therapy. During intravenous UFH infusions the aPTT should be measured approximately 6 h after initiation of therapy or any dose change. Dose adjustments should be based on the patient's response and the institution-specific therapeutic aPTT range (see Table 1.3) (5).

Table 1.2 Monitoring Tests for Parenteral Anticoagulants

Table 1.3 Sample Protocol for Heparin Dose Adjustments (33)

Reduced response to UFH can be seen in patients with myocardial infarction or acute VTE (2). This presumably occurs as a result of variations in plasma concentrations of heparin-binding proteins. Another form of resistance has been reported in patients with acute elevations in factor VIII, which prevents prolongation of the aPTT by UFH (2). Rarely, antithrombin deficiency may also cause resistance, in which case antithrombin concentrate may be infused to restore UFH responsiveness (8). Heparin resistance should be suspected when patients require more than 35,000 IU of intravenous UFH within a 24-h period. In such cases, using anti–factor Xa concentrations to adjust UFH doses is reasonable (2).

Use of the aPTT has several limitations even if institution-specific therapeutic ranges are defined:

1. Multiple variables such as reagent sensitivity, temperature, phlebotomy methods, and hemodilution may result in inaccurate results (5).

2. There is diurnal variation demonstrated in the response of aPTT, with the peak response occurring around 3 a.m. during continuous intravenous infusion. If the UFH infusion rates are adjusted according to values determined during this diurnal variation, subsequent over- or underdosing may occur (9). The clinical consequences of this phenomenon are unknown.

3. The aPTT is prolonged beyond measurable limits when patients require doses of UFH that produce serum concentrations > 1 U/mL. The ACT should be used in these circumstances (e.g., during coronary angioplasty or coronary bypass surgry) (2, 4).

4. During treatment lower-weight heparin fragments accumulate, and continue to have anticoagulant activity, but little effect on aPTT results (5).

5. The data used to determine the currently recommended therapeutic range were not derived from scientifically rigorous study (2).

Increased understanding of these problems associated with UFH therapy have occurred only relatively recently, generating interest in the use of alternative agents such as LMWH in various clinical settings (9)

1.3 Low-Molecular-Weight Heparin (LMWH)

Three LMWH products are available in the United States: dalteparin, enoxaparin, and tinzaparin. The usefulness of LMWHs has been extensively evaluated for a wide array of indications. The LMWHs have largely replaced UFH for the prevention and treatment of VTE and other indications in some hospitals (9).

1.3.1 Pharmacology

Low-molecular-weight heparins are produced by either chemical or enzymatic depolymerization (2). They are fragments of UFH provided in a heterogeneous mixture with approximately one-third the molecular weight of UFH. Because mean molecular weight is specific to each product, various LMWHs have differing activity against factor Xa, thrombin, affinity for plasma proteins, and duration of activity. However, mechanism of action is the same for all products (2). These agents have several advantages over UFH, including a predictable anticoagulation dose response, improved subcutaneous bioavailability, dose-independent clearance, longer biologic half-life, lower incidence of thrombocytopenia, and a reduced need for routine laboratory monitoring (2).

As does UFH, the LMWHs prevent growth and propagation of formed thrombi, allowing the native thrombolysis to dissolve and remove clot. Similar to that of UFH, the main action of LMWHs is to enhance and accelerate the activity of antithrombin by binding to a specific pentasaccharide sequence, although fewer than one-third of LMWH molecules contain the specific sequence necessary to interact with antithrombin (2). The main difference in comparison to UFH is the relative inhibition ratio of factor Xa and thrombin (see Fig. 1.1). Shorter saccharide chain lengths limit the ability of LMWH to bind both antithrombin and thrombin, leading to reduced activity against thrombin (7). Fewer than 50% of LMWH molecules are able to inactivate thrombin, resulting in ratios of antifactor Xa : IIa activity between 4 : 1 and 2 : 1 among the various LMWH preparations. By comparison, UFH has an anti–factor Xa : IIa activity ratio of 1 : 1 (2).

1.3.2 Pharmacokinetics

Unlike UFH, the LMWHs have a more predictable anticoagulation response. This improved pharmacokinetic profile is the result of reduced binding to proteins and cells (2). The subcutaneous bioavailability of LMWHs is about 90% and differs only slightly among the various products. The peak anticoagulation effect is seen around 3–5 h after subcutaneous administration (2). The LMWHs are eliminated mainly renally; therefore patients with renal impairment can show a prolonged biologic half-life (5). Because longer heparin chains are bound to macrophages and rapidly degraded, the duration of antithrombin activity is limited. In contrast, anti–factor Xa activity, which is mediated by smaller heparin molecules, persists for a longer period of time. Thus, the plasma half-life of the LMWH preparations is 2–4 times longer than that of UFH, and the clearance of LMWHs is independent of dose (2).

1.3.3 Dosing

The FDA-approved indications and doses for the LMWHs are product-specific (see Table 1.4). The LMWHs are given in fixed or weight-based doses on the basis of the product and indication. Doses should be based on actual body weight. Studies in obese patients have demonstrated that full weight-based doses do not lead to elevated LMWH concentrations when compared with normal subjects; consequently, dose capping is not recommended (9). To avoid confusion, it is important to note that the dose for enoxaparin is expressed in milligrams, in contrast to dalteparin and tinzaparin, which are expressed in units of anti–factor Xa activity. The LMWHs may be administered via continuous intravenous infusion; however, the typical route is by subcutaneous injection. The LMWHs are dosed every 12–24 h depending on the indication and product.

Table 1.4 FDA-Approved Doses for Low-Molecular-Weight Heparin and Fondaparinuxa

1.3.4 Monitoring

Because the anticoagulant response is predictable, routine laboratory monitoring is not needed to guide LMWH dosing (1). The LMWHs have limited effects on the PT, ACT, and aPTT; therefore, these tests are not useful for monitoring (see Table 1.2) (5). Prior to initiation of LMWH, a baseline complete blood cell count with platelets should be obtained and then monitored periodically to assist in identifying adverse events (see Section 1.7). Because LMWHs require dose modifications with renal impairment, a baseline serum creatinine and calculated creatinine clearance should be determined. Several methods for testing activity of the LMWHs have been explored; measurement of anti–factor Xa activity is the most widely used in clinical practice (2). Few patients require regular monitoring of LMWH; however, it has been suggested that obese or very small patients, patients with renal insufficiency, or pregnant women may benefit from periodic anti–factor Xa monitoring (1). If laboratory monitoring is needed, the anti–factor Xa activity should be drawn after the second or third dose, when steady state is likely to have been achieved. Timing of the lab should be during the peak period of anti–factor Xa activity or approximately 4 h after subcutaneous injection (5). A calibrated LMWH heparin should be used to establish the standard curve for the assay. It is important to note that the therapeutic range for anti–factor Xa activity is not well defined and has not been clearly correlated with efficacy or the risk of bleeding (2). For the treatment of VTE, an acceptable target range for the peak level is 0.6–1.0 IU/mL with twice daily enoxaparin dosing. For once daily dosing likely peak targets are > 1 IU/mL for enoxaparin, 0.85 U/mL for tinzaparin, and 1.05 IU/mL for dalteparin (2). For the prevention of VTE, an acceptable target range for the peak level is 0.2–0.4 IU/mL (4).

1.4 Fondaparinux

Fondaparinux, also referred to as pentasaccharide, is a synthetic molecule consisting of the five critical saccharide units that reversibly bind to antithrombin (see Fig. 1.1) (2). Fondaparinux is the first commercially available agent in a class of anticoagulants that selectively inhibit factor Xa activity (10).

1.4.1 Pharmacology

Fondaparinux shares with the heparin-derived products a mechanism of action that involves reversible binding to antithrombin catalyzing by 300-fold the inactivation of factor Xa, preventing further thrombus generation and clot formation (11). Fondaparinux is not destroyed during this process and once released, can interact with other antithrombin molecules (2). Fondaparinux has no direct effect on thrombin activity at therapeutic plasma concentrations, because its chain length is only 5 units (2). While the benefits of selective inhibition of factor Xa are incompletely defined at present, more efficient control over fibrin generation while preserving thrombin's regulatory functions in the control of hemostasis are potential advantages (11).

1.4.2 Pharmacokinetics

Fondaparinux is rapidly and completely absorbed following subcutaneous administration and does not bind to red blood cells or other plasma proteins (12). Peak plasma concentrations are achieved approximately 2 h after a single dose and at 3 h following repeated daily doses. Fondaparinux is eliminated primarily unchanged in the urine. The terminal elimination half-life is 17–21 h. Following discontinuation of fondaparinux, the anticoagulant effect persists for 2–4 days in patients with normal renal function (12).

1.4.3 Dosing

Fondaparinux has received FDA approval for the prevention of VTE and for the treatment of DVT or PE in conjunction with warfarin (see Table 1.4) (12). In the setting of VTE prevention, following orthopedic (hip fracture, hip replacement, and knee replacement) or abdominal surgery, the dose of fondaparinux is 2.5 mg injected subcutaneously once daily starting 6–8 h following surgery. Adequate hemostasis should be achieved prior to initiation of fondaparinux because there is a significant relationship between the timing of the first dose and the risk of major bleeding complications when fondaparinux is administered too early. Patients who weigh less than 50 kg should not be given fondaparinux for VTE prophylaxis (12). The usual duration of prophylactic therapy is 5–9 days, but it may be given following hospital discharge for up to 21 days (12). For the treatment of DVT or PE, the fondaparinux dose is administered subcutaneously once daily with a fixed dose covering a range of patient weights. Dosage for patients weighing 50–100 kg should be 7.5 mg; patients weighing more than 100 kg should receive 10 mg, and those under 50 kg should receive only 5 mg (12).

1.4.4 Monitoring

Because of the predictable anticoagulant response, routine laboratory monitoring is not recommended for most patients receiving fondaparinux (see Table 1.2) (1). A complete blood cell count should be measured at baseline and monitored periodically to detect the possibility of occult bleeding (12). Fondaparinux is contraindicated if the creatinine clearance is less than 30 mL/min, so baseline kidney function should be determined before therapy begins. Periodic monitoring of kidney function is necessary for patients at risk of developing renal failure with discontinuation of fondaparinux should the creatinine clearance level drop below 30 mL/min. Signs and symptoms of bleeding should be monitored daily, particularly in patients with a baseline creatinine clearance between 30 and 50 mL/min (12). Fondaparinux does not alter coagulation tests such as the aPTT and PT, so these tests are unreliable measurements of fondaparinux's effect. Anti–factor Xa activity can be monitored during fondaparinux treatment; however, therapeutic ranges have not been identified (2). Additionally, the anti-Xa assay should be calibrated appropriately utilizing fondaparinux as the reference standard and should not be compared to the activities of UFH or the LMWHs (2).

1.5 Idraparinux

Idraparinux is an analog of fondaparinux that has an extended duration of effect and was developed for administration once weekly by subcutaneous injection (10). Because of concerns regarding a drug that increases bleeding risk with duration of effect persisting for a week, a novel biotinylated formulation of idraparinux (SSR 126517) has been developed. This experimental formulation can be rapidly reversed with the intravenous administration of avidin, an egg-white protein (10). Avidin binds to biotin to form a stable complex that is renally cleared within minutes. This quickly terminates the anticoagulant effect of SSR 126517 (13). Neither idraparinux nor SSR 126517 is currently commercially available.

1.6 Drug–Drug Interactions

The parenteral anticoagulants have limited potential for pharmacokinetic interactions with other medications; however, clinically relevant pharmacodynamic interactions are possible. In general, concurrent use of other medications that increase the risk of bleeding, such as antiplatelet agents or oral anticoagulants, should be avoided when possible during parenteral anticoagulant therapy. When coadministration of other antithrombotic agents is necessary, vigilant monitoring for bleeding complications is required (12, 14).

1.7 Adverse Events

1.7.1 Hemorrhage

Bleeding is the most common adverse effect seen with parenteral anticoagulant medication (3). Any anatomic site can be affected. Severity ranges from minor bleeding such as epistaxis, gingival bleeding, and bruising from minor trauma, to life-threatening gastrointestinal and intracranial hemorrhage. Lack of a universally accepted definition of major bleeding complicates any comparison of bleeding rates reported in the medical literature. A commonly used definition of major bleeding is one that results in a decrease of 2 g/dL or more in hemoglobin concentration and/or transfusion of at least 2 IU of packed red blood cells or whole blood as well as any bleeding into a critical anatomic space such as the central nervous system, intraocular space, or pericardium (3). Epidural and spinal hematomas resulting in long-term or permanent paralysis have been reported with the use of LMWH and fondaparinux necessitating the need for careful monitoring for symptoms of neurological compromise (12, 14–16). The rates of major bleeding reported in clinical trials for patients receiving therapeutic doses of anticoagulants are similar; for UFH, 0%–2%; for the LMWHs, < 3%; and for fondaparinux, ∼ 1% (3, 12, 14). The frequency of major bleeding is purported to be less with LMWH than with UFH, although this has not been consistently demonstrated in clinical trials (3).

Evidence consistently linking anticoagulation intensity to the risk of bleeding is limited. However, prophylactic or low-dose regimens are associated with major bleeding less frequently than are regimens that achieve therapeutic anticoagulation (3). Individual patient risk factors, such as age, previous gastrointestinal bleeding, thrombocytopenia, heavy alcohol consumption, and preexisting sources of bleeding, appear to be more predictive of bleeding risk than anticoagulation intensity (5). To minimize the potential for bleeding complications, parenteral anticoagulants should not be administered to patients with contraindications to therapy. General contraindications applicable to all anticoagulants include active major bleeding, hemophilia or other bleeding diatheses, severe liver disease (with elevated PT), severe thrombocytopenia (platelet count < 20, 000 mm3), and malignant hypertension. With fondaparinux the risk of major bleeding appears to be related to weight; in patients who weigh less than 50 kg, fondaparinux is contraindicated for VTE prophylaxis, and the treatment dose is only 5 mg every 24 h (12). Fondaparinux is also contraindicated in severe renal insufficiency (creatinine clearance < 30 mL/min) and bacterial endocarditis (12).

Because hemorrhage can occur at any site and produce a variety of clinical manifestations, close monitoring for signs and symptoms of bleeding is crucial (2, 3). Hematocrit and blood pressure should be monitored prior to therapy and regularly thereafter. For example, hematocrit could be checked every 5–10 days during the first 2 weeks of therapy with less frequent monitoring thereafter to monitor for occult bleeding. Patients and providers should be aware of symptoms indicative of bleeding such as severe headache, joint pain, chest pain, abdominal pain, black tarry stools, frank hematuria, or bright-red blood per rectum.

1.7.2 Reversing Anticoagulant Effects

When major bleeding occurs, parenteral anticoagulants should be stopped immediately and the underlying bleeding source identified and corrected. For UFH and LMWHs, intravenous protamine sulfate can be administered to reverse the anticoagulant effects (2).

Protamine sulfate has native anticoagulant activity, but when administered with UFH, forms a stable salt that results in the loss of anticoagulation activity of both drugs. Protamine should be administered via slow IV infusion to avoid hypotension and anaphylactoid-like symptoms (1). Because protamine is derived from fish sperm, allergic reactions to protamine are possible in patients with fish allergies and also in patients who have undergone vasectomy or previous treatment with protamine-containing insulin preparations (2). Pretreatment with corticosteroids and antihistamines may prevent this problem (4). A protamine dose of 1 mg per 100 units of UFH up to a maximum of 50 mg should reverse the effect of UFH within 5 min and last for approximately 2 h. The protamine dose should be calculated taking into account only the dose of UFH given during the previous 3–4 h (4). The patient's aPTT should be closely monitored in order to assess the response to protamine and detect anticoagulant “rebound” that may occur with large heparin overdoses, subcutaneous UFH, or renal failure. In these instances anticoagulant activity can return several hours after protamine administration, and multiple doses or prolonged infusion of protamine may be necessary (1).

Although there is no proven method for complete reversal of LMWH activity, protamine is recommended when major bleeding occurs during LMWH therapy (2). Because of the limited affinity for shorter LMWH chains, protamine incompletely neutralizes the anti–factor Xa activity of LMWH. The estimated neutralization, by protamine, of LMWH anti–factor Xa activity is 60%–75%; anti–factor IIa activity is completely neutralized (2, 4). Protamine should be administered at a dose of 1 mg per 1 mg of enoxaparin or 1 mg/100 anti–factor Xa units of dalteparin or tinzaparin administered in the previous 8 h. If bleeding continues, a second protamine sulfate dose of 0.5 mg/100 anti–factor Xa can be given. If more than 8 h have elapsed since the LMWH dose was given, smaller doses of protamine sulfate can be used. If the LMWH was administered more than 12 h ago, the use of protamine sulfate is not recommended (1).

A specific antidote to reverse the effect of fondaparinux is not currently available. If uncontrollable bleeding occurs during fondaparinux therapy, recombinant factor VIIa may be effective (1). Data suggest that recombinant factor VIIa leads to improved thrombin generation when administered as an antidote to fondaparinux (17). Indiscriminant use of recombinant factor VIIa should be avoided as arterial and venous thromboembolic events have occurred with use outside the labeled indications (18).

1.7.3 Osteoporosis

Osteoporosis is a nonhemorrhagic complication associated mostly with UFH. Heparin molecules bind to osteoblasts, causing the release of factors that stimulate osteoclast activity, leading to a net loss of bone mass (1). While the risk of osteoporosis appears to be less with LMWH, presumably due to limited bone cell affinity, development of osteopenia has been reported (1). Osteoporosis risk is particularly high when doses of UFH ≥ 20, 000 IU per day are administered for more than 6 months, especially during pregnancy. However, clinical trials evaluating bone mineral density in pregnant women exposed to either LWMH or UFH are equivocal, and bone appears to remineralize after delivery (19). According to in vitro data, the risk of osteoporosis with fondaparinux appears to be limited, if not absent; however, more data are needed (2).

1.7.4 Heparin-Induced Thrombocytopenia

Two types of thrombocytopenia associated with heparin use have been described. Up to 30% of patients develop a benign, mild transient reduction in platelet count, referred to as non-immunity-mediated heparin-associated thrombocytopenia (HAT; previously called HIT type 1) during the first 4 days of heparin therapy (20). Intervention is unnecessary with HAT as platelet counts generally rebound to baseline values despite continued heparin use (20). In contrast, immunity-mediated heparin-induced thrombocytopenia (HIT; formally known as HIT type 2) is a potentially life-threatening prothrombotic antibody-mediated adverse effect associated with heparin use (21). Without prompt recognition and treatment, up to 30% of patients with HIT will suffer thrombotic complications or die while receiving heparin therapy (20).

In contrast to HAT, platelet counts associated with HIT typically begin to fall ≥ 5 days following initiation of heparin, reaching the lowest levels around days 7–14. Delayed thrombocytopenia can be observed up to 20 days, and begin several days after heparin has been discontinued in patients naive to heparin therapy (delayed-onset HIT). Heparin-induced thrombocytopenia can also occur within 24 h of heparin initiation in patients exposed to heparin within the previous 3 months, and especially the previous 30 days (21). Platelet counts commonly fall below 150,000 mm3 but rarely go lower than 20,000 mm3. Even if overt thrombocytopenia does not occur, a drop in platelet count greater than 50% from baseline is considered indicative of HIT (21).

The pathogenesis of HIT involves heparin binding to platelet factor 4 (PF4) forming a highly antigenic molecule that stimulates the production of immunoglobulin (Ig) G antibodies. Heparin-induced antibody formation can occur in 10%–20% of patients treated with heparin, although few develop HIT (21). In patients who develop HIT, the heparin–PF4–IgG complexes bind to the Fc receptor on platelets, leading to activation and further release of PF4 and procoagulant microparticles and increased thrombin generation (21). The net result is paradoxical increased risk of thrombotic events secondary to platelet activation, endothelial damage, and thrombin generation despite moderate to severe thrombocytopenia. Antibodies to the heparin/PF4 complex are transient, and reportedly become undetectable within a median of 85 days (21). Consequently, patients with a history of HIT should be tested for HIT antibodies prior to any future use of UFH. Although there are few data regarding the use of UFH in patients with a remote history of HIT, these patients should receive alternative anticoagulant agents for most indications until more rigorous data are available (21).

The frequency of HIT varies depending on the type of heparin (bovine UFH > porcine UFH > LMWH), duration of therapy (longer > shorter), type of patient (surgical > medical > obstetrical), gender (female > male), and to a lesser extent the dose (therapeutic > prophylactic) and route of administration (intravenous > subcutaneous) (21).

Thrombosis is the most common clinical complication of HIT. Venous thrombosis is the most common thrombotic HIT complication, with most patients developing proximal DVT, although PE occurs in 25% of patients. Arterial thrombosis occurs less commonly; limb artery occlusion, stroke, and myocardial infarction are the most common (21). Skin lesions occur in 10%–20% of patients, with HIT ranging from painful, localized erythematous plaques to widespread dermal necrosis. Amputation in such cases is frequently required. Mortality due to HIT with acute thrombosis may be as high as 50%, emphasizing the need for prompt recognition and treatment (21).

The diagnosis of immunity-mediated HIT is based on clinical findings— mainly new thrombosis shortly after the development of thrombocytopenia—and on laboratory tests confirming the presence of antibodies to heparin or platelet activation induced by heparin (22). Thrombocytopenia is the most common initial event suggesting the diagnosis of HIT; therefore, platelet count monitoring is fundamental to recognizing HIT, especially in clinical situations where the risk of HIT is high (e.g., in postsurgical patients). Detailed recommendations regarding platelet count monitoring are available (21). In general, a baseline platelet count should be obtained before UFH therapy is initiated. If the patient has received UFH within the previous 100 days, or if previous UFH exposure is uncertain, a repeat platelet count should be performed within 24 h. Monitoring platelet counts every other day for 14 days or until UFH therapy is discontinued, whichever occurs first, is recommended for patients who are receiving therapeutic doses of UFH (21). The timecourse and magnitude of thrombocytopenia distinguish immunity-mediated HIT from HAT. One should immediately suspect HIT when thrombosis and skin lesions occur in any patient on UFH or LMWH therapy (22).

The diagnosis of HIT should be confirmed by laboratory testing to detect the presence of heparin antibodies. The optimal test for laboratory confirmation of immunity-mediated HIT is unclear, and neither of the two available types of assay (functional or platelet activation and antigen assays) is specific for the HIT syndrome, although both are sensitive in detecting HIT antibodies (21). For patients who are receiving or have received heparin within the previous 2 weeks, investigating for a diagnosis of HIT is recommended if the platelet count falls by > 50%, and/or a thrombotic event occurs, between days 5 and 14 (inclusive) following initiation of heparin, even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia has occurred (21).

The goal of therapy in patients with HIT is to reduce the thrombosis risk by decreasing thrombin generation and platelet activation. The Eighth ACCP Consensus Conference on Antithrombotic Therapy has established recommendations for the treatment of HIT (21). Once the diagnosis of HIT is established or strongly suspected, all sources of heparin, including heparin flushes, should be discontinued and an alternative anticoagulant agent should be initiated. Even in the absence of thrombosis, patients with HIT are at extremely high risk for subsequently developing serious thrombotic complications without treatment. Because the time required for reporting of diagnostic laboratory results can be prolonged, it is crucial that alternate anticoagulant agents be initiated in a timely fashion to prevent new thrombosis (22). Direct thrombin inhibitors (lepirudin, argatroban, and bivalirudin) are the drugs of choice for the acute treatment of HIT with or without thrombosis. Long-term therapy with warfarin should be initiated only after substantial platelet count recovery has been documented (e.g., > 150, 000/ mm3). Warfarin should initially be overlapped with direct thrombin inhibitor therapy for a minimum of 5 days and until the full anticoagulant effect of warfarin has been achieved to reduce the risk of inducing further thrombosis secondary to inhibition of proteins C and S (21). If warfarin has already been initiated when HIT is diagnosed, reversing therapy with vitamin K (5–10 mg either intravenously or orally) is recommended. Fondaparinux may prove to be a promising alternative for managing HIT as it is devoid of in vitro cross-reactivity to HIT antibodies and has been used successfully in a few HIT case reports (23). The LMWHs are not recommended for use in HIT because they have nearly 100% cross-reactivity with heparin antibodies by in vitro testing (21). The occurrence of immunity-mediated HIT should be clearly documented in the patient's medical record.

1.7.5 Other Adverse Effects

Other common reactions seen with injectable anticoagulants include local injection site reactions. These include mild local irritation, pain, hematoma, ecchymosis, and erythema (12, 14, 16, 24). Because UFH and the LMWHs are pork-derived, patients with pork allergies may experience severe systemic allergic reactions following the administration of these medications. Synthetically produced fondaparinux may be an alternative for patients with pork allergies or who wish to avoid porcine products for religious reasons. Tinzaparin contains sodium metabisulfate, which may cause severe allergic or asthmatic episodes in susceptible people (16). All available LMWH multidose vials contain benzyl alcohol, which has been associated with “gasping syndrome” when administered to premature neonates (14–16).

1.8 Special Populations

1.8.1 Renal Failure

The LMWHs and fondaparinux are cleared primarily through the kidneys; thus appropriate dosing of these agents in the setting of renal failure is important. Randomized controlled trials used to establish the safety and efficacy of LMWH (and fondaparinux) generally excluded patients with severe renal insufficiency [creatinine clearance (CrCl) ≤ 30 mL/min] (1). Pharmacokinetic studies demonstrate a strong correlation between clearance of LMWH effect (as measured by anti–factor Xa activity) and CrCl; therefore, there is a potential for accumulation following multiple doses (1). The risk of major bleeding has been shown to increase when patients with severe renal insufficiency are administered full therapeutic doses of enoxaparin (25). Increased bleeding risk is less significant with prophylactic enoxaparin doses (25). The pharmacokinetics of dalteparin and tinzaparin are less well characterized in renal insufficiency, but some studies suggest a lower degree of accumulation with tinzaparin (2).

Half of the recommended enoxaparin dose should be administered in patients with creatinine clearance < 30 mL/min, (e.g., therapeutic doses of 1 mg/kg once daily instead of every 12 h and prophylactic doses of 30 mg once daily instead of every 12 h) (14). Because there are few data on the use of the other LMWHs in patients with severe renal insufficiency, no recommendations can be made regarding dose adjustments. Given that few published data are available regarding the use of LMWH in the setting of renal insufficiency, some experts recommend measuring anti–factor Xa activity if therapy is continued for more than a few days. Experts also recommend that UFH be given preferentially over the LMWHs, when possible, in patients with severe renal impairment (1). Data on the use of LMWH in patients with end-stage renal disease receiving hemodialysis is very limited, thus UFH is preferred for these patients, as well (2).

Fondaparinux is contraindicated in patients with severe renal impairment (CrCl < 30 mL/min) (12).

1.8.2 Obesity

Increasing numbers of obese patients are requiring parenteral anticoagulants, a situation that poses a clinical dilemma as most parenteral anticoagulants are dosed according to weight. Unfractionated heparin should be administered using recommended dosing strategies and adjusted according to laboratory values. All LMWHs have been studied in obese patients to varying maximum weights, up to 144 kg with enoxaparin, 190 kg with dalteparin, and 165 kg with tinzaparin (26–29). When dosage was based on total body weight, or without capping of doses, anti–factor Xa levels were maintained at appropriate treatment levels. Additionally, no increase in the risk of bleeding was seen in obese patients versus nonobese patients when dosed per body weight (1). Current recommendations suggest dosing LMWHs in obese patients on the basis of actual body weight. Monitoring anti–factor Xa levels can be considered for morbidly obese patients. Because the dose is 10 mg for all patients >100 kg, some prefer fondaparinux for VTE treatment in obese patients.

1.8.3 Pediatrics

Medical advances have lead to increasing numbers of children who require antithrombotic therapy (30). Yet, the overall incidence of children requiring anticoagulant therapy is comparatively small, thus limiting the data available to provide recommendations for parenteral anticoagulant use in this population. Most dosing and treatment recommendations are derived from the recommendations for adults (30). Unfortunately, for multiple reasons, pediatric patients differ dramatically from adults in their responses and requirements for anticoagulant medications (30). Because limited studies exist, expert opinion from those who deal frequently with anticoagulation in children should be sought.

Unfractionated heparin can be used in children with treatment doses adjusted to an anti–factor Xa level of 0.35–0.7 IU/mL. Dose requirements of UFH, per kilogram, in children are typically higher than in adults, with the highest requirements occurring in infants < 2 months of age (30). With improved pharmacokinetic profiles, LMWHs have become popular in the treatment of pediatric patients despite the fact that safety and effectiveness data in children are lacking. Reduced need for routine monitoring with LMWH is especially attractive as many pediatric patients have limited venous access (30). Suggested therapeutic doses for enoxaparin are 1.5 mg/kg every 12 h for infants < 2 months old and 1 mg/kg every 12 h for those > 2 months old. The suggested dose for dalteparin is 86–172 U/kg every 24 h, keeping in mind that neonates appear to require higher doses per kilogram than do older children or adults (30). Suggested tinzaparin dosing for children < 2 months is 275 U/kg once daily and 175 U/kg once daily for children aged 10–16 years (30). Children between the ages of 2 months and 10 years should receive once daily tinzaparin doses between 175 and 275 U/kg. Unfortunately, weight-based LMWH dosing tends to provide less predictable response in children compared to adults. Until more data are available, it is prudent to periodically monitor anti–factor Xa activity in children during long-term use (30).

Fondaparinux in pediatric populations has not been studied. However, increased risk of bleeding seen in adult patients weighing less than 50 kg should be of particular concern for fondaparinux use in children.

1.8.4 Pregnancy

Thromboembolic complications are the leading cause of maternal death in the developed countries of the world (31). Because of a multitude of biological changes, there is a three- to fivefold increased risk of clotting during pregnancy. This risk increases dramatically during the post-partum period, with an estimated risk of ≥ 20 times that of a nonpregnant female. Venous thromboembolism occurs approximately 4 times more frequently than arterial clotting (31).

During pregnancy anticoagulation is indicated to prevent and treat venous thromboembolism, and for embolism associated with mechanical heart valves and to prevent recurrent pregnancy loss associated with antiphospholipid antibody syndrome (32). The choice of anticoagulant therapy is important to maternal and fetal health. Because the oral anticoagulant warfarin crosses the placenta and is associated with teratogenicity and fetal bleeding complications, heparin-related compounds such as UFH or LMWH, which do not cross the placenta, are the anticoagulants of choice during pregnancy (32).

For some patients at high risk of developing thrombosis (e.g., history of VTE with previous pregnancy or recurrent pregnancy loss associated with antiphospholipid antibody syndrome), prophylactic heparin therapy may be started when pregnancy is confirmed (32). For acute VTE during pregnancy, treatment doses of UFH or LMWH should be initiated and continued throughout pregnancy (see Tables 1.1 and 1.4 for acute VTE dosing). Anticoagulation should continue for at least 6 weeks postpartum with either heparin or warfarin. For initial treatment with UFH, the intravenous route is preferred for the first 5 days (32). Because volume of distribution and renal function change during pregnancy, anti–factor Xa monitoring has been suggested for women receiving either UFH or LMWH (19, 32).

Anticoagulation use during the last trimester of pregnancy and the peripartum period can increase the risk of maternal hemorrhage. To minimize the risk of excessive bleeding during delivery, induction of labor is recommended in order to facilitate planning for the discontinuation of anticoagulant therapy. In most cases withholding UFH or LMWH for 24 h prior to induction is sufficient (32).

Osteoporosis and osteopenia are also of concern following long-term use of UFH or LMWHs during pregnancy. Because the LMWHs have less effect on bone formation, they may be preferred during pregnancy. However, UFH has been used successfully in pregnant patients without evidence of osteoporosis (19). Unfractionated heparin or the LMWHs can be continued during breastfeeding (32).

While fondaparinus is an FDA pregnancy category B drug such as dalteparin, enoxaparin, and tinzaparin, there is very limited information, mainly from case reports, regarding its use during pregnancy. Additionally, the extended half-life of fondaparinux can make labor management difficult. Unfractionated heparin and the LMWHs should remain the anticoagulants of choice during pregnancy until more data on the use of fondaparinux are available.

1.8.5 The Elderly

The risk of bleeding complications with the use of anticoagulants increases with age (3). Decreased renal function or low body weight associated with aging may contribute to this observation with injectable anticoagulant use in the elderly. Therefore, careful assessment of renal function should be conducted prior to initiation of therapy with renally adjusted doses utilized when appropriate. A more recent study of tinzaparin used in conjunction with warfarin for acute treatment of DVT or PE in elderly patients with renal insufficiency demonstrated an increased risk of death when compared to UFH. Although the dose of tinzaparin was not adjusted to account for the renal dysfunction, the manufacturer recommends considering an alternative agent for anticoagulation in this population (16).

Recommendations for adjusting parenteral anticoagulant dose based strictly on age are limited, with the exception of enoxaparin. For patients 75 years of age and older receiving enoxaparin for acute ST (segment)-elevation myocardial infarction (STEMI), a reduction in dose is recommended (0.75 mg/kg subcutaneously every 12 h with no bolus dose) (see Table 1.4).

1.8.6 Patient Education

Patients receiving any anticoagulant should be taught the symptoms of excess anticoagulation or bleeding such as hematuria, hematemesis, or bright-red blood per rectum. Symptoms of underanticoagulation such as unilateral limb swelling, chest pain, or stroke symptoms should be reviewed as well. Patients should be instructed to report any such symptoms for immediate evaluation.

For agents administered by subcutaneous injection, the patient or patient's agent should be instructed in correct subcutaneous administration technique. Injections should be performed in the abdominal area or the upper outer part of the thigh while the patient is in a supine or seated position. To eliminate the possibe loss of medication, any air bubbles noted in the syringe should not be removed prior to administration. The patient pinches a layer of skin between the thumb and forefinger, and then introduces the entire length of the needle into a skin fold at a 90° angle. The plunger should be pushed to the bottom of the syringe to ensure that the entire dose is administered (12, 14–16, 24). Some prefilled syringes have automatic safety mechanisms to prevent inadvertent needle sticks. Each product should be reviewed to determine the correct technique for deploying the needle guard. Injection sites should be alternated between right and left sides. In order to minimize bruising, the injection site should not be rubbed following drug administration.

1.9 Conclusion

A sound understanding of the basic pharmacology of parenteral anticoagulants is necessary in order to facilitate the safe and effective clinical use of these agents. The reader is directed to chapters detailing the use of these agents in specific disease states. When used appropriately, parenteral anticoagulants should continue to improve outcomes and prevent complications in the hospitalized patient.

References

1. Geerts WH, Bergqvist D, Pineo GF, et al., Prevention of venous thromboembolism, Chest 2008;133: 381S–453S (in ACCP8). [Note: This article was originally published in American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 8th edition (ACCP8). For brevity, all Chest journal articles that originated in that source will be denoted “in ACCP8” (in parentheses) in reference lists in this book.]

2. Hirsh J, Bauer KA, Donati MB, et al., Parenteral anticoagulants, Chest 2008;133: 141S–159S.

3. Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment, Chest 2008;133: 257S–298S.

4. Nutescu E, Dager WE. Heparin, low molecular weight heparin, and fondaparinux, in Gulseth M, ed., Managing Anticoagulation Patients in the Hospital Bethesda: American Society of Health-System Pharmacists, 2007: 177–202.

5. Hirsh J, Raschke R, Heparin and low-molecular-weight heparin, Chest 2004;126: 188S–203S.

6. Ma Q, Tobu M, Schultz C et al., Molecular weight dependent tissue factor pathway inhibitor release by heparin and heparin oligosaccharides, Thromb Res 2007;119: 653–661.

7. Hirsh J, Anand SS, Halperin JL, Fuster V, Guide to anticoagulant therapy: Heparin: A stat ement for healthcare professionals from the American Heart Association, Circulation 2001;103: 2994–3018.

8. Antithrombin (recombinant) prescribing information, Ovation Pharmaceuticals, May 2010 (available at http://www.gtc-bio.com/products/atrynprescribing.pdf).

9. Hull RD, Pineo GF, Heparin and low-molecular-weight heparin therapy for venous thromboembolism: Will unfractionated heparin survive ? Semin Thromb Hemost 2004;30(Suppl 1): 11–23.

10. Savi P, Herault JP, Duchaussoy P, et al., Reversible biotinylated oligosaccharides: A new approach for a better management of anticoagulant therapy, J Thromb Haemost 2008; 6: 1697–1706.

11. Bauer KA, New Anticoagulants. Hematology, American Society of Hematology Education Program, Document 2006450–456.

12. Arixtra prescribing information, GlaxoSmithKline, Sept. 2009 (available at http:// us.gsk.com/products/assets/us_arixtra.pdf).

13. Gross PL, Weitz JI, New anticoagulants for treatment of venous thromboembolism, Arterioscler Thromb Vasc Biol 2008;28: 380–386.

14. Lovenox prescribing information, Sanofi-Aventis Pharmaceuticals, Sept 2009 (available at http://products.sanofi-aventis.us/lovenox/lovenox.html).

15. Dalteparin prescribing information, Eisai Inc., May 2010 (available at http://www. fragmin.com/pdf/fragmin_PI.pdf).

16. Tinzaparin prescribing information, Leo Pharma Inc., May 2010 (available at http://www.innohepusa.com/w-site/innohepusa/innohepusa.nsf/0/1701912F6731BEFEC12576F00032E0F7/$File/INNOHEP_PI_(November_2009).pdf).

17. Bijsterveld NR, Moons AH, Boekholdt SM, et al., Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers, Circulation 2002;106: 2550–2554.

18. Recombinant factor VII prescribing information, Novo Nordisk, May 2010 (available at http://www.novosevenrt.com/pdfs/PI_novosevenrt.pdf).

19. Clark NP, Delate T, Witt DM, Parker S, McDuffie R, A descriptive evaluation of unfractionated heparin use during pregnancy, J Thromb Thrombol 2009;27: 267–273.

20. Shantsila E, Lip GY, Chong BH, Heparin-induced thrombocytopenia. A contemporary clinical approach to diagnosis and management, Chest 2009;135: 1651–1664.

21. Warkentin TE, Greinacher A, Koster A, Lincoff AM, Treatment and prevention of heparin-induced thrombocytopenia, Chest 2008;133: 340S–380S (in ACCP8).

22. Arepally GM, Ortel TL, Clinical practice. Heparin-induced thrombocytopenia, N Engl J Med 2006;355: 809–817.

23. Efird LE, Kockler DR, Fondaparinux for thromboembolic treatment and prophylaxis of heparin-induced thrombocytopenia, Ann Pharmacother 2006;40: 1383–1387.

24. Unfractionated heparin prescribing information from various manufacturers, May 2010 (available at http://www.drugs.com/mmx/heparin-sodium.html).

25. Lim W, Dentali F, Eikelboom JW, Crowther MA, Meta-analysis: Low-molecular-weight heparin and bleeding in patients with severe renal insufficiency, Ann Intern Med 2006;144: 673–684.

26. Sanderink GJ, Le LA, Jariwala N, et al., The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers, Clin Pharmacol Ther 2002;72: 308–318.

27. Smith J, Canton EM, Weight-based administration of dalteparin in obese patients, Am J Health Syst Pharm 2003;60: 683–687.

28. Spinler SA, Inverso SM, Cohen M, et al., Safety and efficacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: Analysis from the ESSENCE and TIMI 11B studies, Am Heart J 2003;146: 33–41.

29. Wilson SJ, Wilbur K, Burton E, Anderson DR, Effect of patient weight on the anticoagulant response to adjusted therapeutic dosage of low-molecular-weight heparin for the treatment of venous thromboembolism, Haemostasis 2001;31: 42–48.

30. Monagle P, Chalmers E, Chan A, et al., Antithrombotic therapy in neonates and children, Chest 2008;133: 887S–968S (in ACCP8).

31. James AH, Jamison MG, Brancazio LR, Myers ER, Venous thromboembolism during pregnancy and the postpartum period: Incidence, risk factors, and mortality, Am J Obstet Gynecol 2006;194: 1311–1315.

32. Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J, Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy, Chest 2008;133: 844S–886S (in ACCP8).

33. Dobesh PP, The Heparin Consensus Group, Unfractionated heparin dosing nomograms: Road maps to where?, Pharmacotherapy, 2004;24(8 Pt 2): 142S–145S.

Chapter 2

Pharmacology of Vitamin K Antagonists

Jaekyu Shin and Steven R. Kayser

2.1 Introduction

Initially introduced as a rodenticide, vitamin K antagonists are currently a mainstay for the management of thrombotic diseases in clinical practice (1). Various vitamin K antagonists are used worldwide (Table 2.1). They are chemically divided into two groups: indanediones and coumarin derivatives. Indanediones are used less commonly than the coumarin derivatives because indanediones are associated with an increased incidence of hypersensitivity reactions. Warfarin, named for the Wisconsin Alumni Research Foundation in honor of the foundation that supported warfarin research during the 1940s–1950s, is the most widely used coumarin derivative because of its more predictable anticoagulation effect and duration of action. Hence, this chapter focuses on warfarin.

Table 2.1 Various Vitamin K Antagonists Used Globally

ChemicalGroupNameCommentsIndandionesFluindione PhenindioneHigher incidences of hypersensitivity reaction than coumarin derivativesPhenindione has a higher incidence of hypersensitivity reactions than fluindioneUnavailable in the United StatesCoumarin derivativesDicoumarolPrototype of coumarin derivativesWeak and unpredictable anticoagulation effectUnavailable in the United StatesEthyl biscoumacetateRapid onset but short duration of actionUnavailable in the United StatesPhenprocoumonMore potent than warfarin; to switch from phenprocoumon to warfarin, multiply phenprocoumon weekly dose by 2.3Long half-life (144 h)Less dependent on hepatic metabolismWidely used in Europe but unavailable in the United StatesAcenocoumarolMore potent than warfarin; to switch from acenocoumarol to warfarin, multiply acenocoumarol weekly dose by 2.08Short half-life (10 h)Many drug interactions via cytochrome P450 2C9Widely used in Europe but unavailable in the United StatesWarfarinMost widely used oral anticoagulant in the worldPredictable anticoagulation effect and duration of actionGood bioavailability

Sources: Various (2–6).

2.2 Pharmacodynamics

Vitamin K is an essential cofactor for the posttranslational γ-carboxylation of glutamyl residues on the vitamin K–dependent coagulation factors (II, VII, IX, and X) and anticoagulation proteins (proteins C and S) (Fig. 2.1). Vitamin K1