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INTRODUCTION

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Key Clinical Questions

  • Image not available. Why is a dosing nomogram important to use in UFH therapy?

  • Image not available. What is the appropriate prophylaxis dose of LMWH in obese patients?

  • Image not available. When may oral anticoagulation safely be initiated in a patient who has developed heparin-induced thrombocytopenia (HIT)?

  • Image not available. How do you safely transition between parenteral anticoagulants and oral anticoagulants?

  • Image not available. Should an initial loading dose be administered to patients receiving warfarin?

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Thrombosis is a major cause of morbidity, requires or prolongs hospital admission, and often necessitates long-term medical intervention to reduce the likelihood of recurrent events. Anticoagulants are the cornerstone for prevention and acute management of thrombosis. Despite their effectiveness in preventing thrombosis and reducing propagation, anticoagulants are often associated with adverse drug reactions and medication errors and remain a major target for health improvement efforts. While hospitalized patients are at risk for developing thrombosis, they are also at elevated risk for hemorrhagic complications resulting from invasive procedures, organ dysfunction, gastrointestinal stress-related mucosal damage, medication use, and concealed coagulopathies. Anticoagulation management requires thoughtful consideration in agent selection, route of administration, body weight, renal and hepatic function, and concomitant drug therapy to achieve optimal outcomes.

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For over 50 years, unfractionated heparin (UFH) and vitamin K antagonists (VKAs) had been the primary anticoagulants prescribed in practice. A new group of oral anticoagulants has emerged in the marketplace with a wide range of indications, creating more options for clinicians, but also more challenges in drug and patient selection. This chapter focuses on the mechanisms of action, pharmacokinetics, pharmacodynamics, clinical indications, complications of therapy, and reversal options for antithrombotic pharmacotherapy in critically ill patients.

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ANTICOAGULANT PHARMACOLOGY

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Anticoagulant agents exert their therapeutic benefit by interfering with the coagulation cascade through receptor binding with circulating blood clotting factors. Of these clotting factors, thrombin (IIa) and activated factor X (Xa) are believed to play the most critical role in hemostasis. Anticoagulants ultimately attenuate thrombin generation, preventing the generation of insoluble fibrin, the final step in coagulation. Anticoagulants are administered in low doses for thromboprophylaxis and higher or therapeutic doses for acute thrombosis treatment.

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Unfractionated heparin, low-molecular-weight heparin (LMWH), and fondaparinux contain a pentasaccharide sequence that binds to and potentiates the action of antithrombin (AT), an endogenous small protein molecule that inactivates several enzymes of the coagulation system (Figure 254-1). Fondaparinux is a synthetic analog of this naturally occurring pentasaccharide. The heparin-AT complex inactivates coagulation factors XIIa, IXa, XIa, Xa, and thrombin. Since these agents depend on the presence of AT for clotting factor inhibition, they are considered indirect anticoagulants. The active pentasaccharide sequence responsible for catalyzing AT is found on one-third and one-fifth of the chains of UFH and LMWH, respectively.

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Figure 254-1

Mechanisms of oral and parenteral anticoagulants.

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Vitamin K antagonists (eg, warfarin, acenocoumeral) inhibit the enzyme vitamin K epoxide ...

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