Prevention and treatment of thrombus with anticoagulants have been primary goals of medicine for half a century. Previously known as antithrombotics, current guidelines recommend the term anticoagulants because of the multiple effects beyond thrombin inhibition. 1,2 Anticoagulants can be divided into indirect anticoagulants including unfractionated heparin (UFH), low- molecular-weight heparin (LMWH), heparinoids or synthetic heparins or direct anticoagulants including direct thrombin inhibitors (DTIs), and the oral vitamin K antagonist, warfarin.^1,2

Anticoagulation is a high-risk treatment with potentially adverse drug events resulting from the complexity of dosing, monitoring, and adherence^3,4,5 (Table 6-1). Anticoagulant-related medication errors and bleeding events with have been linked to an increased risk for stroke, myocardial infarction, and mortality.⁶ Based on one study, warfarin, along with insulin, was estimated to be responsible for one in every seven adverse drug events treated in emergency departments and more than 25% of all the estimated hospitalizations.⁷ An analysis of malpractice claims filed in the 1990s for a New England malpractice company revealed that anticoagulants were responsible for 8% of claims. Of these claims, 60% were considered preventable.⁸ Because of the increased potential for adverse events and concern for medication safety, The Joint Commission has implemented the safe use of anticoagulants as part of its 2008 National Patient Safety Goals.⁹

Unfractionated Heparin

For indications requiring rapid anticoagulation, UFH has traditionally been the drug of choice for indications requiring rapid anticoagulation. It is a water-soluble heterogeneous mucopolysaccharide with complex effects on both the coagulation mechanism and blood vessels. UFH exerts its anticoagulant effect by interacting with antithrombin III, dramatically increasing its ability to bind and neutralize thrombin and other activated clotting factors. Given intravenously (IV), the onset of action is immediate. However, subcutaneous administrated heparin has a variable absorption, and the onset of action may be delayed.^2,10 The half-life of heparin is dose dependent, and anticoagulant effects range from 1 to 5 hours when given IV. UFH appears to be degraded and cleared primarily by the reticuloendothelial system, but a small amount of undegraded heparin is traceable in the urine. Its anticoagulant half-life may be prolonged in patients with renal insufficiency or hepatic cirrhosis and possibly shortened in patients with pulmonary embolism.^2,10 Occasionally, differences in the plasma concentrations of heparin-binding proteins may affect a patient’s response to heparin. Because of significant variability and changes in patient response over time, UFH requires monitoring and periodic adjustment.²

The typical prophylactic dose of UFH is 5000 units every 8 to 12 hours.¹¹ When full anticoagulation is indicated, a weight-based IV bolus followed by a continuous infusion is preferred. The initial dose of IV heparin is commonly a bolus of 80 units/kg followed by an infusion of 18 units/kg/h¹² (Table 6-2). For non-obese patients, the actual body weight should be used to calculate the initial UFH dose. For obese patients, using the actual body weight to calculate the initial dose is controversial, and some experts recommend using an adjusted body weight instead.^2,11 Because various heparin dose-adjustment nomograms are available and commercially available activated partial thromboplastin time (aPTT) reagents may vary in their responsiveness to heparin, establishing institution-specific guidelines and therapeutic aPTT ranges is recommended.^13,14,15 An aPTT reagent should be obtained at baseline, 6 hours after initiating the heparin infusion, and 6 hours after each dose change per the institutional-specific therapy range until required steady state is reached.¹⁵ Achieving a therapeutic aPTT in the first 24 hours after initiating full anticoagulation is critical and has been shown to lower the risk of venous thromboembolism (VTE).¹²

Low-Molecular-Weight Heparins

LMWHs are smaller heparin fragments produced by chemical or enzymatic depolymerization of UFH. Methods of cleavage and isolation vary for different commercially produced products. Enoxaparin, dalteparin, and tinzaprin are some of the presently available LMWHs. Compared with UFH, the LMWHs have less nonspecific binding, greater resistance to inactivation by platelet factor 4, greater anti–factor Xa activity, greater inhibition of thrombin generation, longer half-lives, and more reliable anticoagulation effect.^2,14,16,17 LMWHs are administered in fixed or weight-adjusted doses for thromboprophylaxis and weight-adjusted doses for therapeutic purposes^2,10 (see Table 6-2). Laboratory monitoring is not generally necessary.² However, in several patient populations (i.e., elderly patients, pregnant patients, and those with renal insufficiency), anti-Xa levels may be beneficial.^11,18 Current guidelines recommend the use of UFH over LMWH in patients with severe renal impairment (renal clearance <30 mL/min).¹¹

Factor Xa Inhibitor

Fondaparinux, a synthetic pentasaccharide, is an antithrombin-dependent indirect inhibitor of factor Xa. Fondaparinux has a higher anti-Xa activity than LMWHs and a high specificity for antithrombin, and it does not bind to other plasma proteins.² Because it is too short to bridge antithrombin to thrombin, fondaparinux does not increase the rate of thrombin inhibition by antithrombin. Its half-life is approximately 17 hours in young, healthy patients.¹⁹ Fondaparinux is dosed subcutaneously once a day. The prophylactic dose may need to be reduced by 50% in patients with renal clearance less than 50 mL/min, and fondaparinux is contraindicated in patients with renal clearance less than 30 mL/min.² Fondaparinux does not bind to protamine, and if uncontrollable bleeding occurs, recombinant factor VIIa may be an option^2,20 (see Table 6-2).

Direct Thrombin Inhibitors. A recombinant derivative of hirudin, lepirudin is a 65–amino acid polypeptide that irreversibly binds with high specificity to thrombin.^2,21 Administered as an IV infusion, the dose is adjusted to achieve a target aPTT ratio of 1.5 to 2.5. Because of renal excretion, lepirudin dosing should be reduced when the renal clearance is less than 60 mL/min, and it is contraindicated in patients with renal clearance less than 30 mL/min^2,22 (see Table 6-2). Hirudin antibodies may develop in up to 40% of patients treated with lepirudin. Most of these antibodies have no clinical impact. However, in some situations, hirudin antibodies can prolong the plasma half-life of lepirudin, resulting in drug accumulation.²³ Of clinical importance, anaphylaxis may occur if patients with antibodies are reexposed to lepirudin.²

Argatroban is a small, synthetic DTI derived from arginine that is highly selective and binds reversibly to thrombin.²⁴ It inhibits both free and clot-bound thrombin. It is not antigenic and does not interact with or induce heparin-dependent antibodies.^25,26 It is administered as an IV infusion, and the dose is adjusted to maintain the aPTT ratio in the 1.5 to 3.0 range.² Dosing adjustments are recommended in patients with hepatic dysfunction. Recent literature notes that dosing adjustments may be appropriate to minimize excessive anticoagulation in critically ill patients with multiple organ dysfunctions and coronary artery bypass graft patients^27,28 (see Table 6-2).

Bivalirudin is a semisynthetic 20–amino acid polypeptide analog of hirudin. It is a reversible inhibitor of thrombin with an estimated half-life of 25 minutes, thereby allowing recovery of thrombin activity^2,23 (see Table 6-2).It is approved for use in patients with unstable angina undergoing percutaneous coronary intervention.^29,30 As an alternative to heparin, bivalirudin has been given during cardiac surgery as intraoperative anticoagulation.^31,32,33

Heparin-Induced Thrombocytopenia

The American College of Chest Physician (ACCP) guidelines estimates a 1% to 5% risk of heparin-induced thrombocytopenia (HIT) in patients receiving UFH for 1 to 2 weeks.³¹ The incidence of HIT varies depending on a number of different factors. Therapeutic UFH versus prophylactic UFH, the duration of UFH exposure, the timing of UFH repeat exposure, and surgical patients are potential factors that affect the risk of HIT.^25,26,34 The immune-mediated platelet activation and thrombin generation seen during HIT may lead to severe thrombotic complications. HIT differs from the non–immune-mediated heparin- associated thrombocytopenia (HAT). HAT is a benign, mild reduction in platelet counts seen with heparin, and no clinical sequelae are associated with this benign phenomenon. However, platelet counts can decrease greater than 50% of baseline and commonly decrease below 120,000/μL in cases of HIT. Heparin binding to platelet factor-4(PF-4), stimulating the production of IgG antibodies and the complex binding to the Fc receptor on the platelets, causes the cascade of events that increases the risk of thrombotic activity in the presence of severe thrombocytopenia, which is HIT.^{25,26,34,35,36,37}

Non-heparin agents (lepirudin, argatroban, danaparoid, bivalirudin, and fondaparinux) are recommended for use in patients with acute HIT whether or not it is complicated by thrombosis.³¹ Warfarin should not be given to treat patients with HIT because of the risk of venous limb gangrene or skin necrosis. In addition, warfarin should only be given at a time of adequate anticoagulation with drug therapy that reduces thrombin generation and the platelet count is greater than 150,000/μL.³¹

Oral Anticoagulation

The vitamin K antagonist warfarin exerts its anticoagulant effect by inhibiting synthesis of vitamin K–dependent clotting factors II (prothrombin), VII, IX, and X as well as the natural anticoagulant proteins C and S.^10,38,39 Warfarin is equally absorbed as both oral and IV forms. It is highly bound to albumin and is eliminated almost exclusively through hepatic metabolism via the cytochrome P450 system.^10,38 Warfarin has no effect on previously formed circulating coagulation factors, so its full antithrombotic activity is delayed for 7 to 15 days. Proteins C and S are inhibited more rapidly because of their shorter half-lives^10,40 (Table 6-3). Reductions in the concentration of natural anticoagulants before clotting factors are depleted may lead to a paradoxical hypercoagulable state during the first few days of warfarin therapy. Patients should receive an acute-acting anticoagulant in the presence of an acute thrombosis while transitioning to warfarin.^10,38

When initiating warfarin therapy, it is a challenge to predict the precise warfarin dose that a patient will require. Most patients can start with 5 mg daily.^{10,38,41,42,43} Patients who are younger and otherwise healthy could initiate therapy with a higher dose (7.5 mg).^10,38 A more conservative therapy of less than 5 mg (2 mg, 3 mg, or 4 mg dose) should be considered in elderly patients and those with heart failure, liver disease, poor nutritional status, a high risk of bleeding, or potential medication interactions.^10,38,43 Additionally, the influence of genotypes on warfarin maintenance dosing has been validated. However, to date, the evidence does not suggest that genotyped-guided therapy will improve anticoagulation control and prevent or reduce the risk of bleeding.⁴⁴ Therefore, the subsequent doses are determined based on International Normalized Ratio (INR) response. At initiation of therapy, dose adjustments should not be made more frequently than every 2 to 3 days. The response to a dose change should be measured at least every 1 to 3 days until steady state is achieved. When a rapid anticoagulant effect is required, heparin or LMWH should be administered concurrently, and the acute anticoagulant product should overlap until the INR has been in therapeutic range for at least 2 consecutive days.^38,43 This overlap is important because the full anticoagulant effect will not be reached until a minimum of 5 to 7 days after initiating warfarin therapy. Recommended goal range and target INR are based on the therapeutic indication. For most indications, an INR range of 2.0 to 3.5 is acceptable with a target INR of 2.5 to 3.0.^10,38