Anticoagulants

Standardization of heparin potency is based on in vitro comparison with a known standard. A unit of heparin is defined as the volume of heparin-containing solution that will prevent 1 mL of citrated sheep blood from clotting for 1 hour after the addition of 0.2 mL of 1:100 calcium chloride. Heparin must contain at least 120 United States Pharmacopeia (USP) units per milliliter. Because the potency of different commercial preparations of heparin may vary greatly, the heparin dosing should always be prescribed in units, and most heparin is porcine in origin.

Pharmacokinetics

Heparin is a highly charged acidic molecule administered by intravenous (IV) or subcutaneous (SC) injection. The pharmacokinetics of heparin are based on measurements of its biologic activity using an anti-Xa assay. Over the range of heparin concentrations used clinically, the dose-response relationship is not linear for multiple reasons, including the need for AT to potentiate its effect, the effects of temperature, its highly charged nature that causes protein binding, and the variability of anticoagulation responses. The precise pathway of heparin elimination is uncertain, and the influence of renal and hepatic disease on its pharmacokinetics is less than with other anticoagulants. Heparin binds to many different proteins, which can affect its anticoagulant activity and contributes to heparin resistance.¹¹

Laboratory Evaluation of Coagulation

The anticoagulant response to heparin varies widely especially in critically ill patients with alterations in AT and other plasma proteins. Different tests are used to monitor UFH and other anticoagulants as follows.²

Activated Partial Thromboplastin Time

Heparin treatment is usually monitored to maintain the ratio of the activated partial thromboplastin time (aPTT) within a defined range of approximately 1.5 to 2.5 times normal values, typically 30 to 35 seconds. An excessively prolonged aPTT (>120 seconds) is readily shortened by omitting a dose because heparin has a brief elimination half-time. When low-dose heparin is used, laboratory tests may not be required to monitor treatment because the dosage and schedule are well known. However, some hospital laboratories have changed to anti-Xa assays instead of aPTT monitoring because of the variability of responses, with low-dose regimens targeting levels of 0.3 to 0.5 unit/mL and high-dose regimens targeting levels 0.5 to 0.8 unit/mL.

Activated Clotting Time

At higher heparin concentrations like those typically used during cardiopulmonary bypass, the activated clotting time is used to monitor anticoagulation. The activated clotting time (ACT) is performed by mixing whole blood with an activating substance that has a large surface area, such as celite (diatomaceous earth—silicon dioxide) or kaolin (clay—aluminum silicate). This is a contact activation through the classic intrinsic pathway where factor XII initiates activation of the clotting cascade. The activator speeds up the clotting time to normal values of approximately 100 to 150 seconds, depending on the device. Several commercially available timing systems used clinically to measure the ACT are based on detecting the onset of clot formation. Nevertheless, results between different commercial devices to measure the ACT may not be interchangeable, especially if the type of activator (celite or kaolin) is different.

Heparin effect and its antagonism by protamine are commonly monitored in patients undergoing cardiovascular procedures by measuring the ACT. Because the ACT is easy to use and reliable for high heparin concentrations (>1.0 unit/mL), it has become the mainstay of heparin anticoagulation monitoring in perioperative management and for cardiac catheterization. In addition to the presence of a heparin effect, the ACT may be influenced by hypothermia, thrombocytopenia, presence of contact activation inhibitors (aprotinin), and preexisting coagulation deficiencies (fibrinogen, factor XII, factor VII). With aprotinin therapy, the recommendation is to use kaolin-ACT rather than a celite-ACT determination as kaolin binds to aprotinin to minimize its effect.

For cardiac surgery, a baseline value for the ACT is determined (a) before the IV administration of heparin, (b) 3 to 5 minutes after administration, and (c) at 30-minute intervals, thereafter. The ACT response to heparin is not linear for multiple reasons, including the need for AT for its effectiveness and because of several other factors that affect ACT. During cardiopulmonary bypass, the target ACT value is still controversial but often considered adequate if the ACT is longer than 350 seconds, although most cardiac surgical centers target an ACT of longer than 400 seconds. The need to measure ACT repeatedly is emphasized by the fourfold variation in heparin sensitivity between patients and the threefold variation in the rate at which heparin is metabolized. Furthermore, ACT values can be misleading during cardiopulmonary bypass with respect to heparin-induced anticoagulation because of the effects of hypothermia and hemodilution on the measurement system.¹²

Clinical Uses

Heparin is used extensively for multiple purposes including the prevention and treatment of venous thrombosis and pulmonary embolism, for acute coronary syndromes, and for perioperative anticoagulation for extracorporeal circulation and hemodialysis. When administered intravenously, heparin has an immediate onset of action, whereas SC administration results in variable bioavailability with an onset of action in 1 to 2 hours.

Heparin-Induced Thrombocytopenia

Thrombocytopenia due to UFH is common and can begin within hours in patients exposed to heparin. However, a more severe and even life-threatening syndrome develops in 0.5% to 6.0% of patients, manifesting as severe thrombocytopenia (50% drop in platelet count or <100,000 cells/mm³), that can be associated with thrombotic events (heparin-induced thrombocytopenia with thrombosis). This severe response typically develops after 4 to 5 days of heparin therapy and is caused by heparin-dependent antibodies to platelet factor IV that trigger platelet aggregation and result in thrombocytopenia (see the more detailed discussion in Physiology of Hemostasis, Chapter 27 Physiology of Hemostasis).¹³

Allergic Reactions

Heparin can cause allergic reactions, but these are rare and present in a manner typical of other hypersensitivity reactions. In patients that do experience immediate reactions, heparin-induced thrombocytopenia (HIT) should also be suspected due to the presence of preformed antibodies. Rapid IV infusion of large doses of heparin usually causes minimal hemodynamic changes.¹³

Reversal of Heparin-Induced Anticoagulation with Protamine

Protamine is one of the few agents available for reversing anticoagulation. Protamine is a strongly alkaline (nearly two-thirds of the amino acid composition is arginine), polycationic, low-molecular-weight protein found in salmon sperm. The positively charged alkaline protamine combines with the negatively charged acidic heparin to form a stable complex that is devoid of anticoagulant activity. These heparin–protamine complexes are removed by the reticuloendothelial system. Clearance of protamine by the reticuloendothelial system (within 20 minutes) is more rapid than heparin clearance and that may explain, in part, the phenomenon of heparin rebound. The dose of protamine required to antagonize heparin is typically 1 mg for every 100 units of circulating heparin activity. A more specific dose of protamine is calculated by heparin-protamine titration. Most clinicians give too much protamine because they reverse based on the total dose or heparin administered without accounting for heparin elimination prior to the administration of protamine. Heparin has a half life of approximately one hour, so determinations of protamine dosing should include considerations of the circulating heparin level for reversal. (See also “Protamine” in Chapter 29, Procoagulants.)

Low-Molecular-Weight Heparins

Enoxaparin and dalteparin are two commonly administered low-molecular-weight heparins (LMWHs) derived from standard commercial-grade UFH by chemical depolymerization to yield fragments with a mean molecular weight of 4,000 to 5,000 daltons. Depolymerization of heparin results in a change in its anticoagulant profile, pharmacokinetics, and effects on platelet function. Compared with heparin, which has an anti-Xa to anti-IIa activity of about 1:1, enoxaparin has a corresponding ratio that varies between 4:1 and 2:1.¹⁴ The pharmacokinetics of enoxaparin and dalteparin between patients are more consistent than heparin because these drugs bind less avidly to proteins than heparin. This contributes to better bioavailability at low doses. Although protection against venous thromboembolism (VTE) in high-risk medical and surgical patients is often thought to be better with LMWH than with heparin, LMWH’s effect is greatly prolonged with renal failure and anticoagulants such as UFH should be used in this population. Therefore, care should be taken to delay surgery for 12 hours after the last dose of LMWH in patients with normal renal function and longer with renal dysfunction. Protamine does not neutralize LMWH.^2,14

Spinal and Epidural Hematomas

The risk of spontaneous hematoma formation may be increased in the presence of LMWH and indwelling epidural catheters for administration of postoperative analgesia and by concomitant use of other drugs that affect hemostasis (nonsteroidal antiinflammatory drugs, platelet inhibitors) and by traumatic or repeated attempts to accomplish entry into the epidural or subarachnoid space. This increased risk of hematoma formation is a consideration when selecting regional anesthesia in patients being treated with LMWH preparations. Recommendations for management of patients for regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy are reported in American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition).¹⁵

Fondaparinux

Fondaparinux is a synthetic anticoagulant composed of the five saccharide units that make up the active site of heparin that binds AT, such as LMWH, to inhibit factor Xa but has no direct activity against thrombin. Administered subcutaneously, fondaparinux is rapidly absorbed and has an elimination half-time of 15 hours, allowing for once daily administration. Metabolism does not occur and the drug is eliminated by the kidneys and should not be used in patients with renal failure. Clinical uses of fondaparinux include prevention of deep vein thrombosis (DVT) and pulmonary embolism and as an alternate anticoagulant in patients with HIT. Because of its long duration of action, it is used primarily in patients with HIT or concerns about sensitization.¹⁶

Danaparoid

Danaparoid is a glycosaminoglycuronan that is derived from porcine intestinal mucosa and consists of a mixture mostly of dermatan sulfate, and chondroitin sulfate. This low-molecular-weight heparinoid compound attenuates fibrin formation principally by binding AT. Elimination of danaparoid is predominately through the kidneys. Danaparoid is effective in decreasing the incidence of DVT following total hip arthroplasty and was used for the treatment of HIT; this agent is no longer available in the United States (it was removed from the U.S. market in 2002 due to a shortage in drug substance) but is still in use in other countries.

Prophylaxis against Venous Thromboembolism

Surgical procedures have been associated with a 20-fold increase in risk for VTE, which is understandable considering that the majority of surgical patients have one or more risk factors for developing VTE.¹⁷ The incidence of DVT is 10% to 40% among general surgery patients, and higher still in high-risk surgery patient populations (e.g., orthopedic, thoracic, cardiac, and vascular surgery).^2,3 Fortunately, thromboprophylaxis is known to effectively reduce VTE in a cost-effective manner.² However, despite their effectiveness, there are specific challenges regarding the use of currently recommended anticoagulants.⁷

To prevent VTE, patients are treated with anticoagulants. Although SC heparin and LMWH are commonly used, multiple novel agents are also approved for different indications including fondaparinux, rivaroxaban, and dabigatran with different indications depending on the country. Enoxaparin and dalteparin are commonly used LMWHs. Before the availability of LMWH, low-dose heparin, 5,000 units subcutaneously every 8 to 12 hours, was a common regimen. In those with renal failure or renal dysfunction, heparin and warfarin are the only drugs minimally affected because of nonrenal clearance.

Among surgical patients, those undergoing total hip replacement are at unique risk for developing DVT and many of the studies for approval of new anticoagulants have focused on this group and other orthopedic patients. The risk of DVT is more protracted after hip surgery than after general surgery, when it usually develops during the first few postoperative days. The surgical technique for hip surgery, which kinks the femoral vein, seems to stimulate proximal DVT in the operated leg, whereas calf vein thrombosis is more likely to develop in either leg. Another effect unique to hip surgery is impairment of venous hemodynamics, which may last several weeks in the operated leg. Indeed, there are significantly fewer venous thromboembolic complications in patients undergoing elective hip replacement when prophylaxis with LMWH is given for 1 month rather than only during the hospitalization. VTE is also a common, life-threatening complication of major trauma. Pulmonary embolism has been observed to occur in 2% to 22% of patients with major trauma, and fatal pulmonary embolism is the third most common cause of death in patients who survive the first 24 hours.^7,17

Direct Thrombin Inhibitors: Parenteral Agents

An important class of anticoagulants that high-risk surgery patients at risk for HIT may receive are the direct thrombin inhibitors, including bivalirudin, argatroban, lepirudin, and desirudin (Table 30-1). Bivalirudin is also commonly used for cardiac interventional procedures. The direct thrombin inhibitors also vary in their binding affinities for thrombin. Desirudin, lepirudin, and bivalirudin bond in a bivalent manner to thrombin by interacting with both the catalytic site and fibrinogen-binding site. Bivalent direct thrombin inhibitors show higher affinity and specificity for thrombin compared with univalent direct thrombin inhibitors, which bind to the catalytic site only. Direct thrombin inhibitors vary substantially in their pharmacokinetic properties in terms of half life and metabolism. There are also differences in immunogenicity between the direct thrombin inhibitors and with 40% to 70% of patients developing antihirudin antibodies after 4 or more days of treatment.¹⁸

Bivalirudin

Bivalirudin, a synthetic analog of hirudin with a half-life of 25 minutes, has been widely studied in patients with and without acute coronary syndromes undergoing percutaneous coronary intervention (PCI). This agent is indicated for use in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA); in patients with or at risk for HIT or HIT with thrombosis syndrome (HITTS) undergoing PCI; and with provisional use of glycoprotein (GP) IIb/IIIa inhibitors in patients undergoing PCI. Although it is a polypeptide, bivalirudin is considered a safe anticoagulant in patients with HIT. In patients with HIT antibodies undergoing cardiopulmonary bypass, bivalirudin provided safe and effective anticoagulation, with a 94% success rate for the procedures.¹⁹ Further, multiple studies have demonstrated its application as a heparin replacement in patients who are HIT positive and require on or off pump cardiac surgery, although this is an off-label use for the drug.^19–21

Argatroban

Argatroban is an injectable, synthetic, univalent direct thrombin inhibitor indicated for prophylaxis or treatment of thrombosis in patients with or at risk of HIT undergoing PCI. It has a relatively short half-life of 40 to 50 minutes, and anticoagulation returns to baseline when stopping it after approximatrly 4 hours.²² Patients with HIT are likely to have renal dysfunction and most of the agents used for HIT are all primarily renally eliminated. Argatroban is hepatically eliminated, thus no dose adjustments are required in patients with renal impairment. As lepirudin is renally eliminated and bivalirudin is partially (~20%) renally eliminated, their use may require dose adjustment in renally impaired patients to avoid accumulation. Antibodies to argatroban have not been detected after prolonged or repeated use due to its low molecular weight.²³

Lepirudin and Desirudin

Lepirudin and desirudin are recombinant hirudins, synthetic analogs of hirudin, the direct thrombin inhibitor first isolated from leeches as Hirudo medicinalis is the name of the leech. These proteins are manufactured by recombinant methods. Lepirudin is approved for use in patients with HIT and associated thromboembolic disease to prevent further thromboembolic complications. Lepirudin was initially reported for cardiac surgical patients; however, bleeding was a major problem due to its ability to irreversibly inhibit thrombin. HIT patients receiving lepirudin generate antibodies and require close monitoring (using aPTT) to avoid bleeding complications. In patients with renal dysfunction the drug may have a prolonged half-life.^16,23

Desirudin (another recombinant hirudin) is approved for use in Europe and now in the United States for the prevention of VTE after total hip or knee replacement surgery and has been studied extensively in patients with stable angina or acute coronary syndromes undergoing PTCA. Antigenicity and anaphylaxis are also reported, although the risk of hypersensitivity to desirudin appears relatively low. Because desirudin is primarily eliminated by the kidneys, patients with renal impairment require monitoring and the aPTT can be used.¹⁶

Oral Anticoagulants

Vitamin K Antagonists—Warfarin

Oral anticoagulants are derivatives of 4-hydroxycoumarin (coumarin). Warfarin is the most frequently used anticoagulant because of its predictable onset and duration of action and its excellent bioavailability after oral administration (Table 30-2). Treatment usually begins with an oral warfarin dose of 5 to 10 mg, and the average maintenance dose is 5 mg; however, the dose varies widely among individuals due to pharmacogenetic differences. Warfarin has been the only oral agent available until the recent approval of new agents that are described in the sections that follow. Disadvantages of warfarin include delayed onset of action, the need for regular laboratory monitoring, and difficulty in reversal should a surgical procedure create concern about bleeding.³