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HISTORY AND EPIDEMIOLOGY
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Antithrombotics have numerous clinical applications, including in the treatment of coronary artery disease, cerebrovascular events, hypercoagulable states, deep vein thrombosis (DVT), and pulmonary embolism (PE). The antithrombotics are a diverse group of xenobiotics that are widely studied and constantly in the process of therapeutic evolution.
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The origins and discovery of antithrombotics are extraordinary.6,29,156,259 The discovery of modern-day oral anticoagulants originated after investigations of a hemorrhagic disorder in Wisconsin cattle in the early 20th century that resulted from the ingestion of spoiled sweet clover silage. The hemorrhagic agent, eventually identified as bishydroxycoumarin, would be the precursor to its synthetic congener warfarin (named after the Wisconsin Alumni Research Foundation). Warfarin was rapidly marketed as both a medicine and a rodenticide. “Superwarfarins” were subsequently developed for the rat population that had developed increasing genetic resistance to warfarin.
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The origins of the anticoagulant heparin are equally fascinating. A medical student initially attempting to study ether soluble procoagulants derived from porcine intestines serendipitously found that, over time, these apparent “procoagulants” actually prevented normal blood coagulation. The phospholipid anticoagulant responsible for this effect would later be identified as a variant form of heparin. Shortly thereafter, the water-soluble mucopolysaccharide termed heparin (because of its abundance in the liver) was discovered. Unfractionated heparin (UFH) is a mixture of polysaccharide chains with varying molecular weights. After the identification of the active pentasaccharide segment of heparin in the 1970s, multiple low-molecular-weight heparins (LMWHs) were isolated, and synthetic forms were created.
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Hirudin, a 65–amino acid polypeptide, was produced by the salivary glands of the medicinal leech (Hirudo medicinalis).256 Antistasin and antistasinlike proteins are naturally secreted by the Mexican leech, Haementeria officinalis, and the earthworm.106,370 These xenobiotics have not been used therapeutically; however, they inspired the development of the synthetic factor inhibitors, such as direct thrombin inhibitors (DTIs) and factor Xa inhibitors.
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In the late 19th century, human urine was noted to have proteolytic activity with specificity for fibrin. A substance found to be an activator of endogenous plasminogen leading to the consumption of fibrin, fibrinogen, and other coagulation proteins was isolated and purified and given the name urokinase. Streptokinase, a protein produced by β-hemolytic streptococci, tissue plasminogen activator (t-PA), and other synthetic thrombolytics were later discovered. Although known to exist for many years, ancrod, a purified derivative of Malayan pit viper, only recently gained therapeutic attention as a naturally occurring antithrombotic.
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In the early 20th century, the antithrombotic properties of aspirin were noted in anecdotal reports of patients having a predisposition to bleeding while taking aspirin. Clinicians also noted lower rates of myocardial infarction (MI), and studies to elucidate the effects of aspirin on coagulation soon followed with further research exposing the role of platelet aggregation in thrombosis.251 These discoveries led to the development of the antiplatelet xenobiotics.
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The diversity of these antithrombotics led to ever-increasing use in many fields of medicine. Although warfarin is the most common oral anticoagulant in use today because of its utility in patients with cerebrovascular disease, cardiac dysrhythmias, and thromboembolic disease, the emergence of newly developed oral antithrombotics has changed the landscape of modern anticoagulation. During the period from 2011 to 2015, the American Association of Poison Control Centers has listed anticoagulants in the top 25 categories associated with the largest number of fatalities (Chap. 130). The total number of cases of reported antithrombotic exposures to the American Association of Poison Control Centers was 96,498 with 130 deaths during that 5-year period (Chap. 130). During that time period, new antithrombotics such as apixaban, edoxaban, and ticagrelor joined the market. In 2011, dabigatran and warfarin led the US Food and Drug Administration (FDA) Safety Information and Adverse Event Reporting Program’s list of adverse drug events, with 3,781 reports of serious adverse events associated with dabigatran, including 542 patient deaths. By comparison, warfarin alone accounted for 1,106 reports with 72 deaths.255 Since then, the FDA is continually reviewing dabigatran and initiated its own study that demonstrated lower risks of death, stroke, and intracranial hemorrhage but higher risks of gastrointestinal (GI) bleeding in patients anticoagulated with dabigatran compared with warfarin.371
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Balance Between Coagulation and Anticoagulation
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An understanding of the normal function of the coagulation pathways is essential to appreciate the etiology of a coagulopathy. This section summarizes the critical steps of the coagulation cascade. For additional details, readers are referred to Chap. 20 and several reviews.135,252,257,304
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Coagulation consists of a series of events that prevent blood loss and assist in the restoration of blood vessel integrity. Although the traditional understanding of the events that occur in the coagulation cascade,91,231 as discussed later, adequately describe in vitro events, the current understanding emphasizes some distinct differences that occur in vivo.135,257,304 Despite these differences, an understanding of the traditional model is most useful for interpreting the results of diagnostic tests of coagulation.
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Within the cascade, coagulation factors exist as inert precursors and are transformed into enzymes when activated. Activation of the cascade occurs through one of two distinct pathways, the intrinsic and extrinsic systems (Fig. 58–1).91,231 After being activated, these enzymes catalyze a series of reactions that ultimately converge to generate thrombin with the subsequent formation of a fibrin clot.
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The intrinsic pathway is activated by the complexation of factor XII (Hageman factor) with high-molecular-weight kininogen (HMWK) and prekallikrein or vascular subendothelial collagen. This results in sequential activation of factor XII, active kallikrein, active factors IX to XI, and prothrombin (factor II) (Fig. 58–1). Prothrombin is converted to thrombin in the presence of factor V, calcium, and phospholipid. The integrity of this system is usually evaluated by determining the partial thromboplastin time (PTT).
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In the extrinsic or tissue factor–dependent pathway, a complex is formed between factor VII, calcium, and tissue factor, which is released after injury. A calcium- and lipid-dependent complex is then created between factors VII and X. The factor VII–X complex subsequently converts prothrombin to thrombin, which promotes the formation of fibrin from fibrinogen (Fig. 58–1). The integrity of this pathway is usually assessed by determining the prothrombin time (PT or international normalized ratio {INR}120). The distinction between PT and INR is discussed in Chap. 20.
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Activation of factor X provides the important link between the intrinsic and extrinsic coagulation pathways. Additional evidence that tissue factors can activate both factors IX and X suggests that there are more interrelations between the two pathways.275 Furthermore, cell surfaces facilitate the process of clotting. Platelets are also known to interact with proteins of the coagulation cascade through surface receptors for factors V, VIII, IX, and X.142,265,339 As a final step, factor XIII assists in the cross-linking of fibrin to form a stable thrombus.
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Antithrombin (AT), and proteins C, S, and Z serve as inhibitors, maintaining the homeostasis that is required to prevent spontaneous clotting and keep blood fluid. Protein C, when aided by protein S, inactivates two plasma factors, V and VIII.46,73,135 Protein Z is a glycoprotein (GP) molecule that forms a complex with the protein Z–dependent protease inhibitor (ZPI) which, in turn, inhibits the activated factor X (Xa).380 Antithrombin complexes with all the serine protease coagulation factors (factor Xa, factor IXa, and contact factors, including XIIa, kallikrein, and HMWK), except factor VII.46,135,304
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Thrombolytics such as streptokinase, urokinase, anistreplase, and recombinant tissue plasminogen activator (rt-PA) enhance the normal processes that lead to clot degradation.257
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Thrombosis is initiated when exposed endothelium or released tissue factors lead to platelet adherence and aggregation, the formation of thrombin, and cross-linking of fibrinogen to form fibrin strands.135,257,304 This results in a hemostatic plug or thrombus formation. Thrombus formation, in turn, leads to generation of plasmin from plasminogen, which causes fibrinolysis and eventual dissolution of the hemostatic plug.74,75 Thus, the fibrinolytic system is a natural balance against unregulated coagulation. Thrombolytic therapy increases fibrinolytic activity by accelerating the conversion of plasminogen to plasmin, which actively degrades fibrin.74,75 After the administration of thrombolytics, a drug-induced coagulopathy ensues, and fibrin degradation products (FDPs) are elevated secondary to the rapid turnover of clot.
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DEVELOPMENT OF COAGULOPATHY
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Impaired coagulation results from decreased production or enhanced consumption of coagulation factors, the presence of inhibitors of coagulation, activation of the fibrinolytic system, or abnormalities in platelet number or function. Platelets are involved in the initial phases of clotting after blood vessel injury by assisting in the formation of the fibrin plug.
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Decreased production of coagulation factors results from congenital and acquired etiologies. Although congenital disorders of factor VIII (hemophilia A), factor IX (Christmas factor Hemophilia B), factor XI, and factor XII (Hageman factor) are all reported, their overall incidence is still quite low. Clinical conditions that result in acquired factor deficiencies are much more common and result from either a decrease in synthesis or activation. Factors II, V, VII, and X are entirely synthesized in the liver,135,257,304 making hepatic dysfunction a common cause of acquired coagulopathy. In addition, factors II, VII, IX, and X also require postsynthetic modification by an enzyme that uses vitamin K as a cofactor,353,358,359 such that vitamin K deficiency (from malnutrition, changes in gut flora secondary to xenobiotics, or malabsorption), and inhibition of vitamin K cycling (from warfarin) are capable of impairing coagulation.
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Excessive consumption of coagulation factors usually results from massive activation of the coagulation cascade. Massive activation occurs during severe bleeding or disseminated intravascular coagulation (DIC). The latter results from infection, such as sepsis, and from conditions that introduce tissue factor into the blood, such as neoplasms, snake envenomations, stagnant blood flow, diffuse endothelial injury secondary to hyperthermia, ruptured aortic aneurysm, or aortic dissection. The hallmark of a consumptive coagulopathy is a depressed concentration of fibrinogen with an elevation of FDPs. This combination suggests the rapid turnover of fibrin in the coagulation process. In the other coagulopathic conditions, the failure to activate the coagulation cascade is associated with normal or high fibrin concentrations and low FDPs because of limited clot formation.
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Hypothermia is a well-known cause of DIC leading to death.365 Canine studies show decreased fibrinogen, factor II, and factor VII concentrations when cooled to 68°F (20°C) while a simultaneous rise in factor V concentration occurs.140 In vitro studies show increased coagulation time, clot formation time, and maximum clot strength in hypothermic whole-blood samples from healthy volunteers.103,311 In addition, thrombocytopenia occurs secondary to sequestration in the spleen, liver, and splanchnic circulation.301,355 Infants with hypothermia have an increased risk for intracranial and pulmonary hemorrhage.62
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Inhibitors of the coagulation cascade (circulating anticoagulants) are of two types: immunoglobulins to coagulation factors or antibodies to phospholipid membrane surfaces. Immunoglobulins develop without obvious cause, are part of a systemic autoimmune disorder, or result from repeated transfusions with exogenous factors (as occurs in patients with hemophilia).162,209,330 Antibodies to factors V, VII to XI, and XIII are described.35,330 The clinical syndromes associated with antibody inhibitors are similar to those associated with deficiencies of the particular coagulation factors involved. Antiphospholipid antibodies are directed against phospholipid membrane surfaces and β2-GP I, also known as apolipoprotein H. This protein is essential in preventing hemostasis by inhibiting adenosine diphosphate (ADP)–induced platelet aggregation, inhibiting activation of the intrinsic pathway of the coagulation cascade, and inhibiting both platelet-mediated factor Xa and factor VII activation. Therefore, destroying β2-GP I creates a prothrombotic clinical status.324,325,334 Paradoxically, this antibody creates a prolonged PTT because the antibody also binds to most phospholipid-containing PTT reagents. This reduction in amount of active reagent results in a falsely elevated PTT.162,209
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Gastrointestinal decontamination should be performed on patients who are believed to have potentially significant life-threatening ingestions unless they already present with significant bleeding. For patients who present after a few hours of ingestion, gastric emptying is not indicated (Chap. 5). In general, a single dose of activated charcoal (AC) decreases absorption of some anthrombotics and should be given unless contraindicated.272,377,391 Oral cholestyramine enhances warfarin elimination,299 but no studies are available that compare these two therapies or evaluate the role of combined AC and cholestyramine therapy. Therefore, early administration of AC after ingestion is the preferred form of GI decontamination, even for patients who overdose on warfarin. In addition to general supportive measures, the patient should be placed in a supervised medical and psychiatric environment that offers protection against external or self-induced trauma and permits observation for the onset of coagulopathy.
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Blood transfusion is required for any patient with a history of blood loss or active bleeding who is hemodynamically unstable, has impaired oxygen transport, or is expected to become unstable. Although a transfusion of packed red blood cells (PRBCs) is ideal for replacing lost blood, it cannot correct a coagulopathy, so patients will continue to bleed. Massive transfusion protocols (MTPs) aim to correct coagulopathy with an array of blood products, electrolytes, and antifibrinolytics. If available, it is reasonable to use an MTP for unstable patients. If an MTP is not available, whole blood is reasonable in severe cases because it contains many components, including platelets, white blood cells, and non–vitamin K–dependent factors.
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VITAMIN K ANTAGONISTS
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Warfarin and “Warfarinlike” Anticoagulants
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The vitamin K antagonist (VKA) anticoagulants can be divided into two groups: (1) hydroxycoumarins, including warfarin, difenacoum, coumafuryl, fumasol, prolin, ethyl biscoumacetate, phenprocoumon, dicumarol, bishydroxycoumarin, and acenocoumarin, and (2) indanediones, including chlorophacinone, diphacinone, diphenadione, phenindione, and anisindione. Regardless of the classification, their mechanism of action involves inhibition of the vitamin K cycle. Vitamin K is a cofactor in the postribosomal synthesis of clotting factors II, VII, IX, and X (Fig. 58–2). The vitamin K–sensitive enzymatic step that occurs in the liver involves the γ-carboxylation of 10 or more glutamic acid residues at the amino terminal end of the precursor proteins to form a unique amino acid γ-carboxyglutamate.104,353,358,359 These amino acids chelate calcium in vivo, which allows the binding of the four vitamin K–dependent clotting factors to phospholipid membranes during activation of the coagulation cascade.400
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Vitamin K is inactive until it is reduced from its quinone form to a quinol (or hydroquinone) form in hepatic microsomes. This reduction of vitamin K must precede the carboxylation of the precursor factors. The carboxylation activity is coupled to an epoxidase activity for vitamin K, whereby vitamin K is oxidized simultaneously to vitamin K 2,3-epoxide (Fig. 58–2).358,399 This inactive form of the vitamin is converted back to the active form by two successive reductions.104,233,277,395 In the first step, an epoxide reductase (known as vitamin K 2,3-epoxide reductase) uses reduced nicotinamide adenine dinucleotide (NADH) as a cofactor to convert vitamin K 2,3-epoxide to a quinone form.270,271,358 Subsequently, the quinone is reduced to the active vitamin K quinol form (Antidotes in Depth: A18).
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Warfarin is a racemic mixture of R warfarin and S warfarin enantiomers. In humans, S warfarin is approximately 2.7 to 3.8 times more potent than R warfarin.37 Warfarin and all warfarinlike compounds inhibit the activity of vitamin K 2,3-epoxide reductase, as is demonstrated by the observation of elevated concentrations of vitamin K 2,3-epoxide.69,403 Vitamin K quinone reductase is also inhibited by warfarin and its related compounds (Fig. 58–2).104,121 This reduction in the cyclic activation of vitamin K subsequently inhibits the formation of activated clotting factors.
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Pharmacology of Vitamin K Antagonists
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Oral warfarin is well absorbed, and peak serum concentrations occur approximately 3 hours after administration.357 Because only the free warfarin is therapeutically active, concurrent administration of xenobiotics that alter the concentration of free warfarin, either by competing for binding to albumin or by inhibiting warfarin metabolism, markedly influences the anticoagulant effect.24,126,357 The pharmacologic response to warfarin is a polygenic trait with approximately 30 genes contributing to its therapeutic effects.195 Readers are referred to a review of xenobiotics and foods that potentiate warfarin’s effects.398 Although vitamin K regeneration is altered almost immediately, the anticoagulant effect of warfarin and other warfarinlike anticoagulants is delayed until the existing stores of vitamin K are depleted and the active coagulation factors are removed from circulation. Because vitamin K turnover is rapid, this effect is largely dependent on factor half-life (t1/2), with factor VII (t1/2 ∼5 hours) depleted most rapidly.126 For a prolongation of the INR to occur, factor concentrations must fall to approximately 25% to 30% of normal values.72 Assuming complete inhibition of the vitamin K cycle, this suggests that most patients require at least 15 hours (three factor VII half-lives) before the effect of warfarin is evident on the INR.123 In fact, because complete inhibition does not occur, the onset of coagulation is delayed even further.
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Because the half-life of warfarin in humans is 35 hours, its duration of action is documented to be as long as 5 days.50,357 On average, it takes approximately 6 days of warfarin administration to reach a steady-state anticoagulant effect.
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R warfarin is metabolized by enzymes CYP1A2 and CYP3A4, and S warfarin is metabolized by CYP2C9. Whereas R warfarin is metabolized by side-chain reduction to secondary alcohols that are subsequently excreted by the kidney, S warfarin is metabolized by hydroxylation to 7-hydroxy warfarin, which is excreted into the bile.357 The elimination of S warfarin is more rapid than that of R warfarin.49
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Dosing of warfarin and other VKAs is problematic in many patients. In one study, genetic polymorphisms of the vitamin K epoxide reductase complex 1 (VKORC1) and CYP2C9 genes were the strongest predictors of interindividual variability in the anticoagulant effect of warfarin.195 Pharmacogenomic research with complex xenobiotics, such as warfarin, improves safety of treatment and predicts or prevents interactions with other xenobiotics. Although the FDA has approved a commercially available test to identify variants within these genes,193 current guidelines do not advocate genetic testing to guide VKA dosing.154
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Within the coumarin group are two 4-hydroxycoumarin derivatives, difenacoum and brodifacoum, that differ from warfarin by their longer, higher molecular weight polycyclic hydrocarbon side chains. Together with chlorophacinone, an indandione derivative, they are known as superwarfarins or long-acting VKAs.
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Long-acting VKAs were designed to be effective rodenticides in warfarin-resistant rodents.230 Their mechanism of action is identical to that of the traditional warfarinlike anticoagulants, as demonstrated by increased concentrations of vitamin K 2,3-epoxide after administration.48,51,56,210,277 The ability of these xenobiotics to perform as superior rodenticides is attributed to their high lipid solubility and concentration in the liver.210,230,277 They also saturate hepatic enzymes at very low concentrations, as demonstrated by zero-order elimination after overdose.56 These factors make them about 100 times more potent than warfarin on a molar basis.210,230,277 In addition, they have a longer duration of action than the traditional warfarins.210,230,277 For example, to obtain 100% lethality in a mouse, more than 21 days of feeding with a warfarin-containing rodenticide (0.025% anticoagulant by weight of bait) is required.230 Similar efficacy is achieved with a single ingestion of brodifacoum (0.005% anticoagulant by weight of bait).230 Furthermore, more concentrated liquid formulations, such as brodifacoum (0.5% anticoagulant), are available through illegal vendors and are implicated in prolonged coagulopathy in humans.138 It should also be noted that although ingestion of these xenobiotics is the most common route of exposure and subsequent cause of toxicity, dermal absorption of liquid preparations occurs, also resulting in a coagulopathy.344
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Clinical Manifestations
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Although intentional ingestions of warfarin-containing products are uncommon, adverse drug events resulting in excessive anticoagulation and bleeding frequently occur. The risk of bleeding during VKA therapy depends on a myriad of factors, including the intensity of anticoagulation, patient characteristics, and comorbid conditions. Clearly, the most serious complication of excessive anticoagulation is intracranial bleeding, which is reported to occur in as many as 2% of patients on long term therapy, which is an 8- to 10-fold increase in risk compared with patients who are not anticoagulated.125,126,405 The overall risk of major bleeding in patients can be estimated using tools such as the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly (HAS-BLED) score, which was prospectively validated in patients with atrial fibrillation.225,285 Bleeding ranges between 1 and 12.5 episodes per 100 patient-years, with a higher risk in patients with multiple risk factors.285 Another study showed that patients older than the age of 80 years have a cumulative incidence of major bleeding at 13.1 per 100 person-years with major bleeding defined as bleeding at serious sites (eg, intracranial, retroperitoneal, intraspinal, or pericardial) or bleeding that results in blood transfusion or death. Patients between the ages of 65 and 80 years have a lower risk of 4.7 major episodes of bleeding per 100 person-years.176 Major bleeding complications are associated with a fatality rate as high as 77%.239 In patients with intracranial bleeding a decreased level of consciousness and an increased size of hematoma are predictors of poor prognosis.419 Somewhat surprisingly, the degree of INR elevation was not associated with worse outcome.419
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Many cases of intentional overdose of long-acting VKAs in humans are reported. The clinical courses of these patients are characterized by a severe coagulopathy that last weeks to months, often accompanied by consequential blood loss. Most patients do not seek medical care until bruising or bleeding is evident,19,56,57,119,170,194 which often occurs many days after ingestion. The most common sites of bleeding are the GI and genitourinary tracts. In one study describing 12 patients with surreptitious ingestion of oral anticoagulants, nine were health care professionals.271 These patients presented with bruising, hematuria, hematochezia, and menorrhagia. Bleeding into the neck with resultant airway compromise is a rare but life-threatening complication.43
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Patients with unintentional ingestions must be distinguished from those with intentional ingestions because the former demonstrate a low likelihood of developing a coagulopathy and have rare morbidity or mortality. Most patients (usually children) are entirely asymptomatic and have a normal coagulation profile after an acute unintentional exposure. Typical warfarinlike rodenticides contain only small concentrations of anticoagulant, 0.005% (or 5 mg of brodifacoum per 100 g of product). A 10-kg child would require an initial dose of 10 g of rodenticide (8 pellets, each of which is approximately 25 mm in size). These quantities are far greater than those that occur in typical “tastes.” Thus, single small unintentional ingestions of warfarin-containing rodenticides pose a minimal threat to normal patients.190 Prolongation of the INR is unlikely with a single small ingestion of a long-acting VKA rodenticide. Clinically significant anticoagulation is even rarer. In a combined pediatric case series, prolongation of the INR occurred in only 8 of 142 children (5.6%) reported with single small ingestions of long-acting VKAs.28,189,190,342 Only one child in this group was reported to have “abnormal prolonged bleeding,” but this required no medical attention.342 In a single case report, a 36-month-old child developed a coagulopathy manifested by epistaxis and hematuria, with anticoagulation persisting for more than 100 days after a presumed, but unwitnessed, single unintentional ingestion of brodifacoum.366 Clinically significant coagulopathy can result, however, after small repeated ingestions. Two children reportedly became poisoned by repeated ingestions of a long-acting anticoagulant. One child presented with a neck hematoma that compromised his airway and the other with a hemarthrosis.151 Similarly, a 7-year-old girl required multiple hospitalizations over a 20-month period after repeated unintentional ingestions of brodifacoum.32 Finally, a 24-month-old child who presented with unexplained bruising and a PT greater than 125 seconds was the victim of brodifacoum poisoning secondary to Munchausen syndrome by proxy, which is currently called pediatric condition falsification (Chap. 31).15
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Laboratory Assessment
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Although warfarin concentrations are useful to confirm the diagnosis in unknown cases and to study drug kinetics,155,268 the routine use of simple and inexpensive measures such as INR determination seems more appropriate (Table 58–1). When blood loss is evident, serial determinations of hemoglobin concentration are indicated.
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For patients with an acute and significant long acting VKA overdose, daily INR evaluations for 2 days are adequate to identify most patients at risk for coagulopathy. Earlier detection through direct coagulation factor analysis is available but is typically reserved to trend patients with known coagulopathy for treatment purposes.155,170 Concentrations of long-acting VKAs can now be measured, although they are usually only performed in reference laboratories.199,268 We recommend that children with possibly significant exposures be followed up with at least a single INR at least 48 hours after the exposure. Even though significant toxicity from long-acting VKAs is rare, it should be recognized that the reported benign courses of exposures in children are somewhat misleading. Multiple retrospective studies suggest that children with unintentional acute exposures do not require any follow-up coagulation studies.256,260,279,332 However, this conclusion and approach to management is an unjustified attempt to decrease the cost of “unnecessary” coagulation studies. There are clearly insufficient data to justify this conclusion because many of these “exposed” children were never documented to have ingested long-acting VKAs (Chap. 130). We recommend that clinicians continue to manage these children as possibly significant exposures and that all children be followed up with at least a single INR at a minimum of 2 days after the exposure. A baseline INR is usually unnecessary but is reasonable if there is a suspicion of an antecedent ingestion. A baseline INR is also helpful when chronic exposure is suspected.
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Treatment of Vitamin K Antagonist–Induced Coagulopathy
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Life-threatening bleeding secondary to VKA toxicity should be immediately reversed with factor replacement followed by vitamin K1 (Table 58–1). The American College of Chest Physicians (ACCP) and the FDA recommend factor replacement with four-factor prothrombin complex concentrate (PCC) as a first-line treatment for major bleeding in the setting of VKA-induced coagulopathy.172 This recommendation is reasonable given the ease of administration as compared with fresh-frozen plasma (FFP). Most countries use traditional four-factor PCC, which contains concentrated factors II, VII, IX, X, C, and S. Dosing of PCC is based on INR and body weight. The typical doses range between 25 and 50 units/kg with the largest dose based on a maximum weight of 100 kg. The PCC is contained in both 500-unit and 1,000-unit vials. However, the factor IX content of each vial is variable: 500-unit vial may contain between 400 to 620 units/vial, and a 1,000-unit vial may contain between 800 and 1,240 units/vial. Each individual vial states the actual factor IX content in each bottle, and the dosage should be based on the actual factor IX content in each vial.88 Most forms of PCC, contain small amounts of heparin. These heparin-containing PCCs are contraindicated in patients with a history of heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia and thrombosis syndrome (HITT). In those cases, factor eight inhibitor bypassing activity (FEIBA), an activated prothrombin complex concentrate (aPCC), is recommended. Activated aPCCs contain factors II, VII, IX, and X in inactive and activated forms. Factor eight inhibitor bypassing activity is typically used to treat patients with hemophilia A and B. Unfortunately, FEIBA has not been studied extensively in the setting of VKA-induced coagulopathy. Therefore, there is no standard dose for coagulopathy reversal. Typical doses for treating bleeding or for perioperative management range between 50 and 100 units/kg with the dose based on the amount of factor VIII inhibitor bypass activity.23 Despite its increased cost, the rationale for using PCC instead of FFP includes less risk of infection transmission.172 In addition, small-volume factor replacement is preferable in patients at risk of volume overload, such as patients with heart failure, chronic kidney disease (CKD), or intracranial bleeding.2 Unfortunately, there are only a few studies comparing PCC with FFP in reversing coagulopathy. These studies show that PCC safely produces complete INR reversal faster than FFP with more consistent factor IX replacement.95,185,234 However, unequal factor replacement in these small studies favors more factor replacement in patients receiving PCC.315 Fresh-frozen plasma is rich in active vitamin K–dependent coagulation factors and will reverse oral anticoagulant-induced coagulopathy in most patients. In general, approximately 15 mL/kg of FFP should be adequate to reverse any VKA-induced coagulopathy.87 However, the specific factor quantities and volume of each unit may be varied, leading to an unpredictable response.234 In addition, delay to FFP administration is accentuated by requirements for blood type matching and thawing. Therefore, we recommend in acute major bleeding in the setting of VKA-induced coagulopathy the use of PCC as the preferred reversal agent.
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Activated recombinant factor VII (rFVIIa) is approved for patients with hemophilia or various factor inhibitors and has successfully reversed warfarin toxicity.284 The safety of off-label rFVIIa to reverse VKA coagulopathy is unclear. Preliminary data using rFVIIa suggested its utility for bleeding secondary to warfarin-induced excessive anticoagulation and a case series showing beneficial effects in four patients with long acting VKA toxicity.420 However, adverse outcomes, such as arterial thrombotic events, occur at higher than acceptable rates. Initial concerns for thromboembolic adverse events were raised when review of the FDA’s Adverse Event Reporting System database found that the majority of these complications arose in patients who received rFVIIa for off-label purposes. Cerebrovascular accident, acute MI, PE, venous thrombosis, and clotted devices all occurred at higher rates in off-label applications.269 The Factor Seven for Acute Hemorrhagic Stroke Trial (FAST) showed that arterial thromboembolic adverse events increased in a dose-dependent fashion with the administration of rFVIIa.102 A subsequent meta-analysis confirmed that an increased rate of arterial thrombosis occurs in patients who receive rFVIIa.219 The risk of continued bleeding versus the benefit of rapid reversal of coagulopathy with rFVIIa is unknown, and further experience with rFVIIa is necessary to determine its safety and efficacy in anticoagulant-induced bleeding. We do not recommend routine use of rFVIIa for reversing VKA-associated coagulopathy. If FFP, PCC, and FEIBA are not available, then it is reasonable that rFVIIa be given in life-threatening situations.1 It should also be noted that if rFVIIa is used, assays based on PT are inaccurate and should be avoided when administering rFVIIa.191
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Treatment with vitamin K1 takes several hours to activate enough factors to reverse a patient’s coagulopathy,234,278 and this delay is potentially fatal. Repetitive, large doses of vitamin K1 (on the order of 60 mg/d or greater) are reported in some patients with massive ingestion.155,271 If complete reversal of INR prolongation occurs or is desirable (as in most cases of life-threatening bleeding) and the underlying medical condition of the patient still requires some degree of anticoagulation, the patient can then receive anticoagulation with heparin after the bleeding is controlled and clinical stability restored. Heparin anticoagulation was used without apparent bleeding complications in 25% of patients in one cross-sectional study.402
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Vitamin K1 is preferable over the other forms of vitamin K; the other forms are ineffective183,262,270,373 are potentially toxic,17 and are unavailable in the United States. Parenteral administration of vitamin K1 (phytonadione) is traditionally preferred as initial therapy by many authors, but success can also be achieved with early oral therapy, especially when the coagulopathy is not severe.56 In most cases, the patient can be switched to oral vitamin K1 for long-term care. Vitamin K1 can be administered intramuscularly, subcutaneously, intradermally, or intravenously. Although intravenous (IV) therapy has the most rapid onset of action of all routes of delivery, its use as the sole therapeutic is still associated with a delay of several hours278,395 and carries the added risk of anaphylactoid reactions.302 The use of low doses and slow rate of administration reduces this risk335 (Antidotes in Depth: A18). In cases in which oral administration is undesirable, for example, with significant GI bleeding the subcutaneous (SC) route should not be used because absorption is erratic. In this case, we recommend the IV route of administration of vitamin K1 because the benefits outweigh the risks.
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For patients with non–life-threatening bleeding, the clinician must evaluate whether anticoagulation is required for long-term care. In patients not requiring chronic anticoagulation we recommend treating even small elevations of the INR with vitamin K1 alone to prevent deterioration in coagulation status and reduce the risk of bleeding. In contrast to ingestions of warfarin, we recommend not to give prophylactic vitamin K1 to asymptomatic patients with unintentional ingestions of long-acting warfarinlike anticoagulants because (1) if the patient develops a coagulopathy, it will last for weeks, and the one or two doses of vitamin K1 given will not prevent complications; (2) a gradual decline in coagulation factors occurs over the first day of anticoagulation, so an individual would not be expected to develop a life-threatening coagulopathy in 1 or 2 days; and (3) after vitamin K1 is administered, the onset of an INR abnormality will be delayed, which could impair the ability of the clinician to recognize a coagulation abnormality, possibly requiring the patient to undergo an unnecessarily prolonged observation period.
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For patients requiring chronic anticoagulation we agree with the ACCP guidelines for the management of patients with elevated INRs (Table 58–2). It should also be noted that low-dose vitamin K is safe to administer to patients with mildly elevated INRs (4–10) to decrease the INR more rapidly; however, one study did not demonstrate decreased bleeding in the treatment group.86 Furthermore, simply omitting warfarin doses is usually adequate for a patient without active bleeding who has an INR between 4 and 9.86
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It is often unclear why patients with consistent therapeutic dosing have seemingly random elevations in their INR. A case-control study identified the following risk factors associated with overanticoagulation from VKAs: previous medical history of increased INR, antibiotic therapy, fever, and concomitant use of amiodarone and proton pump inhibitors.60 Clinicians should pay particular attention to patients with these conditions, and close monitoring of coagulation profiles should be performed.60
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Treatment of Long-Acting Vitamin K Antagonist Overdoses
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In patients with unintentional, small ingestions of long-acting VKAs, the risk of coagulopathy is low. However, it takes days to develop coagulopathy. Administration of AC is recommended to prevent absorption in acute ingestions if no contraindication exists.190,342
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Treatment of a patient with a coagulopathy resulting from a long-acting anticoagulant overdose is essentially the same as the treatment of oral anticoagulant toxicity with certain exceptions. Although initial parenteral vitamin K1 doses as high as 400 mg have been required for reversal,57 daily oral vitamin K1 requirements are often in the range of 50 to 200 mg. Recent experience in both animals and humans suggests that parenteral vitamin K1 therapy is not required after initial stabilization (Antidotes in Depth: A18).56,411
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In one case report, a 2-year-old child with confirmed brodifacoum-associated coagulopathy developed anemia, epistaxis, ecchymosis and GI bleeding. She developed an anaphylactoid reaction after several doses of IV vitamin K1. Patients typically tolerate IV vitamin K1 well as long as it is administered appropriately. In stable patients, oral vitamin K is recommended. However, because oral vitamin K was not available at this hospital, the patient received five plasma exchange treatments, which resulted in normalization of her coagulation studies. In addition, repeat brodifacoum concentrations were undetectable after her third plasma exchange treatment.94 Because there are other less invasive methods of correcting VKA-induced coagulopathy and lack of established experience with plasma exchange beyond this case report, we do not recommend plasma exchange therapy for VKA-induced coagulopathy.
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Long-acting VKAs are metabolized by the cytochrome P450 system.16,270 In a rat model, the duration of coagulopathy was shortened by administering phenobarbital, a CYP3A4 inducer.16 Although phenobarbital has never been systematically studied in humans, this approach was used by several authors in isolated human cases of long-acting anticoagulant toxicity.57,183,226,366,393 These anecdotal reports suggest some improvement with phenobarbital therapy, but the risk of sedation in a patient who might be prone to bleeding complications outweighs any purported benefit.
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Patients with long-acting VKA overdose should be followed until their coagulation studies remain normal without treatment for several days. This usually requires daily or even twice-daily INR measurements until the INR is at the lower limit of the therapeutic range. Monitoring of serial INR measurements should allow for a gradual decrease in vitamin K1 requirement over time. Periodic coagulation factor analysis (particularly factor VII), however, provides an early marker of toxicity resolution.170 An anticoagulated patient will require weeks to months of close observation for both psychiatric and medical management. A critical superwarfarin concentration below which anticoagulation does not occur is not defined.57 In one case report, brodifacoum was observed to follow zero-order elimination kinetics.56
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Nonbleeding Complications of Vitamin K Antagonists
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Warfarin therapy is associated with three nonhemorrhagic lesions of the skin: urticaria,323 purple toe syndrome,122 and warfarin skin necrosis.77,193,202,242,384 Although warfarin skin necrosis was once thought to be a rare and idiosyncratic reaction,193,202 more recent evidence suggests a link between this disorder and protein C deficiency.202,384 Protein C synthesis is also dependent on vitamin K.73 Patients who are homozygotes for protein C deficiency have an increased incidence of thrombosis and embolic events, such that they often require long-term anticoagulant therapy.73 Because the half-life of protein C is shorter than that of many of the vitamin K–dependent coagulation factors, protein C concentrations fall rapidly during the first hours of warfarin therapy. This results in an imbalance that actually favors coagulation, and skin necrosis results because of microvascular thrombosis in dermal vessels.242,384 Although warfarin skin necrosis is more common in patients with protein C deficiency, this disorder is also described in patients with protein S and AT deficiencies.77 Unfortunately, these deficiencies are neither necessary nor sufficient to account for the incidence of warfarin necrosis.77 If necrosis occurs, warfarin should be discontinued, and heparin should be initiated to decrease thrombosis of postcapillary venules. Some patients also require surgical debridement.314
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The purple toe syndrome, in contrast to warfarin-induced skin necrosis, is presumed to result from small atheroemboli that are no longer adherent to their plaques by clot (Fig. 17–13).
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Warfarin-related nephropathy (WRN) is a well-recognized form of nonhemorrhagic warfarin toxicity. In patients with CKD, an acute increase in the INR above 3 was associated with an increase in serum creatinine and accelerated reduction in kidney function. The etiology of the WRN is attributed to acute tubular injury and glomerular bleeding, demonstrated by the finding of red blood cell (RBCs) filling Bowman’s capsule and RBCs casts obstructing glomeruli on specimens from kidney biopsies.54,55 Further studies that retrospectively reviewed kidney function in patients on long-term warfarin anticoagulation showed 33% of patients with CKD and 16.5% of patients without CKD developed WRN. Warfarin-related nephropathy is associated with a mortality rate of 31.1%, a significant increase in risk compared with 18.9% in patients without WRN.54
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An additional major nonhemorrhagic complication of warfarin therapy is warfarin embryopathy. Most warfarin-induced fetal abnormalities occur during weeks 6 to 12 of gestation, but central nervous system (CNS) and ocular abnormalities can develop at any time during gestation (Chap. 30).158,354
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Conventional heparin also known as unfractionated heparin C or unfractionated heparin (UFH) is a heterogeneous group of molecules within the class of glycosaminoglycans.180 The heparin precursor molecule is composed of long chains of mucopolysaccharides, a polypeptide, and carbohydrates. The main carbohydrate components of heparin molecules include uronic acids and amino sugars in polysaccharide chains. Heparin for pharmaceutical use is extracted from bovine lung tissue and porcine intestines.328
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Heparin inhibits thrombosis by accelerating the binding of AT to thrombin (activated factor II) and other serine proteases involved in coagulation.232,308 Thus, factors IX to XII, kallikrein, and thrombin are inhibited. Heparin also affects plasminogen activator inhibitor, protein C inhibitor, and other components of coagulation. The therapeutic effect of heparin is usually measured through the activated PTT. The activated clotting time (ACT) is more useful for monitoring large therapeutic doses or in the overdose situation.201
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Low-molecular-weight heparins are 4,000- to 6,000-Da fractions obtained from conventional heparin.128 As such, they share many of the pharmacologic and toxicologic properties of conventional heparin.45 The various LMWHs (eg, nadroparin, enoxaparin, dalteparin) are prepared by different methods of depolymerization of heparin; consequently, they each differ to a certain extent regarding their pharmacokinetic properties and anticoagulant profiles. The major differences between LMWHs and conventional heparin are greater bioavailability, longer half-life, more predictable anticoagulation with fixed dosing, targeted activity against activated factor X, and less targeted activity against thrombin.45,128 As a result of this targeted factor X activity, LMWHs have minimal effect on the activated PTT, thereby eliminating either the need for, or the usefulness of monitoring. They are therefore administered on a fixed dose schedule. However, in certain instances (eg, patients with CKD, pregnancy), monitoring of anti–factor Xa activity is performed to assess adequacy of anticoagulation and to prevent the risk of bleeding.159 Controversy exists as to whether such testing is clinically necessary,44 but studies have not shown significant benefit in determining risk of thromboembolic recurrence or consistent risk of major bleeding. We do not recommend the routine testing of anti–factor Xa activity.
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Studies investigating LMWHs for the prevention of thromboembolic disease after hip surgery and trauma, in patients with stroke or DVT, in pregnancy, and in other conditions where anticoagulation with heparin would otherwise be indicated (eg, at the onset of oral anticoagulation therapy) are numerous. Low-molecular-weight heparins have a minimal risk in pregnancy246 because they do not cross the placenta,124,356 and they are therefore preferred for the treatment or prophylaxis of thromboembolic disease in pregnancy.306 Most studies demonstrate a lower incidence of embolization; however, there is still a trend toward increased bleeding.30,152,220 The PROTECT trial, which compared dalteparin and UFH in terms of rates of proximal leg DVT, PE, and major bleeding in critically ill patients, found that patients randomized to the dalteparin group had statistically fewer PE. This study found no statistically significant differences in proximal DVT and major bleeding rates.153
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Because of the large size of heparin and negative charge, the molecule is unable to cross cellular membranes. These factors prevent oral administration, and heparin must be administered parenterally. After parenteral administration, heparin remains in the intravascular compartment, in part bound to globulins, fibrinogen, and low-density lipoproteins, resulting in a volume of distribution of 0.06 L/kg in humans.118,273 Because of its rapid metabolism in the liver by a heparinase, heparin has a short duration of effect.232 Although the half-life of elimination is dose dependent and ranges from 1 to 2.5 hours,232,241,273 the duration of anticoagulant effect is usually reported as 1 to 3 hours.232 Dosing errors or drug interactions with thrombolytics, antiplatelet drugs, or nonsteroidal antiinflammatory drugs increase the risk of bleeding.161 Low-molecular-weight heparins are nearly 90% bioavailable after SC administration and have an elimination half-life of 3 to 6 hours.137 Anti–factor Xa activity peaks between 3 and 5 hours after dosing.137 Low-molecular-weight heparins are renally eliminated and patients with stage 4 or 5 CKD are at increased risk of toxicity.386 Although there are insufficient data guiding therapeutic LMWH dosing in patients with severe CKD, some advocate dose reduction to decrease the risk of bleeding. However, no dosage regimens are provided.154
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Clinical Manifestations
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Intentional overdoses with heparin are rare.238 Most reported cases involve iatrogenic toxicity in hospitalized patients.136,145,238,276,326 These cases involved the administration of large amounts of heparin as a consequence of misidentification of heparin vials, during the process of flushing IV lines, and secondary to IV pump malfunction. Significant bleeding complications occurred in several cases, including at least one fatality.136 However, intentional overdoses of LMWHs are reported, although none of them were fatal.58,254
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Similar adverse effects to UFH are also reported with LMWHs and include epidural or spinal hematoma, intrahepatic bleeding,173 abdominal wall hematomas,13 psoas hematoma after lumbar plexus block,192 and intracranial bleeding in patients with CNS malignancy.98 Although these complications were all reported in patients who received the LMWH enoxaparin, there are no data to suggest differing toxicities among LMWHs.
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For therapeutic anticoagulation, the effect of heparin is usually monitored with activated partial thromboplastin time (aPTT). Most hospitals have heparin nomograms that recommend heparin dose alterations based on aPTT, although these nomograms need to be individualized by each hospital because of the variation expected from the particular aPTT reagent and laboratory technology used. For patients undergoing cardiovascular procedures, the ACT is used to monitor them because they require higher dose heparin.137 More recently, an anti-Xa assay specific for heparin was FDA approved. Heparin dosing is titrated based on the anti-Xa assay results, with therapeutic ranges higher than prophylactic ranges. Goal ranges also differ depending on whether LMWH or UFH is being used.
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In patients with heparin resistance, in whom extremely high doses of heparin are required to accomplish a therapeutic aPTT, anti-Xa activity is recommended to guide heparin dosing. Despite lower heparin dosing and subtherapeutic aPTTs, patients monitored with anti-Xa activity had similar rates of recurrent thromboembolism and bleeding compared with the patients who were given high-dose heparin to maintain therapeutic aPTTs in a prospectively collected randomized control trial.221
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Low-molecular-weight heparins are usually administered at fixed doses for venous thromboembolism (VTE) prophylaxis or at weight-based doses for VTE treatment. Laboratory monitoring is not done unless patients are pregnant, have CKD, or are obese. In these cases, anti-Xa activity is measured, with target ranges varying based on agent and dosing regimen.137 In patients without the aforementioned risk factors, monitoring and dose adjustment are of no benefit compared with fixed-dose regimens of LMWH.5 In addition, several studies show no correlation between anti-Xa activity and bleeding propensity.18,215,389
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After stabilization of the airway and breathing and circulation is ensured, the physician should be prepared to replace blood loss and reverse the coagulopathy, if indicated. Because of the relatively short duration of action of heparin, observation alone is indicated if significant bleeding has not occurred. For a patient requiring anticoagulation, serial aPTT determinations will indicate when it is safe to resume therapy. If significant bleeding occurs, either removal of the heparin or reversal of its anticoagulant effect is indicated. Because heparin has a very small volume of distribution, it can be effectively removed by exchange transfusion.326 Although this technique has been used successfully in neonates, protamine has also safely been given to neonates without a history of fish allergy or previous exposure to protamine or protamine-containing insulin.253 Exchange transfusion to remove heparin should be performed in neonates with significant bleeding if protamine is contraindicated.
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When severe bleeding occurs, protamine sulfate partially neutralizes UFH7 (Table 58–1). Protamine is a low-molecular-weight protein found in the sperm and testes of salmon, which forms ionic bonds with heparin and renders it devoid of anticoagulant activity.232 One milligram of protamine sulfate injected intravenously neutralizes 100 units of UFH.232 The dose of protamine should be calculated from the dose of heparin administered if known and assuming the approximate half-life of heparin to be 60 to 90 minutes; the amount of protamine should not exceed the amount of heparin expected to be found intravascularly at the time of infusion. As with other foreign proteins, protamine administration is associated with numerous adverse effects such as hypotension, bradycardia, and allergic reactions. Because approximately 0.2% of patients receiving protamine experience anaphylaxis, a complication that carries a 30% mortality rate, we recommend that protamine be reserved for patients with life-threatening bleeding (Antidotes in Depth: A19).173 Clinicians should be aware that excess protamine administration does result in paradoxical anticoagulation, but this should not deter clinicians from administering protamine in life-threatening situations.
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Because of the severe adverse effects associated with protamine, research has focused on safer methods to reverse heparin anticoagulation. These agents include heparinase,248 synthetic protamine variants,387,388 and platelet factor 4 (PF4). These therapies are not widely available, and their efficacy and safety are not established.
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If life-threatening bleeding occurs after LMWH administration we also recommend treating patients with protamine. Several studies show that protamine partially reverses LMWHs such as enoxaparin, dalteparin, and tinzaparin. In one case report of a 10-fold dosing error of enoxaparin, protamine effectively reversed the anticoagulant effects.404 In a series of 14 bleeding patients given protamine to reverse LMWH, bleeding ceased in two-thirds of the patients. These data, however, are complicated by repeat dosing of protamine as well as administration of other procoagulant antidotes such as clotting factors and vitamin K in a subset of patients. In addition, patients received protamine between 30 minutes and 48 hours after their last dose of LMWH.379 Approximately 1 mg protamine will neutralize 100 anti–factor Xa units, and 1 mg of enoxaparin will neutralize 100 anti–factor Xa units for up to 8 hours after LMWH administration.137 A second dose of 0.5 mg protamine per 100 anti–factor Xa units is reasonable if bleeding continues. If more than 8 hours has elapsed, a smaller dose of protamine should be administered. The maximum dose of 50 mg should not be exceeded.137 The appropriate dosages for protamine are described in detail in the Antidotes in Depth: A19. The newer experimental protamine variants appear to be effective against LMWHs but are not yet clinically available.387,388 Interestingly, there is one case report of recombinant activated factor VII (rFVIIa) reversing the effects of LMWH in the setting of postoperative acute kidney injury (AKI),96,249,264 and there is also a single case report demonstrating efficacy at reversing severe bleeding caused by enoxaparin.175 Based on this limited reported experience, we do not recommend rFVIIA for LMWH-associated bleeding.
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NONBLEEDING COMPLICATIONS
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Postoperative thrombocytopenia that occurs in the first 1 or 2 days after surgery usually results from platelet consumption. This early fall in platelet count tends to cause concern for a drug-induced thrombocytopenia called HIT because postoperative VTE prophylaxis with heparin is usually started simultaneously.392 However, postoperative thrombocytopenia usually improves by the third postoperative day, distinguishing itself from HIT, which typically occurs between days 5 and 10 after heparin initiation. In patients who were previously treated with heparin, HIT-related events sometimes occur within 24 hours after reexposure.223
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Heparin-induced thrombocytopenia affects up to 5% of patients receiving heparin.223,392 Heparin stimulates platelets to release PF4, which subsequently complexes with heparin to provoke an IgG response, causing platelet aggregation and thrombocytopenia.14,416 A more severe form of thrombocytopenia, HITT (formerly known as HIT-2 or the white clot syndrome), occurs in up to 55% of patients with untreated HIT.223 The antibodies against the heparin–PF4 complex activate platelets, which leads to platelet–fibrin thrombotic events.14,416
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Patients present with either hemorrhagic or thromboembolic complications. Low-molecular-weight heparin is also associated with thrombocytopenia (isolated HIT) and less frequently with HITT.223 Consequently, when HITT occurs, LMWH is contraindicated.223 Treatment of patients with HIT includes discontinuation of heparin or LMWH and immediate use of alternative anticoagulant such as lepirudin, argatroban, or danaparoid.68,223 In addition to HIT and HITT, necrotizing skin lesions286 and hyperkalemia from aldosterone suppression274 also rarely occur in patients receiving heparin therapy. These patients should not receive heparin or LMWH again, not even in low doses to maintain venous patency.
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Some additional complications of heparin use include osteoporosis, which mostly occurs in patients on long-term therapy with UFH.174 A small percentage of these patients develop bone fractures if treated continuously for more than 3 months. Data for LMWHs are limited, and the incidence of osteoporosis is less compared with UFH.174 In 2008, an outbreak of adverse events was linked to heparin contaminated with oversulfated chondroitin sulfate.227 The contaminated heparin, which was found in at least 10 countries, originated in China.38 Many patients developed anaphylactoid-type reactions with at least 100 reported deaths.227
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DIRECT THROMBIN INHIBITORS
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Hirudin and its congeners (lepirudin and desirudin) are used in patients with acute coronary syndromes, the prevention of thromboembolic disease, and in patients with HITT.36,322,329 Desirudin is at least as effective as UFH and without an increased risk of bleeding or thrombocytopenia. However, in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) Iib study of patients with unstable angina or non–Q wave MI, there was an increase in the number of blood transfusions in patients who received desirudin compared with those who received heparin.338 This increased risk of bleeding compared with heparin has caused desirudin to fall out of favor. Instead bivalirudin and argatroban tend to be used more often, especially in the setting of HITT. In fact, initial studies using bivalirudin during coronary artery angioplasty for unstable or postinfarction angina showed that it is a safe substitute for heparin with lower bleeding rates.36 Unfortunately, all of these DTIs are short acting and require parenteral administration.
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Because of the potential therapeutic limitations of warfarin (eg, dosing, risk of bleeding, narrow therapeutic window), direct oral anticoagulants were developed with directed activity against specific clotting factors. The proposed benefits of these medications include the convenience of fixed dosing and avoidance of close therapeutic monitoring. Ximelagatran was one of the first DTIs that was as effective as warfarin in the treatment of stroke prevention, nonvalvular atrial fibrillation, and DVT.168 Ximelagatran had many advantages over warfarin, including rapidity of onset, fixed dosing, stable absorption, decreased risk of drug interactions, and lack of necessity for therapeutic monitoring.168 However, in 2006, drug manufacturers abandoned ximelagatran after noticing a high rate of hepatic failure. Countries that had approved ximelagatran withdrew the medication from the market.
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Subsequently, dabigatran was approved for systemic anticoagulation in patients with nonvalvular atrial fibrillation in the United States and many other countries. Later it was approved for the treatment and prophylaxis of VTE. The Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial demonstrated that dabigatran administration was associated with lower rates of systemic embolic events, with similar rates of bleeding, compared with anticoagulation with warfarin.81 However, subsequent evaluation of the data acquired from the RE-LY trial demonstrates that patients 75 years of age and older an increased risk of extracranial bleeding when compared with those taking warfarin.110 In multiple noninferiority trials, dabigatran demonstrated similar efficacy to enoxaparin in reducing VTE without increasing bleeding risk after hip joint replacement.114,115
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Thrombin has four separate binding sites, each of which is specific for substrate, inhibitor, or cofactors.368 Whereas bivalent DTIs, such as hirudin and bivalirudin, bind the active site and one of two exosites (binding sites outside of the active site), univalent DTIs, such as dabigatran, bind just the active site97 (Fig. 58–3). By directly inhibiting thrombin, anticoagulation is possible without the need for AT.329 In addition, inhibiting thrombin also inhibits platelet activation because thrombin is a potent and direct-acting platelet activator. Unlike heparin, DTIs are able to enter clots and inhibit clot-bound thrombin because of their small size, offering the distinct advantage of restricting further thrombus formation.
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Desirudin, bivalirudin, and argatroban are all administered parenterally. Desirudin is given as SC injections for VTE prophylaxis. Although the dosing for desirudin is 15 mg as a subcutaneous injection every 12 hours, this dose should be decreased or stopped in patients with stage 3 or greater CKD. In addition, patients previously treated with the hirudins develop antibodies, creating the potential for anaphylaxis with repeat dosing.137 Bivalirudin is also an analogue of hirudin. It is used in patients with HITT who require cardiac catheterization or cardiopulmonary bypass surgery.137 Argatroban binds noncovalently to the active site of thrombin to function as a competitive inhibitor.137 It is metabolized by CYP3A4/5 in the liver and is particularly useful in patients with CKD.137
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Dabigatran is orally administered as dabigatran etexilate. This prodrug has no anticoagulant properties, and serum esterase coverts it to dabigatran, the active drug.347 At therapeutic doses, peak concentrations occur in 2 hours (Table 58–3). Approximately 35% of dabigatran is protein bound; 85% is eliminated renally, with 78% of it is eliminated within the first 24 hours. Its mean terminal half-life is approximately 8 to 12 hours.37 Contraindications to dabigatran are active hemorrhage or a hypersensitivity reaction to dabigatran. The manufacturer recommends either dose adjustment or avoidance of concomitant administration of P-glycoprotein inhibitors in patients with renal insufficiency. It also recommended to avoid coadministration of rifampin, a P-glycoprotein inducer.39 P-glycoprotein activity prevents enteric absorption of dabigatran, and rifampin augments this activity, resulting in subtherapeutic dabigatran serum concentrations.
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Clinical Manifestations
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Intentional overdoses with the DTIs are rare events. Although there are reports of patients who develop significant coagulopathy after unintentional ingestion of excess dabigatran,64,261,409 the more common scenario is that patients become overanticoagulated because of improper dosing in patients with CKD or failure to adjust dosing in patients who develop AKI. In general, the parenterally administered medications have short elimination half-lives, and iatrogenic medication administration errors, if recognized, are often less risky than those that are longer acting.
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Dabigatran, the newest of the DTIs, is orally administered with a longer duration of action. Since its approval in 2010, bleeding was rapidly recognized as a complication of therapy. Only recently has a specific monoclonal antibody reversal xenobiotic, idarucizumab (Praxbind), been approved by the FDA. In 2011, the FDA released an advisory announcing that a review of postmarketing reports of serious bleeding associated with dabigatran use was initiated. In addition, dabigatran leads the list of fatalities reported to the MedWatch system. There are many published case reports of patients bleeding while anticoagulated with dabigatran. Patients may have been subjected to increased risk of bleeding because of risk factors such as increased age or CKD. In New Zealand and Australia, a significant number of bleeding events, including intracranial bleeding, GI bleeding, hematuria, and hemoptysis, were reported in the period immediately after the approval of the medication. Up to 25% of the reports in this series involved errors in prescribing practices.160 In particular, off-label use of dabigatran for anticoagulation in the setting of mechanical heart valves led to valve thrombosis.70,293 Cardiac tamponade from hemopericardium, fatal epistaxis, serious GI bleeding, postoperative bleeding complications, and intracranial bleeding are all reported.26,65,107,340,367 In addition, clinicians have expressed difficulties in treating hemorrhage in trauma victims while anticoagulated with dabigatran.85
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Furthermore, several questions regarding other adverse effects related to dabigatran use have been raised. A meta-analysis comparing patients anticoagulated with dabigatran versus warfarin, enoxaparin, or placebo showed higher rates of MI or acute coronary syndrome.372 Additionally, though clinical trials implied that discontinuation of dabigatran does not cause rebound thrombosis, the authors of anecdotal reports of thrombotic events after cessation of dabigatran anticoagulation have questioned whether thrombosis is caused by rebound or just sequelae from underlying hypercoagulability or illness.364
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Laboratory Assessment
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Monitoring the anticoagulant effect in the setting of DTI use is complex. For bivalirudin and argatroban, serial aPTT measurements are commonly used to estimate the degree of anticoagulation.137 Admittedly, the aPTT is not a good test because the degree of anticoagulation does not follow a linear relationship. This is particularly emphasized with dabigatran, the most recently developed DTI. For example, the aPTT increases at higher dabigatran concentrations, but the relationship is nonlinear, with the aPTT plateauing at dabigatran concentrations greater than 200 ng/mL.346,378 Furthermore, the PT and INR are usually elevated, but they do not correlate with the anticoagulant effect of dabigatran.349,378 Dilute thrombin time (dTT) and ecarin clotting time (ECT) are proposed as more accurate reflections of the anticoagulation effect.378 Several assays are used to measure serum dabigatran effect using the dTT assay. In these assays, standards with known dabigatran concentrations are used. Unfortunately, none of these modalities are FDA approved.105,317,348 Ecarin clotting time is a laboratory assay that uses ecarin, a derivative of saw-scaled viper venom, as the reagent to activate prothrombin. Although some hospitals are able to obtain a thrombin time (TT) in a clinically relevant time, the dTT and the ECT are usually unavailable.
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Treatment of Direct Thrombin Inhibitor–Induced Coagulopathy
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In the event of an acute ingestion of dabigatran, AC is indicated based on data from an in vitro model.377 It should be noted that there have been at least two cases of intentional dabigatran overdose that were managed via orogastric lavage and AC. The initial dabigatran concentrations were later found to be 970 ng/mL and 4,170 ng/mL, respectively.261,410 Based on a small prospective study with dabigatran assays, the average peak concentration in patients receiving therapeutic dosing of dabigatran was 112.7 ± 66.6 ng/mL.317 However, because both patients after intentional dabigatran overdoses cases did not have bleeding complications, they were observed until the resolution of coagulopathy. One patient was given FFP for an aPTT of 79s (normal, 23–37 s)and an INR of 3.3. The other patient was noted to have a mild coagulopathy with an aPTT of 48.8 s and an INR of 1.3.261,410 An overdose of argatroban was successfully treated with FFP in a case report.415 With the widespread dabigatran use, the first of the novel oral anticoagulants, the absence of a reversal agent became a potentially deadly complication. The manufacturer fast-tracked the development of idarucizumab (Praxbind), a monoclonal antibody targeting dabigatran.374,375 In murine and human studies, idarucizumab administration results in normalization of a battery of functional clotting assays, including clotting time, aPTT, and TT.321 In a prospective study containing 90 patients who received 5 g of IV idarucizumab for urgent reversal of dabigatran-induced coagulopathy, reversal of coagulopathy occurred in 100% of patients despite 18 deaths in the study population. Study investigators noted that hemostasis in bleeding patients was restored at a median of 11.4 hours after administration of idarucizumab. In addition, antidotal therapy restored ECT and dTT in 88% to 98% of the patients. In patients undergoing an emergent procedure, normal intraoperative hemostasis was noted in 85% of cases. There are a significant number of limitations with this particular study. It should be noted that in addition to idarucizumab, 56% of patients received some type of blood products, including PRBCs, FFP, platelets, cryoprecipitate, PCCs, or whole blood. Thrombotic events were noted in five patients. One thrombotic event (simultaneous DVT and PE) occurred within 72 hours of idarucizumab administration in a single patient. Other complications noted were left atrial thrombus at 9 days, DVT at 7 days, MI at 13 days, and ischemic stroke at 26 days. Unfortunately, there was no control group to determine if morbidity or mortality outcomes were changed by administration of idarucizumab. In addition, dabigatran concentrations in enrolled patients ranged between 5 and 3,600 ng/mL with a median of 132 and 114 ng/mL in the two study groups.287 Although the majority of patients in the RE-LY trial had dabigatran concentrations less than 1,000 ng/mL, the literature reports exceedingly high dabigatran concentrations in many patients, particularly in patients who have kidney injury or in patients who have intentionally overdosed on dabigatran. The standard dose of idarucizumab, 5 g, will be insufficient in reversing coagulopathy in patients with these extremely high dabigatran concentrations.
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There are many case reports describing the use of idarucizumab in various clinical scenarios. It has been used in life-threatening bleeding, intentional overdose, and therapeutic accumulation secondary to kidney injury and in the preoperative or preprocedural setting.47,140,165,166,235,282,303,307,319,331,351,363 At least one case report showed continuation of life-threatening GI bleeding despite receiving recommended dosing of idarucizumab.4 One report described using idarucizumab in conjunction with hemodialysis to achieve normal coagulation function.235 It should be noted that several case reports demonstrated a rebound drug effect after administration of idarucizumab. One case described a patient with a massive dabigatran overdose with an initial dabigatran concentration of 3,337 ng/mL. After receiving idarucizumab, the patient’s dabigatran concentration fell to 513 ng/mL, with improvement in his coagulopathy. However, 7 hours after receiving idarucizumab, the patient’s294 dabigatran concentration rebounded to 1,126 ng/mL with corresponding increases in INR, PT, and aPTT.309 Dabigatran rebound after idarucizumab treatment is noted in other case reports.169 Some advocate for idarucizumab administration before thrombolytic therapy for acute ischemic cerebrovascular accidents in patients anticoagulated with dabigatran. In these case reports, patients received 5 g of idarucizumab followed by t-PA without adverse consequence.31,139,187,263,320,327 Some clinicians routinely recommend idarucizumab treatment before thrombolytic therapy for acute ischemic stroke.100,139 However, given the paucity of data and lack of a formal clinical trial, this should not be the standard of care as case reports cannot determine the efficacy and safety of this practice.
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Before the FDA approval of idarucizumab in 2015, the manufacturer suggested several strategies to treat patients with significant bleeding while anticoagulated with dabigatran. Transfusion of RBCs and FFP in addition to supportive care were the mainstays of treatment (Table 58–1). Recombinant factor FVIIa, PCCs, and hemodialysis were also used, but these interventions are incompletely studied. In a murine study of dabigatran, collagenase-induced intracranial hematoma expansion was inhibited in a dose-dependent fashion by PCC with the best results at 100 units/kg, the equivalent of 200% factor replacement. In the same study, high-dose PCC decreased but did not normalize the tail vein bleeding time. Recombinant factor VIIa was ineffective in limiting intracranial hematoma volume, and FFP limited intracranial hematoma size in the mice given a lower dose of dabigatran.418
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However, conclusions based on data obtained from murine studies should be interpreted with caution when treating humans. First, the hemostatic therapies used in these murine experiments are human derived, and cross-species effects cannot be predicted. Second, these mice had prolongation of their tail vein bleeding times, but dabigatran at therapeutic doses does not change bleeding time in humans.186 Another study done in healthy humans found that aPTT, endogenous thrombin potential lag time, TT, and ECT did not decrease with the administration of four-factor PCC.108
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One ex-vivo study showed that after a single dose of dabigatran in healthy volunteers, FEIBA decreased endogenous thrombin potential and lag time, and thrombin generation increased in a dose dependent fashion.237 In a murine study, aPCC reduced bleeding time at low doses. Unfortunately, at high doses, this effect was reduced.376
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Hemodialysis for dabigatran removal remains a controversial intervention. A single study showed that after a subtherapeutic dose of dabigatran in patients with stage 5 CKD, the extraction ratios were up to 68% at 4 hours after the initiation of hemodialysis.350 Although this suggests that dabigatran is effectively removed from the serum, the greater implication of this finding is unknown. This study did not address the safety of hemodialysis in bleeding patients who are actively bleeding or the possibility of rebound concentrations after hemodialysis.349,350 Several published case reports demonstrated significant drug rebound after hemodialysis in bleeding patients, up to 87% of the initial dabigatran concentration within 2 hours after the cessation of hemodialysis.63,64,340 In one case, hemodialysis was not effective in stopping bleeding, and despite massive transfusion of RBCs, FFP, and platelets, deaths from exsanguination occurred. In some cases, a repeat hemodialysis session or continuous venovenous hemodiafiltration (CVVHD) was performed in anticipation of posthemodialysis rebound. Although they were successful in decreasing serum dabigatran concentrations, they did not normalize the aPTT or the TT.340
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Although the safety and efficacy of these adjunctive therapies are unknown, they are reasonable in patients with serious bleeding if idarucizumab is not available or if a patient continues to have life-threatening hemorrhage despite idarucizumab administration. Repletion of blood volume and coagulation factors with PCC is reasonable. If maximal efforts at repletion of blood volume and coagulation factors are ineffective, then hemodialysis followed by CVVHD is reasonable if the patient can tolerate the procedure hemodynamically.
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Ciraparantag is a “universal antidote” being developed to reverse the activity of a number of anticoagulants, including the oral DTIs, the factor Xa inhibitors, and the heparins.9-11 Clinical trial results have yet to be published.
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Rivaroxaban was the first orally active direct factor Xa inhibitor approved for VTE and stroke prophylaxis and treatment. Development of this class of drugs started in the 1980s after the discovery of antistasin, a naturally occurring factor Xa inhibitor found in leeches. After screening a library of more than 200,000 compounds, a pharmaceutical company was able to identify structures that inhibit factor Xa. After structure optimization, rivaroxaban was created for clinical trials.283
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Numerous clinical trials investigated the efficacy and safety of rivaroxaban.22,113,114,188,203,369 Compared with warfarin, rivaroxaban prevented more strokes or systemic thromboembolic events and significantly reduced the number of intracranial hemorrhages in patients with nonvalvular atrial fibrillation.281 The most recent published trial compared the use of rivaroxaban compared with placebo in patients with acute coronary syndrome. There was a significant risk reduction in death attributed to any cardiac cause or stroke. However, rivaroxaban-treated patients had statistically significant increased rates of major and intracranial hemorrhages.243
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Apixaban is another oral factor Xa inhibitor that is approved by the FDA for VTE prophylaxis in patients with atrial fibrillation. Numerous studies showed benefit of apixaban in preventing VTE in specific populations while simultaneously lowering mortality or specific types of bleeding, such as intracranial hemorrhage.80,147,150,203-206
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In trials investigating the use of apixaban in patients with recent acute coronary syndrome, excess bleeding caused early cessation of trials; however, most patients were concurrently treated with dual antiplatelet therapy.3,76
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Edoxaban is the newest of the approved factor Xa inhibitors based on studies for VTE prophylaxis in patients with atrial fibrillation and for the treatment of VTE disease.66,71,111,143,144,171,296,396,414 Studies with edoxaban demonstrated promising results compared with enoxaparin in post–orthopedic surgery VTE prophylaxis, although it is not currently FDA approved for this indication.129-132,297 The risk of hemorrhage compared with enoxaparin varies among the many studies.52,66,71,129-132,414 Compared with warfarin in patients with nonvavular atrial fibrillation, the ENGAGE AF-TIMI 48 trial demonstrated a lower risk of cardiovascular death and hemorrhage, including intracranial hemorrhages and fatal bleeding.111,143,144,396 However, a study demonstrated the addition of an antiplatelet agent, such as aspirin, to edoxaban therapy in patients with atrial fibrillation resulted in a higher risk of hemorrhage compared with patients who received warfarin in conjunction with a single antiplatelet agent.412
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Factor Xa inhibitor development continues. Betrixaban is undergoing clinical trials to determine its efficacy and safety in VTE prophylaxis.79
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The factor Xa inhibitors are ideal anticoagulants because their site of action is the intersection of the intrinsic and extrinsic pathways, preventing thrombin activation.59 These synthetic drugs reversibly inhibit factor Xa without any cofactor requirements. Theoretically, this class of anticoagulants is safer than the DTIs because they do not completely neutralize thrombin.
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Rivaroxaban and apixaban selectively bind free and clot-bound factor Xa without inhibiting related serine proteases, including thrombin, trypsin, plasmin, or other activated clotting factors.116 In addition, rivaroxaban and apixaban inhibit tissue factor or collagen-induced thrombin formation. In vitro, the factor Xa inhibitors hinder tissue factor–induced platelet aggregation.116,408 Rivaroxaban does not directly inhibit platelet aggregation, and concomitant aspirin use does not affect the pharmacokinetics or safety of rivaroxaban in studies of healthy humans.59,116,196
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Rivaroxaban has an oral bioavailability of approximately 80%.397 Inhibition of factor Xa peaks approximately 3 hours after administration of the rivaroxaban. This inhibition lasts for approximately 12 hours.198 However, kidney or liver disease lengthens its duration of action (Table 58–3). Dosing varies by indication and kidney function. The manufacturer provides recommended dose adjustments for each indication based on kidney function.
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Approximately one-third of rivaroxaban is eliminated unchanged by the kidneys, and one-third is metabolized to an inactive form and excreted by the kidney. The remaining one-third is metabolized by the CYP3A4-dependent and -independent pathways in the liver and then excreted fecally. Concomitant use of CYP3A4 inhibitors or P-glycoprotein inhibitors is contraindicated because of increased risk of drug accumulation of up to 160%.164,397
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In the future, rivaroxaban could be a suitable anticoagulant alternative in patients with HITT because in vitro studies do not show platelet aggregation or activation in the presence of HITT antibodies or release of PF4 from platelets.390 Future studies proving efficacy and safety are needed before these xenobiotics can be recommended for use in patients with HITT.
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In preclinical studies, the oral bioavailability of apixaban is approximately 66%. Apixaban is primarily distributed to the blood compartment and is approximately 87% protein bound.116 Peak serum concentrations occur between 1 and 3 hours postingestion. There are multiple elimination pathways, suggesting that patients with either renal or hepatic impairment should be able to tolerate apixaban well. Approximately 25% of apixaban is excreted in the urine, and the majority of apixaban is excreted fecally between 24 to 48 hours after ingestion.116,295 Simultaneous administration of strong CYP3A4 inhibitors is contraindicated with apixaban.
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Apixaban is approved in the United States for stroke prevention in patients with nonvalvular atrial fibrillation, for VTE prophylaxis, and for VTE treatment.80,150 Dosing is based on indication. The manufacturer recommends either decreasing the dose or avoiding coadministration of apixaban if strong inhibitors of CYP3A4 and P-glycoprotein are administered.53
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Edoxaban is approved for the treatment of nonvalvular atrial fibrillation and for the treatment of DVT and PE. The dosage varies by indication. For patients with atrial fibrillation, the dosage also depends on creatinine clearance. Edoxaban is not recommended for patients with creatinine clearance less than 95 mL/min. Patients with VTE disease should receive edoxaban after 5 to 10 days of treatment with a parenteral anticoagulant.89,310 The manufacturer also notes that coadministration of rifampin, due to CYP3A4 induction, and coadministration of other anticoagulants are contraindicated.89,247 The prescribing information provided by the manufacturers of edoxaban also recommend a maximum dose of 30 mg/day for patients with body weight less than 60 kg.89
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Edoxaban is orally administered and has a bioavailability of 61.8%.240,250 P-glycoprotein appears to be the key factor as a transporter of edoxaban. Edoxaban metabolism is minor, and the compound is largely excreted in the urine and feces.250 Approximately 35% of an oral dose is eliminated renally, and 49% of the oral dose is excreted in the feces.240 Peak edoxaban concentrations occur 1 to 2 hours after ingestion, and the terminal half-life is 10 to 14 hours.89
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Clinical Manifestations
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Hemorrhage is the most concerning consequence of the factor Xa inhibitors, even at therapeutic doses. However, hemorrhage does not always occur in overdose. There are reports of no hemorrhage despite acute overdoses of both rivaroxaban and apixaban. In a multi–poison control center study involving 223 rivaroxaban or apixaban exposures, 12 patients involved suicide attempts, and none of these patients developed hemorrhage, although confirmation of ingestion was not verified in all cases.345 A case report describes a 21-month-old girl who developed an INR of 3.5 approximately 12 hours after ingesting an unknown quantity of rivaroxaban. She did not have any hemorrhagic consequences.245 Another case report describes a 71-year-old man who intentionally ingested 1,940 mg of rivaroxaban, resulting in an INR of 7.2 drawn 2 hours after ingestion and rivaroxaban concentration of 160 ng/mL drawn 3 days after ingestion. He never developed bleeding, and he was monitored until his coagulopathy resolved. He did not receive any blood products or reversal agents.300 In another case, a 42-year-old man intentionally ingested multiple pharmaceuticals, including 1,400 mg of rivaroxaban. He never developed any bleeding, but given his INR of 2.4 drawn 5 hours after ingestion, he was given 1 g of tranexamic acid and 3,000 units of PCC. He was discharged 1 day after this ingestion without any bleeding or adverse events.224 There are many other cases reporting massive intentional factor Xa inhibitor overdose, resulting in abnormal coagulation studies or supratherapeutic concentrations.20,212,213 More predictably, bleeding occurs at therapeutic doses. In the previously mentioned multi–poison control center study, all bleeding events occurred in patients on long-term anticoagulant therapy.345 Another case report describes a 58-year-old man taking 10 mg of rivaroxaban per day who developed prolonged rectal bleeding 31 days after initiating treatment for prophylaxis after hip replacement.40
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Some studies done in healthy volunteers show that rivaroxaban inhibits factor Xa activity and prolongs PT, aPTT, and LMWH activity in a dose-dependent fashion.197,198 Unfortunately, PT and aPTT are not reliable measures of the anticoagulant effect of rivaroxaban because results vary widely depending on the reagent used. Thrombin generation assays are prolonged, and endogenous thrombin potential is decreased. Unfortunately, these assays are not readily available in most medical centers. Chromogenic anti–factor Xa activity reliably measures rivaroxaban effect over a large range of concentrations.316
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Studies investigating the effect of apixaban on hematologic laboratory studies are limited, but multiple in vitro studies show that aPTT and PT increase in a dose-dependent fashion. The Heptest, a newly developed clotting assay that measures anti-Xa and anti-IIa activity, correlates best with the antithrombotic effect of apixaban. Unfortunately, it is not widely available because it is not yet FDA approved.105,116,407
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Treatment of Factor Xa Inhibitor–Induced Coagulopathy
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A study in healthy volunteers demonstrated that rivaroxaban absorption, as defined by area under the concentration–time curve, is decreased after AC administration up to 8 hours after a single oral dose of rivaroxaban. Absorption is decreased by 43% if AC is administered within 2 hours of a rivaroxaban ingestion. Activated charcoal given 8 hours after rivaroxaban ingestion resulted in a 29% decrease in absorption.272 Another study showed that AC at 2 hours and 6 hours after single-dose apixaban ingestion also reduced apixaban absorption by 50% and 28%, respectively. In this study, the half-life of apixaban decreased from 13 hours to 5 hours after AC was administered at either 2 hours or 6 hours after apixaban ingestion. 391 The administration of AC after an acute overdose is therefore recommended (Table 58–1). A single human study evaluated the use of four-factor PCC in reversing patients given rivaroxaban 20 mg twice daily for 2.5 days. The PT and endogenous thrombin time rapidly normalized after administration of 50 units/kg of PCC.108 Rivaroxaban anticoagulated rabbits showed improvements in coagulation assays after treatment with PCC and rFVIIa. However, these agents were clinically ineffective in achieving hemostasis.146 Because of its high protein binding, hemodialysis is unlikely to be an effective adjunct method to accelerate rivaroxaban removal.
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Preliminary in vitro studies show that four-factor PCC may improve thrombin generation and coagulation parameters in blood aliquots treated with apixaban.117 However, there are no human studies with clinically relevant outcomes to support the use of PCC in factor Xa-associated bleeding.
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Although edoxaban is the newest of the factor Xa inhibitors, hemorrhage remains a concern. There is a report of diffuse alveolar hemorrhage in addition to the bleeding complications mentioned in the numerous clinical trials.267 There are few studies evaluating reversal methods. There is one human study evaluating four-factor PCC in the reversal after a single dose of edoxaban. In this study, participants received 10, 25, or 50 units/kg of 4 factor PCC after a single dose of edoxaban. Participants then underwent punch biopsy, and coagulation studies and clinical bleeding were evaluated. After 50 units/kg of 4 factor PCC the bleeding duration and endogenous thrombin potential normalized. However, the PT and bleeding volume were only partially reversed.417 There are two animal studies showing that rFVIIa and FEIBA are effective in reversing edoxaban-induced coagulopathy.133,167 However, given that these agents have not been studied in for this indication in humans, neither rFVIIa nor FEIBA are recommended as treatment for edoxaban-induced coagulopathy.
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Although the half-lives of the factor Xa inhibitors are substantially shorter than that of warfarin, normalization of hemostasis because of drug clearance often requires more than 24 hours without intervention. During this time, supportive measures such as restoration of intravascular volume are helpful but do not correct the xenobiotic-induced coagulopathy. Prothrombin complex concentrates at a starting dose of 25 units/kg appears to be the only antidote that improves laboratory parameters immediately after infusion, but their effect on hemostasis is unknown. Regardless, in the case of life-threatening bleeding, PCC is reasonable to attempt to achieve hemostasis. Their peak coagulation effect should occur immediately after administration. In severe cases, repeat doses may need to be administered. The risk of thrombosis is unknown, and providers should be aware of this adverse effect when administering PCC. If PCC is unavailable, FEIBA should be used as a second-line agent. If both PCC and FEIBA are unavailable, it is reasonable to use rFVIIa with the caveat that the risk of thrombosis is higher with this drug compared with PCC and FEIBA.
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Andexanet alfa (Andexxa) is a recombinant protein recently FDA approved for reversal of anticoagulation caused by factor Xa inhibitors. This antidote was developed by altering the structure of factor X. Although the drug still binds factor Xa inhibitors, it has been altered to inhibit the catalytic activation of thrombin, and the factor Va binding site, which is necessary for anticoagulation, is no longer present.229 Studies in healthy elderly volunteers demonstrated that andexanet alfa administration given to patients who had achieved a steady-state concentration of either apixaban or rivaroxaban resulted in rapid reduction in plasma-free inhibitor concentrations and increased thrombin formation. Antifactor Xa activity decreased by more than 90% immediately after andexanet alfa infusion but rebounded to placebo concentrations within 1 to 2 hours.337 In an open-label single-group study, andexanet alfa was given to patients who had ingested a factor Xa inhibitor within 18 hours of acute major bleeding onset. After infusion of andexanet alfa, 79% of patients achieved hemostasis and antifactor Xa activity decreased 12 hours after andexanet alfa infusion. Thrombotic events occurred in 6% of patients within 3 days of andexanet alfa infusion, and 15% of the patients died. An unclear number of patients received blood products such as PRBCs, FFP, or PCC. There was no control group to determine if there were any changes in patient outcomes such as morbidity or mortality resulting from andexanet alfa adminstration (Antidotes in Depth: A17).82
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Pentasaccharides are synthetic anticoagulants that possess activity against factor Xa and are used for the prevention and treatment of VTE. Fondaparinux is the only pentasaccharide currently available for clinical use.217 The pentasaccharide binds to AT with an affinity higher than that of heparin facilitating the formation of the AT–factor Xa complex. After this complex forms, fondaparinux dissociates from the AT–factor Xa complex and can bind and activate additional AT.137 Routine measurements of coagulation are not generally performed. When the degree of anticoagulation needs to be assessed, the fondaparinux-specific anti-Xa assay is the most helpful. The pentasaccharides have long half-lives and have no reliable reversal agent if bleeding occurs; they do not bind to protamine.137 Patients with stage 3 CKD should have their dose reduced 50%; fondaparinux is contraindicated in patients with stages 4 and 5 CKD.137 No controlled trials are available yet. However, normalization of coagulation studies and thrombin generation occurred after healthy volunteers received fondaparinux followed by rFVIIa.34 In a case series of eight patients who received 90 mcg/kgof rFVIIa for hemorrhage, only 50% of patients had favorable outcomes. Anti-Xa activity remained unchanged, and none of the patients had any thrombotic complications. However, many of these patients were on other antithrombotics, including antiplatelet drugs. With respect to PCCs, a single trial investigated the use of PCC and aPCC to reverse fondaparinux-induced anticoagulation. In this study, the effect of PCC could not be assessed because the coagulation assay was incompatible with the formulation of PCC used. However, the addition of aPCC to plasma samples from fondaparinux-treated volunteers reversed thrombin generation time. This study was an ex vivo study, and further studies are required before PCC can be routinely recommended for the purpose of reversing fondaparinux-induced coagulopathy.112 If a patient develops significant bleeding from fondaparinux, based on opinion only, it is reasonable to administer 25 to 50 units of PCC in addition to standard supportive measures.
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ANTICOAGULANT APTAMERS
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Aptamer anticoagulants are small nucleic acid molecules that are currently under development to target specific blood coagulation proteins.266 They are direct protein inhibitors and function similarly to monoclonal antibodies.266 Specific aptamers that are currently being studied include the anti–factor IX aptamer, the anti–activated protein C aptamer, and the anti–factor VIIa aptamer.149 These xenobiotics may have future clinical utility because their anticoagulant effects appear to be easier to control, and consequently safer, compared with the most commonly used anticoagulants.
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Although not yet approved, pegnivacogin is an RNA aptamer that inhibits factor IX and is undergoing human trials to evaluate its efficacy and safety. Several clinical trials are being conducted in healthy volunteers and patients with coronary artery disease.289,291 The effects of pegnivacogin mimic hemophilia B, also known as Christmas disease. By inhibiting factor IX, the conversion of factor X to factor Xa is inhibited.382 Studies show that approximately 1 mg/kg of pegnivacogin inhibits more than 99% of factor IX. Pharmacokinetic studies demonstrate a half-life of pegnivacogin to be approximately 100 hours with stable antithrombotic effects lasting for 30 hours.288,289 Similar to the heparins, pegnivacogin anticoagulation should be monitored with aPTT because previous studies have demonstrated that the degree of factor IX inhibition correlates well with aPTT.289 Unfortunately, despite its theoretical benefits, an unexpectedly high number of participants in the most recent clinical trial developed severe allergic reactions after pegnivacogin administration, causing the trial to be terminated early. In this study, pegnivacogin was being compared with bivalirudin in patients undergoing percutaneous coronary intervention (PCI). At the point of the trial’s termination, there was no obvious difference in reduction of bleeding compared with the bivalirudin group.222 Further studies demonstrated that these allergic reactions are the result of anti–polyethylene glycol antibodies.290 Because this aptamer is a synthetically tailored nucleic acid sequence, its antidote is easily manufactured. By creating a complementary aptamer that possesses a nucleic acid sequence that binds to pegnivacogin through Watson-Crick base pairing, it can effectively neutralize the original xenobiotic by creating an inactive complex. In fact, pegnivacogin is being studied in conjunction with anivamersen, the complementary aptamer to pegnivacogin.381
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The fibrinolytic system is designed to remove unwanted clots while leaving those clots protecting sites of vascular injury intact. Plasminogen exists as a proenzyme that is converted to the active form, plasmin, by plasminogen activators.74,75 The actions of plasmin are nonspecific in that it degrades fibrin clots and some plasma proteins and coagulation factors.395 Inhibition of plasmin occurs through α2-antiplasmin.395 Tissue plasminogen activator is released from the endothelium and is under the inhibitory control of two inactivators known as tissue plasminogen activator inhibitors 1 and 2 (t-PAI-1 and t-PAI-2).74,75,257,395 Under physiological conditions, endogenous t-PA does not induce a fibrinolytic state because there is no fibrin to initiate the conversion of plasminogen to plasmin. However, exogenous t-PA administration results in supraphysiological concentrations that promote a fibrinolytic state.395
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With their diverse indications in acute MI, unstable angina, arterial and venous thrombosis and embolism, and cerebrovascular disease, the thrombolytics are commonly used.27 Readers are referred to a number of reviews for specific indications and dosing regimens.84,208,280,341,395,401 Although all fibrinolytics enhance fibrinolysis, they differ in their specific sites of action and duration of effect. Tissue plasminogen activator is produced by recombinant DNA technology, and it is clot specific (ie, it does not increase fibrinolysis in the absence of a thrombus). Newer thrombolytics such as reteplase and tenecteplase possess longer half-lives that facilitate administration via bolus dosing rather than infusion.395 On the other hand, streptokinase, urokinase, and anistreplase are not clot specific. Tissue plasminogen activator has the shortest half-life and duration of effect (5 minutes and 2 hours, respectively) and anistreplase the longest (90 minutes and 18 hours, respectively).280,341 Streptokinase has the additional risk of potential severe allergic reaction on rechallenge, limiting its use to once in a lifetime. In fact, streptokinase is no longer used in the United States.
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Thrombolytics such as monteplase, lanoteplase, pamiteplase, and desmoteplase are used in other countries or are currently being evaluated for therapeutic use.228 These fibrinolytics have longer half-lives and are administered via single or repeated bolus injections. They also have increased fibrin selectivity but no apparent improvement in mortality compared with t-PA.184
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A number of contraindications preclude the use of fibrinolytics. Undesired bleeding occurs because of clot destruction at vascular compromised sites and destruction of coagulation factors from plasmin generation.395 Risk factors for bleeding, such as recent surgery or bleeding, known vascular lesions, malignancy, or prior intracranial hemorrhage, are contraindications for fibrinolytic administration.
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Clinical Manifestations
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Although the incidence of bleeding requiring transfusion is as high as 7.7% after high-dose (150 mg) t-PA and 4.4% after low-dose t-PA,84 the incidence of intracranial hemorrhage with t-PA appears to be similar to the newer fibrinolytics (monteplase, tenecteplase, reteplase, and lanoteplase).383 The addition of heparin to thrombolytic therapy increases the risk of bleeding. Reviews of multiple trials suggest that life-threatening events such as intracranial hemorrhage occur in 0.30% to 0.58% of patients receiving anistreplase, 0.42% to 0.73% of patients receiving alteplase, and 0.08% to 0.30% of patients receiving streptokinase.401 Regardless of the thrombolytic used, the frequency of bleeding events is similar, with the exception that lanoteplase has a decreased incidence of significant hemorrhage.93
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Patients with minor hemorrhage complications caused by the fibrinolytic agents should receive supportive care as necessary, with focus on volume replacement and attempts to control the bleeding if possible. However, for patients with significant bleeding such as intracranial hemorrhage, it is reasonable to administer fibrinogen and coagulation factor replacement with cryoprecipitate, FFP, or PCC.318 One study showed that after thrombolytic-induced intracranial hemorrhage, coagulopathy went untreated in 45% of cases.148 A recent study of 3,894 patients showed that the mortality rate associated with postfibrinolytic intracranial hemorrhage is up to 52%, and the rate of intracranial hematoma expansion is 26.8%. When studied, postfibrinolytic patients with expanding intracranial hematomas tended to have severe hypofibrinogenemia, highlighting the need for cryoprecipitate repletion.413 If fibrinogen and factor replacement are ineffective, then antifibrinolytics such as aminocaproic acid and tranexamic acid are recommended (Table 58–1). These fibrinolytics prevent activation of plasmin by competing with fibrin to bind to plasminogen and plasmin. Although a significant amount of fibrinolysis has already occurred, competitive inhibition of further plasmin-activated fibrinolysis is theoretically helpful in cases of life-threatening bleeding despite no clinical evidence available to show improved morbidity or mortality. Aminocaproic acid is also able to prevent the binding of t-PA to fibrin. Not only can these antifibrinolytics prevent fibrinolysis, but they can also reverse excessive fibrinolysis,318,395 although it is not well studied in the setting of fibrinolytic therapy.
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Aminocaproic acid is administered orally or intravenously. When administered intravenously, a loading dose of 4 to 5 g over 1 hour is followed by an infusion of 1 to 1.25 g/h with a maximum of 30 g given in 24 hours. The infusion should be stopped before 24 hours if the bleeding has ceased. Aminocaproic acid should not be given to patients with hematuria. These patients are at risk for developing obstructive AKI from ureteral clots that cannot be lysed. There are also rare reports of myopathy and muscle necrosis.395 Although theoretically, aminocaproic acid could reverse hemorrhage after fibrinolytic therapy, there are no case reports or studies supporting its use in this situation.
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Tranexamic acid is also reasonable to administer orally or intravenously. It is currently approved for the treatment of menorrhagia and is dosed at 1 g orally four times a day for four days.395 It is also used in hemophiliac patients undergoing cardiac surgery. However, recent studies received significant attention for the use of tranexamic acid in patients with traumatic hemorrhage. The CRASH-2 study, a multicentered randomized controlled trial evaluating outcomes of patients receiving tranexamic acid with traumatic bleeding found that infusion of 1 g over 10 minutes, followed by 1 g over 8 hours, resulted in a significant reduction in mortality rate. In addition, the risk of arterial thrombosis, as well as fatal and nonfatal thrombosis, was significantly reduced compared with control participants who received placebo.305 A case report describes the successful use of tranexamic acid in a patient who developed an intracranial hemorrhage after thrombolytic therapy. After receiving 1.675 g of IV tranexamic acid, repeat computed tomography and magnetic resonance imaging of the brain revealed no hematoma expansion, and the patient did not develop any thrombotic complications.127 In the Japanese Observational Study for Coagulation and Thrombolysis in Early Trauma (J-OCTET) study, early administration of tranexamic acid resulted in lower rates of mortality, including in the subset of patients with primary brain injury.336 An additional study demonstrates that tranexamic acid also has a protective effect on gut barrier function, particularly in ischemia-reperfusion injuries.99
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Unfortunately, aminocaproic acid and tranexamic acid are associated with generalized tonic-clonic seizures in up to 7.6% of patients. The precise mechanism of seizures is not known. In murine studies, competitive antagonism of glycine receptors is suggested. When the mice were treated with isoflurane and propofol, seizure activity ceased.211
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In summary, patients with severe bleeding, such as intracranial hemorrhage, after t-PA administration, replacement of coagulation factors and fibrinogen is recommended as soon as possible. While there are no significant studies using tranexamic acid or aminocaproic acid in factor and fibrinogen replacement failure, in patients who are gravely ill, tranexamic acid and aminocaproic acid could theoretically help decrease bleeding if all other measures fail. Because mortality rates in this population are so high, it is reasonable to recommend this intervention despite the lack of evidence.
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Under normal conditions, vascular endothelium provides thromboregulators that prevent thrombus formation. When the endothelium becomes compromised, exposed collagen triggers two cascades of events to promote platelet aggregation. First, a tissue factor–mediated pathway indirectly activates platelets. Tissue factor, either from the damaged vessel wall or carried in the blood, complexes with factor VIIa and activates factor IX and the extrinsic pathway of the coagulation cascade. Thrombin then directly stimulates further platelet adhesion.134 Second, when von Willebrand factor (vWF) adheres to the exposed endothelium, platelet GP Ib-V-IX binds to the vWF and anchors platelets to the site of vascular injury. In addition, platelet GP VI and Ia tether the platelets to exposed collagen90,134,200 (Fig. 58–4).
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After platelet adhesion, modulators such as ADP and thromboxane A2 (TXA2) maintain platelet activation.90,134,395 Intracellular signaling results in the release of arachidonic acid (AA) via phospholipase A2. Next, AA is converted into prostacyclin via cyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2). This stimulates the production of TXA2, which further propagates platelet activation and aggregation90,182 (Fig. 58–5).
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These mediators recruit more platelets to the area of vessel injury. Glycoprotein IIb/IIIa is expressed on the surface of the platelets and allows platelet cross-linking via this receptor with vWF acting as a bridge.90,134
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Thrombus formation perpetuates platelet aggregation and adhesion to the vessel wall. Platelet GP IIb/IIIa activation results in further thrombus formation by binding fibrinogen and vWF, essential to the linking of platelets.90
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Antiplatelet therapies aim to decrease platelet activation or aggregation by inhibiting one of the steps in the many pathways, leading to GP IIb/IIIa activation of platelets.
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CYCLOOXYGENASE INHIBITORS
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Widespread use of aspirin as an antiplatelet drug is associated with significantly decreased vascular events. Aspirin acetylates the COX-1 enzyme, prevents substrate binding to the enzyme, and results in irreversible inhibition of TXA2 generation. Daily low-dose aspirin fully inhibits COX-1 function and subsequent platelet aggregation because platelets are unable to regenerate COX-1.109 However, although aspirin irreversibly inhibits COX-2, larger doses of aspirin are required to decrease COX-2–mediated processes because of rapid synthesis of new COX-2.109
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Aspirin dosed between 75 and 150 mg showed the best odds reduction in preventing MI and stroke compared with other doses.12,109 In fact, high-dose aspirin causes inhibition of other downregulators of platelet adhesion such as endothelium-derived prostacyclin. Although effective in preventing vascular events, the risks of bleeding and GI irritation are real. In a randomized trial comparing low dose (70–150 mg/d) and standard-dose (300–325 mg/d) aspirin in patients with acute coronary syndrome, standard-dose aspirin conferred an increased risk of GI bleeding without significant additional cardiovascular benefit.177 However, even daily low-dose aspirin resulted in a significantly increased risk of GI bleeding compared with nonaspirin use, but this risk is outweighed by the benefits of cardiovascular disease and stroke prevention.394
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CYCLIC ADENOSINE MONOPHOSPHATE MODULATORS
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Phosphodiesterase Inhibitors
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Cilostazol is a phosphodiesterase inhibitor marketed for the treatment of intermittent claudication secondary to peripheral vascular disease (PVD). By increasing cyclic adenosine monophosphate (cAMP), vasodilation is achieved by inhibiting myosin light-chain kinase, essential for smooth muscle contraction. Additionally, cAMP inhibits platelet aggregation. Small trials demonstrate that cilostazol improves walking distances, decreases arterial thrombosis, and improves rethrombosis rates in patients with PVD. In the Cilostazol for Prevention of Secondary Stroke (CSPS) study, cilostazol was not inferior to aspirin in preventing secondary stroke. However, because of its common GI adverse effects and headache, a high rate of discontinuation precludes this xenobiotic from being more widely used.109
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Adenosine Reuptake Inhibitors
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Dipyridamole has antiplatelet properties, although its mechanism of action is not completely known. Evidence suggests that by inhibiting degradation of cAMP and by blocking adenosine reuptake, intracellular cAMP accumulates and inhibits platelet aggregation.109,395 Dipyridamole also has antiinflammatory properties by decreasing monocyte gene expression of chemokines.400 Dipyridamole 200 mg is marketed alone or in combination with 25 mg of aspirin (Aggrenox).
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Randomized studies demonstrate a significant reduction in stroke in high-risk patients taking dipyridamole with aspirin compared with patients taking aspirin alone. However, many patients discontinue dipyridamole because of headache.101,157 Unfortunately, compared with clopidogrel, dipyridamole and aspirin offer no improvement in stroke prevention and an increase in the risk of major bleeding.313
+++
ADENOSINE DIPHOSPHATE RECEPTOR INHIBITORS
++
Platelets require stimulation of P2Y1 and P2Y12, ADP receptors, to inhibit adenyl cyclase. Cyclic AMP formation decreases as a result of the inhibition of adenyl cyclase, and the platelet loses its ability to activate. Clopidogrel, prasugrel, ticagrelor, cangrelor, and ticlopidine are ADP receptor inhibitors. By increasing cAMP concentrations through inhibition of the P2Y12 receptor, these xenobiotics are able to inhibit platelet activation.109,395
++
Ticlopidine is a first-generation ADP receptor inhibitor. It is typically taken orally at 250 mg twice daily. Despite its rapid absorption with peak plasma concentrations between 1 and 3 hours, peak platelet inhibition occurs 1 week after initiation. Two of the many metabolites are noted to have significantly stronger ADP receptor inhibitor activity than the parent drug. Ticlopidine does not confer an overall reduction of cardiovascular death, stroke, or MI risk,141 but coadministration with aspirin decreases stent thrombosis in some situations.216
++
The relatively high risk of neutropenia and the risks of agranulocytosis, thrombocytopenia, and thrombotic thrombocytopenic purpura–hemolytic uremic syndrome and the development of newer generation ADP receptor inhibitors have rendered the use of ticlopidine nearly obsolete.109,395
++
Clopidogrel irreversibly binds and inhibits ADP receptors. Maximal platelet inhibition is achieved between day 4 and 7 after initiation of maintenance doses but occurs 2 to 4 hours after a 600-mg loading dose.109 Clopidogrel requires conversion via CYP2C19 to form its active metabolite. Up to one-third of patients are resistant to clopidogrel. Many of these patients possess a CYP2C19 genetic polymorphism that results in loss of function, and these patients have an increased risk of major cardiovascular adverse events, especially after coronary artery stenting.109,244 Similarly, concomitant administration of medications that inhibit numerous CYP enzymes may result in decreased efficacy. Further studies are required to determine if dosing modification may improve efficacy in preventing adverse vascular events. 109
++
Clopidogrel is dosed at 75 mg/day. It is commonly administered with aspirin as numerous studies, such as the CREDO, COMMIT, and CLARITY trials, demonstrate that dual antiplatelet therapy to be beneficial in the reduction of vascular events.67,312,352 However, in the ACTIVE trials, warfarin was superior to dual antiplatelet therapy with aspirin and clopidogrel in preventing major vascular events.78 The risk of bleeding remains a major concern associated with the use of clopidogrel, particularly in dual antiplatelet regimens.67,83
++
Another ADP receptor inhibitor, prasugrel, similarly requires conversion to an active metabolite, which occurs within 30 minutes of dosing. CYP2C19 inhibition or concomitant proton pump inhibitor administration does not alter efficacy. A head-to-head comparison of prasugrel and clopidogrel in patients undergoing coronary artery intervention found a decreased incidence of overall vascular adverse outcomes and death and stent thrombosis in patients on prasugrel but no improvement in overall morbidity, mortality, or bleeding events.109,406
++
Cangrelor, approved in 2015, is another ADP receptor inhibitor with rapid onset of action. It has a short half-life, between 2.6 to 3.3 minutes.8 Rates of adverse events such as severe bleeding are favorable compared with clopidogrel when used during PCI.33
++
Ticagrelor is the newest of the ADP receptor inhibitors that exerts its effects by allosterically and reversibly inhibiting the ADP receptor. Absorption is rapid with peak plasma concentrations in approximately 2.5 hours.362 Dosing of ticagrelor includes a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily. The mortality and morbidity associated with ticagrelor has been compared with many other antiplatelet agents. Numerous studies delineate the risks of bleeding, in particular, based on antiplatelet therapy.41,42,258,385
+++
GLYCOPROTEIN IIb/IIIa INHIBITORS
++
Three GP IIb/IIIa inhibitors are available for use with patients with acute coronary syndromes. Abciximab is a monoclonal Fab antibody that binds the GP IIb/IIIa receptor. When administered with heparin and aspirin in patients undergoing coronary artery intervention, stent thrombosis, MI, and mortality all decrease. Abciximab is administered as an IV bolus dose of 0.25 mg/kg is followed by an infusion of 0.125 mg/kg/min. The plasma half-life is short, with plasma concentrations becoming negligible approximately 30 minutes after cessation of the infusion. However, the Fab fragments bind to the platelets and inhibit platelet function for up to 24 hours.395
++
Eptifibatide is a synthetic GP IIb/IIIa inhibitor used in patients with acute coronary syndrome undergoing coronary artery interventions. Its molecular structure is based on snake venom disintegrin. An IV loading dose of 180 mcg/kg is followed by an infusion of 2 mcg/kg/min.395 Dosing in patients with CKD is unstudied, but there is a demonstrable increase in rates of bleeding in patients with a creatinine clearance less than 60 mL/min.298 Tirofiban also inhibits the GP IIb/IIIa receptor and has similar clinical efficacy compared with eptifibatide.395
++
Up to 10% of patients treated with GP IIb/IIIa inhibitors have major bleeding events. Thrombocytopenia can also occur as a result of antigenic recognition of the xenobiotic-bound platelets.109
++
A number of trials examining the efficacy and safety of the GP IIb/IIIa inhibitors describe positive trends in decreasing predefined endpoints such as 30-day mortality, stent rethrombosis, and MI. After evaluation of the combined data from multiple trials, the benefits of GP IIb/IIIa inhibitor therapy without early coronary artery revascularization are unclear when weighing the risks of bleeding. However, with early coronary artery revascularization, adding a GP IIb/IIIa inhibitor is beneficial, although the benefit of treatment in the highest risk patients is uncertain.92,109
+++
DEVELOPMENT OF NOVEL RECEPTOR AND ENZYME INHIBITORS
++
Recent pharmaceutical development has focused on inhibition of several key enzymes or receptors in platelet activation and aggregation. Thromboxane A2 function is inhibited by TXA2 synthase inhibitors or by antagonizing the TXA2 receptor. Clinical trials are currently underway to evaluate the efficacy of inhibiting protease-activated receptors, also called thrombin receptors.361
+++
Laboratory Assessment
++
Bleeding time is traditionally the most useful and widely available used to assess platelet function. However, its popularity has decreased because of its insensitivity, invasiveness, scarring, and high degree of variability. A variety of platelet function assays exist, but few are widely available. The gold standard assay, light transmission aggregometry, is commonly used in specialty laboratories, but it does not reflect physiologic platelet adhesion or aggregation. Furthermore, this test is time consuming and expensive. Several widely used tests to assess platelet function, such as flow cytometry and serum TXA2 assay, are available. Each of these tests has significant disadvantages such as being artifact prone, expensive, nonspecific, or insensitive to select antiplatelet agents. In addition, extrapolating these results to determine a patient’s risk of bleeding or thrombosis is not possible.163
++
When managing bleeding in patients taking antiplatelet xenobiotics, blood transfusion should be used in patients with significant blood loss. However, transfusion of PRBCs will not increase platelet adhesion or aggregation. Unfortunately, the published literature that assesses interventions on bleeding patients maintained on antiplatelet xenobiotics is conflicting, and there is no clear consensus on appropriate reversal strategies and agents. The most widely evaluated intervention is platelet transfusion. The existing studies are small and mostly retrospective. Prospective studies are biased by nonrandomization, specifically by the clinician ultimately deciding whether to transfuse the platelets. Many of these studies show that platelet transfusion is potentially harmful and independently predict increased mortality and bleeding (Table 58–1).21,61 Although transfusing platelets is associated with worse outcomes, it is important to notice that these studies only demonstrate association and not causation. Therefore, blood transfusion to replace lost volume and coagulation factors is reasonable. It is also reasonable to administer platelets to patients in extremis, such as those requiring massive transfusion caused by extensive blood loss.
++
Desmopressin is approved for the treatment of inherited defects of hemostasis and potentiates thrombosis by releasing vWF and factor VIII from the endothelium into the plasma. In these patients, complications such as arterial thrombosis and MI are reported after desmopressin administration.207,218 However, some proposed protocols for reversing antiplatelet xenobiotics in the setting of life-threatening bleeding include desmopressin. Most of these protocols are based on case reports because the majority of the studies evaluated prophylactic desmopressin before surgery to prevent blood loss. A single study evaluated the administration of desmopressin on platelet aggregation and platelet activity in healthy volunteers given a single dose of clopidogrel. They found that platelet reactivity and platelet aggregation increased after desmopressin administration. There was no mention of adverse outcomes in any of the study participants.214 The risk of desmopressin-induced thrombosis in patients taking antiplatelet xenobiotics is unknown; in patients taking antiplatelet medications for atherosclerosis, the risk of thrombosis is greater.214 There is not enough information to routinely recommend the use of desmopressin in this setting at this time.
++
In the case of abciximab, cessation of the infusion results in a rapid decrease in circulating antibodies. If severe bleeding occurs, platelet transfusion after discontinuation of the infusion is effective in restoring platelet activation and aggregation.395 In most cases, discontinuation of eptifibatide and tirofiban results in restoration of normal platelet function within hours. However, patients with renal dysfunction have prolonged platelet inhibition. Both of these xenobiotics are renally cleared, and some have suggested hemodialysis as a means to enhance clearance.360 Although not formally studied, case reports of patients with protracted platelet inhibition in the setting of eptifibatide use and end-stage CKD suggest that hemodialysis restores platelet aggregation capacity.343 However, there are insufficient data at this time to routinely recommend this intervention, especially because initiating hemodialysis typically takes several hours, during which time platelet function typically improves. Unlike abciximab platelet toxicity, transfusion of platelets to patients receiving eptifibatide is believed to be ineffective in restoring platelet function. At therapeutic concentrations, the concentration of these xenobiotics far outnumbers the inhibited GP IIb/IIIa receptors by several orders of magnitude.360 Further studies are required to produce recommendations or guidelines for emergent reversal of antiplatelet xenobiotics to determine if any interventions are effective and offer a favorable risk-to-benefit profile. In the meantime, clinicians should volume resuscitate accordingly with fluids and blood products as necessary.
++
A detailed discussion of snake envenomations is found in Chap. 119 and Special Considerations: SC10; only a few specific issues are discussed here. Snake venoms are composed of a vast number of complex proteins and peptides that interact with components of the human hemostatic system. In general, their functions may be thought of as being procoagulant, anticoagulant, fibrinolytic, vessel wall interactive, platelet active, or as protein inactivators. Additionally, they are more specifically classified based on their specific biologic activity; some of the various mechanisms include individual factor activation, inhibition of protein C and thrombin, fibrinogen degradation, platelet aggregation, and inhibition of serine protease inhibitors (SERPINS). Currently, more than 100 different snake venoms affect the hemostatic system.178,179
++
Figure 58–1 is an overview of their multiple interactions with the coagulation and fibrinolytic systems.236
++
Some of these venom proteins are being used as therapeutically for human diseases. Ancrod, a purified derivative of the Malayan pit viper, Calloselasma rhodostoma (formerly known as Agkistrodon rhodostoma), is therapeutically used because of its defibrinogenating property.25 The mechanism of action of ancrod and other similar xenobiotics is to link fibrinogen end to end and subsequently prevent cross-linking. It is under investigation for the treatment of DVT, MI, PE, acute cerebrovascular thrombosis, HITT, and warfarin-related vascular complications. In a multicenter study of 500 patients with acute or progressing ischemic neurologic events, ancrod showed a favorable benefit-to-risk ratio compared with placebo.333 As expected, an increased risk of bleeding is observed; however, the risk is less than that with thrombolytics.333 Monitoring of fibrinogen concentrations is essential to avoid potential complications because no specific antidote exists. Following envenomation, snakes such as those of the Crotalinae family that induce bleeding, antivenin treatment is indicated.
++
The development of new antithrombotics and the increasing frequency of antithrombotic therapeutic use are associated with complications and adverse outcomes.
A complete understanding of the normal mechanisms of coagulation, anticoagulation, and thrombolysis combined with an understanding of the pharmacology of the xenobiotic and the clinical needs of the patient will allow clinicians to better choose among the complex therapies currently available.
Complications of the antithrombotics should be managed with supportive care, starting with volume resuscitation and blood replacement.
More aggressive interventions and specific reversal therapeutics are necessary depending if the patient is experiencing severe, life-threatening hemorrhage. In these instances, clinical studies do not always ensure a favorable risk-to-benefit profile because further studies are required.
Ongoing development of new antithrombotics will raise new challenges for clinicians as adverse outcomes and bleeding complications arise, and new antidotes will be developed to address these issues.
++
Theresa Kierenia, MD (deceased), and Robert S. Hoffman, MD, contributed to this chapter in previous editions.
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