Fibrinolytic Agents

The generation of plasmin from plasminogen by plasminogen activators (fibrinolytic agents) induces a variety of effects in addition to dissolving fibrin strands, degrading fibrinogen, and inhibiting tissue factor pathway and factor VIII. It also, in high concentrations, causes platelet activation. Thus, fibrinolytic agents have both prothrombotic and antihemostatic properties—the latter of which is often augmented by the concomitant use of anticoagulants and platelet antagonists (see Chapter 12). Bleeding is the most common complication of fibrinolytic (and adjunctive antithrombotic) therapy. The most important predictors of nonintracranial hemorrhage are older age, invasive procedures, low body weight, and female sex (de Jaegre et al, 1992; GISSI 2 Investigators, 1990; GUSTO-III Investigators, 1997; INJECT Investigators, 1995). Predictors of intracranial hemorrhage include age (>65 years), low body weight (<70 kg), hypertension on admission, and alteplase (vs. streptokinase) (GUSTO-III Investigators, 1997). The approach to patient management in cases of fibrinolytic-induced bleeding is summarized in Figure 30.1. It is important to consider antithrombotic agents that may concomitantly increase hemorrhagic potential. Factor VIIa (recombinant; NovoSeven) represents a treatment alternative for life-threatening hemorrhagic complications.

Anticoagulation Clinics and Self-Testing

Oral anticoagulation is a time-tested and effective therapy for patients at risk for thromboembolism (Ansell, 1993). Because of the high risk–benefit ratio of oral vitamin K antagonists, physicians are sometimes reluctant to initiate therapy even for well-established indications (Kutner et al., 1991; McCrory et al., 1995). Furthermore, management is recognized as labor intensive. These factors can be minimized and the benefits of treatment maximized by implementation of an expert model of management that can be achieved with a coordinated and focused system of care known as a coordinated anticoagulation clinic (Ansell and Hughes, 1996). Patient self-testing (and management) may also foster more wide-scale and effective treatment of thromboembolic disorders. The concept of a coordinated anticoagulation clinic (ACC) is not new. Programs focusing on the management of oral anticoagulation have existed in the United States since the late 1950s, and several Scandinavian and other European countries are well known for their coordinated programs (Loeliger et al., 1984), some of which oversee the care of all anticoagulated patients in their respective countries. In the United States, ACCs are growing in number and diversity of services, spurred on by increasing evidence of improved clinical outcomes and cost-effectiveness. The basic elements of a coordinated ACC include (1) a manager or team leader (physician, pharmacist), (2) support staff (nurse practitioner, pharmacist, or physician assistant), (3) standardized record keeping and a computerized database, (4) a manual of operation and practice guidelines, and (5) a formal mechanism for communicating with referring physicians and patients. Currently, most oral anticoagulation therapy in the United States is managed by a patient’s personal physician. In essence, the monitoring and dose titration of patients with thromboembolic disease represents a relatively small proportion of the physician’s overall clinical practice. This approach can be characterized as “traditional” or routine medical care. There may be no specialized system or guidelines in place to track patients or ensure their regular follow-up. An ACC uses a focused and coordinated approach to managing anticoagulation (Ansell et al., 1997).

Platelet Antagonists

Platelet antagonists play an important role in both primary and secondary prevention of atherothrombotic events. Despite their proven benefit, individual response (and protection) varies considerably, emphasizing the importance of developing monitoring tools (tested prospectively in clinical trials) that can better determine the degree of platelet inhibition that is both safe and effective. Platelet function studies were developed originally for the evaluation of patients with unexplained bleeding and have contributed greatly to the understanding, diagnosis, and management of hereditary abnormalities such as von Willebrand disease and Glanzmann’s thrombasthenia (platelet glycoprotein [GP] IIb/IIIa receptor deficiency). Although conventional platelet function studies (turbidimetric aggregometry) have technical limitations that preclude their routine use for gauging antithrombotic therapy, they may provide guidance when hemorrhagic complications arise and in determining pretreatment risk in individuals suspected of having an intrinsic platelet abnormality. The bleeding time, considered an indicator of primary hemostasis (platelet plug formation), is defined as the time between making a small standardized skin incision and the precise moment when bleeding stops. The test is performed with a template, through which the medial surface of the forearm is incised under 40 mmHg standard pressure. A normal bleeding time is between 6 and 10 minutes. Although considered a “standardized” test of platelet function, the bleeding time can be influenced by a variety of factors, including platelet count, qualitative abnormalities, and features intrinsic to the blood vessel wall (George and Shattil, 1991). Platelet adhesion is the initiating step in primary hemostasis. Although platelet binding is an important component of this process, there are many others, including blood flow rate, endothelial cell function, adhesive proteins, and the subendothelial matrix. The original test used for assessing adhesion, platelet retention, was based on adherence to glass bead columns. The current laboratory evaluation of platelet function is based predominantly on turbidimetric platelet aggregometry (also known as light transmission aggregometry). This test is performed by preparing platelet-rich plasma (with platelet-poor plasma as a control) and eliciting an aggregation response with adenosine diphosphate, epinephrine, collagen, arachidonic acid, and ristocetin (Born, 1962).

Fundamentals and Patient Evaluation

Thrombophilia is the term used to describe a tendency toward developing thrombosis. This tendency may be inherited, involving polymorphism in gene coding for platelet or clotting factor proteins, or acquired due to alterations in the constituents of blood and/or blood vessels. An inherited thrombophilia is likely if there is a history of repeated episodes of thrombosis or a family history of thromboembolism. One should also consider an inherited thrombophilia when there are no obvious predisposing factors for thrombosis or when clots occur in a patient under the age of 45. Repeated episodes of thromboembolism occurring in patients over the age of 45 raise suspicion for an occult malignancy. A summary of inherited thrombophilias are summarized in Table 24.1. This list continues to grow, as new genetic polymorphisms and combined mutations are being detected. The prevalence of common thrombophilias is shown in Figure 24.1. Factor V Leiden (FVL) mutation and hyperhomocysteinemia are present in nearly 5% of the general population and are often found in patients with venous thrombosis, while deficiencies of antithrombin (AT), protein C, and protein S are relatively uncommon. Elevated levels of factor VIII (FVIII) are uncovered frequently in the general population and in patients with thrombosis. This is not surprising as FVIII is an acute-phase reactant that increases rapidly after surgery or trauma; however, prospective studies have shown that FVIII elevation in some patients cannot be attributed to a stress reaction and probably represents mutations in the genes regulating FVIII synthesis or release (Kyrle et al., 2000). The same may be true for factors IX and XI. The relative risks for thrombosis among patients with inherited thrombophilias have been determined. While AT mutations are the least common, they are associated with a substantial risk of venous thrombosis; similar risk is seen with protein C and S deficiency. In contrast, the lifetime risk of having a thromboembolic event in an individual heterozygous for FVL is comparatively low (Martinelli et al., 1998). Incidence rates markedly increase with age, and are highest among those with AT deficiency, followed by protein C and protein S, and least with FVL.

Venous Thromboembolism Prophylaxis

Venous thromboembolism represents a true worldwide medical problem that is encountered within all realms of practice. Venous thromboembolism (VTE) occurs in approximately 100 patients per 100,000 population yearly in the United States and increases exponentially with each decade of life (White, 2003). Approximately one-third of patients with symptomatic deep vein thrombosis (DVT) experience a pulmonary embolism (PE). Death occurs within 1 month in 6% of patients with DVT and 12% of those with PE. Early mortality is associated strongly with presentation as PE, advanced age, malignancy, and underlying cardiovascular disease. An experience dating back several decades has provided a better understanding of disease states and conditions associated with VTE (Anderson and Spencer, 2003). Given the potential morbidity and mortality associated with VTE, it is apparent that prophylaxis represents an important goal in clinical practice. A variety of anticoagulants including unfractionated heparin, low-molecular-weight heparin (LMWH), and warfarin have been studied. More recently, two new agents have been developed that warrant discussion. Fondaparinux underwent a worldwide development program in orthopedic surgery for the prophylaxis of VTE. The program consisted mainly of four large, randomized, double-blind phase II studies comparing fondaparinux (SC), at a dose of 2.5 mg starting 6 hours postoperatively, with the two enoxaparin regimens approved for VTE prophylaxis—40 mg qd or 30 mg twice daily beginning 12 hours postoperatively. The results support a greater protective effect with fondaparinux, yielding a 55.2% relative risk reduction of VTE (Bauer et al., 2001; Eriksson et al., 2001; Lassen et al., 2002; Turpie et al., 2001, 2002; ). A European program of three large-scale clinical trials (MElagatran for THRombin inhibition in Orthopedic surgery [METHRO] I, II, and III, and EXpanded PRophylaxis Evaluation Surgery Study [EXPRESS]) (Eriksson et al., 2002a, b, 2003a, b) evaluated the safety and efficacy of subcutaneous melagatran followed by oral ximelagatran compared with LMWH for thromboprophylaxis following total hip replacement (THR) and total knee replacement (TKR) surgery.

Direct Thrombin Inhibitors

The pivotal role of thrombin in all phases of coagulation, cellular proliferation, and cellular interactions involved centrally in inflammatory processes provides an attractive target for pharmacologic inhibition. The development of direct thrombin inhibitors has evolved rapidly to include both intravenous and oral preparations. Hirudin is extracted from the parapharyngeal gland of the medicinal leech Hirudo medicinalis. Several derivatives and recombinant preparations have been developed, including the most widely used agent lepirudin (Refludan). Hirudin binds to both the catalytic and fibrinogen-binding sites of thrombin and thus is considered a bivalent inhibitor. The plasma half-life of hirudin is 50 to 65 minutes, with a biologic half-life of 2 hours (Verstraete et al., 1993). The properties of heparin, hirudin, and bivalirudin are highlighted in Table 16.1. The predominant renal clearance of hirudin must be emphasized for safe clinical use. Hirudin forms a tight complex with thrombin, inhibiting the conversion of fibrinogen to fibrin as well as thrombin-induced platelet aggregation (Verstraete, 1997). These actions are independent of the presence of antithrombin, and also affect thrombin bound to fibrin. On the downside, the ability of thrombin to complex with thrombomodulin, activating protein C, is also inhibited. Hirudin does not bind to platelet factor , nor does it elicit antibodies that induce platelet and endothelial cell activation; thus, it can be safely administered to patients with heparin induced thrombocytopenia (HIT). Hirudin does have weak immunogenicity, so diminished (or rarely increased) responsiveness after repeated dosing is possible. The use of hirudin in the management of heparin-induced thrombocytopenia is discussed in Chapter 29.

Clopidogrel

Clopidogrel, a thienopyridine derivative, is a novel platelet antagonist that is several times more potent than ticlopidine but associated with fewer adverse effects. After repeated 75-mg oral doses of clopidogrel, plasma concentrations of the parent compound, which has no platelet-inhibiting effect, are very low. Clopidogrel is extensively metabolized in the liver. The main circulating metabolite is a carboxylic acid derivative with a plasma elimination half-life of 7.7 ± 2.3 hours. Approximately 50% of an oral dose is excreted in the urine and the remaining 50% in feces over the following 5 days. Dose-dependent inhibition of platelet aggregation is observed 2 hours after a single oral dose of clopidogrel, with a more significant inhibition achieved with loading doses (≥300 mg) by approximately 6 hours. Repeated doses of 75 mg of clopidogrel per day inhibit adenosine diphosphate (ADP)-mediated aggregation, with steady state being reached between day 3 and day 7. At steady state, the average inhibition to ADP is between 40% and 60%. Based on ex vivo studies, clopidogrel is approximately 100-fold more potent than ticlopidine. There are no cumulative antiplatelet effects with prolonged oral administration. The combined administration of clopidogrel (300 mg loading dose) and aspirin yields a readily discernible platelet-inhibiting effect within 90 to 120 minutes. Clopidogrel selectively inhibits the binding of ADP to its platelet receptor (P2Y12) and the subsequent G-protein–linked mobilization of intracellular calcium and activation of the glycoprotein (GP)IIb/IIIa complex (Gachet et al., 1992). The specific receptor has been cloned and is abundantly present on the platelet surface (Hollopter et al., 2001). Clopidogrel has no direct effect on cyclooxygenase, phosphodiesterase, or adenosine uptake. Clopidogrel is rapidly absorbed following oral administration with peak plasma levels of the predominant circulating metabolite occurring approximately 60 minutes later. Administration with meals does not significantly modify the bioavailability of clopidogrel. The available information suggests that clopidogrel offers safety advantages over ticlopidine, particularly with regard to bone marrow suppression and other hematologic abnormalities. Although thrombotic thrombocytopenic purpura (TTP) has been reported with clopidogrel (Bennett et al., 2000), its occurrence (11 cases per 3 million patients treated) is rare, and has not been reported in randomized clinical trials performed to date.

Venous Thromboembolism

Blood clotting within the venous circulatory system, in contrast to arterial thrombosis, occurs at a relatively slow pace in response to stagnation of flow (stasis) and activation of coagulation. As with arterial thrombosis, vascular injury, either direct in the setting of trauma or indirect as a diffuse, systemic inflammatory response (that ultimately causes endothelial cell damage), represents an important stimulus. Venous thrombi are intravascular deposits composed predominantly of erythrocytes and fibrin, with a variable contribution of platelets and leukocytes. In a majority of cases, thrombosis begins in areas of slow flow within the venous sinuses of valve cusp pockets either in the deep veins of the calf or upper thigh or at sites of direct injury following trauma (Kakkar et al., 1969; Nicolaides et al., 1971). Stasis predisposes to thrombosis most profoundly in the setting of inflammatory states and activated coagulation factors. Slowed blood flow impairs the clearance of coagulation proteases, which through bioamplification increases the local concentration of thrombin substrate. If local thromboresistance is impaired, as may be the case with inherited or acquired thrombophilias (see Chapter 24), thrombosis occurs. Blood flow velocity is reduced by indwelling catheters, which also causes focal endothelial injury, peripheral edema, pregnancy, and valve cusp damage from prior venous thrombosis and/or chronic venous insufficiency (Trottier et al., 1995). Although venous thrombosis can occur in a variety of sites, the most common encountered in clinical practice is within the deep veins of the lower extremity. Thrombi developing within the veins of the calf or thigh can serve as a nidus for growth (propagation), which may cause complete venous obstruction, or embolize to the lungs (pulmonary embolism).

Vascular Biology, Thromboresistance, and Inflammation

The delivery of vital substrate to metabolically active tissues and vital organs is achieved and maintained by the cardiovascular system including the heart, macrovasculature, and microvasculature. This life-sustaining process requires a normally functioning vascular endothelium—a multifunctional organ system composed of physiologically responsive cells responsible for vasomotion (vascular tone), thromboresistance, and inflammoresistance. Simply by virtue of its anatomic location, the vascular endothelium is functionally complex. It defines the intra- and extravascular components, serves as a selectively permeable barrier, and provides a continuous lining to the cardiovascular system. The location of the vascular endothelium is vital to its biologic interactions with cells found within the circulation and to the vessel wall itself. The surface activity is augmented in the microcirculation, also known as the resistance bed, where the ratio of endothelial surface to circulating blood is maximal. In most vertebrates, vascular endothelial cells form a single layer of squamous lining cells (0.1–0.5 μm in thickness) joined by intercellular junctions. The cells themselves are polygonal (varying between 10 and 50 μm) and are positioned in the long axis of the vessel, orienting the cellular longitudinal dimension in the direction of blood flow. The endothelial cell has three surfaces: luminal (nonthrombogenic), subluminal (adhesive), and cohesive. The luminal surface is devoid of electron-dense connective tissue. It does, however, possess an exterior coat (or glycocalyx), consisting primarily of starches and proteins secreted by the endothelial cells. Plasma proteins, including lipoprotein lipase, α2-macroglobulin, heparin cofactor II, antithrombin, and albumin, as well as small amounts of fibrinogen and fibrin are adsorbed to the luminal surface. The surface membrane itself adds significantly to thromboresistance by carrying a negative charge that repels similarly charged circulating blood cells. The subluminal (or abluminal) surface adheres to subendothelial connective tissues. Small processes penetrate through a series of internal layers to form myoendothelial junctions with subjacent smooth muscle cells. The cohesive component of the vascular endothelium connects individual endothelial cells to one another by cell junctions of two basic types: occluding (tight) junctions and communicating (gap) junctions. Occluding junctions represent a physical link between adjacent cells, sealing the intercellular space.

Anticoagulants

Anticoagulant therapy, particularly when used in combination with fibrinolytics and less often platelet antagonists, can cause life-threatening hemorrhage. This supports the importance of coagulation proteases in several phases of thrombus development; paradoxically, several anticoagulants can also cause microvascular and macrovascular thrombotic disorders. Hemorrhage is the most common adverse effect associated with warfarin administration. To predict the risk of bleeding, Beyth and colleagues (1998) developed a 5-point scoring system, with 1 point given for each of the following: . . . • Age greater than 65 . . . . . . • History of stroke . . . . . . • History of gastrointestinal bleeding . . . . . . • Specific comorbid conditions (recent myocardial infarction [MI], elevated serum creatinine, hematocrit <30%, or diabetes) . . . Low-risk patients have a score of 0; intermediate-risk patients, 1 or 2; and high-risk, 3 or 4. The risk of bleeding in these three groupings at 12 months was 3%, 8%, and 30%, respectively. Many commonly used medications have significant interactions with warfarin. In 1994, Wells and colleagues (1994) reviewed all reports of warfarin–drug interactions and found original reports totaling 186. Potentiation of warfarin effect was observed with six antibiotics, five cardiac drugs, two antiinflammatory agents, two histamine2-blockers, and alcohol in persons with concomitant liver disease. Inhibition of warfarin effect was noted with three antibiotics, three central nervous system (CNS) drugs, cholestyramine, and sucralfate. An important interaction between acetaminophen and warfarin has also been recognized (Hylek et al., 1998), and certain herbal remedies, such as ginkgo biloba, ginseng, and garlic, may enhance the effects of warfarin. The first step in the management of bleeding is to stop the drug; however, recovery of clotting factor levels may take several days, depending upon the vitamin K content of the patient’s diet and rate of intrinsic metabolism. To rapidly raise coagulant factor concentrations in patients with life-threatening hemorrhage, clotting factor concentrates are given (Makris et al., 1997). The older concentrates were plasma-derived and consisted mainly of activated prothrombin complex factors. They had the disadvantages of thrombogenicity and potential for transmission of infectious agents.