Prophylaxis of Venous and Arterial Thromboembolism

Venous thromboembolism remains a major cause of death and disability among hospitalized patients. Recent estimates suggest that > 250,000 cases are diagnosed yearly in acute care hospitals, with as many, if not more, cases going unrecognized. Some believe that the incidence of venous thromboembolism may be higher, perhaps twice as high, in rehabilitation centers and nursing homes.

DVT and pulmonary embolism are particularly common in elderly patients; the incidence of both of these conditions increases with age, with no particular predilection for sex or race. Additional risk factors for surgical and medical patients are listed in Table 70-2.

The rationale for venous thromboembolism prophylaxis is based on the clinically silent nature of the disease. In fact, most events cause few specific symptoms, and the clinical diagnosis is notoriously unreliable. Beyond the immediate complications of pulmonary embolism, which can lead to death within 30 minutes, unrecognized and untreated DVT can cause long-term morbidity from chronic venous stasis (postphlebitic syndrome) and predispose patients to recurrent venous thromboembolism (see Table 70-3).

The postphlebitic syndrome is characterized by varying degrees of chronic venous stasis and its accompanying manifestations of peripheral edema, stasis dermatitis, and, in the most severe cases, venous ulcers that are difficult to treat. Patients at risk for the postphlebitic syndrome include those with extensive proximal and recurrent DVT, in whom damage and, ultimately, incompetence of the venous valves ensue. The key to prevention is early treatment. Long-term therapy includes fitted support stockings, avoidance of stasis (eg, sedentary life style), leg elevation during periods of inactivity to minimize peripheral edema, and meticulous skin care.

The risk of venous thromboembolism is greatest in the early postoperative or postevent period but varies according to the overall risk profile. After orthopedic procedures, prophylaxis should be continued for 10 to 14 days (or longer if the patient has experienced postoperative complications that delay rehabilitative efforts and ambulation). For patients undergoing general surgery, 5 to 7 days of prophylaxis is probably adequate, with the exception of patients with underlying malignancy (or prior venous thromboembolism in whom a longer period of prevention may be beneficial).

The approach in patients with medical conditions must be individualized. In general, prophylaxis should be continued until full ambulation is resumed. As with venous thromboembolism, strategies for prophylaxis have been developed to prevent arterial thromboembolism in patients at risk. Specific conditions warranting prophylaxis are outlined below.

Orthopedic procedures: The risk of DVT after an orthopedic procedure has been performed is high, particularly when surgery is performed semi-electively or urgently after traumatic fracture.

For total hip replacement, the incidence of proximal DVT (in the absence of prophylaxis) approaches 25%, with an alarming 3 to 4% incidence of fatal pulmonary embolism. Prophylaxis reduces the occurrence of venous thromboembolism by 30 to 50%. The most effective regimens include low-molecular-weight heparin (eg, enoxaparin 30 mg sc q 12 h or 40 mg sc q 24 h), oral anticoagulants (warfarin to target the international normalized ratio [INR] between 2.0 and 2.5), and adjusted-dose IV heparin (titrated to aPTT in the upper range of normal).

For traumatic hip fracture, the approach to DVT prophylaxis remains a substantial challenge because of the concomitant risk of bleeding in these typically elderly patients. The incidence of venous thromboembolism (in the absence of prophylaxis) is about 50%. Either warfarin or low-molecular-weight heparin is the anticoagulant of choice and should be instituted preoperatively whenever possible. Although intermittent pneumatic compression boots are used frequently in clinical practice, there are limited data on their effectiveness.

Total knee replacement is associated with an incidence of DVT approaching 60%. Low-dose subcutaneous heparin and oral warfarin provide marginal benefit. The greatest benefit has been achieved with low-molecular-weight heparin and intermittent pneumatic compression boots; however, the incidence of proximal DVT remains 5 to 10% even with this prophylaxis.

Atrial fibrillation: The formation of thrombi within the atria and atrial appendices (the left far more often than the right) is a well-recognized phenomenon among all patients with atrial fibrillation. Anticoagulation reduces thromboembolism and the most feared and devastating manifestation--stroke. Anticoagulation is recommended for at least 3 weeks before and 4 weeks after successful cardioversion. Transesophageal echocardiography may have a role in identifying patients at low and high risk for thromboembolism.

Atrial flutter: Patients with atrial flutter/fibrillation and atrial flutter with concomitant valvular diseases or a reduced left ventricular function probably warrant treatment with warfarin or, at the very least, further evaluation in the form of transesophageal echocardiography. In the absence of valvular heart disease or compromised left ventricular performance, atrial flutter most likely represents a very low risk condition. Guidelines for managing anticoagulation for patients with atrial flutter have not yet been established; however, some clinicians choose to treat patients with warfarin as they would those with atrial fibrillation.

Acute myocardial infarction: The overall incidence of venous thromboembolism is about 20%; elderly patients and those with infarctions complicated by heart failure, recurrent angina, or ventricular arrhythmias are at greatest risk. Prophylaxis is recommended in the form of low-dose heparin, low-molecular-weight heparin, or intermittent pneumatic compression boots. Comparative trials of low-dose heparin and low-molecular-weight heparin in high-risk medical patients are in progress.

Patients with large infarctions (ejection fraction < 35%), particularly those involving the anterior and apical walls of the myocardium, are at risk for mural thromboses and cardioembolic events. Serial echocardiograms may be a useful diagnostic strategy. Prophylactic therapy includes unfractionated heparin or low-molecular-weight heparin. Warfarin (target INR 2.0 to 3.0) is an effective outpatient therapy and is typically continued for 2 to 3 months after an MI. Patients experiencing a cardioembolic event should receive warfarin therapy for >= 1 year if their ventricular performance remains poor.

Ischemic stroke: In patients with stroke and a paralyzed lower extremity, the incidence of DVT is about 30 to 40%. Both low-dose heparin and low-molecular-weight heparin reduce the occurrence of DVT by at least 50%. Intermittent pneumatic compression boots are likely to be beneficial.

Specific Anticoagulants

There are many different anticoagulants available, many of which have distinct uses, especially as prophylaxis for venous thromboembolism (see Table 70-3). In general, drugs given intravenously, such as heparin or the fibrinolytic agents, are used short-term for hospitalized patients, and oral drugs, such as warfarin and antiplatelet drugs, are used long-term for outpatients. Low-molecular-weight heparins, administered subcutaneously, can be used in almost any setting.

Unfractionated Heparin

Heparin, the most widely used anticoagulant, accelerates the inhibitory interaction between antithrombin and several hemostatic proteins, most notably thrombin and factor X. After IV administration, about one third of circulating heparin molecules bind to antithrombin; the remaining two thirds have minimal anticoagulant activity. Heparin is cleared from the circulation through a combination of a rapid saturable mechanism (binding) and a much slower first-order mechanism (renal).

Unfractionated heparin is indicated in elderly patients at risk of venous or arterial thromboembolism. The prevention of venous thromboembolism is achieved with doses of 5000 U given sc 2 or 3 times/day. Treatment of DVT or pulmonary embolism requires a larger dose, typically initiated as a bolus (60 U/kg) followed by a continuous IV infusion (15 U/kg/hour) to a target aPTT of 1.5 to 2.5 times control. Dose requirements are influenced by body weight and acute-phase responses. The latter is particularly important in clinical practice because acute vascular thrombosis is associated with both inflammation and platelet activation, neutralizing heparin in the circulation (through direct binding) and increasing initial dose requirements. Age and renal function also affect heparin dosing, but minimally.

After its IV administration, heparin binds to vascular endothelial cells, macrophages, and plasma proteins. Because of these complex kinetics, the anticoagulant effect of heparin at therapeutic doses is not linear, although usually both intensity and duration increase as the dose increases. Therefore, the biologic half-life of heparin increases from 30 minutes after an IV dose of 25 U/kg, to 60 minutes after a dose of 100 U/kg, to 150 minutes with a dose of 400 U/kg.

The anticoagulant effects of heparin are usually monitored with the aPTT, a test sensitive to the inhibitory effects of heparin on thrombin and factor X. A therapeutic state of systemic anticoagulation (1.5 to 2.5 times control) is a prerequisite when heparin is used in the treatment of venous and arterial thromboembolic disorders. Because the pharmacokinetics and pharmacodynamics of heparin are complex, frequent monitoring during the course of treatment is required.

The most common adverse effect of heparin is hemorrhage. Other complications include thrombocytopenia (with or without thrombosis), skin necrosis, alopecia, hypersensitivity reactions, and hypoaldosteronism. The risk of bleeding increases with heparin dose (and anticoagulant effect), age, decreasing body weight, trauma, recent surgery, invasive procedures, and the concomitant use of aspirin.

Mild to moderate bleeding should initially be addressed by reducing the heparin dose (particularly if the aPTT is excessively prolonged) or by discontinuing the infusion for 30 minutes. More severe bleeding often requires discontinuation of heparin or, with life-threatening hemorrhage, neutralization with protamine sulfate (1 mg for each 100 U of heparin administered in the preceding 4 hours). However, it may be in the patient's best interest to continue systemic anticoagulation, particularly if the bleeding is not life-threatening and can be adequately controlled with local measures (eg, manual pressure over a site of vascular trauma).

Low-Molecular-Weight Heparin

Low-molecular-weight heparins (LMWHs) are used for DVT prophylaxis and in the treatment of DVT and acute coronary syndromes (unstable angina, MI without ST-segment elevation).

LMWH can be given IV or subcutaneously. Dosing strategies (eg, prophylactic dose: enoxaparin 30 mg sc bid or 40 mg sc daily; treatment of DVT or acute coronary syndromes: enoxaparin 1 mg/kg sc bid) have been established that, because of predictable bioavailability and pharmacokinetics, yield a safe and effective plasma concentration (peak anti-Xa level of about 1.5 U/mL and steady state level of about 0.5 U/mL). Because of their short chain length and unique anticoagulant properties (factor Xa inhibition), LMWHs do not prolong the aPTT and are not fully neutralized (about 60%) by protamine sulfate.

The bleeding risk associated with LMWH administration is similar to or slightly lower than the risk observed with unfractionated heparin and is related to dose and molecular weight (higher molecular weight fractions cause a greater risk of bleeding).

Warfarin

Like heparin, warfarin is a frequently used anticoagulant in clinical practice. Warfarin is indicated for elderly patients at risk of thromboembolism (venous or arterial) as well as for those with established thromboembolism.

Warfarin is rapidly absorbed from the gastrointestinal tract after oral administration, reaches maximal plasma concentration in 90 minutes, and has a circulating half-life of 36 to 42 hours. It circulates bound to plasma proteins, particularly albumin. The dose-response profile of warfarin differs among individuals and is influenced by pharmacokinetic and pharmacodynamic factors. Conditions that affect the availability of vitamin K also influence warfarin response (see Table 70-4).

The hepatic clearance (metabolism) of warfarin declines with age. Thus, it is considered safe to initiate warfarin therapy at lower doses (<= 5 mg/day) in the elderly. Some studies have suggested that the elderly are more prone to hemorrhagic complications with warfarin use. Nonetheless, most elderly patients in need of prolonged anticoagulation can be treated safely and effectively with warfarin if treatment includes education, meticulous attention to comorbid illnesses and concomitant drugs, and dose monitoring through a coordinated anticoagulant program.

Bleeding is the most common complication of long-term warfarin therapy. Other complications include skin necrosis and thrombosis in protein C-deficient patients. The risk of bleeding is directly influenced by the intensity of anticoagulant therapy, age, renal insufficiency, and occult disease of the gastrointestinal and genitourinary tracts.

The anticoagulation effect of warfarin can be reduced or entirely reversed by lowering the dose, discontinuing treatment, administering vitamin K, or replacing the defective coagulation factors with fresh frozen plasma. The amount of green leafy vegetables in the diet substantially alters warfarin response.

The prothrombin time (PT) is the method most commonly used for monitoring warfarin therapy. The PT increases in response to depression of three of the four vitamin K-dependent coagulation proteins--factors II, VII, and X. In the initial stages of warfarin administration, prolongation of the PT primarily reflects factor VII depression (shortest half-life). The desired level for the PT (and its corresponding INR) varies according to the disease being treated. For example, an INR of 1.5 to 2.0 may be adequate for DVT, but an INR of 3.0 may be required to treat thromboembolism associated with the cardiolipin syndromes.

The prevention of venous thromboembolism following orthopedic surgical procedures is achieved with a target INR of 2.0 to 2.5, while treatment requires an INR of 2.0 to 3.0. The prevention of arterial thromboembolism in patients with atrial flutter, atrial fibrillation, and mural thrombosis is effectively achieved with an INR of 2.0 to 3.0. The target INR for patients with mechanical heart valves is 2.5 to 3.5.

Direct Thrombin Anticoagulants

Direct thrombin anticoagulants, including hirudin, bivalirudin, and argatroban, have yielded mixed results in clinical trials; hemorrhagic events are a major concern. Although use in arterial thrombotic disorders may be limited, hirudin (lepirudin-recombinant hirudin) has shown promise in the management of heparin-induced thrombocytopenia and for DVT prophylaxis. Investigation of factor Xa antagonists (oral, intravenous), tissue factor pathway inhibitor, and other unique anticoagulant compounds is ongoing.

Fibrinolytic Agents

The available fibrinolytic agents, including tissue plasminogen activator (t-PA), streptokinase (SK), anisoylated plasminogen-streptokinase activator complex (APSAC), urokinase, and 3rd-generation agents recombinant plasminogen activator (r-PA), novel plasminogen activator (n-PA), and TNK-tPA convert the inactive proenzyme plasminogen to the active enzyme plasmin, which then is responsible for dissolution of fibrin.

Evidence suggests that elderly patients with acute MI derive significant benefit from fibrinolytic-based reperfusion; however, their risk of serious hemorrhage, including intracranial bleeding, is increased. Fibrinolytic agents have also been used in the treatment of elderly patients with ischemic stroke. The most encouraging results have been achieved with t-PA when administered within 3 hours of symptom onset. Before fibrinolytic agents are administered for ischemic stroke, careful screening, including a scan of the brain, must be undertaken to exclude hemorrhagic stroke.

Fibrinolytic agents may also be considered for patients with massive pulmonary embolism. As with other indications, careful screening must be undertaken to exclude those at risk for hemorrhagic complications.

Severe bleeding occurs in about 5% of patients treated with fibrinolytic agents (see Table 70-5). However, most patients also receive adjuvant treatment with antiplatelet agents (aspirin) and anticoagulants (heparin). This practice probably increases the risk of bleeding, particularly if careful coagulation monitoring is not carried out in the first 24 to 48 hours.

To counter the effects of fibrinolytic agents when bleeding occurs, fresh frozen plasma provides factors V and VIII, 2-antiplasmin, and plasminogen activator inhibitor. Cryoprecipitate (1 U/10 kg) is the preferred source of fibrinogen (200 to 250 mg/10 to 15 mL) and factor VIII (80 U/10 to 15 mL). If the platelet count is low (< 80,000/µL), platelets (6 to 10 U random donor) should be given. Desmopressin (0.3 mg/kg IV over 20 minutes) can be used to correct qualitative platelet abnormalities. Persistent and potentially life-threatening hemorrhage unresponsive to standard measures (as outlined above) may require antifibrinolytic therapy with aminocaproic acid or tranexamic acid. This intervention should be used with caution because it may precipitate serious thrombotic complications.

Platelet Antagonists

Platelets participate in the thrombotic process by adhering to an abnormal surface, aggregating to form an initial platelet plug, stimulating further aggregation, and triggering the coagulation cascade.

Aspirin irreversibly acetylates cyclooxygenase, impairing prostaglandin metabolism and thromboxane A₂ synthesis, thereby inhibiting platelet aggregation in response to collagen, adenosine diphosphate, and thrombin. Adherence and platelet release, however, are not affected. Aspirin's inhibitory effect persists for the life span of the platelet (7 ± 2 days), because platelets lack the synthetic capacity to regenerate cyclooxygenase. The antithrombotic effect of aspirin can be achieved with doses ranging from 160 to 325 mg/day (and possibly lower); maintenance of 80 to 160 mg/day is probably adequate in most clinical settings. Although nonsteroidal anti-inflammatory drugs also inhibit cyclooxygenase, they do so in a reversible manner. These compounds have not been adequately tested in large randomized clinical trials for this purpose.

Aspirin is indicated for primary and secondary prevention of MI and stroke and is also used in combination with clopidogrel or ticlopidine after intracoronary stent procedures. The addition of low-dose aspirin to warfarin may be beneficial for patients with mechanical heart valves; such is particularly indicated in patients who have experienced thrombotic events while taking appropriately adjusted warfarin doses.

Platelet glycoprotein IIb/IIIa antagonists--abciximab, tirofiban, and eptifibatide--are indicated for patients with acute coronary syndromes and those undergoing high-risk percutaneous coronary interventions. They completely block in vitro platelet aggregation induced by agonists thought to function in vivo.

Ticlopidine is structurally distinct from all other antiplatelet agents. It is a potent inhibitor of platelet aggregation induced by adenosine diphosphate and variably inhibits aggregation provoked by collagen, epinephrine, arachidonic acid, thrombin, and platelet-activating factor. Ticlopidine also inhibits the platelet release action and may impair platelet adhesion as well.

Ticlopidine has been used in the treatment of transient ischemic attacks, strokes (particularly those occurring while aspirin is already being taken), and unstable angina and after placement of an intracoronary stent (probably the most common indication). Neutropenia and thrombotic thrombocytopenic purpura are infrequent but potentially life-threatening complications.

Clopidogrel reduces the risk of MI (and recurrent MI) among patients with atherosclerotic vascular disease. Its adverse effect profile, based on experience to date, is superior to that of ticlopidine, and its relatively long half-life permits once-daily dosing.