Pulmonary Embolism
Thrombi that embolize to the lungs will lodge within either the lobar arteries or the distal main pulmonary artery; occasionally they will straddle the pulmonary artery bifurcation (saddle embolus). Smaller thrombi can travel more distally. A pulmonary embolism causes several physiologic changes. Stimulation of irritant receptors causes alveolar hyperventilation, which increases the respiratory rate. Gas exchange becomes impaired because the affected lung tissue is ventilated but not perfused. Initially, this alveolar "dead space," and later the development of intrapulmonary shunting, causes bronchoconstriction and hypoxemia. Atelectasis and edema caused by the loss of alveolar surfactant can develop within hours. A decrease in the cross-sectional area of the pulmonary arterial bed, hypoxia, and the release of humoral factors by activated platelets (eg, serotonin and thromboxane) increase pulmonary vascular resistance. Even so, an acute embolic event in a healthy individual will not generate a mean pulmonary artery pressure greater than 40 mm Hg.⁴ Pulmonary hypertension can result in right ventricular failure and, infrequently, decrease cardiac output. The severity of hemodynamic compromise, and hence symptoms, is dependent on the extent of arterial obstruction and the presence or absence of pre-existing cardiopulmonary disease.

More than 150 years ago, German pathologist Rudolf Virchow identified a triad of factors-stasis, endothelial injury, and alterations in blood coagulability-that predispose an individual to the development of thrombosis (Table 1). His finding is still valid today. Thrombophilia (the tendency to develop thrombosis) can be inherited, acquired, or both. Prior to 1993, a heritable cause of thrombophilia was identified in fewer than 20% of affected patients. However, since the discovery of factor V Leiden (Arg506Gln mutation) and the prothrombin gene mutation G20210A, this percentage has risen dramatically. Still, many cases of venous thromboembolism remain idiopathic. Extensive testing for the presence of a thrombophilic state can be quite costly. Screening should be reserved for patients who sustain their first event prior to 50 years of age, have a history of recurrent events, or who have a first-degree relative with a venous thromboembolic event that also occurred prior to the age of 50.⁵

Deep Vein Thrombosis
The typical symptoms of DVT include leg pain, edema, erythema, and warmth in the affected area. Physical examination might also reveal distention of collateral veins and a palpable cord if there is an associated superficial vein thrombosis. Homans's sign (calf pain upon sudden dorsiflexion of the foot) and Lowenberg's sign (calf pain in response to lower pressure than expected upon inflation of a sphygmomanometer cuff) are insensitive and nonspecific findings.⁶

Using a clinical model in a symptomatic patient can help the clinician estimate the probability that DVT is present.⁷ However, it is still necessary to perform an objective test because similar findings can be seen in patients with a musculoskeletal disorder (eg, a muscle or tendon tear, muscle strain, or knee injury), edema due to inactivity, a lymphatic disorder, venous reflux, Baker's cyst, or cellulitis.⁸ Moreover, objective testing should be performed on patients in whom there is a high clinical suspicion because DVT is often asymptomatic.

Pulmonary Embolism
Pulmonary embolism is also characterized by a constellation of nonspecific signs and symptoms that are associated with other diseases (Table 2). The most common symptoms in individuals without preexisting cardiopulmonary disease are dyspnea, pleuritic chest pain, cough, leg edema, leg pain, hemoptysis, and palpitations.⁹ The most common findings on physical examination are tachypnea, rales (crackles), tachycardia, a fourth heart sound, accentuation of the second heart sound (closure of the pulmonic valve), DVT, and diaphoresis.⁹ Nearly 50% of patients with DVT have an asymptomatic pulmonary embolism at the time of their diagnosis.¹⁰

Deep Vein Thrombosis:

D-dimers
D-dimers are formed when plasmin degrades cross-linked fibrin. They can be measured by enzyme-linked immunosorbent assay (ELISA), a whole-blood agglutination test (eg, SimpliRED), or a latex agglutination test. Elevated levels of D-dimers are found in nearly all patients with venous thromboembolic disease as well as in patients with active cardiopulmonary disease or malignancy and in those who have experienced recent surgery or trauma. Therefore, D-dimer measurement is most useful in excluding a diagnosis of venous thromboembolic disease. In patients who are clinically suspected of having DVT, a D-dimer level of less than 500 ng/mL on ELISA testing has a negative predictive value of 95%.¹¹

Duplex Ultrasonography
Duplex ultrasonography combines two modalities: B-mode imaging (brightness modulation) and color Doppler techniques (Figure 1). It is used to detect the presence of intraluminal echoes (the visual representation of a thrombus) and to assess blood-flow characteristics (including its presence, direction, and variation with respiration). In a symptomatic patient, an inability to fully compress a vein and thereby obliterate its lumen is a clear sign (> 95% sensitivity and specificity) of proximal DVT.¹² This test is less sensitive for the detection of calf vein thrombosis. The advantages of duplex ultrasonography are its wide availability and its noninvasiveness. Its drawbacks include the fact that it is operator-dependent and can be difficult to perform on obese patients, patients with significant tenderness or edema, and patients whose limbs are in a cast or other immobilizing device. Moreover, duplex ultrasonography cannot always accurately distinguish between an acute and chronic thrombus.

Contrast Venography
Contrast venography remains the gold standard for diagnosing DVT, but it is rarely used as the initial diagnostic test because of patient discomfort, exposure to contrast material, and limitations of availability. During this procedure, a tourniquet is placed around the limb distally to occlude only the superficial veins. Contrast material is injected into a superficial vein on the dorsum of the foot, and it travels through perforating veins to reach the deep system. An intraluminal filling defect or an abrupt cut-off of contrast is consistent with DVT (Figure 2). Venography is more sensitive than duplex ultrasonography in detecting calf vein thrombosis, and it can be used to demonstrate the presence of reflux. Contrast-induced thrombosis can occur.

Other Tests
Impedance plethysmography uses electrodes placed around the calf to measure changes in blood volume (proximal venous obstruction increases blood volume and decreases electrical impedance). Although this test is highly sensitive and specific for detecting proximal DVT, it has become less popular since duplex ultrasonography has become widely available. Radioactive fibrinogen (I¹²⁵) has only historical importance since it was withdrawn from the market. A new test (Acutect) is based on 99mTc-apcitide, which binds to glycoprotein IIb/IIIa receptors on activated platelets; because this test requires further validation, it is not widely used. Magnetic resonance venography has a sensitivity and specificity approaching that of contrast venography, but it is cost-prohibitive as a screening test.¹³

Pulmonary Embolism:

Electrocardiography
In patients with pulmonary embolism, the electrocardiogram might be normal or it might reveal sinus tachycardia. In patients with a large embolus, patterns consistent with right heart strain are often seen. Patterns include right-axis deviation, right bundle branch block, P-wave pulmonale, an S₁Q₃T₃ pattern (a prominence of S waves in lead I, Q waves in lead III, and T-wave inversion in lead III), nonspecific ST-T-wave changes, and arrhythmias (Figure 3).

Chest Radiography
Findings on chest radiographs are also nonspecific. Pleural effusions, atelectasis, elevation of a hemidiaphragm, and pulmonary infiltrates are often seen in patients with a pulmonary embolism. Hampton's hump (a wedge-shaped opacity along the pleural surface), Westermark's sign (decreased vascularity), and Palla's sign (an enlarged right descending pulmonary artery) are classic radiographic findings, but they are only occasionally seen (Figure 4).

Arterial Blood Gas
Results of arterial blood gas analysis can be normal in patients with a small pulmonary embolism as well as in younger individuals who have a larger embolus without preexisting cardiopulmonary disease. A low PaO₂ level, a normal or low PaCO₂ level, and an elevated alveolar-arterial oxygen gradient (> 20 mm Hg) are findings consistent with the diagnosis of a pulmonary embolism.

Lung Scintigraphy
Lung scintigraphy, also known as ventilation perfusion scanning, is based on the pathophysiologic principle that a pulmonary embolism causes an area of "mismatch" in which a lung segment is ventilated but not perfused (Figure 5). A recent chest radiograph is necessary for the proper interpretation of a lung scintigram because many other cardiopulmonary diseases also cause ventilation and/or perfusion defects. The presence of interstitial fibrosis or adenopathy or a history of pulmonary embolism can produce a false-positive result. Ventilation images are obtained with a gamma camera that records inhaled radioactive aerosols. A photoscanner detects intravenously injected isotope-labeled macroaggregates of albumin to form the perfusion image. The location and number of mismatched areas are used to determine whether the patient has a high, intermediate, or low probability of pulmonary embolism. A pretest clinical suspicion improves the diagnostic accuracy of the test and therefore should be documented (Table 3).¹⁴

Computed tomography (CT)
Spiral (helical) CT is often used in lieu of lung scintigraphy because of its wider availability, its ease of operation and interpretation, and its capability to assess primary pulmonary disease. On CT, a pulmonary embolus will appear as a partial or complete intraluminal filling defect (Figure 6). If blood is able to flow around the thrombus, a "railway track sign" might be seen. This test requires contrast and should be performed with caution in patients with renal insufficiency. The presence of adenopathy can lead to a false-positive result. CT is more sensitive in detecting emboli in the main, lobar, and segmental pulmonary arteries than in detecting peripheral emboli.¹⁵

Echocardiography
Echocardiography, both transthoracic and transesophageal, is becoming a more important tool for evaluating patients with pulmonary embolism. Nearly 50% of hemodynamically stable patients who present with a pulmonary embolism will have echocardiographic evidence of right ventricular dysfunction, which is associated with an increase in mortality.¹⁶ This information can be helpful in determining whether or not a patient should receive thrombolytic therapy. The use of echocardiography to visualize a pulmonary embolism has been reported, but this test should still be considered only as an adjunct to other diagnostic modalities until further studies have been performed.

Pulmonary Angiography
Pulmonary angiography is the gold standard for diagnosing pulmonary embolism. Radiocontrast dye is injected after percutaneous catheterization of a vein. An intraluminal filling defect or an abrupt cut-off of the vessel is diagnostic (Figure 7). Although pulmonary angiography is relatively safe, it is time-consuming, expensive, invasive, and carries the risks associated with contrast exposure. It is usually reserved for cases where confirmation of the diagnosis is required or intervention will be pursued.

THERAPY

Heparin
Heparin is an animal-derived large polysaccharide that binds to endogenous antithrombin. This heparin-antithrombin complex catalyzes the inactivation of several activated coagulation factors, including factor Xa and IIa (thrombin). Heparin can be administered by either intravenous infusion or subcutaneous injection. Its plasma half-life is generally 1 to 2 hours, although the duration lengthens with higher doses. Heparin is primarily cleared from the circulation by the reticuloendothelial system. A baseline complete blood count with platelets and an activated partial thromboplastin time (aPTT) should be documented prior to initiating therapy. Weight-based dosing (an 80 U/kg bolus followed by 18 U/kg/h) is associated with a lower risk of recurrent thromboembolism.¹⁷ The appropriate dose is determined by the aPTT value. The target value is 1.5 to 2.5 times the mean control value (which corresponds to 0.3 to 0.6 U/mL on the amidolytic anti-factor Xa assay) and should be checked 6 hours after a dose adjustment. Adverse drug reactions include bleeding, heparin-induced thrombocytopenia, and osteoporosis with prolonged use.

Low-Molecular-Weight Heparin (LMWH)
A LMWH is a small heparin fragment whose mechanism of action is similar to that of unfractionated heparin. However, LMWH has less nonspecific binding to proteins, which results in a longer plasma half-life (4 h) and a more predictable dose-response relationship. Laboratory monitoring is usually not necessary, but it must be performed with a chromogenic anti-Xa assay (rather than the aPTT measurement) 4 hours after a dose has been given (therapeutic range: 0.6 to 1.0 IU/mL in most laboratories). LMWH is as effective as unfractionated heparin for the treatment of DVT, and it might be associated with a lower risk of bleeding.¹⁸ Studies have demonstrated that LMWH is similarly efficacious and safe in treating pulmonary embolism.^19,20

In appropriate patients, LMWH can facilitate the outpatient treatment of venous thromboembolic disease because it is administered subcutaneously.^21,22 Although the incidence of heparin-induced thrombocytopenia and osteoporosis is lower with LMWH than with unfractionated heparin, caution should be used in obese patients and in those with renal insufficiency because of the renal clearance of LMWH.

Two drugs approved by the Food and Drug Administration (FDA) for the treatment of venous thromboembolism are enoxaparin sodium (Lovenox®) and tinzaparin sodium (Innohep®). The dose of enoxaparin sodium is 1 mg/kg twice daily, and the dose of tinzaparin sodium is 175 anti-Xa U/kg daily; both are administered subcutaneously. Dalteparin sodium (Fragmin®) is FDA-approved only for prophylaxis of DVT.

Warfarin
Warfarin is an oral drug that inhibits gamma-carboxylation of the vitamin K-dependent coagulation factors II, VII, IX, and X. Although a prolongation of the prothrombin time (PT) can begin in 5 to 7 hours after drug administration due to the short half-life of factor VII, warfarin's ability to fully exert its anticoagulant effect can take as long as 72 hours, which is the half-life of factor II. Warfarin and heparin can be started on the same day, but concomitant administration of these drugs for 4 or 5 days is recommended.²³ Warfarin also inhibits carboxylation of natural anticoagulant proteins C and S resulting in a rapid decline of their levels. This poses a theoretical risk for a venous thromboembolic event in patients who have a deficiency of proteins C and S at baseline or who have a hypercoagulable state. Starting the patient on the expected daily dose (eg, 5mg) rather than administering a loading dose can minimize excess anticoagulation (and potential bleeding) and avoid an extreme decline in protein C levels without significantly prolonging hospitalization.²⁴

Historically, the appropriate dose of warfarin was determined by monitoring the PT. The international normalized ratio (INR) was developed in response to the significant variability in thromboplastin reagents. The target INR in the treatment of venous thromboembolic disease is 2.0 to 3.0.²⁵ Higher-intensity anticoagulation is associated with an increase in bleeding. Cytochrome P-450 enzymes in the liver metabolize warfarin. Multiple drug interactions have been reported due to alterations in intestinal absorption, interference with cytochrome P-450 enzyme metabolism, and effect on plasma protein binding. Limiting the use of aspirin, nonsteroidal anti-inflammatory medications, and alcohol is recommended. Patients must also be instructed to avoid consumption of foods that contain a significant amount of vitamin K (eg leafy green vegetables, soybean, green tea, and a wide variety of herbal supplements).

Recommendations regarding the duration of therapy are still evolving, although some general guidelines do exist. Therapy should be individualized for each patient according to their personal preference, age, comorbidities, and likelihood of recurrence (Table 4).

Inferior Vena Cava Filters
Inferior vena cava filters are used to prevent the pulmonary embolization of a thrombus. Several FDA-approved filters are available (ie, TrapEase, Greenfield stainless steel, Greenfield titanium, Vena Tech, Bird's Nest, and Simon Nitinol) (Figure 8). Despite a paucity of controlled clinical trials demonstrating the effectiveness of these filters, they are indicated for patients with or at high risk for venous thromboembolism in whom anticoagulation drug therapy is contraindicated as well as for patients who experience recurrent thromboembolism despite adequate anticoagulation. They are also indicated as an adjunct to surgical pulmonary embolectomy or pulmonary thromboendarterectomy.²⁶ Although inferior vena cava filter placement decreases morbidity and mortality at 12 days, it is associated with an increased risk of recurrent DVT at 2 years.²⁷

Thrombolytic Therapy
Thrombolytic agents convert plasminogen into plasmin. Plasmin degrades fibrin and causes thrombi to rapidly dissolve. However, a complete resolution of a thrombus is rare in the venous circulation. The indications for thrombolytic therapy are a massive iliofemoral DVT (especially in the case of phlegmasia cerulea dolens) (Figure 9) and pulmonary embolism that is accompanied by hemodynamic instability. Nevertheless, thrombolytics have not been shown to decrease mortality in these patients.²⁶ Konstantinides et al reported that thrombolytics did lower 30-day mortality in clinically stable patients with right ventricular dysfunction.²⁸ However, because enrollment in this study was not randomized, these results should be interpreted with prudence. Bleeding is a serious complication of thrombolytic therapy, and it can occur at vascular puncture sites, within the gastrointestinal tract, or in the retroperitoneum. Thrombolytics also carry a 1% to 2% risk of intracranial bleeding, so their potential benefits should be weighed against these bleeding risks.²⁶

Streptokinase and tissue plasminogen activator (tPA) are the two FDA approved thrombolytic agents for venous thromboembolic disease. Streptokinase is administered as an intravenous 250,000 IU bolus over 30 minutes followed by 100,000 IU/h over 24 hours for a pulmonary embolism or up to 72 hours for a DVT. The recommended dose of tPA for thrombolysis of a pulmonary embolism is 100 mg over 2 hours also given intravenously.

Pulmonary Embolectomy
Surgical embolectomy rarely is performed. It should be reserved for patients who have a massive pulmonary embolism and hemodynamic instability despite heparin and cardiopulmonary support, who either fail thrombolytic therapy or have a contraindication to it.²⁶ Even in the hands of an experienced surgical team, postoperative mortality is high. In contrast, surgical thromboendarterectomy for chronic thromboembolic disease with pulmonary hypertension can improve functional status, and it carries a mortality rate of less than 10% in symptomatic patients.²⁹

Many patients who are diagnosed with venous thromboembolic disease recover completely. However, morbidity is associated with two long-term complications: chronic thromboembolic pulmonary hypertension and post-thrombotic syndrome. Chronic pulmonary thromboembolism with pulmonary hypertension is seen in up to 5% of patients as a result of the incomplete resolution of a thrombus.³¹ These patients are functionally limited because of progressive exertional dyspnea, chest pain, syncope, and lower-extremity edema. Surgical thromboendarterectomy may be considered in patients with hemodynamic compromise, accessible disease, and few comorbid conditions.

Post-thrombotic syndrome is characterized by leg pain, edema, other signs of venous insufficiency, and eventually leg ulceration as a result of prolonged venous hypertension. At least 30% of patients with venous thromboembolism develop this chronic debilitating disease.³² The risk of developing post-thrombotic syndrome depends on the speed of vein recanalization and development of ipsilateral recurrent events, but not necessarily the extent of thrombosis. Sized-to-fit compression stockings are the mainstay of therapy, which may decrease the risk of post-thrombotic syndrome by 50%.³³

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