Definition and causes

Deep venous thrombosis (DVT) and pulmonary embolism (PE) represent different manifestations of the same clinical entity referred to as a venous thromboembolism (VTE). Venous thrombosis occurs when red blood cells, fibrin and, to a lesser extent, platelets and leukocytes, form a mass within an intact vein. A pulmonary embolism results when a piece of thrombus detaches from a vein wall, travels to the lungs, and lodges within the pulmonary arteries. More than 70% of all pulmonary emboli originate in the pelvic and deep veins of the lower extremities. ¹ The superior vena cava, upper extremity veins, and right chambers of the heart are less common sources.

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Prevalence and risk factors

The exact incidence of venous thromboembolism is unknown. Clinical signs and symptoms are nonspecific and screening tests are not always sensitive enough to detect disease in asymptomatic patients. Population studies have suggested that the overall age- and gender-adjusted annual incidence of VTE is 1 to 2 per 1000 people. ^2,3 More than one third of these cases represent recurrent disease. ² Among those with symptomatic VTE, one third present with pulmonary embolism (PE), whereas two thirds present with isolated DVT. ⁴ Extrapolation of the data suggests that more than 250,000 cases of VTE are diagnosed annually in the United States. At least 50,000 of these cases are fatal; available autopsy data suggest that this figure is probably a significant underestimation of actual mortality.

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. In more recent years, these factors have been better characterized (Table 1 ). Thrombophilia, the tendency to develop thrombosis), can be inherited, acquired, or both. Before 1993, a heritable cause of thrombophilia was identified in fewer than 20% of affected individuals. Since the discovery of factor V Leiden (Arg506Gln mutation) and the prothrombin gene mutation G20210A, this percentage has risen dramatically. However, the cause remains unknown in many patients with VTE.

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Pathophysiology and natural history

Deep Venous Thrombosis

Venous thrombi typically develop within a deep vein at a site of vascular trauma and in areas of sluggish blood flow, such as valve cusps and the venous sinuses of the calf. Accumulation of fibrin and platelets causes rapid growth in the direction of blood flow, potentially reducing venous return. Endogenous fibrinolysis results in partial or complete resolution of the thrombus. Residual thrombus will organize. Incomplete recanalization of the vein often results in narrowing of the lumen and valvular incompetency. An extensive collateral network can develop.

Pulmonary Embolism

Thrombi that embolize to the lungs will lodge within the lobar arteries or 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 results in alveolar hyperventilation and increased respiratory rate. Gas exchange becomes impaired because the affected lung tissue is ventilated, but not perfused. This alveolar dead space and subsequent development of intrapulmonary shunting cause 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 (e.g., 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 of higher than 40 mm Hg. ⁵

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Outcomes

Death occurs in approximately 6% of DVT cases and 12% of PE cases within 1 month of diagnosis. ⁴ Many patients recover completely after a VTE event. However, there are two long-term complications associated with significant morbidity—chronic thromboembolic disease with pulmonary hypertension and post-thrombotic syndrome. Chronic pulmonary thromboembolic disease with pulmonary hypertension is seen in up to 5% of patients after a PE as a result of incomplete resolution of thrombus. ⁶ Pulmonary hypertension can result in right ventricular failure. The severity of hemodynamic compromise, and hence symptoms, is dependent on the extent of arterial obstruction and the presence or absence of preexisting cardiopulmonary disease. These patients are functionally limited because of progressive exertional dyspnea, chest pain, syncope, and lower extremity edema.

Post-thrombotic syndrome is characterized by leg pain, edema, other signs of venous insufficiency and, in some cases, leg ulceration as a result of prolonged venous hypertension. At least 30% of patients with a DVT develop this chronic debilitating disease. ⁷ The risk of 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 and, if used shortly after diagnosis of a DVT, may decrease the risk of post-thrombotic syndrome by 50%. ⁸

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Signs and symptoms

History and physical examination are typically nonspecific and insensitive for the detection of VTE. However, diagnostic methods, such as the ventilation perfusion scan, require that a clinical assessment be made before the test's performance. It is equally important to have a high index of suspicion for the presence of a DVT, PE, or both in light of the associated mortality with this disease state.

Deep Venous Thrombosis

Typical symptoms of DVT include leg pain, edema, erythema, and warmth in the affected limb. Physical examination might also reveal distention of collateral veins and, when associated with superficial venous thrombosis, a palpable cord. Homans' sign (calf pain on sudden dorsiflexion of the foot) and Lowenberg's sign (calf pain in response to lower pressure than expected on inflation of a sphygmoma-nometer cuff) are insensitive and nonspecific findings. ⁹ Phlegmasia cerulea dolens, a rare clinical manifestation of DVT, is characterized by massive edema, severe pain, and limb cyanosis. It is a limb- and life-threatening condition, requiring immediate and aggressive intervention. It remains necessary to perform an objective test for the diagnosis of DVT to differentiate it from a musculoskeletal disorder (e.g., a muscle or tendon tear, muscle strain, or knee injury), edema caused by inactivity, lymphatic disorder, venous reflux, Baker's cyst, or cellulitis. ¹⁰

Pulmonary Embolism

The signs and symptoms of pulmonary embolism are also nonspecific. The most common symptoms in individuals without preexisting cardiopulmonary disease are dyspnea, pleuritic chest pain, cough, leg edema, leg pain, hemoptysis, and palpitations. ¹¹ 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. ¹¹ Almost 50% of patients with DVT have an asymptomatic pulmonary embolism at the time of diagnosis. ¹² The differential diagnosis of PE includes cardiovascular diseases (e.g., aortic dissection, angina, congestive heart failure, pericarditis), pulmonary diseases (e.g., asthma, exacerbation of chronic obstructive pulmonary disease, pneumonia, pneumothorax), musculoskeletal conditions, esophageal spasm, malignancy, and anxiety.

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Diagnosis

One or more tests are required to confirm the presence of a DVT, PE, or both. Objective testing should be performed on patients in whom there is a high clinical suspicion of VTE because this disease is often asymptomatic. The test(s) of choice will depend on the clinical probability of disease, test availability and local expertise, patient's comorbidities, and cost.

Deep Venous Thrombosis

Clinical Prediction Models

Validated clinical prediction rules are available to help the clinician obtain a reliable assessment of the pretest probability that a DVT is present. The Wells clinical model assigns a point system to a limited number of risk factors, signs, and symptoms, which, when totaled, characterizes the patient as having a low, intermediate, or high likelihood of a DVT. ¹³ When combined with D-dimer testing, the Wells model describing individuals as DVT likely or DVT unlikely, and can be used to exclude the presence of a DVT without requiring any imaging. ¹⁴

D-Dimer Testing

D-dimers are formed when plasmin degrades cross-linked fibrin. D-dimer assays, which vary in their sensitivities and specificities, can be measured using an enzyme-linked immunosorbent assay (ELISA), a whole-blood agglutination test (e.g., SimpliRED), or a latex agglutination test. Elevated levels of D-dimers are found in almost 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 venous thromboembolic disease. For example, in patients who are clinically suspected of having a DVT, a D-dimer level lower than 500 ng/mL on ELISA testing has a negative predictive value of 95%. ¹⁵

Duplex Ultrasonography

Duplex ultrasonography combines two modalities, B-mode imaging (brightness modulation) and color Doppler techniques (Fig. 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 compress a vein fully and obliterate its lumen is a clear sign (more than 95% sensitivity and specificity) of a proximal DVT. ¹⁶ This test is less sensitive for the detection of calf venous thrombosis. The advantages of duplex ultrasonography are its wide availability, portability, cost, and noninvasiveness. However, 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. Despite these limitations, it remains the preferred imaging modality for the diagnosis of DVT.

Contrast Venography

Contrast venography remains the reference standard for diagnosing DVT, but is rarely used as the initial diagnostic test because of patient discomfort, required 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 travels through perforating veins to reach the deep system. An intraluminal filling defect or an abrupt cutoff of contrast is consistent with DVT. Venography is more sensitive than duplex ultrasonography in detecting calf venous thrombosis and can be used to demonstrate the presence of reflux. Contrast-induced thrombosis has been reported.

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. Magnetic resonance venography (MRV) has a sensitivity and specificity approaching that of contrast venography. ¹⁷ It has the added benefit of high sensitivity and specificity for the detection of DVTs below the knee and in the pelvis. ¹⁸ Lack of widespread availability and cost currently limit its use. Computed tomography venography (CTV) also allows visualization of the iliac, pelvic, and inferior vena cava veins and is highly sensitive and specific for the detection of DVTs. ¹⁹ Some centers advocate its use when performed in combination with CT pulmonary angiography as a single comprehensive examination for suspected thromboembolic disease. CTV not only can be used to identify the source of a pulmonary embolism, but also combined CTV-CT angiography (CTA) has a higher diagnostic sensitivity than CTA alone for the detection of a PE. ²⁰

Pulmonary Embolism

Clinical Prediction Models and D-dimer

Scoring systems to determine the pretest probability of PE are also available. The most commonly used prediction rule is the Wells model, which scores a limited number of symptoms, signs, and risk factors to calculate a pretest probability of PE. This model is especially effective when combined with the results of ventilation perfusion scanning. ²¹ It has similarly been demonstrated that a low pretest clinical probability using the Wells model combined with a negative D-dimer can be used to exclude the presence of a PE without the need for additional diagnostic testing. ²²

Electrocardiography

The electrocardiogram may be normal or may demonstrate sinus tachycardia. In patients with a large embolus, patterns consistent with right heart strain are often seen. These patterns include right axis deviation, right bundle branch block, P wave pulmonale, 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.

Chest Radiography

Findings on chest radiographs are also nonspecific. Pleural effusions, atelectasis, elevation of a hemidiaphragm, and pulmonary infiltrates may be detected. 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 are only seen occasionally.

Arterial Blood Gas Determination

The arterial blood gas analysis can be normal in patients with a small pulmonary embolism as well as in younger individuals without preexisting cardiopulmonary disease who have a larger embolus. A low Pao₂ level, a normal or low Paco₂ level, and an elevated alveolar-arterial oxygen gradient (higher than 20 mm Hg) are findings suggestive of a PE.

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. A recent chest radiograph is necessary for proper interpretation to exclude other cardiopulmonary diseases that cause ventilation or perfusion defects, or both. The presence of interstitial fibrosis, adenopathy, or a history of PE can yield 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 developing a pulmonary embolism. A pretest clinical suspicion improves the diagnostic accuracy of the test and therefore should be documented (Table 2 ). ²³

Computed Tomography Angiography

Spiral (helical) CTA is often used in lieu of lung scintigraphy because of its wider availability, its ease of operation and interpretation, and its capability for assessing primary pulmonary disease. On CTA, a PE will appear as a partial or complete intraluminal filling defect (Fig. 2). If blood can 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. When compared with conventional pulmonary angiography, spiral CTA is approximately 90% sensitive and 95% specific for the detection of PE. ²⁴ When used in combination with a clinical prediction rule, CTA has a 92% to 96% predictive value (positive or negative) with a concordant clinical assessment. ²⁰

Echocardiography

Echocardiography, both transthoracic and transesophageal, is becoming a more important tool for evaluating patients with PE. Almost 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. ²⁵ Echocardiographic findings may be helpful in determining whether a patient should receive thrombolytic therapy. ²⁶ The use of echocardiography to visualize a pulmonary embolism has been reported, but this test should still be considered an adjunct to other diagnostic modalities until further studies have been performed.

Pulmonary Angiography

Pulmonary angiography is the reference standard for diagnosing pulmonary embolism. Radiocontrast dye is injected after percutaneous catheterization of a vein. An intraluminal filling defect or an abrupt cutoff of the vessel is diagnostic. Although pulmonary angiography is relatively safe, it is time-consuming, expensive, invasive, and carries the risks associated with contrast exposure. It is typically reserved for patients for whom confirmation of the diagnosis or intervention is required.

Summary

• The American Academy of Family Physicians and the American College of Physicians have recently published a clinical practice guideline summarizing the current approaches for the diagnosis of venous thromboembolism
• Recommendation 1: Validated clinical prediction rules should be used to estimate pretest probability of venous thromboembolism, both DVT and PE, and as the basis of interpretation of subsequent results.
• Recommendation 2: In appropriately selected patients with low pretest probability of DVT or PE, obtaining a high-sensitivity D-dimer is a reasonable option and, if negative, indicates a low likelihood of VTE.
• Recommendation 3: Ultrasound is recommended for patients with an intermediate to high pretest probability of DVT in the lower extremities.
• Recommendation 4: Patients with an intermediate or high pretest probability of pulmonary embolism require diagnostic imaging studies.

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Treatment

The goals of VTE treatment are the prevention of clot propagation, prevention of embolism, and prevention of recurrent thrombosis. Therefore, the mainstay of therapy is anticoagulation.

Anticoagulation

Unfractionated 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 factors Xa and IIa (thrombin). Heparin can be administered by 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 before initiating therapy. Weight-based dosing (an 80-U/kg bolus followed by 18 U/kg/hr) is associated with a lower risk of recurrent thromboembolism. ²⁸ The appropriate dose is determined by the aPTT. The target value is laboratory-specific and calculated for the aPTT reagent and coagulometer used, correlating the target range with an amidolytic antifactor Xa assay level of 0.3 to 0.7 IU/mL. An aPTT should be checked 6 hours after any dose adjustment. Heparin resistance, the requirement of unusually high doses of heparin to achieve a therapeutic aPTT, may occur because of increased drug clearance, antithrombin deficiency, nonspecific binding to acute phase proteins, elevations in heparin-binding proteins, and elevations in factor VIII levels. Adverse drug reactions include bleeding, heparin-induced thrombocytopenia, and osteoporosis with prolonged use.

Heparin-induced thrombocytopenia (HIT) is a potentially devastating complication of therapy with unfractionated heparin or low-molecular-weight heparin. More than one half of all patients who develop HIT will experience a thrombotic complication, most commonly DVT and PE, although arterial events are not infrequent. Once the diagnosis of HIT is suspected, heparin should be discontinued and a direct thrombin inhibitor started. ²⁹

Low-Molecular-Weight Heparin

Low-molecular-weight heparin (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 hours) and a more predictable dose-response relationship. Compared with unfractionated heparin, LMWH exhibits primarily antifactor Xa activity with only limited anti-IIa activity. Laboratory monitoring is usually not necessary, but can be performed with a chromogenic anti-Xa assay (rather than an aPTT) 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 might be associated with a lower risk of bleeding. ³⁰ Studies have demonstrated that LMWH is similarly efficacious and safe in treating pulmonary embolism. ^31,32 In appropriate patients, LMWH can facilitate the outpatient treatment of venous thromboembolic disease because it is administered subcutaneously. ^33,34 The incidence of heparin-induced thrombocytopenia and osteoporosis is lower with LMWH than with unfractionated heparin. LWMH is cleared by the kidneys.

Two drugs approved by the U.S. 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 or 1.5 mg/kg once 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 DVT prophylaxis.

Factor Xa Inhibitors

This class of anticoagulants include direct inhibitors, which are antithrombin-independent and bind directly to the active site of factor Xa, and indirect inhibitors, which work by enhancing antithrombin inhibitory activity against factor Xa. Fondaparinux, a small synthetic pentasaccharide, is an indirect Xa inhibitor. Once bound, it causes a conformational change in the antithrombin molecule, greatly enhancing antithrombin's ability to neutralize factor Xa. It does not have any activity against factor IIa and therefore does not affect routine anticoagulation tests. Fondaparinux does not bind to other plasma proteins and is almost 100% bioavailable with subcutaneous administration. Therefore, laboratory monitoring is not required and it can be administered once daily. The high affinity bond between fondaparinux and antithrombin results in a prolonged half-life of 17 to 21 hours and the drug is excreted unchanged in the urine. Caution should be used when administering the drug to those with renal insufficiency. Fondaparinux does not bind to platelets or platelet factor 4. Idraparinux, a highly sulfated derivative of fondaparinux, is an investigational agent whose plasma half-life is 130 hours, which allows it to be given subcutaneously on a once-weekly basis. Several oral direct factor Xa inhibitors are also under clinical development.

Fondaparinux sodium (Arixtra), the sole FDA-approved factor Xa inhibitor, appears to be as safe and effective as unfractionated heparin and LMWH for the treatment of venous thromboembolism. ^35,36 The dose of fondaparinux sodium is 7.5 mg for patients weighing 50 to 100 kg, 5 mg for patients less than 50 kg, and 10 mg for patients more than 100 kg, all administered subcutaneously once daily.

Warfarin

Warfarin is an oral drug that inhibits the gamma carboxylation of the vitamin K–dependent coagulation factors II, VII, IX, and X. Although a prolongation of the prothrombin time (PT) can begin 5 to 7 hours after drug administration because of the short half-life of factor VII, warfarin's ability to exert its anticoagulant effect fully can take as long as 72 hours, 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. ³⁷ Warfarin also inhibits the carboxylation of natural anticoagulant proteins C and S, resulting in a rapid decline of their levels. This may increase the risk for thrombosis in patients who have a deficiency of proteins C and S at baseline or who have a hypercoagulable state. The choice of the starting dose should be tailored to the individual patient, but using a loading dose (i.e., more than 20 mg) is not recommended. The appropriate dose of warfarin should be determined by monitoring the international normalized ratio (INR), which was developed in response to the significant variability in thromboplastin reagents. The target INR for the treatment of venous thromboembolic disease is 2.0 to 3.0. ³⁸ 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 because of 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 drugs, and alcohol is recommended. Patients must also be instructed to avoid consumption of foods that contain a significant amount of vitamin K (e.g., leafy green vegetables, soybeans, green tea, and a wide variety of herbal supplements).

Direct Thrombin Inhibitors

Direct thrombin inhibitors bind directly to thrombin. They do not bind to plasma proteins or to platelet factor 4. There are several commercially available FDA-approved drugs for use in patients with HIT, patients undergoing percutaneous coronary interventions, or both. Ximelagatran, an oral prodrug of the thrombin inhibitor melagatran, underwent extensive clinical study, but the FDA denied its approval in 2004 because of concerns related to hepatotoxicity and the potential for an increased risk of coronary events; it was discontinued in 2006. Other oral direct thrombin inhibitors are in clinical development.

Duration of Anticoagulation

Recommendations regarding the duration of therapy continue to evolve. Therapy should be individualized for each patient according to personal preference, age, comorbidities, and likelihood of recurrence (Table 3 ). An elevated plasma D-dimer level after discontinuing anticoagulation may be associated with an increased risk of recurrent thrombosis. ³⁹ Increased recurrence rates have also been noted in those who have had a DVT and are found to have residual thrombosis detected by compression duplex ultrasound. ⁴⁰ Repeat testing, as well as periodic reassessment of the risk-benefit ratio of anticoagulation therapy, should be performed in patients prescribed indefinite anticoagulation. ⁴¹ A recently published study has de-monstrated that peak thrombin generation lower than 400 nm after anticoagulant therapy for an initial spontaneous VTE has been discontinued is associated with a low risk of recurrence, ⁴² a finding suggesting that we may be able to identify subgroups of patients who may not require indefinite anticoagulant therapy.

Prevention of Embolism

Inferior Vena Cava Filters

Inferior vena cava filters are used to prevent the pulmonary embolization of a thrombus. Several FDA-approved filters are available (i.e., TrapEase, Greenfield stainless steel, Greenfield titanium, Vena Tech, Bird's Nest, and Simon Nitinol). Despite a paucity of controlled clinical trials demonstrating the effectiveness of these filters, they are indicated for use in patients with or at high risk for venous thromboembolism, in whom anticoagulation drug therapy is contraindicated, and in patients who experience recurrent thromboembolism despite adequate anticoagulation. ⁴¹ 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. ⁴³ As a result, several optional vena cava filters (retrievable and convertible) have been approved by the FDA and may be favored for use when the contraindication to anticoagulation is temporary. ⁴⁴

Thrombolytic Treatment

Thrombolytic agents convert plasminogen into plasmin. Plasmin degrades fibrin and causes thrombi to dissolve rapidly. However, complete resolution of a thrombus is rare in the venous circulation. Absolute indications for thrombolytic therapy are a massive iliofemoral DVT, especially in the case of phlegmasia cerulea dolens, and a pulmonary embolism that is accompanied by hemodynamic instability. Nevertheless, thrombolytics have not been shown to decrease mortality in these patients. ⁴¹ It has been suggested that thrombolytics lower 30-day mortality in clinically stable patients with right ventricular dysfunction. ⁴⁵ However, because enrollment in this study was not randomized, the results should be interpreted with prudence. Bleeding is a serious complication of thrombolytic therapy and 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. ⁴¹

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/hr over 24 hours for a pulmonary embolism or up to 72 hours for a DVT. The recommended dose of tPA for PE thrombolysis is 100 mg over 2 hours intravenously.

Pulmonary Embolectomy

Surgical embolectomy is rarely 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. ⁴¹ 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. ⁴⁶

Summary

• The American College of Physicians and the American Academy of Family Physicians have recently published a clinical practice guideline ⁴⁷ summarizing the current approaches for the management of venous thromboembolism:
• Recommendation 1: LMWH rather than unfractionated heparin should be used whenever possible for the initial inpatient treatment of DVT. Either unfractionated heparin or LMWH is appropriate for the initial treatment of pulmonary embolism.
• Recommendation 2: Outpatient treatment of DVT, and possibly PE, with LMWH is safe and cost-effective for carefully selected patients and should be considered if the required support services are in place.
• Recommendation 3: Compression stockings should be used routinely to prevent post-thrombotic syndrome, beginning within 1 month of diagnosis of proximal DVT and continuing for a minimum of 1 year after diagnosis (for discussion, see earlier, “Pathophysiology and Natural History”).
• Recommendation 4: There is insufficient evidence to make specific recommendations for types of anticoagulation management of VTE in pregnant women (for discussion, see later, “Considerations in Special Populations”).
• Recommendation 5: Anticoagulation should be maintained for 3 to 6 months for VTE secondary to transient risk factors and for more than 12 months for recurrent VTE. Although the appropriate duration of anticoagulation for idiopathic or recurrent VTE is not definitively known, there is evidence of substantial benefit for extended-duration therapy.
• Recommendation 6: LMWH is safe and efficacious for the long-term treatment of VTE in select patients, and may be preferable for patients with cancer.

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Prevention and screening

Prevention

Thromboprophylaxis decreases morbidity and mortality in hospitalized patients. Patients who undergo orthopedic surgery, have a history of VTE, or have one of several medical comorbidities (malignancy, cardiopulmonary or neurologic disease) have an increased risk of VTE. Risk stratification for each patient is necessary to determine the need for and modality of prophylaxis. Mechanical devices (e.g., elastic graduated stockings, intermittent pneumatic compression) and chemical regimens (e.g., low-dose unfractionated heparin and LMWH) reduce, but do not eliminate, the risk of venous thromboembolism. ⁴⁸ The use of aspirin alone for VTE prophylaxis is not recommended for any patient group. ⁴⁸

Screening

Screening for asymptomatic DVT after orthopedic surgery has been advocated by some clinicians. However, because of the lack of evidence that this approach effectively reduces the risk of symptomatic VTE and the associated increased cost, current guidelines recommend against this approach. ⁴⁸ Extensive testing for the presence of a thrombophilic state can be costly. Screening should be reserved for patients who sustain their first event before 50 years of age, have a history of recurrent events, or have a first-degree relative with a venous thromboembolic event that also occurred before the age of 50. ⁴⁹

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Considerations in special populations

Warfarin therapy is contraindicated during pregnancy. Warfarin can cross the placenta, resulting in an embryopathy, central nervous system (CNS) abnormalities, and/or bleeding in the fetus. LMWH is the treatment of choice during pregnancy. ⁵⁰ When compared with unfractionated heparin, LMWH has improved bioavailability and decreased risk for HIT and heparin-induced osteoporosis, and requires less monitoring. However, LMWH has a higher volume of distribution and increased rate of clearance during pregnancy, so periodic monitoring of anti-Xa levels may be required. Because of an increased VTE risk postpartum, anticoagulation should be continued for 6 weeks after delivery.

The optimal dose of LMWH is not well established for patients who are morbidly obese or have renal insufficiency. In these patient populations, periodic monitoring of anti-Xa levels may be prudent. Patients with cancer who have had a VTE event have an increased risk of recurrent thrombosis. LMWHs have been shown to be more efficacious in reducing this risk than warfarin. ^51,52 It is recommended that most cancer patients who have a VTE receive LMWH for the first 3 to 6 months of long-term anticoagulant therapy. ⁴¹

Summary

• The history and physical examination are typically nonspecific and insensitive for detecting venous thromboembolism. However, using a validated clinical prediction rule to estimate the pretest probability of thrombosis will increase the likelihood of disease detection and help determine the diagnostic test(s) of choice.
• The goals of VTE treatment are prevention of clot propagation, prevention of embolism, and prevention of recurrent thrombosis. Therefore, the mainstay of therapy is anticoagulation.
• Recommendations regarding treatment duration continue to evolve. Using current guidelines, therapy should be individualized according to personal preference, age, comorbidities, and likelihood of recurrence.
• Thromboprophylaxis is recommended to decrease morbidity and mortality in hospitalized patients.

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Suggested Readings

• The pharmacology and management of the vitamin K antagonists. Chest. 126: 2004; 204S-233S.
• Use of antithrombotic agents during pregnancy. Chest. 126: 2004; 627S-644S.
• Antithrombotic therapy for venous thromboembolic disease. Chest. 126: 2004; 401S-428S.
• Prevention of venous thromboembolism. Chest. 126: 2004; 338S-400S.
• Guidelines for the use of retrievable and convertible vena cava filters: Report from the Society of Interventional Radiology Multidisciplinary Consensus Conference. J Vasc Interv Radiol. 17: 2006; 449-459.
• Joint American Academy of Family Physicians/American College of Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism: Current diagnosis of venous thromboembolism in primary care: A clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Fam Med. 5: 2007; 57-62.
• Review of the evidence on diagnosis of deep vein thrombosis and pulmonary embolism. Ann Fam Med. 5: 2007; 63-73.
• Management of venous thromboembolism: A clinical practice guidelines fromm the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 146: 2007; 204-210.