Pathophysiology

Venous thrombi are composed predominantly of fibrin and red cells and have a variable platelet and leukocyte component. The formation, growth, and dissolution of venous thromboemboli represent a balance between thrombogenic stimuli and protective mechanisms. The factors that predispose to the development of DVT are venous stasis, activation of blood coagulation, and vascular damage. The protective mechanisms that counteract these thrombogenic stimuli include (1) the inactivation of activated coagulation factors by circulating inhibitors (e.g., antithrombin III, α₂-macroglobulin, α₁-antitrypsin, and activated protein C); (2) clearance of activated coagulation factors and soluble fibrin/polymer complexes by the reticuloendothelial system and liver; and (3) dissolution of fibrin by fibrinolytic enzymes derived from plasma and endothelial cells, and digestion of fibrin by leukocytes.

Acquired and inherited risk factors for VTE have been identified and are shown in Table 62-1. The risk of VTE increases when more than one predisposing factor is present.^7,8

TABLE 62-1 Factors Predisposing to Development of Venous Thromboembolism

Activated protein C resistance is the most common hereditary abnormality predisposing to VTE. The defect results from substitution of glutamine for arginine at residue 506 in the factor V molecule, making factor V resistant to proteolysis by activated protein C. The gene mutation is commonly designated factor V Leiden and follows autosomal dominant inheritance. Patients who are homozygous for the factor V Leiden mutation have a markedly increased risk of thromboembolism and present with clinical thromboembolism at a younger age (median 31 years) than those who are heterozygous (median age 46 years).^7,9 Factor V Leiden is present in approximately 5% of the normal Caucasian population, 16% of patients with a first episode of DVT, and up to 35% of patients with idiopathic DVT.^7,9,10

Prothrombin G20210A is another gene mutation that predisposes to VTE. It is present in approximately 2% to 3% of apparently healthy individuals and in 7% of those with DVT.⁹ An inherited abnormality cannot be detected in up to 40% to 60% of patients with idiopathic DVT, suggesting that other gene mutations are present and have an etiologic role.

Historically, VTE usually occurred in sick hospitalized patients. The burden of illness from VTE has shifted to the community setting such that most patients now present as outpatients to their primary care physician or to the emergency room. The main reason for this shift is the greatly reduced length of hospital stay for most surgical procedures or medical conditions and the discharge of patients from the hospital either before the period of risk of VTE has ended or where there is already the presence of subclinical venous thrombi that subsequently evolve and lead to symptomatic DVT or PE. The shift in burden of illness from the hospital to the community setting has led to an emphasis on effective and safe methods for outpatient diagnosis and management.

Pulmonary embolism originates from thrombi in the deep veins of the leg in 90% or more of patients.^11–13 Other less common sources of PE include the deep pelvic veins, renal veins, inferior vena cava, right ventricle, and axillary veins. Most clinically important PE arise from thrombi in the popliteal or more proximal deep veins of the leg. Pulmonary embolism occurs in 50% of patients with objectively documented proximal vein thrombosis; many of these emboli are asymptomatic.¹¹ Usually only part of the thrombus embolizes, and 50% to 70% of patients with angiographically documented PE have detectable DVT of the legs at the time of presentation.¹² The clinical significance of PE depends on the size of the embolus and the cardiorespiratory reserve of the patient.

Clinical Features

The clinical features of DVT include leg pain, tenderness and swelling, a palpable cord, discoloration, venous distention, prominence of the superficial veins, and cyanosis. The clinical diagnosis of DVT is highly nonspecific because none of the symptoms or signs is unique, and each may be caused by nonthrombotic disorders. Patients with relatively minor symptoms and signs may have extensive DVT, whereas those with florid leg pain and swelling, suggesting extensive DVT, may have negative results on objective testing. Thus, objective testing is mandatory to confirm or exclude a diagnosis of DVT.^14–16

The location of the initial DVT has an impact on the incidence of recurrence; thus the presence of an ilial femoral vein thrombosis was shown to have a higher rate of recurrent VTE compared with popliteal vein thrombosis.¹⁷ Also, there is a high correlation between venographic results as measured by the Marder Score and recurrence of VTE.¹⁸

The clinical presentation of PE depends on the size, location, and number of emboli, and on the patient’s underlying cardiorespiratory reserve. The clinical manifestations of acute PE generally can be divided into several syndromes that overlap considerably: (1) transient dyspnea and tachypnea in the absence of other associated clinical manifestations; (2) pulmonary infarction or congestive atelectasis (also known as ischemic pneumonitis or incomplete infarction), which includes pleuritic chest pain, cough, hemoptysis, pleural effusion, and pulmonary infiltrates on the chest x-ray; (3) right ventricular failure associated with severe dyspnea and tachypnea; (4) cardiovascular collapse with hypotension, syncope, and coma (usually associated with massive PE); and (5) less common and highly nonspecific clinical features including confusion and coma, pyrexia, wheezing, resistant cardiac failure, and unexplained arrhythmia.

The prognosis for long-term survival and recurrent VTE may be worse for patients presenting with PE as opposed to DVT. This may be a reason to treat patients presenting with PE more aggressively in the future, but at the present time, anticoagulant management for each entity is identical. Various studies have attempted to identify risk factors for recurrent VTE, including fatal PE, in patients presenting initially with PE. Factors contributing to recurrent VTE include length of initial hospitalization, presence of cancer, older age, hospitalization for multiple injuries, and surgery within 3 months.^19,20 Risk factors for an adverse outcome include factors such as older than age 70, hypotension, congestive heart failure, chronic obstructive pulmonary disease (COPD), cancer, presence of a DVT, and right ventricular hypokinesis on echocardiography. Using a standardized Pulmonary Embolism Severity Index²¹ and measurement of troponin and beta-type natriuretic peptides are useful in the initial diagnosis and in estimating prognosis in patients presenting with PE.^22–27

Etiology and Pathogenesis

Pulmonary embolism occurs in at least 50% of patients with objectively documented proximal vein thrombosis.¹ Many of these emboli are asymptomatic. The clinical importance of PE depends on the size of the embolus and the patient’s cardiorespiratory reserve. Usually only part of the thrombus embolizes, and 30% to 70% of patients with PE detected by angiography also have identifiable DVT of the legs.^11,12 Deep vein thrombosis and PE are not separate disorders but a continuous syndrome of VTE in which the initial clinical presentation may be symptoms of either DVT or PE. Therefore, strategies for diagnosis of VTE include both tests for detection of PE (lung scanning, computed tomography [CT], or pulmonary angiography)^8–10 and tests for DVT of the legs (ultrasound or venography)^11–13

Prevention of Venous Thromboembolism

Over the years, numerous clinical trials have been carried out for the prevention of VTE, particularly in patients undergoing orthopedic surgery and in hospitalized medical patients. Agents tested include heparin, low-molecular-weight heparin, fondaparinux, warfarin, and more recently, specific inhibitors of activated factor X or thrombin. In addition, medical devices and, in particular, intermittent pneumatic compression alone or in addition to pharmacologic agents have been studied. Effective prophylaxis against VTE is now available for most high-risk patients; prophylaxis is more effective for preventing death and morbidity and more cost-effective than treatment of the established disease. Evidence-based recommendations for the prevention of VTE are available.^5,6

Assessment of Clinical Probability

Management studies over the past 2 decades have demonstrated that patients can be assigned categories of pretest probability using decision rules such as the Geneva Score or the approach of Wells.^28–34 With the shift of the burden of thromboembolic disease to the out-of-hospital population, these clinical probability guidelines have proven to be extremely useful in stratifying patients into low, moderate, or high risk for the diagnosis of PE. However, the prevalence of PE in these categories is not sufficiently low or high to withhold further investigations altogether based on the clinical probability assessment. The measurement of a D-dimer or performance of an objective diagnostic test is mandatory to exclude or confirm the presence of PE in many patients. The assessment of pretest probability and measurement of the D-dimer have now been integrated into diagnostic algorithms for PE (using either CT angiography [CTA] or ventilation/perfusion [V/Q] scanning) and for DVT (using ultrasonography to objectively confirm the diagnosis^28–34 (Figures 62-1, 62-2, and 62-3).

Figure 62-1 Integrated strategy for diagnosis of deep venous thrombosis (DVT) using clinical probability assessment, measurement of D-dimer, and ultrasonography of legs as primary diagnostic tests. If clinical probability is low (i.e., DVT unlikely and D-dimer negative), no further investigations are required. If D-dimer is positive, proceed to ultrasonography of legs; then either treat or stop investigations. If clinical probability is high (i.e., DVT likely) D-dimer measurement need not be carried out; proceed directly to ultrasonography of legs. If negative, options are to repeat ultrasound in 1 week or in some cases to perform an ascending venogram.

Figure 62-2 Integrated strategy for diagnosis of suspected pulmonary embolism (PE) using clinical probability assessment, measurement of D-dimer, and ventilation/perfusion (V/Q) scan as primary imaging test.

Patients with low clinical probability (i.e., PE unlikely, negative D-dimer) need no further investigation. If D-dimer is positive, V/Q scan performed; if not diagnostic, proceed to ultrasound. Then either treat or repeat ultrasound in 1 week. Patients with high probability (i.e., PE likely) need not have D-dimer measured but should proceed directly to V/Q scan. If V/Q scan not diagnostic, options are to perform CTA, pulmonary angiography, or ultrasonography of legs. If ultrasonography is negative, either repeat in 1 week or perform pulmonary angiogram.

Figure 62-3 Integrated strategy for diagnosis of pulmonary embolism (PE) using clinical probability assessment, measurement of D-dimer, and computed tomography angiography (CTA) as primary imaging test. Patients with low clinical probability (i.e., PE unlikely, negative D-dimer) need no further testing, but if D-dimer is positive, they should proceed to CTA, and if this is nondiagnostic, to ultrasonography of legs. Then either treat or repeat ultrasound in 1 week. Patients with high clinical probability (i.e., PE likely) need not have D-dimer measured but should proceed directly to CTA. If CTA is not diagnostic, options are to perform ultrasonography of legs or proceed to pulmonary angiogram. If ultrasound of legs is negative, options are to repeat in 1 week or proceed to pulmonary angiography.

Differential Diagnosis

The differential diagnosis in patients with suspected PE includes cardiopulmonary disorders for each of the modes of presentation (see Clinical Features). For the presentation of dyspnea and tachypnea, they include atelectasis, pneumonia, pneumothorax, acute pulmonary edema, bronchitis, bronchiolitis, and acute bronchial obstruction. For pulmonary infarction exhibited by pleuritic chest pain or hemoptysis, they include pneumonia, pneumothorax, pericarditis, pulmonary or bronchial neoplasm, bronchiectasis, acute bronchitis, tuberculosis, diaphragmatic inflammation, myositis, muscle strain, and rib fracture. For the clinical presentation of right-sided heart failure, they include myocardial infarction, myocarditis, and cardiac tamponade. For cardiovascular collapse, they include myocardial infarction, acute massive hemorrhage, gram-negative septicemia, cardiac tamponade, and spontaneous pneumothorax.

Diagnostic Imaging

Integrated Strategies for Diagnosis of Pulmonary Embolism

Figure 62-3 summarizes the approach to diagnosis of suspected PE using CTA or CTA-CTV as the primary imaging test. Figure 62-2 summarizes the approach to diagnosis using V/Q scanning for settings in which CTA capabilities are not available. Figure 62-3 summarizes the approach to the diagnosis of DVT using ultrasonography. The specific approach used will depend on the local availability of technology, expertise with the different diagnostic techniques, and individual patient circumstances.

An appropriately validated assay for plasma D-dimer, if available, provides a simple and rapid first-line exclusion test in patients with low, intermediate, or unlikely clinical probability. The appropriate use of D-dimer can reduce the need for more expensive imaging tests without compromising patient safety. If a validated D-dimer test is not available or the patient has high clinical probability for PE, diagnostic imaging should be employed. If capability for combined CTA-CTV exists, that is the preferred approach for most patients because it provides a definitive basis to give or withhold antithrombotic therapy in about 90% of patients. Lung scanning may be indicated as the first-line imaging test in women of reproductive age, because the radiation exposure to the breast is significantly less than with CTA.⁵³

When other approaches are inconclusive, selective pulmonary arteriography should be done unless contraindications exist, because the risk of arteriography in properly selected patients is less than the risk of unnecessary anticoagulant therapy.

Clinical Course of Venous Thromboembolism

Proximal DVT is a serious and potentially lethal condition. Untreated proximal vein thrombosis is associated with a 10% rate of fatal PE. Inadequately treated proximal vein thrombosis results in a 20% to 50% risk of recurrent VTE events.^54,47,55 Prospective studies of patients with clinically suspected DVT or PE indicate that new venous thromboembolic events on follow-up are rare (≤2%) among patients in whom proximal vein thrombosis is absent by objective testing.^50–52 The aggregate data from diagnostic and treatment studies indicate that the presence of proximal DVT is the key prognostic marker for recurrent VTE.

Thrombosis that remains confined to the calf veins is associated with low risk (≤1%) of clinically important PE. Extension of thrombosis into the popliteal vein or more proximally occurs in 15% to 25% of patients with untreated calf vein thrombosis.¹¹ Patients with documented calf vein thrombosis should receive either anticoagulant treatment to prevent extension or undergo monitoring for proximal extension using serial noninvasive tests.

The postthrombotic syndrome is a frequent complication of DVT.^56,57 Patients with postthrombotic syndrome complain of pain, heaviness, swelling, cramps, and itching or tingling of the affected leg. Ulceration may occur. The symptoms usually are aggravated by standing or walking and improve with rest and elevation of the leg. A prospective study documented a 25% incidence of moderate to severe postthrombotic symptoms 2 years after the initial diagnosis of proximal DVT in patients who were treated with initial heparin and oral anticoagulants for 3 months.⁵⁶ The study also demonstrated that ipsilateral recurrent DVT is strongly associated with subsequent development of moderate or severe postthrombotic symptoms. Thus prevention of ipsilateral recurrent DVT likely reduces the incidence of the postthrombotic syndrome. Application of a properly fitted graded compression stocking, as soon after diagnosis as the patient’s symptoms will allow and continued for at least 2 years, is effective in reducing the incidence of postthrombotic symptoms, including moderate to severe symptoms.⁵⁸

Chronic thromboembolic pulmonary hypertension is a serious complication of PE. Historically, thromboembolic pulmonary hypertension was believed to be relatively rare and occur only several years after the diagnosis of PE. A prospective cohort study provides important information on the incidence and timing of thromboembolic pulmonary hypertension.^59–61 The results indicate that thromboembolic pulmonary hypertension is more common and occurs earlier than previously thought. On prospective follow-up of 223 patients with documented PE, the cumulative incidence of chronic thromboembolic pulmonary hypertension was 3.8% at 2 years after diagnosis despite state-of-the-art treatment for PE. The strongest independent risk factors were a history of PE (odds ratio 19) and idiopathic PE at presentation (odds ratio 5.7).⁵⁹ Further clinical studies on identification and prevention of chronic thromboembolic pulmonary hypertension are needed.

Objectives and Principles of Antithrombotic Treatment

The objectives of treatment in patients with established VTE are to (1) prevent death from PE, (2) prevent morbidity from recurrent DVT or PE, and (3) prevent or minimize the postthrombotic syndrome.

Recommendations for treatment of established VTE are linked to the strength of the evidence from clinical trials using the approach for grading evidence of the American College of Chest Physicians (ACCP) guideline committee.⁵⁵ Recommendations classified as 1A are supported by evidence from scientifically valid randomized clinical trials (grade A evidence), and the results provide a clear risk-to-benefit conclusion (grade 1). Such recommendations should be implemented for most patients. Grade 2A recommendations also are supported by definitive clinical trial evidence (grade A), but the results indicate a less clear risk-to-benefit conclusion (grade 2); therefore, such recommendations may or may not be appropriate for the individual patient. The remaining grades of recommendation are based on nondefinitive evidence (grade B or C) and are less strong.

Anticoagulant Therapy

Anticoagulant therapy is the treatment of choice for most patients with proximal DVT or PE (grade 1A). Absolute contraindications to anticoagulant treatment include intracranial bleeding; severe active bleeding; malignant hypertension; or recent brain, eye, or spinal cord surgery. Relative contraindications include recent major surgery, recent cerebrovascular accident, active gastrointestinal tract bleeding, severe hypertension, severe renal or hepatic failure, and severe thrombocytopenia (platelets < 50,000/µL).