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Venous Thromboembolism Guidebook

Gelfand, Eli V. MD*; Piazza, Gregory MD; Goldhaber, Samuel Z. MD

Critical Pathways in Cardiology: A Journal of Evidence-Based Medicine: March 2002 - Volume 1 - Issue 1 - p 26–43
Articles

This venous thromboembolism guidebook incorporates evolving contemporary concepts in diagnosis and management of pulmonary embolism (PE) and deep venous thrombosis (DVT) into a user-friendly menu. The purpose of this document is to provide a literature-based review of the current clinical approach to venous thromboembolism and up-to-date references for further study in this important topic.

* Author Information Department of Medicine and the Cardiovascular Division, Brigham and Women's Hospital; and the Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.

Address for correspondence: Dr. Samuel Z. Goldhaber, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. E-mail: sgoldhaber@partners.org

The authors caution that the information contained herein is meant solely as a guideline. Each patient situation is unique, and readers are strongly encouraged to use their best clinical judgment when particular questions arise. Although we make every effort to keep this information updated, the field is rapidly changing.

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Risk Factors For Venous Thromboembolism

Inherited Risks

The inherited risk factors include:1,2

* Factor V Leiden and activated protein C resistance: increased risk of first DVT/PE and recurrent pregnancy loss. It is unclear whether the Factor V Leiden mutation increases risk of recurrent DVT/PE.

* Prothrombin gene mutation 20210: increases risk of DVT/PE two- to threefold. It is also associated with cerebral vein thrombosis.

* Hyperhomocystinemia (almost always acquired; rarely inherited).

* Antithrombin III deficiency.

* Protein C deficiency.

* Protein S deficiency

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Acquired Risks

The acquired risks include:3–9

* Lupus anticoagulant/antiphospholipid antibody syndrome: The risk of recurrent thrombosis is high in this population. Therefore, whenever possible, patients with DVT or PE who also have the antiphospholipid-antibody syndrome should be maintained with a target international normalized ratio (INR) of at least 3.0 usually with indefinite duration of anticoagulation.

* Malignancy: incidence of newly diagnosed cancer after a first episode of venous thromboembolism is elevated for at least 2 years. Subsequently, the risk has been shown to be lower among patients treated with oral anticoagulants for 6 months than among those treated for 6 weeks.

* Age

* Congestive heart failure

* Chronic renal disease: especially nephrotic syndrome

* Hypertension

* Surgery/trauma/hospitalization with immobility

* Pregnancy/oral contraceptives/hormone replacement therapy: third-generation oral contraceptives are especially thrombogenic. Hormone replacement therapy including estrogen alone and estrogen/progesterone combinations increases venous thromboembolism risk two- to fourfold. Caution should also be exercised with selective estrogen receptor modulators such as tamoxifen and raloxifene because both have been shown to increase risk of venous thromboembolism.

* Medical or family history of PE/DVT

* Environmental risks

* Obesity: up to a threefold increase in PE risk with body mass index >29.

* Cigarette smoking: more than a doubling of risk among heavy smokers (>35 cigarettes/day)

* Immobility, including coach class air travel

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Hypercoagulable Workup

* High yield: “The Big Four”

1. Activated protein C resistance (Factor V Leiden)

2. Plasma homocysteine level

3. Lupus anticoagulant/antiphospholipid antibody screen

4. Prothrombin gene mutation 20210

* Low yield: “The Little Four”

1. Antithrombin III

2. Protein C

3. Protein S

4. High levels of factor VII

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Diagnosis

Diagnostic Highlights

* D-dimer enzyme-linked immunosorbent assay (ELISA) is an excellent screening test for PE. It is widely available, rapid, and inexpensive.

* An integrated approach to PE diagnosis in essential.

* Spiral computed tomography (CT) scan of the chest cannot reliably detect important but distal PE.

* A negative finding on venous ultrasound of the legs does not exclude PE.

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Clinical Clues to Pulmonary Embolism

History

Dyspnea is the most frequent symptom, and tachypnea is the most frequent sign of PE. Whereas dyspnea, syncope, or cyanosis usually indicates a massive PE, pleuritic chest pain, cough, or hemoptysis often suggests a small embolism located distally near the pleura. In older patients who complain of vague chest discomfort, the diagnosis of PE may not be apparent unless signs of right heart failure are present. Unfortunately, because acute coronary ischemic syndromes are so common, one may overlook the possibility of life-threatening PE and may inadvertently discharge these patients from the hospital after the exclusion of myocardial infarction with serial cardiac enzymes and electrocardiography.

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Physical Examination

Young and previously healthy individuals may simply appear anxious but otherwise seem deceptively well, even with an anatomically large PE. They need not have “classic” signs such as tachycardia, low-grade fever, neck vein distension, or an accentuated pulmonic component of the second heart sound. High-grade fever may occur rarely, and fever is not limited to patients with pulmonary hemorrhage or infarction. Sometimes, a paradoxical bradycardia occurs.

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Differential Diagnosis of Pulmonary Embolism

The differential diagnosis of PE includes:10

* Myocardial infarction

* Chronic obstructive pulmonary disease exacerbation

* Aortic dissection

* Pneumonia or bronchitis

* Congestive heart failure (“left-sided”)

* Cardiomyopathy with global ventricular dysfunction

* Primary pulmonary hypertension

* Asthma

* Pericarditis and pericardial tamponade

* Intrathoracic malignancy

* Rib fracture

* Pneumothorax

* Costochondritis

* “Musculoskeletal pain”

* Anxiety

* Cholecystitis or splenic pathology (transmitted pleuritic discomfort from subdiaphragmatic irritation)

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Blood Tests

Arterial Blood Gases

Arterial blood gases play little useful role in diagnostic evaluation or triage of patients with suspected PE; in fact, arterial blood gas results are often misleading. The room air PO2 and the alveolar-arterial oxygen (A-a O2) gradient do not differ between those who have PE at angiography and those suspected of PE who have normal pulmonary angiograms. Furthermore, about one fifth to one quarter of patients with angiographically proven PE have normal PO2 on room air and normal (A-a O2) gradients. Therefore, room air PO2 and the (A-a O2) gradient should not be used to screen for or “rule out” PE.11,12

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Cardiac Troponins

Although neither sensitive nor specific for the detection of PE, cardiac troponins may have a unique role in risk stratification of PE patients. In a study of 56 patients with documented PE, cardiac troponin T (cTnT) was measured within 12 hours of admission. cTnT was elevated (>=0.1 μg/L) in 32% of patients with moderate to massive PE but not in patients with small PE. An elevated cTnT correlated with an increased prevalence of in-hospital death (odds ratio 29.6), prolonged hypotension and cardiogenic shock (odds ratio 11.4), need for resuscitation (odds ratio 18.0), and need for pressor support (odds ratio 37.6). cTnT remained an independent predictor of 30-day mortality (odds ratio 15.2). Troponins are probably elevated because of microinfarction of the right ventricle without coronary atherosclerosis. Measuring troponin levels routinely may help improve risk stratification in patients with PE and identify a high-risk population in which more aggressive therapy may be warranted.13

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Plasma D-dimer Enzyme-Linked Immunosorbent Assay/Latex FDPs

The D-dimer enzyme-linked immunosorbent assay (ELISA) is an excellent screening test for PE. The plasma D-dimer ELISA has a high sensitivity and a high negative predictive value and therefore can be used to help exclude PE. In an overview of nine trials, the ELISA had a sensitivity of 97%, specificity of 45%, positive predictive value of 50%, and negative predictive value of 94%. D-dimer alone can exclude PE in up to 30% of patients without the need for further costly imaging studies. The quantitative plasma D-dimer ELISA level is elevated (greater than 500 ng/mL) in more than 90% of patients with PE, reflecting plasmin's breakdown of fibrin into D-dimers and indicating endogenous (though clinically ineffective) thrombolysis. A qualitative latex agglutination D-dimer, which is more readily available and less expensive than an ELISA, can be obtained initially; if elevated, the ELISA will also be elevated. The latest available latex D-dimer assays have demonstrated an overall sensitivity of 96%, specificity of 45% and negative predictive value of 98%, making this a useful test to exclude venous thromboembolism in patients with low or moderate pretest probability of disease.

D-dimer levels are not specific and will be elevated in postoperative patients and in patients with myocardial infarction, sepsis, or almost any systemic illness.14–16

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Electrocardiogram

Electrocardiographic findings in pulmonary embolism include:17,18

* Incomplete or complete right bundle branch block.

* S in lead I and aVL greater than 1.5 mm.

* Transition zone shift to V5.

* Q waves in leads III and aVF but not in lead II.

* QRS axis greater than 90° or indeterminate axi.

* Low limb lead voltage.

* T wave inversion in leads III and aVF or in leads V1-V4.

* Concurrent deep S wave in lead I, Q wave and T wave inversion in lead III (“SIQIIITIII pattern”).

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Imaging Tests for Diagnosis of Pulmonary Embolism

Chest Radiograph

The chest radiograph serves as an integral part in the formulation of clinical suspicion for PE and may help suggest alternative pathology as the cause of the patient's presentation. A normal or near normal chest radiograph in a dyspneic patient may suggest PE. However, because many PE patients have comorbid conditions with abnormal chest radiographic findings, the diagnosis of PE should not be excluded on the basis of abnormalities typical of other cardiopulmonary conditions. Well-established abnormalities include focal oligemia (Westermark sign), a peripheral wedged-shaped density above the diaphragm (Hampton hump), or an enlarged right descending pulmonary artery (Palla sign).

Based on a recent review of the International Cooperative Pulmonary Embolism Registry (ICOPER), the most common chest radiograph interpretations in patients with PE are as follows:19

* Cardiac enlargement (27%)

* Normal (24%)

* Pleural effusion (23%)

* Elevated hemidiaphragm (20%)

* Pulmonary artery enlargement (19%)

* Atelectasis (18%)

* Pulmonary infiltrate (17%)

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Ventilation-Perfusion Lung Scanning

Until recently, ventilation-perfusion lung scan (V/Q scan) was the principal imaging modality in the initial workup of PE. Interpreted as high-, intermediate-, and low-probability, V/Q scans have been problematic, providing definitive information less than 50% of the time. Whereas a normal or nearly normal V/Q scan practically excludes the possibility of PE, a high-probability scan in the setting of moderate to high clinical suspicion virtually guarantees the diagnosis. The clinical dilemma arises in the majority of patients who have intermediate-probability V/Q scans. Among these patients, many will ultimately be diagnosed with PE while a significant amount will be ruled out for venous thromboembolism. Therefore, these patients require further testing to evaluate for PE.

The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study indicated that high-probability lung scans identify about only half of the patients with PE. Thus, if one relied on the high-probability scan to detect PE, the diagnosis would be missed in at least half of PE patients (Table 1).81

Table 1

Table 1

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Spiral Computed Tomography of the Chest

Recently, spiral chest CT scanning with contrast has been used with increasing frequency as the initial imaging study for evaluation of PE. Spiral CT scanning requires the peripheral injection of contrast. The sensitivity of spiral CT is highest in identifying PE in the proximal pulmonary arteries. Despite advances in this imaging technology, first-generation, “single-slice” CT still has the potential to miss small segmental or large subsegmental PE that may be clinically significant. Next-generation multislice CT is expected to have better ability than single-slice CT for detecting subsegmental PE because of its shorter image acquisition time, thinner sections, and a more extensive coverage of the entire thorax. At this time, spiral chest CT is an excellent imaging modality when massive central PE is suspected. Spiral CT is also commonly used in the setting of an abnormal chest radiograph where the specificity of V/Q scan interpretation may be limited. Abnormalities seen by spiral chest CT include intraluminal filling defects, enlarged pulmonary arteries, pulmonary hemorrhage and infarction, and pleural effusion. An additional benefit of spiral CT as an initial imaging modality is its ability to evaluate for other etiologies in the differential diagnosis of PE. In a recent study by Bounameaux that included 299 patients all with elevated D-dimers, spiral chest CT had a sensitivity of 70% and specificity of 91%.82 These results were consistent with two prior overviews. The PIOPED II study will determine sensitivity, specificity, positive and negative predictive values of spiral CT for diagnosis of acute PE, using V/Q scan, lower extremity ultrasound and pulmonary angiography as a composite reference test.20–23

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Magnetic Resonance Angiography

Although currently investigational, magnetic resonance imaging has become an extremely promising imaging modality. Recent advances in technique allow high-resolution angiography during a single suspended breath that could potentially provide excellent visualization of small vessels. Currently, magnetic resonance imaging, like CT, does not have spatial resolution of contrast pulmonary angiography and thus has sensitivity limited to the main and segmental vessels. Small initial trials have revealed excellent sensitivity and specificity for the proximal pulmonary vessels. Potential benefits of MRI over spiral CT include the luxury of avoiding the risks of iodinated contrast medium and ionizing radiation, allowing imaging of patients with renal insufficiency and contrast dye allergy. In addition, functional and structural assessment of the right ventricle can be performed during the same study.24,25

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Echocardiography

Echocardiography is an increasingly important tool in the evaluation and treatment of PE. Although it is a relatively insensitive study in screening for PE, echocardiography is a rapid, practical, and sensitive technique for the identification of right ventricular overload secondary to PE. As a screening modality, echocardiography is neither sensitive nor recommended in clinically stable patients. Approximately 60% of patients with proven PE will have normal echocardiograms. In hemodynamically unstable patients where the disease process is unknown, echocardiography may help suggest PE while evaluating for other causes such as tamponade or aortic dissection. When used as a risk stratification tool, echocardiography is an excellent modality for detecting patients with moderate to severe right ventricular dysfunction, which correlates with a high risk of adverse outcomes.

The frequency of echocardiographic signs of PE depends on the population being studied. Important echocardiographic abnormalities observed in PE include:

* Right ventricular dilatation and hypokinesis, which correlates with greater than 30% involvement of pulmonary vascular cross-sectional area with pulmonary emboli on lung scanning. In particular, McConnell sign is highly specific for acute PE: it includes moderate to severe right ventricular free wall hypokinesis with sparing of the right ventricular apex. The border between the hypokinetic right ventricular free wall and normally contracting apex is known as the “hinge point.” A potential explanation for this pattern of regional abnormality is related to the tethering of the right ventricular apex to a hyperdynamic left ventricle.

* Paradoxical motion of the interventricular septum (septal deviation toward the left ventricle as opposed to the right ventricle)

* Tricuspid regurgitation

* Loss of respiratory-phasic changes of the inferior vena cava (IVC) (collapse of the IVC during inspiration)

* Decrease in the difference between left ventricular area during diastole and systole (indicates low cardiac output secondary to right ventricular failure and represents cardiogenic shock)

* Pulmonary hypertension (as calculated by the modified Bernoulli equation)

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Estimation of Pulmonary Artery Systolic Pressure by Echocardiography

Modified Bernoulli Equation:MATH

Pressure Gradient = 4 × V2

where V = peak velocity of the TR jet

4 × V2 + estimated RA pressure = estimated PA systolic pressure

The calculation is most subject to error when RA pressure is estimated and when pulmonic stenosis is present.

Occasionally, right ventricular dysfunction will be observed in the absence of pulmonary hypertension. In these cases, the differential diagnosis should also include cardiomyopathy and right ventricular infarction in addition to acute PE. Right ventricular dilatation and hypokinesis may occur in chronic pulmonary hypertension of any cause. Long-term elevation of right ventricular afterload is usually accompanied by right ventricular hypertrophy. In patients with chronic pulmonary hypertension, the velocity of the tricuspid regurgitant jet may be elevated to a greater level than in patients with acute PE and no underlying cardiopulmonary disease. Disease processes such as primary pulmonary hypertension tend to exhibit more global right ventricular hypokinesis when compared with the regional abnormalities seen in acute PE.

For those patients in whom transthoracic imaging is unsatisfactory, transesophageal echocardiography (TEE) can be carried out. TEE has the potential to diagnose PE by directly visualizing the thrombus rather than indirectly through signs of right ventricle dysfunction. Of particular importance, TEE can provide an assessment of the extent and surgical accessibility of pulmonary thromboembolic disease needed in patients being considered for emergent pulmonary embolectomy. TEE can provide excellent visualization of the main pulmonary artery and right pulmonary artery until it divides into lobar branches. The left pulmonary artery is more difficult to evaluate because of interference from the left main bronchus.

Transesophageal echocardiography may have a unique role in the evaluation of patients with sudden unexplained cardiac compromise and pulseless electrical activity. Occult acute PE should be considered in these patients: a recent series of 1,246 patients presenting with cardiac arrest revealed PE in 5% of patients (of which 63% had pulseless electrical activity). If possible, TEE for evaluation of proximal hemodynamically significant PE should be undertaken as quickly as possible in appropriate patients during resuscitation.26–30

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Contrast Pulmonary Angiography

Contrast pulmonary angiography remains the gold standard study for patients with suspected PE. Pulmonary angiography is best used to resolve the dilemma of nondiagnostic lung scanning, spiral CT, normal venous ultrasonography, and normal echocardiography in the setting of high clinical suspicion. It is an invasive test that carries a small but real risk of morbidity and mortality. Out of 1,111 PIOPED patients, five patient deaths were attributed to complications of pulmonary angiography. Nevertheless, contrast pulmonary angiography is considered to be safe when performed by experienced angiographers.31

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Pulmonary Embolism Diagnosis: An Integrated Approach

An integrated diagnostic approach that includes judicious use of initial screening tests with further imaging studies is essential in making the diagnosis of PE. The following is a proposed protocol for the diagnosis of PE.

As with all medical conditions, the workup for PE should begin with a thorough history and physical examination. As clinical suspicion for PE develops, a chest radiograph and D-dimer ELISA should comprise the initial investigative tests (Figure 1). A negative chest radiograph and D-dimer allow the workup for PE to stop. However, a positive D-dimer warrants an imaging study. In patients with significant abnormality on chest radiography, significant history of pulmonary disease, or suspicion of a massive PE, a spiral chest CT may be ordered (Figure 2). A positive spiral CT requires treatment for PE, whereas in a setting of low clinical suspicion, a negative spiral CT should prompt investigation for an alternative diagnosis. A negative spiral CT scan in a patient whose presentation arouses intermediate or high clinical suspicion for PE indicates that other diagnostic tests are needed, including leg vein ultrasound and, possibly, a pulmonary angiogram. In patients without significant abnormality on chest radiography, a ventilation-perfusion lung scan should be sought (Figure 3). A normal or near normal study requires no further evaluation for PE. Likewise, a high-probability lung scan requires no further study and rather warrants prompt risk stratification and treatment. An intermediate-probability reading poses a diagnostic dilemma and therefore should be followed by further studies. A venous ultrasound to evaluate for DVT as a source of pulmonary emboli should be done and if positive allows for treatment of both the DVT and the suspected PE. A negative venous ultrasound in the setting of continued clinical suspicion calls for invasive evaluation for PE via contrast pulmonary angiography.

Figure 1

Figure 1

Figure 2

Figure 2

Figure 3

Figure 3

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Diagnosis of Deep Venous Thrombosis

Clinical Clues

History: Usually described in the lower extremities, DVT may also be seen in the upper extremities in association with central venous lines and thoracic outlet obstructive syndromes. Lower extremity DVT is often first noticed as an increasingly annoying “pulling sensation” at the insertion of the lower calf muscle into the posterior portion of the lower leg. This insidious feeling can then become more pronounced and accompanied by warmth, swelling, and erythema.

Physical Examination: Tenderness may be present along the course of the involved veins, and a cord may be palpable. Additional signs include increased tissue turgor, distension of superficial veins, and the appearance of prominent venous collaterals. The Homan sign, which is increased resistance or pain during dorsiflexion of the foot, is unreliable and nonspecific.

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Symptoms and signs

* Insidious, progressive, annoying “pulling sensation” where lower calf muscle inserts into posterior aspect of the leg.

* Warmth, swelling, tenderness because of increased tissue turgor/distension.

* Occasional palpable cord and prominent superficial collaterals.

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Differential Diagnosis The differential diagnosis of DVT includes:2

* Phlebitis without thrombosis

* Superficial thrombophlebitis

* Venous insufficiency without acute thrombosis

* Ruptured Baker cyst

* Muscle or soft tissue injury (hematoma)

* Cellulitis

* Lymphangitis

* Lymphedema

* Peripheral edema secondary to congestive heart failure, severe liver disease, renal failure, or nephrotic syndrome

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Imaging Tests

Venous Ultrasonography with Color Doppler

When DVT is suspected, venous ultrasonography should ordinarily be the first test that is ordered. Venous ultrasound is usually excellent for diagnosing or excluding an initial episode of DVT in symptomatic patients. For reasons that are unclear, it is quite insensitive for detection of asymptomatic DVT, particularly after orthopedic surgery or neurosurgical procedures. Venous ultrasound should not be used to rule-in or rule-out PE.

Venous ultrasonography routinely entails a combination (called “duplex”) of vein compression (B mode imaging) and pulsed Doppler spectrum analysis with or without color. Normally, manual pressure of the transducer applied to the surface of the skin will cause the vein walls to collapse. Failure to compress a vein is the cardinal sign of DVT on ultrasound examination. Isolated calf vein thrombosis may be accurately detected on ultrasound examination but this will depend on the skill of the examiner. Venous ultrasound is limited in the abdomen (e.g., pelvic veins) and thorax (e.g., subclavian vein) because these veins cannot be compressed because of anatomic constraints.

The venous ultrasound examination is inadequate for diagnosis of pelvic vein thrombosis. When ovarian or other pelvic vein thrombosis is suspected, magnetic resonance imaging (MRI) and contrast CT are the preferred imaging tests. Ultrasonography may suffice for detection of an extensive upper extremity DVT. However, because the anatomy may hinder the identification of small- and medium-sized thromboses, MRI or contrast venography should be considered.

If the clinical suspicion of DVT is high even though the ultrasound is normal, this discrepancy should be pursued by obtaining another imaging test rather than by relying on the ultrasound examination as the final arbiter. The choice usually lies between contrast venography and MRI. The biggest disadvantage of contrast venography is that with massive DVT, none of the deep veins of the leg can be filled with contrast agent and, therefore, the diagnosis of DVT must be inferred merely by failure to fill the deep venous system. The results from a properly obtained MRI are usually more definitive than contrast venography. MRI can also help determine whether a visualized thrombus is acute, subacute, or chronic. Unlike venography, MRI is noninvasive and, therefore, has greater patient and physician acceptability. No contrast agent is needed, so the risks of anaphylaxis and renal failure are averted.

The diagnoses of recurrent DVT and acute venous insufficiency can mimic each other, yet their management differs drastically. Recurrent DVT requires immediate and intensive anticoagulation, whereas venous insufficiency can be managed by prescribing vascular compression stockings, without hospitalization. Duplex scanning may identify acute thrombus superimposed on chronic thrombus. However, if ultrasound examination is inadequate, MRI or contrast venography is usually recommended when confronted with this diagnostic dilemma.32–37

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Magnetic Resonance Venography

Magnetic resonance venography can provide detailed imaging of the venous system while also estimating the age of thrombus. MRI is most helpful in the evaluation of suspected pelvic vein thrombosis and upper extremity DVT. MR venography is also an excellent second test when the clinical suspicion of DVT is high but the venous ultrasound is negative.

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Contrast Venography

Contrast venography is useful if there is a discrepancy between the venous ultrasound and the clinical evaluation (e.g., low clinical suspicion and positive venous ultrasound or high clinical suspicion and negative venous ultrasound) and to help differentiate acute from chronic thrombosis and acute superimposed on chronic thrombosis. It is important to note that contrast venography may not provide a definite diagnosis when there is complete obstruction of the deep vein that prevents passage of contrast.

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Other Methods

Platelet scintigraphy, which uses 111Indium oxine labeling, has recently been shown to be a potentially useful adjunct in diagnosis of DVT and in evaluation of effects of anticoagulant therapy. Methods involving radiolabeled peptides such as glycoprotein IIb/IIIa receptor antagonists are currently under investigation.38

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Risk Stratification of Patients with Acute Pulmonary Embolism

Pulmonary embolism presents as a broad spectrum of clinical syndromes. These presentations may range from small emboli causing only minimal symptoms to marked hemodynamic instability culminating in cardiogenic shock. The majority of patients fall between these extremes on presentation, and yet some go on to suffer rapid deterioration and adverse outcomes. Traditionally, patients were risk stratified on the basis of hemodynamics and were classified as either “unstable” with a systolic blood pressure less than 90 mm Hg or as “normal.” It is now understood that although most patients present with “normal” hemodynamics, many of these have evidence of right ventricular dysfunction and the potential to experience adverse outcomes if treated as “stable” patients. Thus, risk stratification of the PE patient is an integral part of management because certain subsets of patients are at higher risk for poor outcomes and recurrent disease. These patients, if identified early enough, may benefit from aggressive management strategies such as thrombolysis or embolectomy. Echocardiography and elevated cardiac troponins should be used to risk-stratify patients.

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History and Physical Examination

A recent study evaluating clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER) revealed several variables derived from the histories and physical examinations of acute PE patients that proved to be significant independent predictors of increased mortality at 3 months (Table 2).

Table 2

Table 2

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Echocardiographic Risk Stratification

Echocardiography is an excellent tool for risk stratification and prognostication in patients with acute PE. Several echocardiographic findings including right ventricular dysfunction are well-established predictors of adverse outcomes in PE.

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Right Ventricular Dysfunction

Right ventricular dysfunction has proven to be one of the most powerful predictors of mortality and recurrent PE. Normotensive patients with no evidence of right ventricular dysfunction enjoy excellent outcomes with anticoagulation. There is mounting evidence that normotensive patients with echocardiographic findings of right ventricular dysfunction are not stable and benefit from aggressive interventions such as thrombolysis and embolectomy. The identification of these high-risk patients by echocardiography has brought into question the traditional conservative view of withholding aggressive therapies such as thrombolysis and embolectomy until patients show evidence of hemodynamic instability.10,39

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Persistent Pulmonary Hypertension

Patients with pulmonary artery systolic pressures greater than or equal to 50 mm Hg at admission have been found to be three times more likely to suffer persistent pulmonary hypertension and right ventricular dysfunction at 6 weeks. Patients with evidence of persistent pulmonary hypertension and right ventricular dysfunction had diminished 5-year survival when compared with patients who had normalized their pulmonary artery pressures by 6 weeks.40

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Patent Foramen Ovale

A patent foramen ovale in combination with PE increases the mortality rate.41

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Free-Floating Right Heart Thrombus

Free-floating right heart thrombus is highly correlated with PE and a poor prognosis.42

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Cardiac Troponin

In a study of 56 patients with documented PE, cardiac troponin T (cTnT) was measured within 12 hours of admission. cTnT was elevated (>= 0.1 μg/L) in 32% of patients with moderate to massive PE but not in patients with small PE. An elevated cTnT correlated with an increased prevalence of in-hospital death (odds ratio 29.6), prolonged hypotension and cardiogenic shock (odds ratio 11.4), need for resuscitation (odds ratio 18.0), and need for pressor support (odds ratio 37.6). cTnT remained an independent predictor of 30-day mortality (odds ratio 15.2). Troponins are probably elevated because of microinfarction of the right ventricle without coronary atherosclerosis. Measuring troponin levels routinely may help improve risk stratification in patients with PE and identify a high-risk population in which more aggressive therapy may be warranted.13

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Management

Pulmonary Embolism: Spectrum of Disease

Massive Pulmonary Embolism

For patients presenting with massive PE and cardiogenic shock, thrombolysis is a life-saving intervention. In a small clinical trial, PE patients with hypotension and heart failure were randomized to thrombolysis with streptokinase plus standard anticoagulation versus anticoagulation alone. After enrolling eight patients, the trial was stopped early because all four patients randomized to anticoagulation alone died, whereas all of those who received thrombolysis survived. Three of the four patients that died were found to have right ventricular infarction in the absence of significant coronary disease. This study supports the consensus belief that thrombolysis is effective in averting death from progressive heart failure in patients presenting with cardiogenic shock.43

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Pulmonary Embolism with Normal Blood Pressure and Right Ventricular Hypokinesis on Echocardiogram

Although less than 5% of patients with acute PE present in cardiogenic shock, many more present with normal blood pressures and evidence of right ventricular dysfunction on echocardiogram. In a multicenter randomized controlled trial, 101 PE patients were randomized to receive rt-PA (100 mg/2 hours) followed by heparin versus heparin alone. Among patients with baseline right ventricular dysfunction, 39% of patients randomized to rt-PA improved right ventricular wall motion whereas 2.4% worsened. Of those randomized to heparin alone, 17% demonstrated improvement in right ventricular function whereas 17% worsened. Even more importantly, no clinical episodes of recurrent PE occurred among rt-PA patients while five clinically suspected recurrent PEs (two of which were fatal) were noted in the heparin only group.

These findings suggest that primary therapy (thrombolysis) should be considered in patients with right ventricular dysfunction and “impending hemodynamic instability” who are at high risk for adverse clinical outcomes including recurrent possible fatal events. However, thrombolysis under these circumstances is a debatable indication and a clinical trial is overdue.44–46

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Pulmonary Embolism with Normal Blood Pressure and Normal Right Ventricular Function on Echocardiogram

Patients with normal blood pressures and normal right ventricular function have a good prognosis when treated with anticoagulation.47

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Deep Venous Thrombosis Location and Extent of Disease

Massive Deep Venous Thrombosis

Pelvic vein thrombosis may occur in the setting of conditions such as pregnancy, ovarian cancer, total hip replacement, or trauma and is often found in combination with proximal DVT of the leg. Iliofemoral DVT often leads to chronic venous insufficiency, especially if the clot itself is not managed with primary therapy such as thrombolysis or embolectomy.

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Superior Vena Cava Syndrome

Superior vena cava syndrome is usually caused by catheter-associated thrombosis (see below) or by DVT associated with extrinsic compression (often by tumor or thoracic outlet obstruction) of the subclavian or other major upper extremity veins. Emergency management may include radiation or chemotherapy to reduce the impingement of the tumor on the upper extremity vessels and steroids to reduce associated edema and inflammation. The bulk of the thrombus may be reduced by employing site-directed thrombolytic therapy, administered through a catheter placed by an experienced interventional radiologist.

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Proximal Leg Deep Venous Thrombosis

This is the most common type of DVT. Proximal DVT by definition involves one of the following veins: the common femoral, superficial femoral, the profunda femoris, or popliteal. Beware that the superficial femoral vein, despite its name, is actually a deep vein.

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Upper Extremity Deep Venous Thrombosis

The subclavian, internal jugular, and axillary veins are most often affected. Underlying causes may include indwelling central venous catheters, anatomic lesions such as a cervical rib, or hypercoagulable states either caused by inherited conditions (e.g., Factor V Leiden) or acquired diseases such as adenocarcinoma.

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Isolated Calf Deep Venous Thrombosis

The previous practice of serial observation alone with two to four ultrasound tests over 7 to 14 days in such patients has shifted to routine treatment with anticoagulation. These patients, if untreated, are at risk of suffering proximal propagation of DVT (approximately 30% of patients), paradoxical embolism, and even fatal PE. It is the small calf DVT that can “fit” and “squeeze” through a patent foramen ovale or small atrial septal defect that usually cause paradoxical embolization. Calf vein thromboses may also be significant as a source of chronic pulmonary emboli.2,48

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Recurrent Deep Venous Thrombosis

It may be difficult to distinguish recurrent DVT from acute venous insufficiency, especially with venous ultrasonography. Nevertheless, the distinction is crucial. Patients with recurrent DVT usually require hospitalization for intensive and immediate heparinization, followed by prolonged, sometimes lifelong, outpatient anticoagulation therapy. However, patients with flare-ups of venous insufficiency can almost always be treated at home, without anticoagulation. Such individuals usually obtain moderate improvement with vascular compression stockings that are carefully measured and fitted. If ultrasound examination is indeterminate, MRI or contrast venography can be especially useful in resolving the diagnostic dilemma of recurrent DVT versus venous insufficiency.

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Therapy for Deep Venous Thrombosis and Pulmonary Embolism

Anticoagulation

Patients with normal systemic arterial pressure and normal right ventricular function generally have a good prognosis after PE. For such individuals, secondary prevention is usually adequate with anticoagulation or, if major bleeding from anticoagulation is likely, with placement of an inferior vena caval filter. Anticoagulation is also the foundation for DVT management. Patients with active and major bleeding will need placement of an inferior vena caval filter if they have pelvic or proximal leg DVT. Although the filter will not prevent continued venous thrombosis, it is usually effective in preventing fatal PE arising from the pelvic or deep leg veins.

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Continuous Infusion of Unfractionated Heparin

Dose-adjusted intravenous heparin is the foundation for immediate management of acute PE or DVT. Heparin acts by preventing new thrombus from forming and allowing endogenous fibrinolytic mechanisms to lyse thrombus. If venous thromboembolism is strongly suspected, continuous infusion of unfractionated heparin should be initiated immediately, before lung scanning or venous ultrasonography are undertaken.

For patients with PE, treatment with unfractionated heparin is usually initiated with a bolus of 5,000 to 10,000 U followed by a continuous intravenous infusion with a rate between 1,000 to 1,500 U/h. The rate is titrated to an activated partial thromboplastin time between two to three times normal (approximately 60-80 seconds). Use of heparin nomograms that are weight-based may allow for more rapid attainment of a target activated partial thromboplastin time. A weight-based heparin nomogram was proposed by Raschke and colleagues (Table 3).

Table 3

Table 3

Standard anticoagulation requires continuation of intravenous unfractionated heparin for 5 to 7 days with simultaneous initiation of oral anticoagulants.47,49

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High-Dose, Adjusted Subcutaneous Unfractionated Heparin

This approach is useful for avoiding intravenous lines, but the absorption of unfractionated heparin is hindered by its suboptimal bioavailability. Typically, subcutaneous unfractionated heparin is poorly absorbed during the first few days of administration. Afterwards, the heparin is rather suddenly released from fat depots into plasma, resulting in a pattern of delayed therapeutic anticoagulation in many patients, with subsequent excessive anticoagulation.50

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Low Molecular Weight Heparin

Low molecular weight heparins (LMWH), such as enoxaparin, inhibit activated coagulation factor X (FXa) via conformational change of the antithrombin III molecule. The longer half-life, better bioavailability, and more predictable response of LMWH make it easy to administer subcutaneously without the need for routine laboratory monitoring. Of note, LMWH is renally cleared, unlike unfractionated heparin, which is largely cleared by the liver.

Multiple trials have shown that LMWH (dosed by body weight) is at least as effective and safe as unfractionated heparin in DVT. A meta-analysis of randomized of LMWH versus continuous intravenous heparin for DVT found that LMWH had a 30% decrease in mortality, 40% reduction in major bleeding events, and one-third lower rate of thrombocytopenia when compared with unfractionated heparin. LMWH also allows for shorter hospitalizations, improved physical and social functioning, and overall cost savings.

Currently, the LMWHs, enoxaparin and recently tinzaparin, have been approved for use in the US. The US Food and Drug Administration has approved enoxaparin for outpatient treatment of DVT with or without PE, as a bridge to warfarin. Two dosing regimens exist: 1 mg/kg subcutaneously every 12 hours for both outpatients and inpatients and 1.5 mg/kg subcutaneously once daily for inpatients (Table 4).

Table 4

Table 4

The PTT should not be used to monitor or adjust LMWH dosing because the PTT will often be misleadingly low, despite a therapeutic concentration of LMWH. Instead, the plasma anti-Xa level should be used. This is often called a “heparin level.” The target anti-Xa activity for therapeutic indications is 0.3 to 1.0 anti-Xa IU/mL. Anti-Xa levels should be checked 4 to 6 hours after the second or third dose of LMWH. Patient populations that may require anti-Xa levels include those with renal insufficiency and massive obesity.51–54

Heparin-induced thrombocytopenia (HIT) is more common than is widely believed. HIT is caused by heparin-dependent IgG antibodies that are directed against an antigen complex of heparin and platelet factor 4. HIT IgG causes primarily venous procoagulant effects via platelet and endothelial activation and heparin neutralization. HIT must be distinguished from an early mild decrease in platelet count that generally recovers within 3 days despite continued use of heparin. HIT should be suspected in patients who experience a platelet count decrease of greater than 50% of baseline in association with even small amounts of heparin (such as heparin flush solutions) or in patients who experience new thromboembolic events while receiving heparin. HIT typically occurs 4 to 14 days after initial heparin exposure. Of note, thrombocytopenia from HIT rarely causes bleeding.

Laboratory tests for heparin-induced platelet aggregation are insensitive. The “gold standard” test is an ELISA that measures heparin-platelet factor 4 complexes.

There are several “do's” and “don'ts” in the management of HIT. Warfarin should be avoided because its use in the presence of a procoagulant state can precipitate limb gangrene. Platelet infusions simply add “more fuel to the fire.” IVC filters can result in devastating caval, pelvic, and leg thrombosis. Finally, LMWH, while less likely to initiate HIT, will often cross-react with the IgG antibodies once HIT has occurred. Treatment options for HIT include recombinant hirudin and the recently approved argatroban. Argatroban has a shorter half-life than hirudin and, unlike hirudin, does not require downward dose adjustments for renal insufficiency. Although HIT is not a standard indication, plasmapheresis may also be used.55–57

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Warfarin

After initial therapy with heparin, patients with venous thromboembolism require long-term anticoagulation to prevent recurrent events. Warfarin is extremely effective in preventing recurrence of venous thromboembolism but carries a significant risk of hemorrhage.

In general, “loading” patients with initial doses greater than 5 mg daily has been associated with an increased risk of bleeding events and is not recommended. For most patients with venous thromboembolism, a therapeutic INR range of 2.0 to 3.0 can be achieved within 5 to 7 days. Dose adjustments of greater than 20% of the previous dose should be avoided if possible. Changes in the INR are most reflective of the warfarin dose given 3 to 5 days previously.

Special attention should be paid to drug interactions with warfarin. Acetaminophen, antibiotics such as trimethoprim/sulfamethoxazole and the cephalosporins, and COX-2 inhibitors such as celecoxib can potentiate the effects of warfarin. One percent to two percent of patients have a genetic mutation of cytochrome P450 that causes slow metabolism of warfarin. These patients require less then 2 mg daily of warfarin.

Currently, the standard duration of anticoagulation for upper extremity or isolated calf DVT is 3 months. For proximal leg DVT or PE, 6 months of anticoagulation is recommended. However, the recent DOTAVK trial showed equivalence of shorter anticoagulation (6 weeks for isolated calf DVT and 3 months for proximal leg DVT or PE) to the currently recommended course.58 Patients who suffer from idiopathic DVT or PE and recurrent venous thromboembolism may benefit from longer treatment. The ongoing PREVENT trial is addressing this point. Please contact Dr. Samuel Z. Goldhaber (sgoldhaber@partners.org) to discuss enrolling patients with idiopathic PE or DVT in the NIH-sponsored PREVENT Trial.

The following are tips for outpatient anticoagulation:

* Insist on detailed and explicit communication among physicians and nurses from different disciplines. Make no assumptions about who will regulate anticoagulation.

* Explain to the patient and family the rationale for anticoagulation and the major risks from too intensive therapy (i.e., hemorrhage) and too little therapy (i.e., thromboembolism). The patient and family should understand the relationship between the prothrombin time, international normalized ratio, and dosing adjustments of anticoagulant.

* Consider fingerstick testing of prothrombin time/INR/partial thromboplastin time. Self-management using point-of-care fingerstick INR machines has been shown to reduce the incidence of out-of-range INRs and improve quality of life and patient satisfaction.

* Whenever possible, use a software-supported electronic surveillance system rather than a paper notebook-based system. This system should flag patients in whom an expected laboratory value has not yet been reported.

* Arrange for laboratory values to be reported as the international normalized ratio rather than as the prothrombin time in seconds or as the prothrombin time ratio.

* Consider use of centralized “anticoagulation clinics”.47,58–61

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Paradoxical Thrombosis with Warfarin Alone

Dutch investigators tested the strategy of managing uncomplicated DVT by just using oral anticoagulation without concomitant heparin. They compared this approach with standard anticoagulation that combines heparin with oral anticoagulation until the oral anticoagulation is fully effective. The recurrence rate of symptomatic thrombosis was three times higher in the group that received oral anticoagulation alone. Initiation of warfarin in the presence of active venous thrombosis is believed to cause paradoxical thrombosis because of early depletion of proteins C and S while clotting factors that are inactivated more slowly remain unopposed. Therefore, patients with acute venous thrombosis should receive heparin until oral anticoagulants have become fully effective, a process that usually takes about 5 days.62

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Correction of Excessive Oral Anticoagulation

In the event of excessive oral anticoagulation, low-dose oral vitamin K is recommended over high-dose oral or subcutaneous vitamin K. In general, high doses of vitamin K do not decrease the INR faster than lower doses and instead make the patient temporarily refractory to future anticoagulation. Withholding one to two doses of warfarin and giving 2.5 mg of oral vitamin K has been shown to be effective in reversing excessive anticoagulation.63,64

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Inferior Vena Caval Filters

Indications for IVC filter placement:

Pulmonary embolism or recurrent PE despite adequate anticoagulation

Contraindications to anticoagulation

Open surgical pulmonary embolectomy

Limitations:

IVC filter placement does not address the thrombotic process. (Therefore, whenever possible, patients should be anticoagulated, even if this is not feasible at the time of IVC filter insertion.)

Peripheral leg edema can ensue.

Large venous collaterals can develop and permit PE.

Filters may fail because of technical problems, such as filter tilt or improper deployment of filter legs with the Greenfield filter.

Increased incidence of DVT

Lack of mortality benefit

Although effective for the prevention of PE, IVC filters appear to increase the DVT rate in the absence of concomitant anticoagulation. In a randomized study of 400 patients, IVC filters initially reduced the incidence of PE but at 2 years increased the incidence of DVT to 21% compared with 12% in those without filters (P = 0.02). The mortality rate at 2 years was no different between the two groups. Another study revealed that patients with filters were more likely to be rehospitalized for DVT.

(NOTE: MRI may be performed 10 to 14 days after IVC filter placement.

For suprarenal placement, a Greenfield filter should be used because it is the only IVC filter with data confirming its efficacy and safety in this position.65–67)

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Primary Therapy: Pulmonary Embolism and Deep Venous Thrombosis

Thrombolysis

For PE, thrombolysis is lifesaving in patients with massive PE and cardiogenic shock. Although hemodynamic collapse is an ominous sign, few patients with PE present in cardiogenic shock. Much more commonly, PE patients demonstrate normal systemic arterial pressure combined with occult right ventricular dysfunction that is detectable only on echocardiographic evaluation. The presence of moderate or severe right ventricular hypokinesis, even in the absence of systemic arterial hypotension, implies “impending hemodynamic instability” and suggests that primary therapy for PE with thrombolysis or embolectomy be strongly considered. Thrombolysis has been shown to improve clinical outcomes in patients with preserved blood pressure but worsening right ventricular dysfunction. The efficacy of PE thrombolysis appears to be inversely proportional to duration of symptoms, and delay seems to attenuate resolution of the obstruction on angiography especially outside of a 2-week “window period.”68–71

For DVT, thrombolysis should theoretically restore venous valve patency and function, although this has not been proven. Deep venous thrombolysis is most helpful in patients with upper extremity thrombosis secondary to a long-term indwelling central venous catheter that must remain in place. Thrombolytics may also be used in young otherwise healthy patients with iliofemoral DVT with marked swelling and pain-limiting walking. Unlike thrombolysis in PE, which may be administered peripherally, thrombolytics should be catheter-directed into the DVT. Peripherally administered thrombolytics cannot gain access to the totally obstructed deep venous system.72,73

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Administration of Thrombolytics

All patients being considered for thrombolysis should be meticulously screened for contraindications including:

Intracranial disease

Recent surgery

Recent trauma

Severe or uncontrolled hypertension

Recent prolonged cardiopulmonary resuscitation

Systemic administration regimens:

FDA-approved regimen for acute PE (approved in 1990): t-PA: 100 mg as a continuous peripheral intravenous infusion administered over 2 hours

Other PE thrombolytic regimens (not FDA-approved):

Reteplase: 10 U intravenous over 2 minutes, followed in 30 minutes by another 10 U intravenous

Streptokinase: 1,500,000 U administered over 1-2 hours

(NOTE: None of the FDA-approved regimens for PE thrombolysis employs concomitant heparin. This is an important distinction from thrombolysis in myocardial infarction. At the end of thrombolytic infusion in PE patients, the PTT should be obtained. If the PTT is less than twice the upper limit of normal, heparin may be initiated or resumed without the need of a loading dose. If the PTT is greater than twice the upper limit of normal, the test should be repeated every 4 hours until it falls in the range in which heparin may be administered.)

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Complications

The complications of thrombolysis largely pertain to bleeding, especially intracranial hemorrhage. ICOPER, a registry (not a controlled clinical trial), reported a 3.0% risk of intracranial hemorrhage.10

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Open Surgical Embolectomy

Open surgical embolectomy should be considered as soon as a decision has been made that PE is causing moderate or severe right heart dysfunction and that thrombolysis is contraindicated or has failed. Other indications for surgical embolectomy include persistent right heart thrombi and acute profound hemodynamic or respiratory compromise requiring cardiopulmonary resuscitation. In general, surgical embolectomy is most effective in saddle or main pulmonary artery embolism. Of note, an inferior vena cava filter is often placed postoperatively as the patient cannot be fully anticoagulated acutely after surgery secondary to risks of hemorrhage.74

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Catheter-Assisted Embolectomy

In patients with massive PE evidenced by signs of right heart failure or right ventricular dysfunction on echocardiogram and obstruction of a main artery or two or more lobar arteries, catheter-assisted embolectomy may be considered. This intervention is often elected when thrombolysis is contraindicated and as an alternative to open surgical embolectomy. Catheter-based techniques work best on fresh thrombi and are therefore most effective within the first 5 days of evolution of PE or DVT. Some of the most recent experience with catheter-based techniques involves a suction-catheter that acts by fragmenting thrombus and evacuating the debris.75

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Prevention

Venous thromboembolism prophylaxis should be virtually universal among hospitalized patients. Prophylaxis should be considered even after discharge for immobile or postoperative patients. The various prophylaxis modalities include graduated compression stockings, intermittent pneumatic compression boots, and IVC filters and heparin, warfarin, and aspirin.76

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IVC Filters

While effective for the prevention of PE, IVC filters appear to increase the DVT rate in the absence of concomitant anticoagulation. In a randomized study of 400 patients, IVC filters initially reduced the incidence of PE but at 2 years increased the incidence of DVT to 21% compared to 12% in those without filters (P = 0.02). The mortality rate at 2 years was no different between the two groups. Another study revealed that patients with filters were more likely to be rehospitalized for DVT.65–67

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Prophylactic Anticoagulation

Prophylactic anticoagulation may be accomplished safely and effectively in most hospitalized individuals including both medical and surgical patients.

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Medical Patients

The Medenox study examined the efficacy of the LMWH enoxaparin in preventing all venous thromboembolic events and proximal DVT. The study revealed that enoxaparin at 40 mg subcutaneously daily reduced the incidence of all venous thromboembolic events to 5.5% versus 14.9% for placebo and decreased the risk of proximal DVT to 1.7% versus 4.9% in the placebo arm. Enoxaparin 20 mg subcutaneously daily did not appear to reduce the incidence of venous thromboembolic events. The incidence of adverse events did not differ significantly between the groups. A meta-analysis among medical patients revealed a 52% decrease in risk of major hemorrhage among patients treated with LMWH compared with unfractionated “mini-heparin” (doses of 10,000-15,000 IU daily given in two or three times per day injections).77,78

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Surgical Patients

Among virtually all surgical patients, prophylaxis is of integral importance, as many patients are hypercoagulable after surgery and immobile because of pain or activity restriction. In a study of orthopedic patients, 76% of thromboembolic events after total hip arthroplasty and 47% of the events after total knee arthroplasty were diagnosed after discharge from the hospital. In fact, the risk of DVT and PE remained elevated up to 10 weeks after hip arthroplasty and up to 4 weeks after knee arthroplasty. These findings support the belief that posthospitalization DVT and PE are important problems and that prophylactic anticoagulation should continue after discharge.79

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Hip Fracture Patients

In the PEP trial of hip fracture patients, aspirin was shown to reduce incidence of DVT and PE in patients undergoing surgery for hip fracture and elective arthroplasty when compared to placebo. Similarly proportional reductions in risk were seen in patients also receiving other prophylaxis such as subcutaneous heparin. We do not endorse using aspirin alone for hip fracture venous thromboembolism prophylaxis despite the results of the PEP trial.80

Table 5 provides recommended prophylaxis strategies.

Table 5

Table 5

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