Chapter 56: Venous Thromboembolism

Pulmonary embolism (PE) occurs when clotted blood enters the pulmonary arterial circulation. Most PEs result from deep vein thrombosis (DVT) in the legs, arms, or pelvis and occasionally from the jugular vein or inferior vena cava. The term venous thromboembolism (VTE) includes PE and DVT.

In the United States, approximately 200,000 people will have new or recurrent PE diagnosed each year, and twice that many will have DVT without confirmed PE.¹ VTE collectively affects about 1 in 500 persons per year in North America, and about 1 in every 300 adult ED patients receive the diagnosis (Figure 56-1). The incidence of VTE increases with age, peaking at 1 in 100 per year at age 80. Based on autopsy data, PE is the second leading cause of sudden, unexpected, nontraumatic death in outpatients.² The case fatality rate from PE depends on the hemodynamic severity of the PE, age, and comorbid conditions; the case fatality rate is 45% for PE with circulatory shock, but only about 4% to 5% of patients with PE have shock. In patients with hemodynamically stable PE who are less than 50 years old and without other comorbidities, the case fatality rate is 1%.³

Morbidity from DVT includes PE and the postthrombotic syndrome. The latter is manifested as chronic leg swelling and pain and occurs in about 20% of all ED patients with proximal DVT.⁴ Both DVT and PE present across a spectrum of severity, with recognition of minor forms of the disease, including distal PE (called subsegmental) and distal DVT, usually in the calf or saphenous veins.⁵

Blood clots occur when coagulation exceeds the removal by fibrinolysis. Thrombophilias are conditions that tip the balance of coagulation-fibrinolysis toward excessive clotting. Most guidelines categorize VTE as provoked (or secondary) or unprovoked (idiopathic).⁶ Provoked VTEs are acquired and often time-limited conditions, generally often following recent surgery, trauma, or any condition associated with limb or body immobility; active cancer is a VTE provoker that often persists. Other provoking factors generally include diseases or conditions that impede venous blood flow, infection, chronic disease, estrogen use, pregnancy or initial postpartum interval, and age >50 years (each year after 50 increases the risk). Unprovoked VTE patients have no known risk factors, suggesting an increased tendency to clot.

Most VTEs diagnosed in the ED are unprovoked.^3,7 Patients with unprovoked VTE have a 15% chance of recurrence in the next year compared with 5% for those with a provoked episode. For this reason, those with unprovoked VTE usually receive longer treatment than patients with provoked VTE.⁸ Those with provoked VTE have a higher 1-year death rate, likely from the comorbid conditions (notably cancer).⁹

Venous thrombi that are large enough to cause clinically important PE can form in the popliteal, common femoral, superficial femoral, pelvic, axillary, jugular, and great veins. At least one third of patients with DVT have concomitant PE, even when the patient lacks symptoms of PE.¹⁰ Although 75% to 80% of hospitalized patients with PE have image-demonstrated DVT, only 40% of ambulatory ED patients with PE have concomitant DVT.¹¹

Blood clots that form in the large veins of the legs, especially the femoral and iliofemoral veins, usually begin on the valves, leading to scarring and poor function of the venous valves. This causes pooling of venous blood in the legs, leading to varicose veins, pain, swelling, skin hyperpigmentation, and ulcers, known as the postthrombotic syndrome.⁴ With PE, the correlation between the degree of initial pulmonary vascular obstruction and clinical severity is weak, but patients without prior heart or lung disease generally begin to experience symptoms from PE when approximately 20% of lung vasculature becomes occluded.¹² With larger clot burden, the pulmonary arterial pressure increases, leading to right ventricular dilation and myocardial damage, causing the release of troponin and B-type natriuretic peptide. Right ventricular dilation or injury, as evidenced on CT or echocardiography or suggested by elevated troponin or B-type natriuretic peptide, indicates right heart failure and increased risk of circulatory shock and death.¹³ The two principle mechanisms of death from PE appear to be abrupt near-total pulmonary artery occlusion that leads to pulseless electrical activity and asystole from ischemic effect on the His-Purkinje conduction system. Approximately one third of survivors of large PEs go on to have persistent right heart dysfunction and severe symptoms.¹⁴ Approximately 5% of patients with PE go on to experience chronic pulmonary vascular obstruction, leading to progressive damage to the lung vessels and right heart with disabling dyspnea and pulmonary hypertension, called chronic thromboembolic pulmonary hypertension.

Inherited thrombophilias increase risk of first-time VTE, although most of these patients are unaware of this condition until a clot occurs. The risk of recurrent VTE in those with a known thrombophilia is the same as in those who have had a prior unprovoked VTE absent that condition.¹⁵

With limb immobility, the risk increases depending on joint, as follows: elbow (least), shoulder, ankle, knee, and hip (most). Acute immobilization of the hip and knee in one leg with non–weight bearing causes the greatest risk for VTE, whereas immobilization of the wrist alone probably causes no risk. In addition to the presence of limb immobility, risk of VTE increases with whole-body immobility or neurologic immobility, but not by travel, even if >8 hours.¹⁶

Over half of patients with postoperative PE receive the diagnosis after hospital discharge, and the average time from surgery to PE diagnosis is >10 days. Risk increases with patient age, longer surgery, open surgery, and surgery in which thromboprophylaxis is not used. The highest-risk surgeries include abdominal surgery to remove cancer, joint replacement surgery, and surgery on the brain or spinal cord in the setting of neurologic deficits. However, the risk of recurrence after surgery-provoked VTE is generally lower than for unprovoked VTE, although the 4-year risk of recurrence ranges from 5% to 11% per year depending on the surgical procedure.¹⁷

Thrombogenic potential of cancer varies with host factors, tumor stage, and tumor type. In general, the more undifferentiated the cell type and the larger the tumor burden (especially distant metastasis), the higher is the risk. Cancers that are particularly thrombogenic include adenocarcinoma, glioblastoma, metastatic melanoma, lymphoma, and multiple myeloma.¹⁸ Pancreatic, stomach, ovarian, and renal cell cancers carry notoriously high risk.

Cancers with minimal risk of VTE include localized breast, cervical, prostate, and nonmelanomatous localized skin cancers such as squamous cell carcinoma and basal cell carcinoma not treated with chemotherapy. However, about 10% of patients with advanced-stage breast cancer or with breast cancer undergoing chemotherapy develop symptomatic VTE. VTE risk is high during the induction phase of chemotherapy, especially if treated with L-asparaginase and bolus fluorouracil or tamoxifen. Concomitant treatment with red blood cell growth factors such as erythropoietin increases risk of thrombosis, regardless of tumor type or stage.¹⁸ Similarly, multiple myeloma patients treated with lenalidomide or thalidomide are at high risk of VTE.¹⁹

A family history of VTE increases longitudinal risk of VTE,²⁰ although this has no impact on outcomes.⁷ Although sex does not play a role in first-time VTE, men have more recurrent VTE.⁸

Table 56-1 presents a list of risk factors for VTE relevant to ED practice.

Although smoking causes conditions that increase risk (e.g., cancer) and acts synergistically with obesity and possibly oral contraceptive use, smoking is not an independent risk factor for VTE.⁷

PE symptoms range from none to sudden death. Patients with similar comorbidities and clot burden may have drastically different clinical presentations. Table 56-2 lists factors that affect symptoms.

The hallmark of PE is dyspnea unexplained by auscultatory findings, ECG changes, or clear alternative diagnosis on chest radiograph. Chest pain with pleuritic features is the second most common symptom of PE, although about one half of all patients diagnosed with PE in the ED have no complaint of chest pain.⁷ The classic PE pain is in the thorax between the clavicles and the costal margin that increases with cough or breathing; it is not purely substernal and not manifested from the skin or muscle. Pulmonary infarction can inflict severe focal pain, although most patients with PE and pleuritic chest pain have no radiographic evidence of pulmonary infarction. Pulmonary infarction in basilar lung segments can manifest as referred pain to either shoulder or mimic biliary or ureteral colic. Proximal PE without infarction can also cause pleuritic chest pain without focal pain.

HISTORY

In addition to the common symptoms of chest pain and dyspnea, approximately 3% to 4% of ED patients with PE have syncope, and another 1% to 2% present with new-onset seizure (or convulsion-like activity) or confusion.³ Because about 20% of people have a patent foramen ovale, PE that increases right-sided pressures can lead to right-to-left transit of thrombotic material in the atria and showers into the brain circulation, producing stroke-like symptoms called the paradoxical embolism syndrome. Neurologic symptoms can vary widely, from classic localized findings to staring spells, transient altered mental status, and atypical myelopathy symptoms (e.g., numbness below the waist), all of which can fluctuate.²¹ Presence of a patent foramen ovale worsens the prognosis in PE.

PHYSICAL EXAMINATION

On physical examination, abnormal vital signs suggest acute cardiopulmonary stress in a patient with PE: tachycardia, tachypnea, a low pulse oximetry reading, and sometimes mild fever. Unfortunately, PE does not predictably alter any vital sign; approximately one half of patients with proven PE have a heart rate of <100 beats/min at diagnosis, and approximately one third have abnormal early vital signs that normalize in the ED.²² The mechanism of altered vital signs results in obstruction to blood flow and clot-derived autacoids, which together stimulate adrenergic efferent fibers to the heart and cause ventilation–perfusion mismatch on the lungs. The amount of clot burden does not predict vital sign changes reliably, with no clear correlation between measured clot and initial heart rate or oximetry. Although approximately 10% of patients with PE have an oral temperature of >38°C (100.4°F), <2% of patients with PE have a temperature of >39.2°C (102.5°F).

Most patients with PE have clear lungs on auscultation. Wheezes or bilateral rales make an alternative diagnosis of bronchospasm or pneumonia possible but do not exclude PE. For example, pulmonary infarction may produce rales over the affected lung segment. On heart examination, one may hear a right ventricular S₃ or a split S₂ with a loud second sound. The presence of a percutaneous indwelling catheters in the arm increases the probability of axillary vein thrombosis, although it is less clear whether these lines, dialysis catheters, or pacemaker wires also increase the risk of symptomatic PE.

Patients with DVT complain of extremity pain, swelling, or cramping. A difference of ≥2 cm between right and left leg diameter at 10 cm below the tibial tubercle doubles the likelihood of DVT. Patients presenting with upper extremity catheter-related DVT often complain of hand swelling or tightness around finger rings. About one quarter of patients with DVT have tenderness and redness in the swollen extremity, findings that are similar to those of cellulitis. Calf or saphenous vein clots are more likely to cause thrombophlebitis, defined formally as inflammation (pain, tenderness, redness, and swelling) over a vein secondary to the presence of thrombotic material in the vein. Signs and symptoms of thrombophlebitis can persist after the vein has recannulated and the clot has dissolved entirely. Calf vein thrombosis may cause Homan's sign, which is calf pain elicited by passive foot dorsiflexion; this test has such low sensitivity and specificity that it has no predictive value.

Proximal DVT that causes complete venous obstruction leads to increased compartmental pressures, manifested as an extremely painful, swollen extremity. A swollen, painful, and pale or white limb with a proximal venous thrombosis is termed phlegmasia alba dolens, whereas a limb with a dusky or blue color is called phlegmasia cerulea dolens. Either condition poses the threat of limb loss, demanding aggressive treatment that can include thrombolysis or catheter-directed thrombectomy.

Routine cardiopulmonary testing in the ED generally demonstrates nonspecific findings in patients with PE. The mean pulse oximetry reading is lower in patients with proven PE than in those without PE (93 ± 2% vs 95 ± 3%), although this one signal may be absent in those with PE. Similarly, the mean partial pressure of oxygen in arterial blood (Pao₂) is lower (73 ± 19 mm Hg vs 80 ± 21 mm Hg), and the difference between the estimated partial pressure of oxygen in the alveoli (Pao₂) and the measured Pao₂, the alveolar-arterial gradient [P(a-a)o₂], is increased. The arterial partial pressure of carbon dioxide (Paco₂) is usually low, reflecting a 20% to 50% increase in minute ventilation to compensate for loss of lung efficiency secondary to the increased dead space. Spontaneously breathing patients with PE also demonstrate a lower end-tidal carbon dioxide compared with healthy individuals.²³

Most patients with PE have a chest radiograph with one or more abnormalities, including cardiomegaly, basilar atelectasis, infiltrate, or pleural effusion; all are nonspecific for PE. In <5% of patients, a wedge-shaped area of lung oligemia (Westermark sign—usually from complete lobar artery obstruction) or peripheral dome-shaped dense opacification (Hampton hump—always indicative of pulmonary infarction) exists. The presence of hypoxemia or dyspnea with clear lungs on physical exam and imaging suggests PE.

The 12-lead ECG is usually nonspecific, with sinus tachycardia or nonspecific ST- and T-wave changes. When PE causes the right ventricular systolic pressure to exceed 40 mm Hg, the ECG can be more specific, including T-wave inversion in leads V₁ to V₄, incomplete or complete right bundle-branch block, and the classic but uncommon S₁-Q₃-T₃ pattern (Figure 56-2).²⁴ A clinical ECG score allows severity assessment in those with diagnosed PE (higher score equates to higher mortality, Table 56-3).²⁵

DECISION RULES AND CLINICAL ASSESSMENT

Estimating the pretest probability for VTE in a patient is the first step in selecting a diagnostic pathway. Figure 56-3 shows one diagnostic algorithm; no singular diagnostic test or algorithm perfectly excludes or diagnoses VTE. Aggressive diagnostic searches can cause harm disproportionate to benefit from hemorrhage associated with anticoagulation for a false-positive result or self-limited small clot diagnosis or from contrast nephropathy. One approach is to test further only in those with pretest probabilities of >2.5%²⁶; those with a pretest probability of PE <2.5% are more likely to be harmed than helped by a diagnostic test, even a d-dimer assay.

The PE rule-out criteria (Table 56-4) reliably forecast a probability of PE that is below the 2.0% test threshold in patients with a gestalt low clinical suspicion.^27,28 The American College of Emergency Physicians' Clinical Guidelines committee provided a 2b recommendation for the PE rule-out criteria rule.²⁹ The PE rule-out criteria rule had an apparently high failure rate in one secondary analysis done in a European population with a prevalence of disease of 27% in conjunction with a low-risk Geneva score.³⁰ However, the subsequent published erratum to the work showed that the PE rule-out criteria rule had 100% sensitivity in the same population when combined with low gestalt pretest probability as designed, which was also the case in other studies.^28,31 Thus, taken together, the weight of the available information indicates that PE can be reliably excluded by the combination of a low gestalt pretest probability plus a negative PE rule-out criteria rule. However, not all patients who have any positive PE rule-out criteria must undergo an objective test for PE, since anyone over 50 years old would be tested with any finding even if suspicion was low. The key is generating a clinical gestalt first and, if low, using the PE rule-out criteria to guide further testing.

Most validated PE prediction systems categorize the patient into one of two (low or above low probability) or three (low, moderate, or higher probability) categories.³³ One method uses a computerized database-derived method based on the method of attribute matching to estimate a discrete numerical percentage probability of PE.²⁶ The Wells' score is the most robust scoring system for categorizing the pretest probability for both PE (Table 56-5) and DVT (Table 56-6).

The Wells' original rules separate patients into low-, moderate-, and high-probability groups. The Wells' DVT and PE scoring systems both reliably produce a stepwise increase in probability of clot presence with higher scores. The Wells' scoring system has been modified to classify patients being evaluated for possible PE into a low-risk (score ≤4) or a non–low-risk group (score >4), which has become a mainstream method of use.³⁴ The Charlotte rule is designed to categorize patients into either a low-risk or non–low-risk group (designated "safe" or "unsafe" in Figure 56-4).

The Wells' rule has a subjective component—clinical judgment of the likelihood of an alternative diagnosis. Both the Charlotte rule and the revised Geneva score (Table 56-7) exclude subjective assessments.

Runyon et al³⁵ studied the accuracy of unstructured, gestalt estimation of pretest probability for PE, grouping patients into low-, moderate-, and high-risk categories (where the cutoffs suggested to the clinicians were <15%, 15% to 40%, and >40%); the measured frequencies of PE were similar when stratified by Wells' or Geneva scores.³³ Moreover, the interobserver agreement for gestalt classification was good (κ = 0.60), and gestalt estimation did not show a decrease in sensitivity based on training level.³⁵ Gestalt estimation is a viable method to estimate pretest probability and is preferred over no estimation.

d-DIMER TESTING

The d-dimer assay is the best blood test to exclude VTE, working on the principle that clots contain fibrin that is degraded naturally through the action of plasmin. Fibrin breakdown liberates the d-dimer protein into the blood. Multiple manufacturers each produce a slightly different assay, but the d-dimer test can be broadly classified as either qualitative or quantitative. Qualitative tests generally have lower diagnostic sensitivity but higher specificity compared with quantitative tests. Quantitative tests are usually done in the central hospital laboratory and require a turnaround time of at least 1 hour. Different d-dimer assays have different thresholds for normal because of different capture antibodies and optical methods of detection. Some laboratories report results in d-dimer mass concentration (e.g., nanograms per milliliter or micrograms per milliliter), and others report fibrinogen equivalent units. Two fibrinogen molecules produce one d-dimer unit, so that the fibrinogen equivalent unit number is twice the d-dimer number for the same measurement. For PE and DVT, the diagnostic sensitivity of automated quantitative d-dimer assays ranges from 94% to 98% and the specificity ranges from 50% to 60%. The d-dimer has a half-life of approximately 8 hours and can be elevated for at least 3 days after symptomatic VTE.

The most common causes of a false-negative or positive d-dimer result are listed in Table 56-8; notably, all risk factors for VTE may elevate the d-dimer level. d-dimer increases with age and should be adjusted upward for age to maintain adequate exclusionary ability. The most common formula studied is age × 10 nanograms/mL (e.g., an 80-year-old patient would have an adjusted threshold for abnormal at 800 nanograms/mL).³⁴ This assumes the conventional d-dimer cutoff of 500 nanograms/mL; in a large multicenter study, this adjusted approach resulted in a very low false-negative rate (0.3%) when used in conjunction with a Wells' score ≤4 or a simplified revised Geneva score <5.³⁴

IMAGING

Chest CT Angiography

Chest CT angiography is the most common imaging modality for PE, identifying a clot as a filling defect in contrast-enhanced pulmonary arteries (Figure 56-5). Equipment with more detector heads (e.g., 64- or 128-head scanners) allows better resolution and observation of filling defects in subsegmental pulmonary arteries. The diagnostic sensitivity and specificity of a technically adequate mutidetector CT scan are about 90%.³⁶ Most CT pulmonary angiography protocols require the patient to lie supine and hold their breath for a few seconds, and the scan requires injection of approximately 120 mL of contrast by a computer-controlled injection device. In most centers, the patient must have a peripheral IV catheter (20 gauge or larger) or an approved indwelling line to allow injection of the contrast, and a central catheter cannot be used for injection.

In addition to clot recognition, a CT scan can detect alternative diagnoses, often pneumonia (8% to 22% of cases).³⁷ Interobserver agreement in identifying segmental or larger filling defects is very good, but interobserver agreement for subsegmental clots is poor. In practice, approximately 10% of CT scans are inadequate from secondary motion artifact or poor pulmonary artery opacification, commonly in obese or very tachypneic patients. Acute life-threatening contrast-triggered anaphylaxis or pulmonary edema is very rare, occurring in about 1 in 1000 patients.³⁸ About 15% of patients undergoing contrast-enhanced chest CT scan develop contrast nephropathy, defined as a 25% or greater increase in the serum creatinine concentration within 2 to 7 days of the examination.^39,40 At present, the only clearly helpful prophylactic measure to reduce contrast nephropathy is hydration with intravenous balanced crystalloid solutions.⁴¹ Other complications from CT scanning include contrast extravasation into a limb that can cause pain or compartment syndrome, and creation of a secondary thrombophlebitis.

Ventilation-Perfusion Lung Scanning

Ventilation–perfusion (V̇ /Q̇) lung scanning can identify a perfusion defect when ventilation is normal. V̇ /Q̇ scanning measures scintillation produced from a gamma ray–emitting atom and yields an image that plots the density of scintillations emitted from the chest using two phases. The perfusion images are usually obtained first and require a peripheral IV catheter for injection and the ability of the patient to sit up and lie down during the procedure. The ventilation component requires the patient to breathe into a nebulizer to inhale an aerosol that contains the isotope. A V̇ /Q̇ scan with homogeneous scintillation throughout the lung in the perfusion portion has nearly 100% sensitivity in excluding PE, regardless of the appearance of the ventilation portion. A V̇ /Q̇ scan with two or more apex central wedge-shaped defects in the perfusion phase (Figure 56-6) with normal ventilation in these regions indicates >80% probability of PE. All other V̇ /Q̇ scan findings are nondiagnostic; taken alone, these cannot exclude or diagnose PE.

PULMONARY ANGIOGRAPHY

Direct pulmonary angiography identifies a clot as a filling defect within the pulmonary artery. This test requires placement of a catheter into the pulmonary artery, usually through the femoral vein, followed by injection of 150 to 300 mL of contrast material. Advantages of direct pulmonary angiography include the ability to demonstrate filling defects in 3-mm or smaller vessels; the ability to measure pulmonary artery pressures; and the potential to treat PE with intrapulmonary catheter–directed modalities or to deploy a vena caval filter. Disadvantages of pulmonary angiography include lack of availability, radiation exposure, and the possibility of contrast-related complications, cardiac dysrhythmias, and rare cardiac or pulmonary arterial perforation.

Venous US

Venous US is the imaging test of choice in DVT; it can be done quickly and does not use ionizing radiation. When performed by experienced ultrasonographers, it has a diagnostic sensitivity of 90% to 95% and a specificity of 95% for DVT, and venous US has a sensitivity of about 40% as a surrogate method to diagnose PE. The mean sensitivity for DVT of US performed by a trained emergency physician compared with the reference imaging test is 96.1% (95% CI, 90.6% to 98.5%), with a weighted mean specificity of 96.8% (95% CI. 94.6% to 98.1%).⁴² However, the details of test performance and training remain important, as two-point compression US may miss some clots and new users require experience with at least 10 examinations before gaining adequate skill.

Compression ultrasonography operates on the principle that normal veins compress but thrombosed veins do not. A 7.5-MHz probe is used to visualize the common femoral, superficial femoral, and popliteal veins for comparison with the adjacent femoral and popliteal arteries. The sonographer manually compresses the probe and compares the flattening of the vein with that of the artery. If the vein compresses completely whereas the artery remains patent, this finding indicates "normal compressibility," and the absence of a thrombus is inferred (Figure 56-7). Conversely, if the vein does not compress, the examination is considered positive for a thrombus. The practice of examining the saphenous, tibial, and peroneal veins varies among centers.

The disadvantages of formal US include the need for specialized equipment and a qualified sonographer and radiologist. The examination can be difficult to perform in obese patients, and the probability of an indeterminate result increases with higher patient body mass index. The compression component of the examination causes pain in some patients and could promote clot embolization. Prior history of DVT can make it difficult to determine if venous noncompressibility represents an old or new clot. Color flow Doppler US can help identify recannulization, suggesting a chronic clot, which may not need anticoagulation.

Venography

Indirect CT venography acquires axial images of the leg veins during the venous return phase minutes after the contrast is injected for chest CT angiography. At present, the low rate of clinical utility, increased gonadal radiation, poor technical resolution, and low interobserver reliability for distal DVT all point away from the value of routine CT venography in the workup of an ED patient with suspected PE.⁴³

Planar venography requires injection of contrast material into a small vein in the foot with a proximal venous tourniquet. Subsequent images detail the entire leg venous system, identifying filling defects anywhere from the distal calf up to the iliac vein. Because alternative diagnostic imaging is readily available and a contrast-induced leg clot can result from the test in 10% to 15% of uses, venography is now rarely performed.

STEP ONE

For a patient to enter a PE testing regimen, he or she should have at least one physiologic manifestation of PE. This may be a symptom (e.g., pain in the chest or torso, a breathing problem, or altered mental status) or a finding (e.g., an abnormal vital sign) that could be produced by a clot in the lung. The physiologic manifestation must be placed in the context of the given patient—an untreated asthmatic patient with shortness of breath and wheezing should be treated first for bronchospasm and reevaluated and not immediately tested for PE. A risk factor for PE in the absence of a known sign or symptom does not mandate testing for PE or DVT.

STEP TWO

After finding a physiologic manifestation of PE, the next step is to ask, "Do I have more than a low initial suspicion for PE?" Low suspicion means that the physician's gestalt interpretation of the overall clinical picture is PE presence of <15%. If the answer to this question is yes, then a diagnostic test is needed. If the answer is no, then it remains possible that PE can be excluded using the PE rule-out criteria rule. If all eight criteria of the PE rule-out criteria rule are met in the setting of a gestalt-based low suspicion, then no further testing is necessary.²⁷ In general, if any one of the eight criteria is not met or a prominent finding exists, order a diagnostic test for PE.

STEP THREE

If PE cannot be excluded with the PE rule-out criteria rule, choose a diagnostic test result that can produce a posttest probability of <2.0%. An age-adjusted quantitative d-dimer assay is the best diagnostic test in patients for whom clinical suspicion is low or moderate based on either gestalt estimation, a Wells' score of ≤4, or a "safe" designation according to the Charlotte rule. Before ordering a d-dimer assay, consider factors could separately elevate the d-dimer concentration and impair the utility (Table 56-9).

STEP FOUR

Test further only those with a positive d-dimer result; base the choice of the next test on patient and facility factors. The algorithm presented in Figure 56-2 is one path. In general, the next best step for a patient with suspected PE and a positive d-dimer result is chest CT angiography. V̇ /Q̇ scan is an option in a pregnant patient or a patients with renal insufficiency or prior adverse reaction to contrast material. Performing lower extremity venous US is another option; it lacks ionizing radiation and its ability to diagnose DVT in a patient with PE symptoms is tantamount to diagnosing PE directly. However, the diagnostic sensitivity of lower extremity US for PE is <40%, so all patients suspected of having PE for whom US findings are negative require pulmonary vascular imaging.

To diagnose VTE, the clinical assessment and diagnostic tests usually must have a probability of 80% or greater, which is achievable with positive CT findings or high-probability V̇ /Q̇ scan results or venous US with findings indicative of DVT. Lesser probability means VTE may be present but is still clinically uncertain.

A low-risk patient with a CT scan demonstrating a large filling defect in the main pulmonary artery surely has a PE. In contrast, a low-risk patient with a CT image that is partially obscured by motion artifact and an eccentric filling defect in a segmental artery with lung consolidation needs more testing. With an indeterminate CT scan, options are venous US and a quantitative d-dimer assay. If the venous US results are positive, assume and treat for PE. If the US results are negative but the d-dimer concentration is eightfold higher than the upper limit of normal, the likelihood of acute VTE is high and supports therapy.

If the patient has no image-detected DVT or PE and has a normal or marginally elevated d-dimer concentration, then further imaging before anticoagulation is started is an option, especially if the patient has any increased risk of bleeding complications. The combination of a small, irregular filling defect on a suboptimal-quality CT angiogram, together with evidence of no DVT, a normal or even marginally elevated d-dimer concentration (<150% of the threshold), and a low-probability V̇ /Q̇ scan result, supports a decision not to initiate anticoagulation in a patient with normal or near-normal vital signs and oxygenation. Commonly, a repeat venous US within 2 to 7 days can help exclude VTE.

Patients with PE detected until after admission from the ED have a higher frequency of altered mental status and preexisting heart or lung diseases.^44,45,46,47 Of those discharged home with PE detected later, the clinical features often are a lack of dyspnea, sharp chest pain or hemoptysis with a pulmonary infiltrate on imaging (an infarct masquerading as infection), or a lower d-dimer concentration and a small distal clot seen on pulmonary vascular imaging.⁴⁶ More evidence is needed to determine if these patients actually benefit from systemic anticoagulation absent concomitant DVT.

Figure 56-8 is one algorithm describing the diagnostic decision making for DVT. Evaluate first using the Wells' criteria for pretest probability of DVT (Table 56-6). Patients with a low pretest probability (score <1) or patients without cancer, a modified Wells DVT score ≤1, and a normal d-dimer result are safely considered negative for DVT; any positive result requires US in this group. Patients with moderate to high Wells' scores or DVT likely (modified Wells DVT score) should undergo US testing, assessing d-dimer only if the US result is negative. In these subjects, assume no clot exists if both US and d-dimer tests are negative; if they have negative US findings and positive d-dimer results, repeat the US 2 to 7 days later.

TREATMENT OF PULMONARY EMBOLISM AND DEEP AND SUPERFICIAL EXTREMITY THROMBOSES

Treatment of VTE requires systemic anticoagulation to prevent further clot formation and allow endogenous fibrinolysis to proceed. In many cases, the initial treatment for VTE is heparin or heparin-like drug. The two most common options are unfractionated heparin or a low-molecular-weight heparin (Table 56-10).⁶ Initial anticoagulation treatment for VTE can also include oral rivaroxaban.⁶ It is anticipated that apixaban will soon have US Food and Drug Administration approval for VTE. Dabigatran can also be used but requires anticoagulation with heparin for several days.

Current data favor the use of low-molecular-weight heparins over unfractionated heparin for treatment of both PE and DVT in terms of composite outcomes (bleeding and death) and cost, although the magnitude of benefit is not large. ⁶ If uncertain about PE presence, the likelihood can guide anticoagulation therapy; the benefit of empiric anticoagulation for 24 hours exceeds the risks (bleeding and heparin-induced thrombocytopenia) for any patient with a pretest probability of PE of >20%.⁴⁸ Delay in administration of heparin to patients with PE is associated with increased mortality, but no study has found that heparin, administered early and prior to imaging, improves morbidity or mortality.

In patients with severe renal insufficiency and acute DVT or PE, most experts recommend unfractionated heparin over low-molecular-weight heparin.⁶ Treat upper extremity DVT the same as lower extremity DVT, and remove any indwelling catheters associated with clot. Heparin interferes with a few of the assays of enzymatic activity (lupus anticoagulant and endogenous proteases) used to diagnose thrombophilia; however, do not delay unfractionated heparin for any added thrombophilia testing when VTE is clearly present, because the evaluation can be postponed to the future. No evidence demonstrates any clinical benefit to a thrombophilia evaluation in guiding the intensity or duration of anticoagulation.⁴⁹

DVT that causes phlegmasia cerulea dolens requires rapid action to reduce the venous pressure. In addition to initiating anticoagulation, place the affected limb at a neutral level; remove constrictive clothing, cast, or dressing; and arrange for consultant-delivered catheter-directed thrombolysis. If no such service is available and emergency transfer cannot be arranged within 6 hours, consider systemic fibrinolytics if there are no absolute contraindications. One regimen is 50 to 100 milligrams of alteplase infused IV over 4 hours.

TREATMENT FOR SUPERFICIAL THROMBOPHLEBITIS

Treatment for localized superficial thrombophlebitis is an oral nonsteroidal anti-inflammatory drug or topical diclofenac gel until symptoms resolve; there is no need for systemic anticoagulation. For extensive superficial vein involvement, full-dose anticoagulation is recommended.⁶ Compression stockings do not aid this condition.⁵⁰

TREATMENT FOR ISOLATED CALF VEIN THROMBOSIS

There are no universally accepted treatment guidelines for thromboses isolated to the calf veins (soleal or gastrocnemius) or the saphenous vein, although many use 3 months of oral anticoagulation. Alternatives include no acute treatment with repeat US in 1 week to identify progression of clot, or outpatient treatment with low-molecular-weight heparin (Table 56-10). Patients with a history of VTE or risk factors for VTE (Table 56-1) should receive 3 months of full-dose anticoagulation when calf thrombosis exists unless contraindications are present.⁶

OUTPATIENT TREATMENT OF PULMONARY EMBOLISM

Patients with DVT diagnosed in the ED are typically discharged after receiving the first dose of low-molecular-weight heparin (Table 56-10) and with anticoagulation continued as an outpatient. More recently, many centers have begun the same practice for carefully selected low-risk patients with PE. Patients with PE and a low risk of death plus adequate home support can qualify for outpatient anticoagulation. The incidence of short-term mortality and the bleeding risk are very low with outpatient treatment, the overall cost of care is less, and the experience is preferred by patients.^51,52 Select low-risk patients using either the Hestia criteria or the Simplified PE Severity Index criteria (Table 56-11).^13,53 If low risk, assess the patient's wishes and ability to comply; if no high-risk features exist (elevated troponin, a B-type natriuretic peptide >100 picograms/mL, pulmonary arterial hypertension on ECG, or bleeding risks), outpatient care after an ED stay (up to 23 hours) is an option; otherwise, short-term hospitalization is a good choice.

In practice, the biggest barrier to ED discharge of any VTE patient is ensuring access to anticoagulation. If warfarin is the long-term anticoagulant, the patient must receive low-molecular-weight heparin until the prothrombin time is adequately prolonged and for at least 5 days.⁶ For low-molecular-weight heparin, patients or their families must learn how to administer subcutaneous injections, have access to drug, have a follow-up appointment where the prothrombin time can be monitored, and have dosing advice given, which are all challenges in some EDs. At this time, only one newer oral anticoagulant, rivaroxaban (Xarelto^®), is approved for both DVT and PE. This drug does not require blood monitoring or dosing adjustment for body size. The primary limitation to rivaroxaban is cost, although the manufacturer offers a patient assistance program, and it is on Medicaid and Medicare formularies.

FIBRINOLYSIS FOR PULMONARY EMBOLISM

PE is classified into three categories based on severity: massive, submassive, and less severe PE. Massive PE patients have a systolic blood pressure of <90 mm Hg for >15 minutes, a systolic blood pressure of <100 mm Hg with a history of hypertension, or a >40% reduction in baseline systolic blood pressure. Submassive PE patients have normal or near-normal blood pressure, but with other evidence of cardiopulmonary stress (Table 56-12).

All other PE cases are classified as "less severe." Patients with low-risk PE should not receive fibrinolysis; those with massive PE (defined as a systolic blood pressure <90 mm Hg or an observed decrease of 40 mm Hg) benefit from fibrinolysis. Patients with more severe submassive PE (i.e., causing right ventricular dilation or hypokinesis, elevated troponin or B-type natriuretic peptide, or persistent hypoxemia with distress) may also benefit from fibrinolysis, including higher survival and better quality of life although at a higher bleeding risk.^54-55

Systemic Fibrinolysis

The best evidence suggests considering systemic fibrinolysis in patients with no contraindications to fibrinolysis and any of the following: cardiac arrest; hypotension; respiratory failure, evidenced by severe hypoxemia (pulse oximetry reading <90%) despite oxygen administration, together with evidence of increased work of breathing; or evidence of right-sided heart strain on echocardiography or elevated levels of troponin T or I, or both (Table 56-12). Major contraindications to thrombolytic therapy include intracranial disease, uncontrolled hypertension at presentation, recent major surgery or trauma (past 3 weeks), and metastatic cancer. Any patient with head trauma from syncope should have a CT scan prior to therapy to detect hemorrhage. Alteplase (tissue plasminogen activator) is the only currently approved agent for PE, dosed 100 milligrams IV over 2 hours. Either enoxaparin (1 milligram/kg SC) or unfractionated heparin (80 units/kg IV bolus followed by 18 units/kg/h) is the anticoagulant, with the activated partial thromboplastin time kept at <120 seconds for unfractionated heparin. Heparin or low-molecular-weight heparin is typically started after the thrombolytic infusion. For further discussion of fibrinolytic agents, see the chapter 239, "Thrombotics and Antithrombotics."

Catheter-Directed Thrombolysis

Two randomized trials have tested the utility of catheter-directed, intrapulmonary delivery of tissue plasminogen activator and found better outcomes than heparin alone, but not better than systemic tissue plasminogen activator.⁵⁶ In view of these study results, as well as the risks of pulmonary arterial catheterization and associated drug delivery delay due to the need to activate the vascular intervention suite, intrapulmonary fibrinolytic delivery is not used in most patients with massive PE.⁵⁷ However, catheter-directed thrombolysis for PE requires a far lower dose of alteplase (approximately 10 milligrams total), which may confer a lower bleeding risk. Thus, catheter-directed thrombolysis is an option for patients over 65 years old, where intracranial bleeding risk is highest.⁵⁴ Alternatively, 50 milligrams of systemic IV alteplase—half of the Food and Drug Administration–approved dose—is an option with safety advantages.⁵⁸ Tiered-dose tenecteplase (TNKase^®: <60 kg: 30-milligram dose; ≥60 to <70 kg: 35-milligram dose; ≥70 to <80 kg: 40-milligram dose; ≥80 to <90 kg: 45-milligram dose; ≥90 kg: 50-milligram dose) appears to offer similar effectiveness as alteplase, although it is not yet approved by the Food and Drug Administration for PE.

Surgical Embolectomy

If available, surgical embolectomy is an option in young patients with large, proximal PE accompanied by hypotension. Because surgical embolectomy is often delayed, the reported mortality rate is approximately 30%. The amount of clot that can be extracted is often extensive, and removal may help limit later cardiopulmonary complications.

Patients with severe PE or receiving any thrombolysis/extraction generally are placed in an intensive care unit (Table 56-13). Outpatient treatment of DVT and PE is favored in low-risk patients who can adhere to therapy. Indications for admission in patients with DVT are listed in Table 56-13.

PREGNANCY

If the general patient has a high pretest probability by Wells' or the revised Geneva score, then proceed to pulmonary vascular imaging.⁶⁰ However, in pregnant women, limiting fetal exposure to radiation and iodinated contrast is preferred.⁶¹ One study measured d-dimer levels in 228 pregnant women with suspected DVT and found a prevalence of DVT in the study population of 6.6%.⁶² See chapter 100, "Maternal Emergencies after 20 Weeks of Pregnancy and in the Postpartum Period" especially the section on thromboembolic disease of pregnancy.

ISOLATED SUBSEGMENTAL PULMONARY EMBOLISM

Isolated subsegmental PE refers to a filling defect seen in one small pulmonary artery, usually <3 mm in diameter and in the absence of DVT; radiologists often do not agree when viewing these images separately. The incidence of subsegmental PE identification has increased sharply with increased resolution of multidetector-row CT scanning, but the clinical significance is unclear.⁶³ This raises concern that subsegmental PE may be a radiographic artifact rather than a true disease. Most experts agree that treatment is best in those with subsegmental PE and active cancer; no strong data support the safety of withholding anticoagulation in others with this finding; most still receive standard anticoagulation for 3 to 6 months.⁶ It is best to discuss the risks and benefits of treatment of subsegmental PE with patients and their physicians to help make the best decision about anticoagulation.

CANCER PATIENTS WITH VENOUS THROMBOEMBOLISM

Current data and guidelines recommend treatment of patients with active cancer with low-molecular-weight heparin for at least 6 months.⁶⁴ Some patients cannot give themselves injections for prolonged periods of time, forcing the choice between oral warfarin versus an oral newer anticoagulant. Pooled data from four newer agent trials in cancer-related VTE (dabigatran, rivaroxaban, and edoxaban) show better outcomes with thrombin or factor Xa inhibitors compared with warfarin.⁶⁵ About 2% of cancer patients undergoing staging and surveillance CT scanning have incidental PE detected. These patients are treated with anticoagulation, often at home if low risk.^66,67