Pulmonary Embolism and Deep Vein Thrombosis

Background and Importance

Each year more than 500,000 people are diagnosed with venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). PE is the third most common cause of cardiovascular death in the United States. PE and DVT occur equally in women and men, and while PE and DVT can occur in any age group, older patients have a much higher incidence, at 1/10,000 in people 20 to 30 years old and 1/100 in people greater than 80 years old. However, even this high incidence grossly understates the importance of PE and DVT to the practice of emergency medicine. Because the clinical presentations of PE and DVT are highly variable, with symptoms and signs that overlap with many common ED diagnoses, PE and DVT are frequently on the differential diagnosis for patients who present with chest pain, dyspnea, syncope, tachycardia, hypoxemia, leg pain, edema, and other nonspecific complaints. The wide demographic range and nonspecific clinical presentation of PE and DVT is why as many as 1 in 10 emergency department (ED) patients are evaluated for possible DVT or PE. Emergency clinicians must, therefore, be knowledgeable and judicious in their approach to PE and DVT.

As illustrated in Figure 74.1 , venous thrombosis occurs when the propensity of blood to coagulate overwhelms endogenous anticoagulant and fibrinolytic systems. Numerous factors associated with the classic triad of venous injury, venous stasis, and hypercoagulability have been associated with an increased risk of VTE in epidemiologic studies ( Table 74.1 ). Emergency clinicians should be aware of factors that might increase a patient’s propensity to clot and should consider these factors when determining whether a patient’s clinical presentation warrants an evaluation for VTE. Important factors include older age, prior history of VTE, active cancer, recent surgery or trauma, recent hospitalization longer than three days, limb immobility, and estrogen use (especially if initiated in the past three months). Thus, the age and comorbid illness of the population served by an ED determine the frequency of VTE diagnoses.

However, not all epidemiologic risk factors are associated with an increased likelihood of an ED diagnosis of VTE ( Table 74.1 ). For example, pregnant women are five times as likely to develop VTE as nonpregnant women of the same age, but only 4% of pregnant women tested for VTE in the ED have the diagnosis, compared to 12% of nonpregnant patients. This is because emergency clinicians have a low threshold to test pregnant patients for VTE. Similarly, travel is associated with a small increase in the absolute risk of VTE, but a history of travel often leads emergency clinicians to test for VTE, so travel does not seem to be associated with VTE in patients tested in the ED. The decision to initiate an evaluation or treatment for VTE should be based on an analysis of the risk PE poses to the patient weighed against the risk imparted by testing and treatment.

As many as 50% of patients diagnosed with PE have no apparent clinical risk factors for PE or DVT at the time of diagnosis. However, the lack of a risk factor known at the time of the ED diagnosis does not mean that an occult risk factor does not exist. Between 4% and 11% of patients with PE or DVT will receive a new cancer diagnosis within 1 year of VTE diagnosis, depending on whether the VTE event is provoked or idiopathic. Genetic or acquired hypercoagulable states are often unknown until a patient has their first thrombotic event. Patients who develop PE or DVT after exposure to heparin may have heparin-induced thrombocytopenia, a hypercoagulable state leading to VTE. While the presence of an occult risk factor may only become known after a patient leaves the ED, a thorough history may suggest occult cancer (e.g., unintentional weight loss) or recent exposure to heparin that would enable the emergency clinician to adjust their assessment of a patient’s risk of PE or DVT.

Anatomy, Pathology, and Pathophysiology of VTE

The venous anatomy of the lower extremity is divided into the deep and superficial systems ( Fig. 74.2 ). The superficial venous system consists primarily of the greater and short saphenous veins and perforating veins. Distal greater saphenous vein thrombi are often referred to as superficial thrombosis, but greater saphenous clots near the connection with the femoral vein should be referred to as DVT. The deep venous system includes the anterior tibial, posterior tibial, and peroneal veins, collectively called the calf veins. Venous thrombi isolated to the calf veins are referred to as distal DVT. The calf veins join together at the knee to form the popliteal vein, which extends proximally and becomes the femoral vein at the adductor canal. Venous thrombi in the popliteal or more proximal veins are referred to as proximal DVT. The femoral vein (previously known as the superficial femoral vein), is joined by the deep femoral vein and then the greater saphenous vein to form the common femoral vein, which subsequently becomes the external iliac vein at the inguinal ligament. Venous thrombi in the proximal femoral and iliac veins are known as iliofemoral DVT.

Knowledge of the venous anatomy is also important for the performance and interpretation of ultrasound of the leg veins. Compression ultrasound, including point-of-care ultrasound, is typically limited to the common femoral, femoral, and sometimes popliteal veins. Duplex ultrasound includes compression ultrasound of the proximal veins as well as Doppler ultrasound of the calf veins. The anatomic location of a DVT also influences prognosis because proximal DVT are less likely to lyse spontaneously, more likely to embolize, and are associated with a greater risk of long-term complications such as post-thrombotic syndrome.

Although 90% of DVT form in leg veins, clots can also form in the arm, around venous catheters, pacemaker wires, or other foreign bodies such as inferior vena cava filters. Other sites of venous thrombosis rarely encountered in the ED include the jugular, ovarian, mesenteric, renal, portal, hepatic, cerebral, and retinal veins.

DVT formation typically begins when monocytes expose blood to tissue factor on their surfaces. This process overwhelms natural anticoagulant and fibrinolytic mechanisms and leads to the aggregation of red blood cells, platelets, and fibrin in the venous sinuses or cusps of the lower extremity deep veins. The formation of a DVT causes vascular congestion which, in turn, causes veins to dilate and valves to become incompetent. The lack of forward venous blood flow leads to venous stasis and further thrombus propagation.

When a DVT embolizes, it flows proximally through the venous system toward the vena cava and the heart. In 3% of cases, a portion of the clot will remain in the right atrium or ventricle, a condition known as clot-in-transit. Clots that pass through the heart and enter the pulmonary arterial circulation are called PE. A PE can be described as saddle if the clot is visualized across the bifurcation of the main right and left pulmonary arteries ( Fig. 74.3A ). More distal PE are typically described according to their anatomic location. Clots may lodge in a main pulmonary artery ( Fig. 74.3B ), or in a lobar ( Fig. 74.3C ), segmental ( Fig. 74.3D ) or subsegmental pulmonary artery branch. PE may extend from a proximal artery into distal branches, and PE frequently fragment, lodging in multiple arterial branches simultaneously.

The physiologic effect of an obstruction in the pulmonary vasculature is variable. Small, subsegmental PE often lyse spontaneously and may be clinically inconsequential. Subsegmental thrombi that do not spontaneously lyse but obstruct blood flow to the lung’s periphery can cause pulmonary infarction, necrosis, pleural inflammation, and severe pleuritic pain. The right ventricle normally pumps through a pulmonary vascular tree with a low resistance to flow, and young individuals without cardiopulmonary disease can tolerate at least 30% obstruction from a clot with minimal symptoms or signs. Larger PE can cause an acute increase in pulmonary artery pressure due to a combination of mechanical obstruction and chemically mediated vasoconstriction of unobstructed pulmonary arteries. Increased right ventricular (RV) afterload (i.e., when the pulmonary artery systolic pressure exceeds 40 mm Hg) can lead the thin-walled right ventricle to dilate and become hypokinetic. As illustrated in Figure 74.4 , with normal PA pressures, the systolic RV is crescentic in cross-section and the left ventricle (LV) is circular. However, with increased PA pressures, the systolic RV dilates asymmetrically towards the intraventricular septum, compressing the LV into a “D” shape on cross-section. This can lead to underfilling of the left ventricle, decreased cardiac output, decreased coronary artery perfusion, myocardial ischemia, circulatory collapse, and death.

Clinical Features

Hallmarks of DVT include unilateral limb pain and swelling, though these findings can be subtle and nonspecific. Patients may report only mild cramping or a sense of fullness in the calf. The clinical signs of DVT may include edema, erythema, and warmth of the affected extremity, tenderness to palpation along the distribution of the deep venous system, dilation of superficial collateral veins, and rarely a palpable venous cord. Figure 74.5A shows a patient with a left leg DVT. To illustrate the difficulty of differentiating DVT from alternative diagnoses based on clinical examination, Figure 74.5B shows a patient with a ruptured Baker cyst in the left leg. Fever suggests an alternative diagnosis, such as cellulitis. Because the left iliac vein is vulnerable to compression by the left iliac artery (May-Thurner syndrome), leg DVT occurs with a slightly higher frequency on the left. Bilateral leg DVT is found in fewer than 10% of ED patients diagnosed with DVT.

More than 90% of upper extremity DVT occur in the presence of an indwelling catheter or similar device. Therefore, arm pain or swelling in the same arm as a catheter, infusion device, or pacemaker wire should raise suspicion for DVT. In the absence of a device, upper extremity DVT tends to occur in the dominant arm of young athletes, a condition known as Paget-Schroetter syndrome. Paget-Schroetter syndrome is an effort-induced form of thoracic outlet syndrome. Repetitive motion of the arm in the setting of hypertrophied scalene muscles or congenital cervical ribs causes compression of the subclavian vein and DVT.

Differential Diagnosis

Box 74.1 lists differential diagnoses for DVT. Venous insufficiency that causes congestion and inflammation is a common alternative diagnosis for DVT, especially since venous insufficiency increases the risk of DVT. Cellulitis is another common consideration. However, in a patient with clinical evidence of cellulitis, the frequency of concurrent DVT is only about 3%. Injuries to the gastrocnemius muscle or Achilles tendon can mimic the pain and swelling of DVT but are usually distinguished by history. Enlargement of the synovial membrane (Baker cyst) can cause popliteal pain and rupture of the cyst into the calf muscles causes inflammation that appears clinically similar to DVT. Spontaneous calf muscle hematomas can also cause pain and inflammatory changes. Many patients with systemic edema (e.g., from heart failure) will have asymmetrical swelling that raises concern for DVT.

Diagnostic Testing

Radiographic Evaluation

An expertly performed and interpreted positive venous ultrasound is sufficient to confirm the diagnosis of DVT. Several approaches to performing venous US are commonly used, and the emergency clinician should be aware of the US protocols used in their practice setting. Whole-leg US is the criterion standard and combines compression US of the proximal veins with ultrasound of the calf and saphenous veins. Whole-leg US is associated with a venous thromboembolism event rate at 3 months of 0.5%. A single normal whole-leg ultrasound excludes DVT regardless of PTP.

Three-point US, also called compression US, images the common femoral, femoral, and popliteal veins. Three-point US, when performed by a certified sonographer and interpreted by a board-certified radiologist, has a sensitivity of 95% and specificity of 95% for DVT. A negative three-point venous duplex ultrasound excludes the diagnosis of DVT in patients with low PTP. However, for patients at high risk, a negative three-point ultrasound is inadequate to exclude DVT as a single test. Patients with high PTP can have DVT ruled out in the ED with a combination of a negative three-point ultrasound and a negative D-dimer. A patient with high PTP, an elevated (or not performed) D-dimer, and a negative three-point ultrasound should be referred for a repeat venous US in 5 to 7 days to ensure their symptoms are not due to a distal (calf vein) DVT that later propagates proximally.

Bedside point-of-care ultrasound (POCUS) performed by a trained emergency clinician is 90% to 95% accurate compared to radiology-performed US. Test characteristics are highest for femoral veins and lowest for saphenous and popliteal veins. POCUS of the upper extremity is not well studied and should be performed by radiology when necessary.

Ultrasound cannot be used to rule out iliac or pelvic vein thrombosis. For this, venography (typically CT) is needed. When duplex ultrasound is not available, the decision to empirically anticoagulate while awaiting the availability of ultrasound imaging should be based on the PTP of DVT, and the risk anticoagulation poses to the patient. Generally, patients with low PTP do not need empirical anticoagulation while they wait for diagnostic imaging.

Magnetic resonance imaging (MRI) can evaluate the pelvic vasculature and inferior vena cava (IVC), which is not possible with ultrasound. Although CT venography can also visualize the pelvic veins and IVC, the accuracy varies across studies, and CT exposes patients to ionizing radiation. MRI does not produce ionizing radiation. Thus, MRI is a reasonable option to evaluate the pelvic veins of patients at high risk for pelvic vein thrombosis (e.g., a patient with gynecologic malignancy and bilateral leg swelling). Its use is limited by cost, availability, and patient tolerance. In only about 20% of patients with pelvic DVT is the clot isolated to the pelvic veins. Therefore, even when pelvic vein DVT is suspected, venous US is still the recommended first test.

Figure 74.6 provides a diagnostic flowchart for DVT that incorporates PTP. Patients with low PTP can have DVT ruled out in the ED with a negative D-dimer or venous US. Patients with high PTP can have DVT ruled out in the ED with a negative D-dimer and venous US. Patients with high PTP, a positive D-dimer, and a negative venous US of the proximal veins should have a follow-up ultrasound one week after ED discharge to look for the propagation of a distal DVT that might not have been detected during the initial ED visit.

Management

Patients with a positive ultrasound and patients with high PTP for whom imaging will be delayed (e.g., until the next day) should have anticoagulation initiated in the ED at the time of diagnosis, unless contraindicated.

Therapeutic anticoagulation for PE and DVT is the same. Options for initial anticoagulation are listed in Table 74.3 . Direct-acting oral anticoagulants (DOACs) are as effective as warfarin at preventing recurrent VTE and are associated with fewer bleeding events, and in particular, intracranial bleeding events. They are well tolerated by patients and do not require injections or monitoring. The DOACs rivaroxaban and apixaban do not require bridging with low-molecular-weight heparin (LMWH) and are the first-choice anticoagulants for most patients with DVT.

For patients with active cancer, LMWH is associated with a lower risk of VTE recurrence than warfarin, but emerging evidence suggests that DOACs are also safe and effective in this population. ^, Concern about the ability to reverse anticoagulation should not dissuade an emergency clinician from starting DOAC therapy. Reversal agents are available for all DOACs ( Box 74.3 ), and bleeding that does occur on DOAC therapy tends to be less severe than bleeding on warfarin. ^, However, DOACs are either contraindicated or not studied for the treatment of DVT associated with pregnancy, severe renal failure, liver failure, antiphospholipid antibody syndrome, and high-risk PE.

Thrombolysis, whether systemic or catheter-directed, for DVT not associated with limb ischemia has not been shown to improve mortality or post-thrombotic syndrome (pain, paresthesia, induration, swelling, discoloration, and ulceration of the leg after DVT) but does increase the risk of bleeding. ^,

Compression stockings can no longer be advocated routinely for DVT, as the data do not support a reduction in post-thrombotic syndrome. However, the reduction in post-thrombotic syndrome may depend on how soon after DVT diagnosis the patient starts wearing the stockings, and some studies do show an improvement in quality of life, so some patients may find them beneficial. ^, Patients should be encouraged to ambulate after anticoagulation for DVT to reduce the incidence of post-thrombotic syndrome.