Pulmonary Embolism: Acute Onset (FL INITIAL Autonomous Practice - Differential Diagnosis)

PE refers to obstruction of the pulmonary artery or one of its branches by material originating elsewhere in the body. PE can be caused by thrombus, tumor, air or fat emboli, but this topic will focus on PE due to thrombus.

PE can be classified by the following:

• The temporal pattern of presentation (acute, subacute, or chronic):
  • Acute
    • Patients with acute PE typically develop signs and symptoms immediately after obstruction of pulmonary vessels.
  • Subacute
    • Some patients with PE may also present subacutely within days or weeks following the initial event.
  • Chronic
    • Patients with chronic PE slowly develop symptoms of pulmonary hypertension over many years (i.e., chronic thromboembolic pulmonary hypertension [CTEPH]).
• The presence or absence of hemodynamic stability (hemodynamically unstable or stable)
  • Hemodynamically unstable PE is also called "massive" or "high-risk" PE.
    • Hemodynamically unstable PE is that which results in hypotension which is defined as:
      • Systolic blood pressure <90 mmHg OR
      • A drop in systolic blood pressure of ≥40 mmHg from baseline for a period >15 minutes OR
      • Hypotension that requires vasopressors or inotropic support
      • Not explainable by other causes such as sepsis, arrhythmias, left ventricular (LV) dysfunction from acute myocardial ischemia or infarction, or hypovolemia.
  • Although hemodynamically unstable PE is often caused by large (i.e., massive) PE, it can sometimes be due to small PE in patients with underlying cardiopulmonary disease. Thus, the term "massive" PE does not necessarily describe the size of the PE as much as its hemodynamic effect.
  • Patients with hemodynamically unstable PE are more likely to die from obstructive shock (i.e., severe right ventricular (RV) failure).
  • Death from hemodynamically unstable PE often occurs within the first two hours, and the risk remains elevated for up to 72 hours after the presentation (Thompson & Kabrhel, 2019).
• Hemodynamically stable PE is defined as PE that does not meet the definition of hemodynamically unstable PE.
  • There is a spectrum of severity within this population ranging from patients who present with small, mildly symptomatic or asymptomatic PE (also known as "low-risk PE") to those who present with mild or borderline hypotension that stabilizes in response to fluid therapy or those who present with RV dysfunction (also known as "submassive" or "intermediate-risk" PE).
• The anatomic location(saddle, lobar, segmental, subsegmental):
  • Saddle PE lodges at the bifurcation of the main pulmonary artery, often extending into the right and left main pulmonary arteries.
    • Approximately 3 to 6% of patients with PE present with a saddle embolus (Thompson & Kabrhel, 2019).
    • Traditionally, saddle PE was associated with hemodynamic instability and death. However, retrospective studies suggest that among those diagnosed with a saddle embolus, only 22% are hemodynamically unstable, with an associated mortality of 5% (Thompson & Kabrhel, 2019).
  • A clot "in transit" through the heart is often classified as a form of PE, even though the thrombus has not yet lodged in a pulmonary artery.
    • Clot-in-transit is associated with high mortality (up to 40%).
  • Most PE moves beyond the bifurcation of the main pulmonary artery to lodge distally in the main lobar, segmental, or subsegmental branches of a pulmonary artery.
  • PE can be bilateral or unilateral, depending on whether they obstruct arteries in the right, left, or both lungs.
  • Smaller thrombi in the peripheral segmental or subsegmental branches are more likely to cause pulmonary infarction and pleuritis.
• The presence or absence of symptoms (symptomatic or asymptomatic):
  • Symptomatic PE refers to the presence of symptoms that usually leads to the radiologic confirmation of PE.
  • Asymptomatic PE refers to the incidental finding of PE on imaging (e.g., contrast-enhanced computed tomography (CT) performed for another reason) in a patient without symptoms.

• Estimates of the incidence of PE in the general population have increased following the introduction of D-dimer testing and computed tomographic pulmonary angiography (CTPA) in the 1990s (Thompson & Kabrhel, 2019).
• One database analysis reported a doubling in the incidence of PE from 62 cases per 100,000 in the five years before 1998 to 112 cases per 100,000 in the seven years after 1998 (Thompson & Kabrhel, 2019).
• Other studies have confirmed increased rates over time (Thompson & Kabrhel, 2019).
• In contrast, a Canadian database reported an incidence rate of PE as 0.38 per 1,000 persons per year, a rate that appeared to be stable between 2002 and 2012 (Thompson & Kabrhel, 2019).
• The overall incidence of PE:
  • Higher in males than females (56 versus 48 per 100,000, respectively) (Thompson & Kabrhel, 2019).
  • With increasing age, particularly in women, PE has an incidence of >500 per 100,000 after 75 years (Thompson & Kabrhel, 2019).
  • It may be reduced by statins (Thompson & Kabrhel, 2019).
• PE mortality
  • In the United States, PE accounts for approximately 100,000 annual deaths (Thompson & Kabrhel, 2019).
  • In Europe, PE accounts for 300,000 deaths annually.
    • In an analysis based on data from five European countries, most VTE-related deaths were due to hospital-acquired PE and most were diagnosed antemortem (Thompson & Kabrhel, 2019).
    • However, many causes of sudden cardiac death are considered secondary to PE, so the actual mortality attributable to PE is difficult to estimate.
  • Deaths from diagnosed PE have been declining, with one study reporting deaths from PE that decreased between 1979-1998, from 191 to 94 per million (Thompson & Kabrhel, 2019). In another study, the mortality risk ratio from PE declined from 138 in 1980-1989 to 36.08 from 2000-2011 (Thompson & Kabrhel, 2019).
  • Overall, mortality from PE appears to be high.
    • Another study reported a 30-day and 1-year mortality rate of 4% and 13%, respectively, and a case-fatality rate that increased with age (Thompson & Kabrhel, 2019).
  • Age-adjusted mortality rates for African-American adults have been reported to be 50% higher than for whites.
  • Mortality rates for whites are 50% higher than those for other races (Asian, American Indian, etc.) (Thompson & Kabrhel, 2019).

The following special populations see an increased incidence of deep vein thrombosis (DVT) and PE:

• Patients with malignancy
• Patients who are pregnant
• Patients with stroke
• Hospitalized medical patients
• Hospitalized surgical patients
• Hospitalized gynecologic patients
• Patients with nephrotic syndrome
• Patients with acute traumatic spinal cord injury
• Patients with total joint arthroplasty or replacement
• Patients with inherited thrombotic disorders

The few studies that have examined risk factors for PE alone confirm that they are similar to those for VTE in general (Thompson & Kabrhel, 2019).

Risk factors can be classified as:

• Acquired
  • Acquired risk factors can be further sub-classified as:
    • Provoking (e.g., recent surgery, trauma, immobilization, initiation of hormone therapy, active cancer)
    • Non-provoking (e.g., obesity, heavy cigarette smoking)
  • Inherited (i.e., genetic)
    • Twenty to thirty genetic risk factors for VTE have been identified, including factor V Leiden and the prothrombin gene mutation (20210-A) (Thompson & Kabrhel, 2019).

Most emboli are thought to arise from lower extremity proximal veins (iliac, femoral, and popliteal), and more than 50% of patients with proximal vein DVT have concurrent PE at presentation (Thompson & Kabrhel, 2019).

Calf vein DVT rarely embolizes to the lung, and two-thirds of calf vein thrombi resolve spontaneously after detection (Thompson & Kabrhel, 2019). However, if untreated, one-third of calf vein DVT extend into the proximal veins, where they have greater potential to embolize.

PE can also arise from DVT in non-lower-extremity veins, including renal and upper extremity veins, although embolization from these veins is less common.

Most thrombi develop at sites of decreased flow in the lower extremity veins, such as valve cusps or bifurcations. However, they may also originate in veins with the higher venous flow, including the inferior vena cava or the pelvic veins, and non-lower-extremity veins, including renal and upper extremity veins.

PE is typically multiple, with the lower lobes involved in most cases (Thompson & Kabrhel, 2019). Once thrombus lodges in the lung, a series of pathophysiologic responses can occur:

• Abnormal gas exchange
  • Impaired gas exchange from PE is due to:
    • Mechanical and functional obstruction of the vascular bed altering the ventilation to perfusion ratio.
    • Inflammation results in surfactant dysfunction and atelectasis, resulting in functional intrapulmonary shunting.
      • Inflammation is also thought to be responsible for stimulating respiratory drive resulting in hypocapnia and respiratory alkalosis.
        • Hypercapnia and acidosis are unusual in PE unless shock is present.
• Cardiovascular compromise
  • Hypotension from PE is due to diminished stroke volume and cardiac output.
  • In patients with PE, pulmonary vascular resistance is increased due to physical obstruction of the vascular bed with thrombus and hypoxic vasoconstriction within the pulmonary arterial system.
    • Increased pulmonary vascular resistance, in turn, impedes RV outflow and causes RV dilation and flattening or bowing of the intraventricular septum. Diminished flow from the RV and RV dilation reduces LV preload, compromising cardiac output.
      • For example, when obstruction of the pulmonary vascular bed approaches 75%, the RV must generate a systolic pressure above 50 mmHg to preserve adequate pulmonary artery flow (Thompson & Kabrhel, 2019). When the RV cannot accomplish this, it fails, and hypotension ensues. As a result, multiple large thrombi are generally responsible for hypotension via this mechanism in patients without underlying cardiopulmonary disease. In contrast, in patients with underlying cardiopulmonary disease, hypotension can be induced by smaller emboli, likely due to a substantial vasoconstrictive response or an inability of the RV to generate sufficient pressure to combat high pulmonary vascular resistance.
• Infarction
  • In about 10% of patients, small thrombi lodge distally into the segmental and subsegmental vessels resulting in pulmonary infarction (Thompson & Kabrhel, 2019).
  • These patients are more likely to have pleuritic CP and hemoptysis, presumed to be due to an intense inflammatory response in the lung and adjacent visceral and parietal pleura.
  • Both impaired gas exchange and inflammation cause hypoxemia (Thompson & Kabrhel, 2019).

The most common symptoms in patients with PE were identified in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) group (Thompson et al., 2019). These symptoms include:

• Dyspnea at rest or with exertion (73%)
  • The onset of dyspnea is frequently (but not always) rapid, usually within seconds (46%) or minutes (26%) (Thompson et al., 2019).
  • Dyspnea may be less frequent in older patients with no previous cardiopulmonary disease.
  • Dyspnea is more likely to be present in patients who present with PE in the main or lobar vessels.
• Pleuritic pain (66%)
  • Approximately 10% of patients present with the symptoms of an infarcted lung, usually due to smaller, more peripheral emboli.
  • Pleuritic pain is typical in this population due to inflammation of the pleura.
• Cough (37%)
• Orthopnea (28%)
• Calf or thigh pain or swelling (44%)
• Wheezing (21%)
• Hemoptysis (13%)
  • Hemorrhage from the infarcted lung is also thought to be responsible for hemoptysis.

Less common presentations include:

• Hemodynamic collapse (<10% each)
• Hoarseness from a dilated pulmonary artery is a rare presentation (Ortner syndrome)
• Presyncope
• Syncope
  • Retrospective studies report syncope as the presenting symptom in 10% or fewer cases.
  • Conversely, among those presenting with syncope, rates of PE ranging from 2% to 17% have been reported (Thompson et al., 2019).
  • Highlighting syncope as a manifestation of PE, 560 patients in an emergency department (ED) with the first episode of syncope who were admitted to the hospital underwent a rigorous investigation for PE involving D-dimer and CTPA.
    • In this population, the prevalence of PE was 17%, higher in those who had no other identifiable etiology for syncope (25%).
    • Although those discharged from the ED did not undergo formal evaluation for PE, when they were included in the analysis, the rate of PE was lower and closer to that seen in other retrospective studies (4%).
    • Syncope may indicate a high burden of thrombus since up to two-thirds of patients with PE who present with syncope have large thrombi located in the mainstem or lobar arteries.
    • The reasons for syncope in patients with PE are poorly understood but may be partially explained by transient arrhythmias as thrombus travels through the heart or transient obstruction as the embolus transits the pulmonic valve (Thompson et al., 2019).
• Transient or persistent arrhythmias (e.g., atrial fibrillation) (Thompson et al., 2019).

Some patients have a delayed presentation over weeks or days. One prospective study reported that patients with a delayed presentation beyond one week tended to have larger, more centrally located PE than patients who presented within seven days (41% versus 26%) (Thompson et al., 2019).

Signs and symptoms of PE may also evolve such that patients who initially present with mild symptoms may become increasingly symptomatic or hemodynamically unstable, sometimes very quickly (minutes to hours). This progression may be secondary to recurrent embolization or progressive pulmonary hypertension secondary to vasoconstriction. Similarly, as a pulmonary infarct evolves, patients may develop progressive dyspnea, hypoxemia, pleuritic pain, and hemoptysis.

Importantly, symptoms may be mild or absent, even in large PE. Although the true incidence of asymptomatic PE is unknown, one systematic review of 28 studies found that, among the 5,233 patients who had a DVT, one-third also had asymptomatic PE (Thompson et al., 2019).

Common presenting signs on physical examination include:

• Tachypnea (54%)
• Calf or thigh swelling, erythema, edema, tenderness, palpable cords (47%)
• Tachycardia (24%)
• Rales (18%)
• Decreased breath sounds (17%)
• An accentuated pulmonic component of the second heart sound (15%)
• Jugular venous distension (14%)
• Fever mimicking pneumonia (3%) (Thompson et al., 2019).

Although upper extremity DVT (UEDVT) embolizes less commonly than lower extremity DVT (LEDVT), symptoms of UEDVT (e.g., arm pain or tightness) should also raise the suspicion of PE.

PE is a common cause of sudden cardiac arrest or circulatory collapse (8%), especially among patients younger than 65.

• Among such patients, either dyspnea or tachypnea is present in 91%.
• A massive PE may result from acute RV failure, increased jugular venous pressure, a right-sided third heart sound, a parasternal lift, cyanosis, and obstructive shock.
• Shock may also develop in patients with smaller PE with severe underlying pulmonary hypertension.
• Transitioning from tachycardia to bradycardia or from a narrow complex to a broad complex tachycardia (i.e., right bundle branch block) is an ominous sign of RV strain and impending shock.
• PE should be suspected anytime there is hypotension accompanied by an elevated central venous pressure that is not otherwise explained by acute myocardial infarction (MI), tension pneumothorax, pericardial tamponade, or a new arrhythmia (Thompson et al., 2019).

Laboratory tests are not diagnostic but alter the clinical suspicion for PE, confirm the presence or absence of alternative diagnoses, and provide prognostic information if PE is diagnosed:

• Complete blood count and serum chemistries
  • Routine laboratory findings include:
    • Leukocytosis
    • Increased erythrocyte sedimentation rate (ESR)
    • Elevated serum lactate dehydrogenase (LDH)
    • Elevated aspartate aminotransferase (AST)
    • Serum creatinine and the estimated glomerular filtration rate (eGFR) help determine the safety of administering contrast for angiography
• Arterial blood gas (ABG)
  • Unexplained hypoxemia in a normal chest x-ray (CXR) setting should raise the clinical suspicion for PE and prompt further evaluation.
  • While ABGs are often abnormal among patients suspected of having PE, ABGs can be normal in up to 18% of patients with PE (Thompson et al., 2019).
  • Abnormal gas exchange may be due to or worsened by underlying cardiopulmonary disease. (Thompson et al., 2019).
  • Common abnormalities seen on ABGs include one or more of the following:
    • Hypoxemia (74%)
    • Widened alveolar-arterial gradient for oxygen (62% to 86%)
    • Respiratory alkalosis and hypocapnia (41%) (Thompson et al., 2019)
  • Hypercapnia, respiratory, or lactic acidosis are uncommon but can be seen in patients with massive PE associated with obstructive shock and respiratory arrest.
  • Abnormal oxygenation may be of prognostic value. For example:
    • Patients with hypoxemia or room air pulse oximetry readings <95% at the time of diagnosis are at increased risk of complications, including respiratory failure, obstructive shock, and death (Thompson et al., 2019).
• Brain natriuretic peptide (BNP)
  • Elevated BNP has limited diagnostic value in patients suspected of having PE (Thompson et al., 2019).
  • However, elevated BNP or its precursor, N-terminal (NT)-proBNP, may be useful prognostically for risk stratification for patients diagnosed with acute PE.
• Troponin
  • Serum troponin I and T levels are useful prognostically but not diagnostically.
  • As markers of RV dysfunction, troponin levels are elevated in 30% to 50% of patients with moderate to large PE and are associated with clinical deterioration and death after PE.
  • Troponin elevations usually resolve within 40 hours following PE, in contrast to the more prolonged elevation after acute myocardial injury (Thompson et al., 2019).
• D-dimer
  • The role of D-dimer in the diagnostic evaluation of suspected PE is discussed below.

ECG abnormalities, although common in patients with suspected PE are nonspecific. The most common findings are:

• Nonspecific ST-segment and T-wave changes (70%)
• Tachycardia (Thompson et al., 2019)

Abnormalities historically considered to be suggestive of PE (S1Q3T3 pattern, RV strain, new incomplete right bundle branch block) are uncommon (less than 10%) (Thompson et al., 2019).

ECG abnormalities that are associated with a poor prognosis in patients diagnosed with PE include:

• Anterior ST-segment changes and T-wave inversion
• Atrial arrhythmias (e.g., atrial fibrillation)
• Bradycardia (<50 beats per minute) or tachycardia (>100 beats per minute)
• Inferior Q-waves (leads II, III, and aVF)
• New right bundle branch block
• S1Q3T3 pattern (Thompson et al., 2019)

Nonspecific abnormalities on CXR are common (e.g., atelectasis, effusion) in PE, but a normal CXR can be seen in 12% to 22% of patients.

• A CXR is typically performed in most patients suspected of PE to look for an alternative cause of the patient's symptoms.
• It is also performed to determine eligibility for ventilation-perfusion (V/Q) scanning.
• A CXR is unnecessary if a CTPA is planned (Thompson et al., 2019).

A Hampton's hump and Westermark's sign are rare but, when present, should raise the suspicion for PE.

• Hampton's hump is a shallow, hump-shaped opacity in the periphery of the lung, with its base against the pleural surface and hump towards the hilum.
• Westermark's sign demonstrates a sharp cut-off of pulmonary vessels with distal hypoperfusion in a segmental distribution within the lung (Thompson et al., 2019).

Whenever PE is suspected, the PTP for PE should be estimated by clinical gestalt assessment or calculated using a validated PTP score (e.g., Wells score, Modified Wells score, or Modified Geneva score). Although gestalt estimates and calculating probability scores have comparable sensitivity when combined with D-dimer testing, meta-analyses suggest that probability scores may have higher specificity and increase the diagnostic yield of CTPA (Thompson et al., 2019).

Although the use of Wells, Modified Wells, or Modified Geneva score is acceptable, based upon extensive validation and clinical experience, the Wells criteria should be applied and the score calculated to determine the probability of having a PE into a three-tiered system of:

• Low (score <2)
• Intermediate (score 2 to 6)
• High (score >6)

Wells criteria and the corresponding points for each include the following:

• Clinical symptoms of DVT (leg swelling, pain with palpation): 3 points
• Other diagnoses less likely than PE: 3 points
• Heart rate >100: 1.5 points
• Immobilization three or more days or surgery in the previous four weeks: 1.5 points
• Previous DVT/PE: 1.5 points
• Hemoptysis: 1 point
• Malignancy: 1 point

Despite validation of the Wells criteria, for unclear reasons, clinicians do not use them or misuse them in 50% of patients (Thompson et al., 2019). In addition, they may not be as accurate in older patients. Wells criteria have been best validated in outpatients presenting with suspected PE. However, one study of hospitalized patients reported a sensitivity and specificity of 72% and 62%, respectively (Thompson et al., 2019). The addition of D-dimer improved the sensitivity and specificity to 99% and 11%, respectively.

The Wells criteria can also be used to classify patients into a two-tiered system of clinical probability of having a PE:

• Patients are likely (score >4)
• Patients are unlikely (score ≤4)

Although it has been validated and is equally as useful, the three-tiered classification of low, intermediate, and high probability is preferred since this classification can be used with PE rule-out criteria (PERC) to reduce the need for unnecessary testing further, and it can also be used to interpret results of V/Q scans more accurately.

PERC was designed to identify patients with a low clinical probability of PE in whom the risk of unnecessary testing outweighs the risk of PE (Thompson et al., 2019). For patients with a low probability of PE (e.g., PTP <15%, Wells score <2), the PERC is applied to determine whether or not diagnostic evaluation with D-dimer is indicated. While some experts measure D-dimer in all low-risk patients, the preference to use PERC is based upon the validity of this approach in this population and the likely reduction (approximately 20%) of unnecessary testing (i.e., D-dimer and imaging) associated with its use (Thompson et al., 2019).

The pulmonary embolism rule-out criteria (PERC rule):

• Age <50 years of age
• Heart rate <100 bpm
• Oxygen saturation on room air >95%
• Absence of hemoptysis
• No exogenous estrogen use
• No prior history of VTE
• Absence of unilateral leg swelling
• No recent surgery or trauma requires hospitalization within the prior four weeks (Thompson et al., 2019).

When the PERC rule is chosen, the following applies:

• For patients with a low probability of PE who fulfill all eight criteria, the likelihood of PE is low, and no further testing is required.
• Further testing with sensitive D-dimer or imaging should be considered for patients who do not fulfill all eight criteria.

In low-risk patients where PERC cannot be applied (e.g., inpatients, critically-ill patients) or PERC is positive, D-dimer testing is indicated, and the following applies:

• When the D-dimer level is <500 ng/mL fibrinogen equivalent units), no further testing is required.
• When the D-dimer level is ≥500 ng/mL, diagnostic imaging should be performed, preferably with CTPA.

PERC is only valid in clinical settings (typically the ED) with a low prevalence of PE (<15%) (Thompson et al., 2019). In clinical settings with a higher prevalence of PE (>15%), the PERC-based approach has been shown to have a substantially weaker predictive value (Thompson et al., 2019). Thus, it should not be used in patients with an intermediate or high suspicion of PE or inpatients suspected of having PE.

An elevated D-dimer alone is insufficient to diagnose PE but can be used to rule out PE. D-dimer testing is best used in conjunction with clinical probability assessment:

• For patients in whom the risk of PE is thought to be low, a normal D-dimer <500 ng/mL effectively excludes PE, and typically no further testing is required. This situation includes patients who have had:
  • A prior PE
  • Hospitalized patients
  • Those with a delayed presentation (Thompson et al., 2019)
• In contrast, an elevated D-dimer >500 ng/mL should prompt further testing with diagnostic imaging.
• For most patients in whom the risk of PE is thought to be intermediate, a normal D-dimer <500 ng/mL also effectively excludes PE, and typically no further testing is required.
  • However, some experts believe that a subset of patients in the intermediate-risk category (e.g., those in the upper zone of the intermediate-range [e.g., Wells score 4 to 6] or patients with limited cardiopulmonary reserve) should undergo imaging based upon the higher probability of PE in these patients, so the sensitivity of D-dimer is not as good.
• For patients in whom the risk of PE is thought to be high, a normal D-dimer is not as helpful for excluding the diagnosis. While a negative D-dimer result reduces the likelihood of PE, it does not sufficiently rule out the diagnosis, with some data suggesting a prevalence of PE of 5% or more in this population (Thompson et al., 2019). These patients should undergo diagnostic imaging, preferably with CTPA.

"Sensitive D-dimer" testing uses quantitative or semiquantitative newer generation immunoturbidimetric, latex-agglutination-based, or rapid enzyme-linked immunosorbent assays (ELISA). These assays are preferred because of their high sensitivity, and accurate results are available quickly (10 to 30 minutes), so prompt decisions regarding imaging can be made. For these assays, a level ≥500 ng/mL is usually considered positive, and <500 ng/mL is considered negative (Thompson et al., 2019).

In contrast, early-generation D-dimer assays (e.g., qualitative rapid ELISA, first-generation latex, and erythrocyte agglutination) are less accurate. In a meta-analysis of 108 studies, when compared with other assays for D-dimer testing, the preferred assays (e.g., rapid semiquantitative ELISAs) were associated with a higher sensitivity (96% versus 90%) and negative predictive value (98 versus 95%) (Thompson et al., 2019).

The sensitivity of D-dimer is lower in patients with subsegmental PE compared with patients with large main, lobar, or segmental PE (53% versus 93%) (Thompson et al., 2019). While D-dimer assays are highly sensitive, their specificity is low, usually between 40% and 60%. D-dimer results are often falsely positive, and the proportion of false-positive results increases with certain clinical conditions and any acute or inflammatory process (e.g., age >50 years, recent surgery or trauma, acute illness, pregnancy or postpartum state, rheumatologic disease, renal dysfunction [eGFR <60 mL/min/1.73 m2]) and sickle cell disease (Thompson et al., 2019).

Adjusted D-dimer levels based on certain criteria have been proposed. D-dimer levels rise with age such that using the traditional cut-off value of <500 ng/mL results in reduced specificity of D-dimer testing in older patients (>50 years), a common population in whom PE. Several studies report its use with the most commonly used formula for age adjustment as:

• Age (if over 50 years) x 10 = cutoff value in ng/mL (Thompson et al., 2019).

However, because many conditions that increase the D-dimer also increase the risk of PE, age adjustment should be used with caution, particularly in patients with non-low probability for PE, until further data become available.

• One meta-analysis of six trials reported that in patients unlikely to have PE by the Wells criteria (score ≤4), compared with a negative fixed level D-dimer, a negative age-adjusted D-dimer was associated with a 5% increase in the proportion of patients in whom imaging can be safely withheld (Thompson et al., 2019).

Alternate D-dimer cut-offs have also been used. In one prospective multicenter study, 3,465 patients with suspected PE from an outpatient setting underwent D-dimer testing and an assessment for the presence and absence of YEARS items (Thompson et al., 2019). YEARS items include three items (that are also in the Wells score), all scored as yes or no:

• Clinical signs of DVT
• Hemoptysis
• PE is the most likely diagnosis

PE was excluded in patients with zero YEARS items and a D-dimer level <1000 ng/mL and patients with ≥1 YEARS item and a D-dimer <500 ng/mL. All other patients underwent CTPA. Using this algorithm, 13% of patients were diagnosed with PE. Among those in whom PE was excluded, 0.6% had symptomatic PE confirmed at three-month follow-up, a rate similar to that reported in studies that utilize fixed D-dimer level testing <500 ng/mL (Thompson et al., 2019). It was estimated that this algorithm would result in a 14% reduction in the number of CT scans performed compared with the Wells rule and a fixed D-dimer level <500 ng/mL. Using age-adjusted D-dimer had no additional value to this algorithm (Thompson et al., 2019).

A similar multicenter prospective observational study of 1,134 ED patients suspected of having PE. It referred for imaging per the treating clinician's discretion and reported a potential 14% reduction in those imaged using YEARS criteria and a negative D-dimer (<1000 ng/mL for YEARS negative patients and <500 ng/mL for YEARS positive patients) (Thompson et al., 2019). The sensitivity and specificity of this strategy were 93% and 55%, respectively. This algorithm requires further validation and needs to be directly compared with algorithms that include PERC and fixed D-dimer level cutoffs before it can be routinely used in practice.

For most patients in whom the suspicion for PE is intermediate, a sensitive D-dimer level should be measured.

• No further testing is typically required when the D-dimer level is <500 ng/mL.
• However, some experts will proceed with diagnostic imaging in select patients, such as:
  • Patients with a limited cardiopulmonary reserve (i.e., patients in whom PE would not be well-tolerated).
  • Patients with PE's clinical probability was in the upper zone of the intermediate-range (e.g., a Wells score of 4 to 6).
• When the D-dimer level is ≥500 ng/mL, diagnostic imaging should be performed, preferably with CTPA.

For most patients in whom the probability of PE is high or in whom the suspicion is low or moderate, and the D-dimer level is elevated (≥500 ng/mL), CTPA should be performed.

When imaging is indicated, CTPA is the imaging modality of choice. A V/Q scan is reserved for patients in whom CTPA is contraindicated, including:

• Advanced heart failure
• High risk of contrast nephropathy (eGFR <30 mL/min/1.73 m2)
• History of moderate or severe contrast allergy
• Hypotension
• Inability to tolerate CT scanning due to morbid obesity or difficulty lying flat.

V/Q scanning may also be indicated when CTPA is inconclusive or additional testing is needed, such as when the clinical suspicion of PE remains high despite negative imaging.

PE is stratified into massive, submassive, and low-risk based upon the presence or absence of hypotension and RV dysfunction or dilation. This stratification is associated with mortality risk (Thompson et al., 2019).

A small percentage of patients with PE present hemodynamic instability or shock (see nomenclature above).

More aggressive therapies than anticoagulation are suggested in patients with PE who are hemodynamically unstable or who become unstable due to recurrence despite anticoagulation. These include:

• Embolectomy in patients in whom thrombolysis is either contraindicated or unsuccessful (surgical or catheter-based).
• Thrombolytic therapy (see below) provided there is no contraindication.

Initial therapies for hemodynamically unstable patients consist of:

• Respiratory support
  • Supplemental oxygen should be administered to target oxygen saturation of ≥90%.
  • Severe hypoxemia, hemodynamic collapse, or respiratory failure should prompt consideration of intubation and mechanical ventilation.
    • Importantly, patients with coexistent RV failure are prone to hypotension following intubation.
      • In this population, it is wise to consult an expert in cardiovascular anesthesia. High plateau pressures should be avoided.
• Hemodynamic support
  • The precise threshold that warrants hemodynamic support depends upon the patient’s baseline blood pressure and whether there is clinical evidence of hypoperfusion (e.g., change in mental status, diminished urine output).
  • Intravenous fluid (IVF)
    • IVF is the first-line therapy for patients with hypotension.
    • In general, small volumes of IVF are preferred; usually, 500 to 1,000 mL of normal saline, followed by vasopressor therapy should perfusion fail to respond to IVF.
    • However, in patients with RV dysfunction, limited data suggest that aggressive fluid resuscitation is not beneficial and may be harmful (Tapson & Weinberg, 2019).
    • The rationale for limiting IVF administration comes from preclinical studies and one small observational study in humans, which reported that small volumes of IVF increase the cardiac index in patients with PE, while excessive amounts of IVF result in RV overstretch (i.e., RV overload), RV ischemia, and worsening RV failure. The patient’s volume status should be carefully assessed, as this could influence the approach to fluid administration.
  • Vasopressors
    • Intravenous vasopressors are administered when adequate perfusion is not restored with IVF.
    • The optimal vasopressor for patients with shock due to acute PE is unknown, but norepinephrine is generally preferred (Tapson & Weinberg, 2019).
    • Options include:
      • Norepinephrine
        • Norepinephrine is this population's most frequently utilized agent because it is effective and less likely to cause tachycardia (Tapson & Weinberg, 2019).
        • Other alternatives include dopamine and epinephrine, but tachycardia, which can exacerbate hypotension, can occur with these agents (Tapson & Weinberg, 2019).
    • Dobutamine
      • Dobutamine is sometimes used to increase myocardial contractility in patients with circulatory shock from PE.
      • However, it also results in systemic vasodilation, which worsens hypotension, particularly at low doses (Tapson & Weinberg, 2019).
        • In order to mitigate the effect of Dobulamine, norepinephrine is initially added to dobutamine. As the dose of dobutamine increases, the effects of dobutamine-induced myocardial contractility exceed those of vasodilation, potentially allowing norepinephrine to be weaned off.
  • Isoproterenol, amrinone, and milrinone have been investigated in animal models but are not useful for hypotension due to acute PE (Tapson & Weinberg, 2019).
• Thrombolytic therapy
  • Thrombolytic agents activate plasminogen to form plasmin, resulting in the accelerated lysis of thrombi. As a result, thrombolytic agents have been used in various thrombotic disorders, including acute MI, stroke, acute PE, and DVT.
  • Evidence from randomized and retrospective observational studies in patients with acute PE indicates that thrombolytic therapy leads to early hemodynamic improvement at the cost of increased major bleeding. The effect of thrombolytic therapy on mortality and the frequency of recurrent thromboembolism remains questionable.
  • Typically, only patients in whom the diagnosis of acute PE has been confirmed should be considered for thrombolytic therapy because the adverse effects can be devastating. For each patient, the indications and potential benefits must be carefully weighed against the risk of adverse events, considering the patient's values and preferences.
  • Indications
    • Persistent hypotension or shock (i.e., a systolic blood pressure <90 mmHg or a decrease in the systolic blood pressure by ≥40 mmHg from baseline) due to acute PE is the only widely accepted indication for systemic thrombolysis (Tapson & Weinberg, 2019).
    • In most cases, systemic thrombolytic therapy should be considered only after confirmed acute PE. Because a pulmonary arteriogram immediately precedes catheter-based therapy, PE can be confirmed at that time when this procedure is undertaken (Tapson & Weinberg, 2019).
    • The decision to administer thrombolysis is strongly influenced by clinical factors unique to the individual patient. For example:
      • While a patient with proven PE-induced shock who is unconscious requiring very high doses of vasopressors is a candidate for immediate intravenous thrombolytic therapy, the indication is not as apparent in a patient who has low blood pressure for 20 minutes but who is awake, alert, and comfortable with a low oxygenation requirement. Thus, it is prudent to adopt a multidisciplinary approach to facilitate the management of patients with PE and help with the decision of thrombolysis. Some centers have incorporated a Pulmonary Embolism Response Team (PERT) to facilitate this process (Tapson & Weinberg, 2019).
  • Most clinicians and society guidelines accept that thrombolysis in patients with acute PE who present with hypotension is likely beneficial and is a widely accepted indication (Tapson & Weinberg, 2019). A similar approach is also appropriate in those whose course is complicated by hypotension assessed to be due to recurrent PE despite anticoagulation.
  • Most societal guidelines also suggest catheter-directed therapies with or without thrombolysis in those patients:
    • As rescue therapy following failed systemic thrombolysis is provided, the necessary local expertise is available (Tapson & Weinberg, 2019).
    • In whom death is likely to occur before systemic thrombolysis can manifest effectiveness (i.e., within hours).
    • With a high bleeding risk.
  • However, it is believed that systemic thrombolysis, even delivered over two hours, is generally faster than a catheter-based therapy with or without lysis, although this may depend on how quickly the latter procedure can be arranged.
  • Few trials have evaluated the effects of systemic thrombolytic therapy in hemodynamically unstable patients, but those that did found a consistent trend toward improved mortality.
    • A meta-analysis that included those trials did a subgroup analysis of 154 patients with massive (high-risk) PE and found systemic thrombolytic therapy decreased the composite endpoint of death and recurrent thromboembolism.
    • Another meta-analysis reported a reduced short-term all-cause mortality in unstable patients with PE treated with thrombolytic therapy compared with those not treated with thrombolytics (Tapson & Weinberg, 2019).
• Empiric anticoagulation
  • The administration of empiric anticoagulation depends upon the risk of bleeding, clinical suspicion for PE and the expected timing of diagnostic tests (Tapson & Weinberg, 2019).
  • There is no optimal prediction tool for assessing bleeding risk in patients with PE. Similarly, while many experts propose using the Wells score to assess the risk of PE, careful clinical judgment is acceptable, and many experts use gestalt estimates.
  • One strategy is shown below:
    • Low risk for bleeding
      • Patients without risk factors for bleeding have a three-month bleeding risk of <2%. In such patients, empiric anticoagulation may be considered in the following patient groups:
        • High clinical suspicion for PE (e.g., Wells score >6)
        • A moderate clinical suspicion for PE (e.g., Wells score 2 to 6), in whom the diagnostic evaluation is expected to take longer than four hours
        • A low clinical suspicion for PE (e.g., Wells score <2), if the diagnostic evaluation is expected to take longer than 24 hours
    • Unacceptably high risk for bleeding
      • Patients with absolute contraindications to anticoagulant therapy (e.g., recent surgery, hemorrhagic stroke, active bleeding) or those assessed by their clinician to be at an unacceptably high risk of bleeding (e.g., aortic dissection, intracranial or spinal cord tumors), empiric anticoagulation should not be administered.
      • The diagnostic evaluation should be expedited so alternate therapies (e.g., inferior vena cava [IVC] filter, embolectomy) can be initiated if PE is confirmed.
    • Moderate risk for bleeding
      • Patients with one or more risk factors for bleeding have a moderate (>3%) to high (>13%) risk of bleeding.
      • In such patients, empiric anticoagulant therapy may be administered on a case-by-case basis according to the assessed risk-benefit ratio and the patient's values and preferences.
      • Additionally, using these bleeding estimates should not preclude clinical judgment when deciding to anticoagulate in this population. For example:
        • A patient with a moderate risk of bleeding might empirically be anticoagulated if there is a high clinical suspicion of PE, severe respiratory compromise, or an expected delay in inserting an IVC filter.
  • Typically, menstruation, epistaxis, and the presence of minor hemoptysis are not contraindications to anticoagulation but should be monitored during anticoagulant therapy.
  • The optimal agent for empiric anticoagulation depends upon the presence or absence of hemodynamic instability, the anticipated need for procedures or thrombolysis, and the presence of risk factors and comorbidities. For examples:
    • Low molecular weight (LMW) heparin may be chosen for patients with hemodynamically stable PE who do not have renal insufficiency, and in whom the rapid onset of anticoagulation needs to be guaranteed (i.e., therapeutic levels are achieved within four hours).
    • In contrast, for most patients who are hemodynamically unstable or become hemodynamically stable following resuscitation and in whom the clinical suspicion for PE is high, immediate anticoagulation with unfractionated heparin (UFH) is preferred, and prompt imaging for definitive diagnosis (usually CTPA) performed in anticipation of a potential need for thrombolysis or embolectomy.
    • Direct thrombin and factor Xa inhibitors should not be used in hemodynamically unstable patients.

A portable perfusion scan can be done at some medical centers for patients with a high clinical suspicion for PE who are hemodynamically unstable and unsafe to transfer to radiology for a CTPA.

When portable perfusion scanning or CTPA is not available or is unsafe, bedside echocardiography (transthoracic or transesophageal) is preferred to obtain a presumptive diagnosis of PE:

• Regional wall motion abnormalities that spare the RV apex (McConnell’s sign)
• RV enlargement/hypokinesis
• Visualization of clot prior to the empiric administration of systemic thrombolytic therapy (i.e., reperfusion therapy)

If bedside echocardiography is delayed or not available, the use of thrombolytic therapy as a life-saving measure should be individualized. If not used, the patient should receive empiric anticoagulation. The initiation of anticoagulation should not be delayed while considering other, more aggressive interventional therapies. A similar approach for select patients with known PE has been suggested whose course becomes complicated by hypotension during anticoagulation in whom the suspicion for recurrent PE despite anticoagulation is high.

For patients with suspected PE who remain hemodynamically unstable and the clinical suspicion is low or moderate, the approach to empiric anticoagulation should be the same as for hemodynamically stable patients. Empiric thrombolysis is not justified in this population.

Additional clinical factors strongly influence the decision to administer thrombolysis. For example, while a patient with proven PE-induced shock who is unconscious requiring very high doses of pressors is a candidate for immediate intravenous (IV) thrombolytic therapy, a patient who has low blood pressure for 20 minutes but who is awake, alert, and comfortable, with a low oxygenation requirement might be considered for anticoagulation alone or an interventional procedure. Thus, when feasible, it is prudent to adopt a multidisciplinary approach to facilitate the management of hemodynamically unstable patients with PE. Some centers have incorporated a PERT to facilitate the process (Tapson & Weinberg, 2019).

For patients in whom hemodynamic stability is restored following brief resuscitation (e.g., for 15 minutes), the following approach is suggested:

• High suspicion of PE
  • For patients with high suspicion for PE, immediate anticoagulation is preferred (provided there is no contraindication) and definitive diagnostic imaging, usually CTPA.
    • This approach is contingent upon prompt access to imaging and staff that can administer cardiopulmonary resuscitation (CPR) or empiric thrombolytic therapy if the patient decompensates during testing.
• Low or moderate suspicion of PE
  • For patients with a low or moderate suspicion of PE, the same approach to diagnosis and empiric anticoagulation should be used for hemodynamically stable patients.

Most patients with PE are hemodynamically stable on presentation (Thompson et al., 2019). In this population of patients, sufficient time is available to adopt a systematic approach for diagnosing PE.

Patients in this group are heterogeneous and have a wide range of presentations and a variable risk of recurrence and decompensation. This group includes those with submassive PE (moderate/intermediate risk) and minor PE (low risk).

Several diagnostic algorithms for hemodynamically stable nonpregnant adult patients with suspected PE have been proposed (Thompson et al., 2019). Their purpose is to efficiently diagnose all clinically important PE while simultaneously avoiding the risks of unnecessary testing. A preferred approach that selectively integrates clinical evaluation, three-tiered PTP assessment, PERC, D-dimer testing, and imaging. CTPA is the imaging modality of choice. However, algorithms that use a V/Q scan are appropriate when CTPA is contraindicated, not feasible, or inconclusive.

The following approach is suggested for most hemodynamically stable (i.e., normotensive) patients with minor/low-risk PE:

• For those in whom the risk of bleeding is low, anticoagulant therapy is indicated.
• For those who have contraindications to anticoagulation or have an unacceptably high bleeding risk, an IVC filter should be placed.
• For those in whom the risk of bleeding is moderate or high, therapy should be individualized according to the assessed risk-benefit ratio and values and preferences of the patient.
  • For example, a patient >75 years old at risk of falling is not an ideal candidate for anticoagulation.
  • Anticoagulation may be considered if an IVC filter cannot be placed (e.g., inability to access the inferior vena cava due to extensive thrombus or tumor).
• For most hemodynamically stable patients, thrombolytic therapy is not recommended (e.g., low-risk patients).

Hemodynamically stable (i.e., normotensive) patients with intermediate-risk/submassive PE who are anticoagulated should be continuously monitored for deterioration. Thrombolysis or catheter-based therapies may be considered case-by-case when the clinician assesses the benefits to outweigh the risk of hemorrhage. Such patients include those with a large clot burden, severe RV enlargement/dysfunction, high oxygen requirement, or severely tachycardic.

The majority of patients with PE are hemodynamically stable on presentation.³ In this population of patients, sufficient time is available to adopt a systematic approach for the diagnosis of PE.

Patients in this group are heterogeneous and have a wide range of presentations, as well as variable risk of recurrence and decompensation. This group includes those with submassive PE (moderate/intermediate risk), and minor PE (low risk).

Several diagnostic algorithms for hemodynamically stable nonpregnant adult patients with suspected PE have been proposed.³ Their purpose is to efficiently diagnose all clinically important PE while simultaneously avoiding the risks of unnecessary testing. An approach is preferred that selectively integrates clinical evaluation, three-tiered PTP assessment, PERC, D-dimer testing, and imaging. CTPA is the imaging modality of choice. However, algorithms that use a V/Q scan are appropriate when CTPA is contraindicated, not feasible, or inconclusive.

The following approach is suggested for most hemodynamically stable (i.e., normotensive) patients with minor/low-risk PE:

• For those in whom the risk of bleeding is low, anticoagulant therapy is indicated.
• For those who have contraindications to anticoagulation or have an unacceptably high bleeding risk, placement of an IVC filter should be performed.
• For those in whom the risk of bleeding is moderate or high, therapy should be individualized according to the assessed risk-benefit ratio and values and preferences of the patient.
  • For example, a patient >75 years of age who is at risk of falling is not an ideal candidate for anticoagulation.
  • Anticoagulation may be considered if an IVC filter cannot be placed (e.g., inability to access the inferior vena cava due to extensive thrombus or tumor).
• For most hemodynamically stable patients, thrombolytic therapy is not recommended (e.g., low-risk patients).

Hemodynamically stable (i.e., normotensive) patients with intermediate-risk/submassive PE who are anticoagulated, should be continuously monitored for deterioration. Thrombolysis and/or catheter-based therapies may be considered on a case-by-case basis when the benefits are assessed by the clinician to outweigh the risk of hemorrhage. Examples of such patients include those who have a large clot burden, severe RV enlargement/dysfunction, high oxygen requirement, and/or are severely tachycardic.

Anticoagulant therapy is indicated for patients with PE in whom the risk of bleeding is low (see below):

• Initial anticoagulation (0 to 10 days)
  • Initial anticoagulant therapy is administered as soon as possible to achieve therapeutic anticoagulation quickly.

Empiric anticoagulation while waiting for test results should be individualized according to the clinical suspicion for PE, the anticipated timing of definitive testing, and the risk of bleeding.

For most patients with acute PE who do not have hemodynamic compromise, thrombolytic therapy is not warranted. Under occasional circumstances, thrombolysis may be considered case-by-case when the clinician assesses the benefits to outweigh the risk of hemorrhage, and the patient’s values and preferences have been considered (Tapson & Weinberg, 2019).

Situations where clinicians typically contemplate thrombolysis, particularly when patients develop signs of deterioration (e.g., increasing tachycardia, clinical signs of shock, worsening right heart dysfunction, worsening blood pressure, significant hypoxemia) despite maintaining a systolic blood pressure >90 mmHg are:

• Cardiopulmonary arrest due to PE (e.g., BP >90 mmHg after resuscitation)
• Extensive clot burden (e.g., large perfusion defects on V/Q scan or extensive embolic burden on CT)
• Free-floating right atrial or RV thrombus
• Severe or worsening RV dysfunction ("submassive PE") (Tapson & Weinberg, 2019)

Although most patients listed in the situations described above may not be initially treated with thrombolysis, they should be anticoagulated and carefully monitored since they are at risk of deterioration, and a decision to administer thrombolytics may need to be made promptly.

The most controversial situation in which thrombolytic therapy is often considered is RV dilation or hypokinesis without systemic hypotension (also known as "submissive" or "intermediate-risk" PE). The rationale for thrombolysis in this population is based on the observation that severe RV dysfunction is associated with a worse prognosis than mild or no RV dysfunction (Tapson & Weinberg, 2019). However, randomized trials have not shown a clear mortality benefit in these patients. This result may be because clinical trials of thrombolytic therapy have not stratified this population based on the degree of RV enlargement or the severity of RV dysfunction. For example:

• This population of patients with acute PE constitutes a spectrum of severity such that patients with severe or worsening RV dysfunction and a markedly elevated BNP level, with a substantial oxygen requirement and an elevated heart rate (e.g., >120/minute), is likely different from patients with mild RV dysfunction, a normal heart rate and no oxygen requirement. Thus, thrombolytic therapy in this population should be individualized, and the benefits and risks (of bleeding) should be carefully weighed on a case-by-case basis.

Several studies have shown improved RV function in association with the administration of thrombolytic agents (systemic and catheter-directed), and one meta-analysis has suggested a possible mortality benefit (Tapson & Weinberg, 2019).

• The largest of these trials was the randomized multicenter trial (PEITHO) trial that compared thrombolytic therapy (tenecteplase) plus heparin with placebo plus heparin in 1,005 patients with acute PE who were normotensive and had evidence of RV dysfunction (i.e., "intermediate-risk PE") (Tapson & Weinberg, 2019).
  • RV dysfunction was confirmed by echocardiography or CT and a positive troponin I/T. Tenecteplase was administered as an IV push with weight-based dosing, and heparin was either UFH or LMW heparin.
    • Thrombolysis, compared with heparin alone, resulted in a reduction in the primary endpoint of death or hemodynamic decompensation seven days following randomization.
    • Subgroup analysis indicated that the differences in outcome were primarily affected by the prevention of further decompensation. There was no difference in 7 days or 30-day mortality.
    • The administration of thrombolytic agents was associated with increased extracranial bleeding, major bleeding, and hemorrhagic stroke.
    • In a prespecified subgroup analysis of patients older than 75 years, therapy benefits were maintained, but rates of extracranial bleeding were higher, suggesting that the risk-benefit may be more favorable in those 75 years old or younger.
    • Long-term follow-up of these patients (approximately 3.5 years) reported no difference in mortality, dyspnea or exercise capacity, RV dysfunction, or CTEPH (Tapson & Weinberg, 2019).

Further randomized trials are needed to identify subpopulations of patients with RV dysfunction where the benefits in mortality outweigh the risk of hemorrhage before it can be routinely used to treat hemodynamically stable acute PE with RV dysfunction. Specifically, more data further stratifying intermediate-risk PE based on the severity of RV dysfunction, biomarkers (troponin/BNP), oxygen requirement, residual DVT, and simple vital sign parameters such as heart and respiratory rate are necessary.

Case reports and series have reported some success from systemic thrombolytic therapy during CPR when the cardiac arrest is due to suspected or confirmed acute PE (Tapson & Weinberg, 2019).

One retrospective study reported a 5% incidence of PE (diagnosed by autopsy, clinically, or echocardiography) in 1,246 cardiac arrest victims (Tapson & Weinberg, 2019).

• Subgroup analysis suggested that thrombolysis was associated with a greater return of spontaneous circulation rate than those who did not receive thrombolysis.

Another retrospective study of 23 patients with pulseless electrical activity (PEA) due to confirmed massive PE reported the return of spontaneous circulation within two to 15 minutes after administering a tissue plasminogen activator at a reduced dose of 50 mg IV push (Tapson & Weinberg, 2019).

In contrast, another randomized study of 233 patients who presented with PEA arrest of unknown etiology reported that compared to placebo, thrombolysis did not improve survival or return of spontaneous circulation (Tapson & Weinberg, 2019).

There remains insufficient data to argue for or against the routine use of thrombolytic therapy during cardiac arrest. However, the decision to administer treatment as a potentially lifesaving maneuver for suspected PE-induced cardiac arrest can be considered case-by-case.

A large clot burden may elevate pulmonary arterial pressure without causing significant RV dysfunction or hemodynamic collapse. A large retrospective study suggested that an obstruction index by CTPA in acute PE >40% was associated with an 11-fold increase in mortality (Tapson & Weinberg, 2019). However, there remains no proof that systemic thrombolysis would reduce this mortality with an acceptable bleeding rate.

Although there is no clear indication for thrombolytic therapy in patients with severe hypoxemia, a free-floating right atrial or RV thrombus (with or without a patent foramen ovale (PFO), the administration of thrombolytic therapy in such rare circumstances may be considered on an individual basis.

In every patient in whom thrombolysis is contemplated, the risk of bleeding should always be considered. The importance of the contraindication should depend on the strength of the indication (Tapson & Weinberg, 2019). For example, a contraindication is of more concern if the indication for systemic thrombolytic therapy is RV dyskinesis than if the indication is shock.

Absolute or major contraindications to systemic thrombolytic therapy in acute PE include:

• Active bleeding or bleeding diathesis
• History of a hemorrhagic stroke
• Intracranial neoplasm
• Nonhemorrhagic stroke within the previous three months
• Recent (i.e., <2 months) intracranial or spinal surgery or trauma

Relative contraindications include:

• Active peptic ulcer
• Age >75 years of age
• The current use of an anticoagulant (e.g., warfarin sodium) that has produced an elevated prothrombin time (PT) ratio is usually expressed as the international normalized ratio (INR)
• Diabetic retinopathy
• History of chronic, severe, poorly controlled hypertension (i.e., systolic blood pressure >200 mmHg or diastolic blood pressure >110 mmHg)
• History of ischemic stroke more than three months earlier
• Noncompressible vascular punctures
• Pericarditis or pericardial fluid
• Pregnancy
• Recent (within two to four weeks) internal bleeding
• Recent invasive procedure
• Severe uncontrolled hypertension on presentation
• Traumatic or prolonged CPR or major surgery less than three weeks earlier (Tapson & Weinberg, 2019)

Thrombolytic therapy may cause moderate bleeding in menstruating women, but it has rarely been associated with major hemorrhage. Therefore, menstruation is not a contraindication to thrombolytic therapy.

As an alternative to thrombolytic therapy, catheter or surgical embolectomy may be warranted if the necessary resources and expertise are available. Whether to pursue one of these approaches should be based on local expertise.

*Only thrombolytic agents approved by the FDA for the treatment of PE are discussed here.

Once the decision to administer thrombolytic therapy has been made, the thrombolytic agent is typically administered via a peripheral IV infusion (Tapson & Weinberg, 2019). Although bolus and catheter-directed routes of administration have been studied, there are less available data.

Unnecessary invasive procedures (particularly arterial punctures) should be minimized while thrombolytic therapy is being administered, and extreme caution should be taken with patients who have had PE-induced syncope with resultant head trauma even if the brain CT is negative.

Anticoagulant therapy is generally discontinued during the thrombolytic infusion. Discontinuing anticoagulants during thrombolysis is consistent with most commonly performed trials in the United States. However, this has not been the case in other trials, particularly in Europe. The potential risk of bleeding with continued anticoagulation and the risk of recurrent embolism while anticoagulation is discontinued is unknown. Full anticoagulation (usually heparin followed by an oral anticoagulant) following clot lysis is typically undertaken. The optimal duration of IV heparin following thrombolysis is unknown. Similarly, the duration of long-term anticoagulation once the patient is stabilized depends on several factors primarily focused on perceived risk for recurrence, with an absolute minimum of three months being required (Tapson & Weinberg, 2019).

In hemodynamically unstable patients, systemic thrombolysis is preferred because of more widespread availability and clinical experience with these agents and the rapidity with which they can be administered in life-threatening situations. Although thrombolytic therapy is rarely administered to hemodynamically stable patients, the optimal method of administration is unknown. Clinical experience suggests that if thrombolytic therapy is to be administered in, for example, intermediate-risk PE, catheter-based therapy rather than systemic therapy may be preferred, provided the expertise is available. This preference is based on clinical experience and the likelihood of a lower risk of bleeding with this method of administration. Systemic thrombolytic therapy is a suitable alternative if local expertise is unavailable for catheter-directed techniques. While several catheter-based techniques are available, only one ultrasound-assisted device has been approved by the FDA.

Intravenous thrombolytic infusion regimens are the most common method of administering thrombolytics. Common regimens that the FDA approves for PE include:

• rtPA (alteplase)
  • 100 mg IV infusion over two hours
• tenecteplase (TNK-tPA)
  • IV push over 5-10 seconds (off-label use only if alteplase unavailable)

Although rtPA (alteplase) is the most commonly used thrombolytic, the superiority of any agent or regimen over another has not been established. The evidence from small randomized trials suggests that shorter infusions (i.e., ≤2 hours) achieve more rapid clot lysis and are associated with lower rates of bleeding than longer infusions (i.e., ≥12 hours) (Tapson & Weinberg, 2019). The FDA-approved infusion duration for rtPA of two hours has been the main reason this drug is commonly chosen and is the only thrombolytic agent that is FDA-approved for acute PE.

An activated partial thromboplastin time (aPTT) can be measured when the infusion of thrombolytic therapy is complete. Heparin should be resumed without a loading dose when the aPTT is less than twice its upper limit of normal. If the aPTT exceeds this value, the test should be repeated every four hours until it is less than twice its upper limit of normal, at which time heparin should be resumed. Another option is to simply restart the heparin infusion without a bolus when the thrombolytic infusion has been infused.

Coagulation assays are unnecessary during infusion of the thrombolytic agent since thrombolytic agents are administered in fixed doses.

The question of whether a lower dose of thrombolytic therapy could expedite the resolution of pulmonary hypertension due to a "moderate" acute PE without significant adverse effects was examined in the Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial.

• Moderate PE was defined as the presence of signs and symptoms of PE plus CTPA demonstrating >70% involvement with embolism in ≥2 lobar arteries or main pulmonary arteries or by a high probability V/Q showing ventilation/perfusion mismatch in ≥2 lobes.
• The 121 patients were randomly assigned to receive heparin (UFH or LMW) alone or the combination of lower-dose rtPA plus heparin. This dose of rtPA was ≤50% of the standard dose (100 mg) for patients weighing 50 kg or more and 0.5 mg/kg for those weighing less than 50 kg.
• Compared with conventional therapy, this lower-dose regimen of rtPA resulted in the following:
  • Lower rates of pulmonary hypertension by echocardiography.
  • Lower pulmonary artery systolic pressures at 28 months.
  • Faster resolution of pulmonary hypertension on admission and at 28 months.
  • Similar rates of bleeding, recurrent PE, and mortality.
• Statistical significance for a rate reduction in recurrent PE was only reached when combined with pulmonary hypertension or mortality as a composite outcome. The sample size was small, and the prevalence of RV dysfunction (<25%) and RV hypokinesis (<7%) in this study was low. In addition, echocardiography is not the optimal tool for determining pulmonary artery pressure; thus, there is no proof that any patients with elevated pulmonary artery pressure had CTEPH (Tapson & Weinberg, 2019).

A retrospective propensity-matched study reported that compared with patients treated with full-dose rtPA (100 mg), patients treated with half-dose rtPA (50 mg) required vasopressor therapy and invasive ventilation less often but needed escalation of therapy more often (Tapson & Weinberg, 2019). Hospital mortality and rates of significant bleeding were similar.

One retrospective analysis compared reduced-dose (half-dose) thrombolysis with catheter-directed thrombolysis and found that both therapies led to similar reductions in the pulmonary artery systolic pressure and RV/LV ratio, but half-dose thrombolysis reduced the duration and cost of hospitalization (Tapson & Weinberg, 2019). Further studies are required before firm conclusions can be drawn from this retrospective study.

Based on this limited evidence, a recommendation cannot be made to implement this lower-dose regimen of rtPA for "moderate" PE. Further prospective studies are needed to validate its efficacy in a larger population of patients with moderate acute PE.

Bolus infusion of thrombolytics may be effective without excess bleeding complications (Tapson & Weinberg, 2019). However, this has not been directly compared to a two-hour infusion of rtPA. More trials comparing the regimens are necessary before routine bolus infusion replaces the more conventional two-hour regimen.

An exception is that bolus infusion of thrombolytic therapy is indicated for patients with imminent or actual PE-related cardiac arrest:

• The impact of bolus infusion was illustrated by a double-blind trial in which 58 patients with acute PE were randomly assigned to receive rtPA (0.6 mg/kg over two minutes) plus heparin or placebo plus heparin (Tapson & Weinberg, 2019). Patients who received rtPA were more likely to have >50% clot resolution and increased perfusion within 24 hours, although there were no detectable differences by the seventh day. There was no major bleeding in either group.
• However, during an arrest or impending arrest, it is more practical to give rtPA using an entire 50 mg vial rather than calculating and preparing a fractional dose based upon patient weight. In adult patients with PE-related arrest, a 50 mg IV bolus of rtPA can be given over two minutes and repeated after 15 minutes in the absence of return of spontaneous circulation (ROSC). This regimen is generally consistent with American Heart Association 2015 guidelines on cardiopulmonary resuscitation, a section on arrest in special circumstances, and 2012 guidelines of the American College of Chest Physicians on antithrombotic therapy for VTE (Tapson & Weinberg, 2019).

If rtPA is unavailable, but tenecteplase is available, a single IV dose of tenecteplase given over five seconds can be given for PE-related cardiac arrest, based upon patient weight as per pharmacy protocol (Tapson & Weinberg, 2019).

Thrombolytics for PE-related arrest are given with systemic anticoagulation (e.g., UFH infusion) (Tapson & Weinberg, 2019).

Thrombolytic agents can be infused directly into the pulmonary artery via a pulmonary arterial catheter (Tapson & Weinberg, 2019). Guidelines suggest that catheter-directed thrombolysis may be considered for patients:

• At high risk of bleeding
• At the risk of death before systemic thrombolysis can manifest itself in effectiveness
• With persistent hemodynamic instability despite systemic thrombolysis (Tapson & Weinberg, 2019)

It should be kept in mind that despite this guideline recommendation, catheter-based therapy can, in fact, rarely be performed faster than systemic lysis. CDT should be reserved for use in centers with appropriate expertise. The potential advantage of catheter-administered thrombolytics is that lower doses of a lytic agent can be administered, thereby reducing the risk of bleeding compared to systemic therapy. In addition, other mechanical interventions can be simultaneously performed to aid clot dissolution (e.g., ultrasound) or mechanical removal (e.g., embolectomy) (Tapson & Weinberg, 2019).

Data regarding this approach come from small prospective trials with mixed results. As examples:

• The initial CDT trial was a study of 34 patients published in 1988 and included 34 patients with persistent hypotension due to acute PE (i.e., high-risk PE). Catheter-directed therapy was compared with intravenous rtPA (100 mg for each route) (Tapson & Weinberg, 2019).
  • In the catheter-based group, the rtPA was delivered directly into the pulmonary arteries with no mechanical lysis. The route of administration had no impact on the degree of reduction of clot burden (determined by pulmonary angiogram) or the mean pulmonary arterial pressure. Both catheter-directed and intravenous rtPA were associated with bleeding at surgical, puncture, and catheter insertion sites.
• The Ultima trial randomized 59 patients with acute, intermediate-risk PE to ultrasound-assisted catheter-directed thrombolysis (USAT) followed by intravenous heparin or intravenous heparin alone (Tapson & Weinberg, 2019).
  • Intermediate risk PE was defined as PE of the main or lower lobe pulmonary artery and echocardiographic evidence of RV enlargement.
    • The USAT regimen consisted of high-frequency ultrasound combined with 10 to 20 mg of rtPA infused over 15 hours.
    • At 24 hours, compared to conventional anticoagulation, USAT resulted in an improved RV: LV ratio, suggesting a hemodynamic benefit.
    • At 90 days, there was no difference in mortality or major bleeding between the groups.
• A retrospective review of 105 cases of massive and submassive PE reported an improved RV/LV ratio in patients treated with CDT-thrombolysis compared with heparin alone without any difference in 90-day mortality or major bleeding (Tapson & Weinberg, 2019).
• Limitations of these trials include:
  • Inadequate power to estimate survival benefit
  • Lack of data describing the effect of thrombolysis over a more extended period (weeks to months) on clinically meaningful outcomes
  • Small sample size
  • Use of echocardiography to assess pulmonary hypertension

Further randomized studies will be needed to clarify the population that would benefit from this approach before CDT can be routinely used for patients with acute PE.

Most patients with ultrasound-proven proximal DVT (i.e., popliteal, femoral, or iliac vein DVT) and most cases of symptomatic distal DVT (below the knee and in the calf veins, i.e., peroneal, posterior, and anterior tibial DVT) should be anticoagulated. Similarly, patients with symptomatic PE and most patients with subsegmental PE should be anticoagulated. For each patient, the decision to anticoagulate must weigh the risk of morbidity and mortality without anticoagulation against the risk of bleeding on anticoagulation.

In all patients, the decision to anticoagulate should be individualized, and the benefits of VTE prevention carefully weighed against the risk of bleeding. Most clinicians agree that patients with a three-month bleeding risk of less than 2% (low risk) should be anticoagulated and that those with a bleeding risk of more than 13% (high risk) should not be anticoagulated (Hull & Lip, 2019).  There is no agreement regarding the preferred approach for patients with a bleeding risk between these values (moderate risk). The decision to anticoagulate in this population must be individualized according to the values and preferences of the patient, as well as the risk-benefit ratio.

Except for patients who are pregnant, have active cancer, or have severely impaired renal function (e.g., creatinine clearance [CrCl] <30mL/minute), the following approach is suggested:

• For most patients with VTE who are hemodynamically stable, one of the following should be chosen:
  • Fondaparinux
  • Oral factor Xa inhibitors: rivaroxaban or apixaban
  • Subcutaneous LMW heparin
  • Intravenous UFH is not suggested
• Direct oral anticoagulants
  • Rivaroxaban and apixaban are the only direct oral anticoagulants that have been studied and approved by regulatory agencies as monotherapy (i.e., no pre-treatment with heparin is necessary) for the treatment of patients with VTE.
    • They may be preferred by those who wish to avoid the burden of injections in whom convenience or oral medication is a personal preference.
    • Importantly, LMW heparin (or UFH) should be administered if there is a delay in obtaining these direct oral anticoagulants (e.g., availability needs to be assured).
  • When prescribing the direct thrombin inhibitor dabigatran or the factor Xa inhibitor edoxaban, a short course of heparin (typically LMW heparin) should be administered for five days before transitioning to oral therapy (i.e., dual therapy) since their efficacy as monotherapeutic agents has not been studied or approved.
    • Importantly, these agents should not be administered simultaneously.
  • These direct oral anticoagulant agents are not suitable for treating hemodynamically unstable PE or massive iliofemoral DVT (e.g., phlegmasia cerulea dolens), where their efficacy has not been adequately studied, and their use may interfere with potential thrombolytic therapy or surgical embolectomy.
• LMW heparin
  • Subcutaneous LMW heparin may be preferred in those in whom oral anticoagulation is not feasible (e.g., poor oral intake, malabsorption) or for those in whom rivaroxaban or apixaban is unavailable (e.g., too costly).
• Fondaparinux
  • Subcutaneous fondaparinux is an acceptable alternative to subcutaneous LMW heparin (e.g., for those who prefer once-daily injections).
• Intravenous (IV) UFH
  • IV UFH must be administered in the inpatient setting and is therefore unsuitable for outpatient therapy. IV UFH is the preferred agent for special populations of patients (Hull & Lip, 2019).  

Warfarin cannot be administered as the only initial anticoagulant for treating patients with VTE. However, when chosen as the long-term anticoagulant, it must be co-administered with heparin so that full anticoagulation is assured.

When choosing an initial anticoagulant, the following patient populations deserve special consideration:

• Renal failure
  • IV UFH is the preferred anticoagulant in those with severe renal failure (e.g., CrCl <30 mL/minute) since the renal adjustment is not required for therapeutic anticoagulation.
• Hemodynamic instability
  • IV UFH is the preferred anticoagulant in hemodynamically unstable patients since thrombolysis, interventional procedure, or surgery may need to be considered in this population.
• Extensive clot burden
  • IV UFH is the preferred anticoagulant for those patients with extensive DVT or phlegmasia cerulea dolens or those with massive or submassive PE, which is based upon an anticipated need for a procedural or surgical intervention. Direct oral anticoagulants and LMW heparin have not been adequately tested in this population.
• Anticipated need for discontinuation or reversal
  • Since IV UFH has a short half-life (three to five hours) and a known reversibility agent (protamine sulfate), it is the preferred anticoagulant for those patients in whom there is a high likelihood that anticoagulation will need to be discontinued or reversed (e.g., patients at risk of bleeding or in need of a procedural or surgical intervention).
• Obesity or poor subcutaneous absorption
  • There is no preferred agent in patients who are obese.
  • However, therapeutic anticoagulation can be assured with IV UFH.
  • IV UFH may also be an alternative to subcutaneous LMW heparin when subcutaneous absorption is potentially poor (e.g., massive edema, anasarca).
• Malignancy
  • For most patients with active malignancy and acute VTE who have a reasonable life expectancy and adequate renal function (CrCl ≥30 mL/minute), LMW heparin is the preferred agent for initial anticoagulation rather than other agents.
• Pregnancy
  • For pregnant women with acute VTE, adjusted-dose subcutaneous LMW heparin is the preferred agent for initial anticoagulation because it has a more favorable safety profile than warfarin.
• Heparin-induced thrombocytopenia (HIT)
  • Patients with acute VTE may have a prior history of HIT or may develop HIT during parenteral therapy with heparin.
    • For both populations, heparin is contraindicated (i.e., UFH, LMW heparin, heparin flushes, heparin-bonded catheters, and heparin-containing medications).
    • Non-heparin anticoagulants are preferred.

Initial anticoagulation refers to systemic anticoagulation administered immediately following the diagnosis of DVT or PE, typically in the first 0 to 10 days. It is often administered while a decision regarding long-term anticoagulation is being made. When the decision is made to administer anticoagulant therapy, it should be started immediately since a delay may potentially increase the risk of life-threatening embolization (Hull & Lip, 2019).

• Options for initial anticoagulation include the following:
  • LMW heparin
    • Preferred anticoagulant for those patients:
      • In whom warfarin, dabigatran, or edoxaban is chosen as the agent for long-term use
      • In whom it is anticipated that therapeutic anticoagulation cannot be assured via the oral route (e.g., malabsorption, vomiting)
      • With active cancer or pregnancy
    • For those in whom rivaroxaban or apixaban are chosen as the oral agent for long-term use, LMW heparin is unnecessary unless these agents are unavailable or delayed.
    • Dosing
      • The initial therapeutic dose of LMW heparin (e.g., enoxaparin, dalteparin) varies by product.
      • Dosing is typically weight-based and renally-adjusted, and all are administered subcutaneously.
      • Typical starting doses are:
        • Enoxaparin
          • 1 mg/kg twice daily (preferred)
          • Alternatively, 1.5 mg/kg once daily can be used in selected non-obese inpatients
          • For home treatment, the twice-daily regimen is better studied and therefore preferred by many experts (Hull & Lip, 2019).
        • Dalteparin 200 units/kg once daily
    • Efficacy
      • Evidence from several randomized trials and meta-analyses has reported that compared with IV and subcutaneous UFH, LMW heparin SQ has higher rates of thrombus regression and lower rates of recurrent thrombosis, major bleeding, and mortality. However, the data are fraught with methodologic flaws, including publication bias in favor of LMW heparin. None of the different formulations appear superior to the other (Hull & Lip, 2019).
      • Data that support the use of LMW heparin include the following:
        • In a 2017 meta-analysis of 29 studies that compared LMW heparin with IV or subcutaneous UFH in patients with acute VTE (DVT or PE), at three months, LMW heparin was associated with the following:
          • Fewer thrombotic complications (e.g., recurrence, extension, embolization)
          • Improved thrombus regression
          • Reduced rates of major hemorrhage
          • Non-significant reduction in mortality (Hull & Lip, 2019)
        • An older meta-analysis of 13 studies of patients with acute VTE performed between 1980 and 1994 reported that, compared with UFH, LMW heparin was associated with a lower rate of both recurrent VTE and major bleeding (Hull & Lip, 2019).
      • Once-daily regimens of LMW heparin appear to be as effective as twice-daily regimens. Meta-analyses of trials directly comparing once versus twice-daily administration found no convincing differences in recurrent thrombosis, major hemorrhage, or mortality (Hull & Lip, 2019).
        • One large randomized trial of 900 patients with symptomatic DVT, a third of whom also had PE, compared enoxaparin, administered as a standard twice-daily regimen (1 mg/kg twice daily) with a lower once-daily regimen (1.5 mg/kg per day) (Hull & Lip, 2019). Although rates of recurrence and hemorrhage were lower with the twice-daily regimen, the difference was not significant and may have been explained by the lower total daily dose administered in the once-daily treatment group.
        • In another meta-analysis, once-daily regimens were associated with lower rates of major bleeding but at the expense of an increased rate of VTE recurrence (Hull & Lip, 2019).
        • Except for enoxaparin, when once-daily dosing is considered, it is preferred to be administered at the same total daily dose as a twice-daily schedule.
    • The LMW heparins have several advantages over UFH:
      • Can be used as an outpatient therapy
      • Duration of the anticoagulant effect is longer, permitting once or twice daily administration
      • Fixed dosing is feasible because the anticoagulant response (anti-Xa activity) correlates well with bodyweight
      • Greater bioavailability when given subcutaneously
      • Laboratory monitoring is not necessary (correlation between anti-Xa activity and bleeding or recurrent thrombosis is poor)
      • Lower risk of HIT (Hull & Lip, 2019)
    • Disadvantages of LMW heparin compared with UFH include:
      • Efficacy is less certain in:
        • Obese populations
        • Older patients who are underweight (<45 kg)
        • Patients with renal failure
      • Higher cost
      • The effect of protamine is incomplete if protamine is used as an antidote for hemorrhage
    • LMW heparin also appears to be as effective as once-daily SQ fondaparinux.
    • Trials directly comparing LMW heparin with oral factor Xa and direct thrombin inhibitors as initial therapies for acute DVT have not been performed.
  • Fondaparinux
    • As an alternative to LMW heparin, fondaparinux is an acceptable anticoagulant for most nonpregnant patients with newly diagnosed VTE (e.g., patients with HIT).
    • Dosing
      • Fondaparinux is typically dosed according to patient weight as 5 mg once daily (<50 kg), 7.5 mg once daily (50 to 100 kg), and 10 mg (>100 kg).
      • The dose should be reduced to 1.5 mg once daily in patients with CrCl in the 20 to 50 mL/minute range.
      • No dosage reduction is required for patients with mild renal impairment (CrCl >50 mL/minute).
    • Efficacy
      • Although SQ fondaparinux is less well studied than either LMW heparin or UFH in this setting, fondaparinux appears to have a similar efficacy and safety profile to LMW heparin (Hull & Lip, 2019).
        • One multicenter trial of 2,205 patients with acute DVT was randomized to receive fondaparinux, 7.5 mg SQ once daily (5 mg in patients weighing <50 kg; 10 mg >100 kg), or enoxaparin 1 mg/kg SQ twice daily with warfarin, for at least five days.
          • There was no difference in the rate of recurrent thromboembolism, major bleeding, or mortality rates between the two treatments.
      • SQ fondaparinux and IV UFH also appear to have similar effects on mortality, recurrent thromboembolism, and major bleeding.
        • A trial randomly assigned 2,213 patients with acute PE to receive either SQ fondaparinux or IV UFH (Hull & Lip, 2019).
          • The trial found no difference in mortality with IV UFH, recurrent thromboembolic events with IV UFH, or major bleeding with IV UFH.
  • IV UFH
    • UFH is our preferred anticoagulant for patients with severe renal failure (e.g., CrCl <30 mL/minute) and for patients in whom there is a high likelihood that acute reversal of anticoagulation will be needed (e.g., procedure or at increased risk of bleeding), as well as, those with hemodynamic instability especially if thrombolysis is being considered, and extensive clot burden (e.g., phlegmasia cerulea dolens, submassive PE).
    • UFH may also be an alternative to LMW heparin in patients suspected to have poor subcutaneous absorption (e.g., edema or obesity).
    • Dosing
      • Initial dosing of SQ Heparin and IV UFH is also weight-based but unaffected by renal insufficiency.
        • Weight-based protocols rather than fixed-dose protocols are preferred because they make pharmacologic sense and improve time spent within the therapeutic range for the aPTT (target range 1.5 to 2.5 times the control) (Hull & Lip, 2019).
      • Using IV UFH protocols may increase the time spent in the therapeutic range for the aPTT. Achieving and maintaining a therapeutic aPTT range can be challenging.
        • For example, one observational study reported that 60% of treated patients failed to achieve an adequate aPTT response during the initial 24 hours of therapy and that 30% to 40% of patients remained subtherapeutic over the next three to four days. These observations led to protocols designed to efficiently achieve and maintain target aPTT goals. Commonly used protocols are:
          • Non-weight based
          • Weight-based (Hull & Lip, 2019)
      • The preference for weight-based protocols is primarily based upon a randomized trial of a mixed population of patients requiring IV UFH for several different indications (venous and arterial thrombosis, unstable angina).
        • In that trial, a weight-based heparin dosing nomogram was compared with a non-weight-based nomogram to maintain an aPTT ratio of 1.5 to 2.3 times control values.
          • Patients treated with the weight-adjusted regimen received a starting bolus dose of 80 units/kg followed by an 18 units/kg per hour infusion. Subsequent adjustments were made every six hours.
            • Patients in the standard care group received a bolus of 5,000 units followed by a 1,000 units/hour infusion. Subsequent fixed-dose adjustments were made every six hours.
              • A higher percentage of patients in the weight-adjusted group achieved a therapeutic aPTT within 24 hours (97% versus 77%) without increasing major bleeding.
              • Recurrent thromboembolism was more frequent in the non-weight-based group (Hull & Lip, 2019).
      • The weight-based protocol is generalizable and widely used routinely in clinical practice.
      • Although not routine, weight-adjusted SQ heparin and UFH have been used anecdotally for patients who declined IV access and had a contraindication to LMW heparin (e.g., severe renal insufficiency) or other anticoagulants. Typically, subcutaneous UFH is given as weight-based dosing of 333 units/kg loading dose followed by 250 units/kg every 12 hours (Hull & Lip, 2019).
      • The optimal dosing of UFH in obese patients is unknown. Most clinicians use ideal body weight to guide dosing and increase the aPTT accordingly to the target. The clinical efficacy of this approach is unknown.
    • Efficacy
      • In the past, IV UFH was the gold standard for initial anticoagulation in patients with DVT until LMW heparin became available.
      • Compared with LMW heparin, IV UFH is associated with slightly higher rates of recurrent thrombosis and major bleeding.
      • The efficacy of IV UFH depends upon achieving a critical therapeutic level as soon as possible, preferably within the first 24 hours of treatment, usually via a continuous IV infusion (Hull & Lip, 2019).
        • The critical therapeutic level of heparin, as measured by the aPTT, is a target aPTT ratio range of 1.5 to 2.5 times the control. This range corresponds to a heparin level of 0.3 to 0.7 units/mL when measured by an anti-Xa assay (Hull & Lip, 2019).
          • Studies that support this target range include the following:
            • One older prospective study of patients with acute DVT reported that compared with an aPTT ratio >1.5, patients with an aPTT ratio <1.5 times the control for three days had a threefold increase in the risk of recurrent thrombosis (Hull & Lip, 2019).
            • A pooled analysis of three randomized trials examined therapeutic or subtherapeutic UFH (mostly IV UFH) for acute proximal DVT (Hull & Lip, 2019). Compared with patients whose aPTT exceeded the therapeutic threshold by 24 hours, failure to achieve a therapeutic aPTT during that time was associated with an increased rate of recurrent thrombosis.
        • Although there is a strong correlation between subtherapeutic aPTT values and recurrent thromboembolism, the relationship between supratherapeutic aPTT (i.e., an aPTT ratio of 2.5 or more) and bleeding is less definite (Hull & Lip, 2019).   Nonetheless, aiming for a therapeutic range with the avoidance of periods of both subtherapeutic and supratherapeutic levels is prudent.
      • The advantages of IV UFH compared with LMW heparin include:
        • Lower cost
        • Safe use in those with renal insufficiency
        • Short half-life, particularly for patients in whom there is a potential need for acute discontinuation (e.g., surgery)
      • Disadvantages include:
        • Infusions of UFH require hospital admission
        • Both SQ and IV UFH are associated with a higher potential for HIT
      • Data that support the efficacy of SQ UFH include the following:
        • One meta-analysis of 16 randomized trials of patients with VTE, when compared with continuous IV UFH for initial anticoagulation, SQ UFH resulted in similar rates of recurrence, mortality), and major bleeding (Hull & Lip, 2019).
        • Other meta-analyses of four randomized trials demonstrated that LMW heparin and SQ UFH have similar effects on mortality, recurrent thromboembolic events, and major bleeding (Hull & Lip, 2019).
  • Oral factor Xa inhibitors or direct thrombin inhibitors
    • Oral factor Xa (rivaroxaban, apixaban, edoxaban) or direct thrombin inhibitors (dabigatran) are attractive candidates as initial oral anticoagulants in patients with acute VTE due to their quick onset of action (peak efficacy one to four hours after ingestion).
    • Rivaroxaban and apixaban were evaluated as anticoagulants without prior administration of heparin (i.e., monotherapy). Consequently, they may be used as the sole initial anticoagulant. However, anticoagulant therapy with heparin should not be delayed while the decision is being made to treat with one of these agents, and assurance must be obtained that the drug is available immediately (as an inpatient or outpatient).
    • In contrast, in trials that evaluated dabigatran and edoxaban, all patients were treated with five days of heparin prior to their administration (i.e., dual therapy). Consequently, a short course of heparin (typically LMW heparin) should be administered alone before transitioning to either dabigatran or edoxaban.
    • Dosing
      • Typical initial doses in those with normal renal function are:
        • Rivaroxaban 15 mg twice daily (for the first three weeks)
        • Apixaban 10 mg twice daily (for the first seven days)
        • Edoxaban 60 mg once daily (and 30 mg once daily in patients with a bodyweight below 60 kg) (after an initial 5 to 10 days of parenteral anticoagulation)
        • Dabigatran 150 mg twice daily (after an initial 5 to 10 days of parenteral anticoagulation)
    • In keeping with the clinical trials that demonstrated their efficacy, in patients who are receiving heparin as the initial anticoagulant, it is suggested that oral factor Xa or direct thrombin inhibitors be given within 6 to 12 hours following the last dose of SQ LMW heparin when administered as a twice-daily regimen, or within 12 to 24 hours for once-daily regimens.
      • Infusions of UFH can be immediately discontinued after administering these oral agents.
    • Many of these agents are renally excreted, so patients with severe renal insufficiency should not be considered for these agents.
      • The distribution of agent and anticoagulant effects in the obese population is unknown.
    • The efficacy and safety of factor Xa and direct thrombin inhibitors as anticoagulants for extensive DVT (e.g., patients with phlegmasia cerulea dolens) or hemodynamically significant PE are unknown. They should not be used in these patients who may receive thrombolytic therapy.
      • Similarly, these agents should not be administered to pregnant patients because their safety and efficacy are unproven in this population.
    • Efficacy
      • Randomized trials of these oral agents in patients with acute VTE examined efficacy and safety in long-term anticoagulation with the same oral agent for three months or more.
        • Compared with conventional courses of LMW heparin or IV UFH followed by long-term anticoagulation with warfarin, these agents had similar rates of recurrent thrombosis and major hemorrhage (Hull & Lip, 2019).
          • However, trials that reported efficacy for dabigatran (direct thrombin inhibitor) and edoxaban (factor Xa inhibitor) used a minimum of five days of anticoagulation with LMW heparin or UFH prior to their administration for long-term oral therapy (i.e., dual therapy) (Hull & Lip, 2019).
          • In contrast, trials of rivaroxaban and apixaban reported the efficacy of both agents as the sole initial anticoagulant (monotherapy).
          • Although short periods (<48 hours) of heparin were allowed prior to randomization, experience with these agents is in keeping with the data that suggest monotherapy with these agents is safe and effective.

The initial duration of heparin therapy varies depending upon the oral agent chosen and whether or not thrombolysis is anticipated:

• Factor Xa and direct thrombin inhibitors
  • When factor Xa and direct thrombin inhibitors are chosen, co-administration with heparin is not warranted. However, short courses of heparin are acceptable in rivaroxaban and apixaban, while typically, five days is required for those on dabigatran and edoxaban.
• Warfarin
  • When administered together with warfarin on day 1, there is no benefit to prolonged courses of systemic heparin beyond a therapeutic INR.
    • Randomized trials have reported that shorter courses of heparin therapy (typically four to five days) plus the initiation of warfarin on day 1 is as effective as longer courses of heparin (10 to 14 days) with the delayed initiation of warfarin (e.g., starting day 5 to 10) (Hull & Lip, 2019).
      • For example, in one randomized trial of patients treated with parenteral heparin for proximal DVT, the initiation of warfarin on day 1 of therapy was associated with an equivalent three-month rate of recurrent VTE when compared with warfarin started on day 5 to 10 of therapy (Hull & Lip, 2019).
        • This approach has the added advantage of minimizing the total number of days a patient requires anticoagulation with heparin, thereby reducing the HIT risk (Hull & Lip, 2019).
        • The same approach is acceptable in clinical practice for patients taking SQ LMW heparin, UFH, and fondaparinux.
• Anticipated thrombolysis
  • Since a small proportion of patients with heavy clot burden in the lower extremity or submassive PE may need thrombolysis, IV UFH is usually administered for an ill-defined period (sometimes up to 48 hours) until the clinician assesses that thrombolysis is not indicated. There are no guidelines to facilitate the duration of heparin under these circumstances.

• CTPA
  • For most patients with suspected PE, CTPA, also called CT pulmonary angiogram with contrast, is the first-choice diagnostic imaging modality because it is sensitive and specific for the diagnosis of PE, especially when incorporated into diagnostic algorithms, and alternate diagnoses may be discovered using this modality (Thompson et al., 2019). The imaging technology is widely available, and, in most settings, the exam can be performed on an urgent or emergent basis. In some cases, if contraindications to CTPA are present but can be readily resolved (e.g., premedication for a contrast allergy) and alternate imaging such as V/Q scanning is not feasible, CTPA may be performed after a short delay (e.g., 8 to 12 hours).
  • CTPA Imaging Protocol
    • CTPA examination acquires thin (≤2.5 mm) section volumetric images of the chest after a bolus administration of IV contrast that is timed precisely for maximal enhancement of the pulmonary arteries.
    • A multidetector (≥16 detector rows) CT scanner is required to achieve sufficient diagnostic performance. Primary axial and multiplanar reformations (commonly in the coronal plane) of the pulmonary arteries are routinely reviewed.
    • For optimal image quality, the patient should be able to hold still and hold their breath for about 30 seconds.
    • A chest CT with contrast not performed as a CTPA but for other indications may incidentally detect pulmonary emboli but is not an adequate exam for excluding suspected PE (Thompson et al., 2019).
  • A CTPA result may be indeterminate for several reasons. This include:
    • Beam hardening artifacts from metallic foreign bodies
    • Large body habitus
    • Patient motion
    • Suboptimal enhancement of the pulmonary artery is usually due to abnormal cardiac output (Thompson et al., 2019).
  • Repeat CTPA for more definitive results may be worthwhile if the factor causing poor image quality can be mitigated (e.g., the patient is more capable of cooperating with positioning and breath-holding instructions). Repeat imaging is unlikely to prove useful if CTPA is nondiagnostic from factors such as scanner technology, body habitus, or indwelling metallic foreign bodies.
  • CTPA may be contraindicated in patients with a history of moderate to severe iodinated contrast allergy or renal insufficiency (eGFR <30 mL/min per 1.73 m2). The risk of these contraindications must be weighed against the clinical importance of performing the CTPA examination and the availability of alternative imaging approaches (e.g., V/Q scan). If clinically feasible, CTPA should be delayed for premedication for the history of allergy or IV hydration for renal insufficiency.
  • The approximate effective radiation dose from CTPA is 10 mSv and varies depending upon patient size, scanner type, and imaging protocol. In young (age <30 years) adults or pregnant patients who are undergoing multiple chest CT exams, minimizing cumulative radiation dose may be a consideration in opting for alternative imaging techniques, including V/Q scanning, venous ultrasound, magnetic resonance pulmonary angiogram (MRPA), if the necessary technology and expertise are available.
  • For patients in whom CTPA is performed, the following applies:
    • A positive CTPA showing a filling defect confirms the diagnosis of PE.
    • A negative CTPA indicates that the likelihood of PE is low.
      • Typically, no further testing is required unless inadequate imaging is suspected (e.g., the contrast bolus is poorly timed, and pulmonary arteries are inadequately opacified) or for another reason, clinical suspicion for PE remains high after negative CTPA.
    • An inconclusive CTPA result may necessitate alternate imaging, such as V/Q scanning.
  • Results interpretation
    • Support for CTPA-based algorithms is derived from a prospective, multicenter cohort study (Christopher study) of 3,306 patients with clinically suspected PE (Thompson et al., 2019).
      • Patients were from an inpatient or outpatient setting and categorized according to the modified Wells score as PE "likely" (score >4) or PE "unlikely" (score ≤4).
        • Patients classified as PE were unlikely underwent sensitive D-dimer testing, where PE was considered excluded when the D-dimer level was <500 ng/mL.
        • PE unlikely patients with a D-dimer level ≥500 ng/mL and PE likely patients underwent CTPA. When the CTPA confirmed PE, patients were anticoagulated.
        • Patients were not treated when CTPA excluded PE or was inconclusive (rarely).
        • At three months follow-ups, the rates of VTE during follow-up were low, as evidenced by the following:
          • Among 1,028 untreated patients in whom PE was excluded by clinical assessment plus D-dimer testing, there was one DVT, four nonfatal, and no fatal PE.
          • Among 1,436 untreated patients with CTPA excluded PE, there were eight DVT, three nonfatal PE, and seven fatal PE.
          • Among 674 treated patients with CTPA-detected PE, there were six DVT, three nonfatal PE, and 11 fatal PE.
    • A similarly designed prospective, multicenter study of 3,346 patients with suspected PE in an ED reported comparable results using age-adjusted D-dimer cutoffs (ADJUST-PE) (Thompson et al., 2019). In ADJUST-PE, patients were classified as PE unlikely or likely.
      • Those who were PE unlikely underwent age-adjusted D-dimer testing (age [if over 50] multiplied by 10 [e.g., normal D-dimer at 60 years is <600 ng/mL]).
      • When the age-adjusted value was negative, no further testing was performed.
      • All other patients underwent CTPA.
        • When CTPA was positive, PE was confirmed, and when CTPA was negative, PE was excluded.
        • Patients with inconclusive CTPA results or in whom CTPA could not be performed had additional imaging (e.g., V/Q scan, serial ultrasound [US], pulmonary angiogram) to diagnose or exclude PE.
        • At three months follow-ups, rates of VTE were low, as evidenced by the following:
          • There were only two cases of nonfatal PE among the 1,141 untreated patients in whom PE was excluded by clinical assessment plus age-adjusted D-dimer testing. Compared with using a fixed D-dimer level of <500 ng/mL, the use of age-adjusted cutoffs resulted in a 12% increase in the number of patients in whom a diagnosis of PE could be safely excluded without further imaging.
          • There were no thromboembolic events among the 673 untreated patients ≥75 years in whom PE was excluded by clinical assessment plus age-adjusted D-dimer testing.
          • Among the 1,481 untreated patients with CTPA excluded PE, there was one DVT, four cases of nonfatal PE, and two indeterminate events.
        • Age-adjusted D-dimer assessments are being increasingly used with a significant institutional variation.
  • Diagnostic Performance
    • Most studies report that CTPA is >90% sensitive and specific for diagnosing PE, especially in the low and intermediate clinical risk groups.
      • The highest sensitivities are reported when CTPA is combined with a moderate to high clinical probability assessment for PE (≥96%) but lower for those with a low suspicion for PE (Thompson et al., 2019).
      • The PIOPED II study reported that the sensitivity and specificity of multidetector CTPA were 83 (90% when combined with high suspicion) and 96%, respectively, using catheter-based pulmonary angiography as the reference standard (Thompson et al., 2019).
      • However, numerous cohort studies that use technically advanced scanners and specific CTPA protocols have since consistently reported a low incidence (<2%) of PE in patients with low to moderate clinical suspicion and a negative CTPA (Thompson et al., 2019).
      • Nevertheless there is a risk of PE in those with a negative CTPA and a high clinical suspicion for PE (up to 5% when a ≤64 detector row multidetector CT [MDCT] is used) (Thompson et al., 2019).
    • CTPA is traditionally considered most accurate for detecting large, main, lobar, and segmental PE, and less accurate for detecting smaller, peripheral subsegmental PE (SSPE). Newer scanners with increased resolution have increased the detection of smaller emboli (Thompson et al., 2019).
      • For example, one systematic review that included 2,657 patients reported improved detection of SSPE by multidetector-row CTPA compared with single-detector row CTPA (Thompson et al., 2019).
    • One commonly cited benefit of CTPA is its ability to detect alternative pulmonary abnormalities that may explain the patient's presenting signs and symptoms (Thompson et al., 2019).
      • In one observational study, 9% of CTPA examinations confirmed PE, while 33% identified an alternative cause of the patient's symptoms (Thompson et al., 2019).
      • In another retrospective review of 641 patients who underwent CTPA for suspected PE, an alternate diagnosis was discovered in 14% of patients who did not have PE, and 15% of these findings required immediate attention (Thompson et al., 2019).

• When imaging is indicated and CTPA cannot be performed or is inconclusive, V/Q scanning is recommended. In some cases, CTPA can be reconsidered if it was previously contraindicated but becomes feasible (e.g., when renal function improves or after premedication for a contrast allergy).
  • Ventilation Perfusion Scan (V/Q scan)
    • V/Q scanning is mostly reserved for patients in whom CTPA is contraindicated or inconclusive or when additional testing is needed.
    • A segmental or subsegmental perfusion defect with normal ventilation is diagnostic of PE. Images are interpreted as high, intermediate, or low probability of PE or normal.
      • All other combinations of V/Q results and clinical probability are nondiagnostic.
    • A normal CXR is usually required prior to V/Q scanning.
      • V/Q scans performed on patients with abnormal CXRs are more likely to result in false positives as the images rarely appear normal, or there is a low probability of PE in such patients.
    • For patients in whom a V/Q scan is performed, management is dependent upon the interpretation of the scan in the context of the pretest clinical probability for PE. Although the Wells criteria were developed after the PIOPED study, it is appropriate to use Wells to stratify risk for interpretation:
      • In patients with a normal or low probability V/Q scan and low clinical probability of PE (e.g., Wells score <2), the diagnosis of PE is excluded. No further testing is necessary.
      • In patients with a high-probability V/Q scan and high clinical probability of PE (e.g., Wells score >6), the diagnosis of PE is confirmed. Immediate treatment is indicated.
      • All other combinations of V/Q scan results and clinical pretest probabilities are indeterminate (inconclusive), and further testing is required (Thompson et al., 2019).
    • The patient is asked to lie still for 30 to 60 minutes for a V/Q scan.
    • The approximate effective radiation dose is less than 2 mSv.
    • Support for using V/Q scanning is based upon the following data:
      • In PIOPED, V/Q scans were reported as one of the following:
        • Normal
        • Low-probability PE
        • Intermediate-probability PE
        • High-probability PE (Thompson et al., 2019)
      • The risk of PE was reported in combination with PTP assessment:
        • Patients with a low clinical probability and a normal or low-probability V/Q scan had a less than 4% chance of having a PE, while those with an intermediate or high probability scan had a 16% and 15% chance of having PE, respectively.
        • Patients with a high clinical probability and a high-probability V/Q scan had a 96% chance of having a PE.
        • Those with a normal V/Q scan had a 0% chance of having PE, and those with a low- or intermediate-probability V/Q scan had a 40% and 66% chance of having PE, respectively.
        • Patients with an intermediate probability of PE and a high-probability V/Q scan had an 88% chance of having PE, while all other combinations had a probability of PE that ranged from 6% to 28%.
    • Most patients have indeterminate scans, which is the major limitation of V/Q scanning since an indeterminate scan is insufficient to either confirm or exclude the diagnosis of PE, necessitating additional testing.
    • One systematic review evaluated over 7,000 patients from 25 prospective studies, 23 of which included V/Q scan-based algorithms (Thompson et al., 2019). Three diagnostic strategies were identified as safely excluding patients with PE over a three-month follow-up:
      • Among patients with a low clinical probability of PE in whom normal D-dimer levels excluded PE, PE occurred in less than 3%.
      • Among patients in whom clinical probability combined with D-dimer assessment was inconclusive, a normal V/Q scan safely excluded PE.
      • For patients with an intermediate-probability V/Q scan, holding therapy was safe until further testing (e.g., catheter-based pulmonary angiography or serial lower-extremity venous ultrasonography).

• Lower-extremity ultrasound (US) with Doppler
  • A new diagnosis of DVT in the setting of symptoms consistent with PE is highly suggestive, although not definitively diagnostic, of PE. However, Doppler ultrasonography is not generally used as an initial test in the evaluation of suspected PE. Instead, because of the low sensitivity of Doppler ultrasonography in this setting, it is reserved for patients suspected of having a PE, but in whom definitive imaging (e.g., CTPA, V/Q scanning) is contraindicated or indeterminate (Thompson et al., 2019).
    • Lower-extremity proximal vein US demonstrating DVT is not diagnostic of PE but can be used to justify treatment.
  • The following approach is suggested when Doppler ultrasonography is used in patients with suspected PE in whom chest imaging is indeterminate or contraindicated:
    • If lower-extremity Doppler ultrasonography is positive, patients can be treated (usually anticoagulation).
    • If Doppler ultrasonography is negative and the clinical suspicion for PE is low or intermediate, it is generally considered safe to withhold anticoagulation and monitor for DVT with serial ultrasonography until chest imaging can be performed (e.g., after treatment of contrast allergy) (Thompson et al., 2019).
    • However, it is unknown whether the same approach can be used in patients with poor cardiopulmonary reserve (i.e., patients that would not tolerate a PE).
      • In these patients, empiric anticoagulation may be appropriate.
      • Although the optimal frequency of serial US exams is unknown, ultrasonography twice a week for two weeks is suggested as appropriate.
        • The safety of serial monitoring for DVT was illustrated in a prospective study of 874 patients with suspected PE who had an adequate cardiopulmonary reserve and a low or intermediate-probability V/Q scan (Thompson et al., 2019). Six serial lower-extremity venous ultrasounds were performed over two weeks, and anticoagulation was administered if the ultrasonography was positive. At three months, fewer than 3% of patients developed PE.
    • If Doppler ultrasonography is negative and the suspicion for PE is high, further imaging or empiric anticoagulation should be attempted. The rationale for this approach is that ultrasonography may be negative in PE, either because the thrombus has traveled to the lung or because clots in the calf or pelvic veins are not readily detected by ultrasonography (Thompson et al., 2019).
    • Whether proximal vein ultrasonography (which detects proximal vein DVT) or whole leg ultrasonography (which detects proximal and calf vein DVT) should be performed is unknown. Although some experts consider whole leg ultrasonography ideal, the choice is often institutionally-determined.
    • When neither CTPA nor V/Q scanning can be performed or are inconclusive, noninvasive testing with lower extremity compression ultrasonography with Doppler to evaluate for coexisting DVT is preferred. If the cumulative radiation dose in a young or pregnant patient is a concern, and if the necessary technology and expertise are available, MRPA could substitute for CTPA but is less sensitive and more dependent on the technologist's experience doing the scan.
• CT Venogram (CTV)
  • CTV of the lower extremities and pelvis with contrast to evaluate for DVT is not routinely performed concurrently with CTPA. CTV, when added to CTPA, may marginally improve diagnostic yield. However, the added effective radiation dose from CTV is approximately 6 mSv, significantly increasing the radiation dose over the entire patient population (Thompson et al., 2019).
• Catheter-based Pulmonary Angiography
  • Demonstrating a filling defect or abrupt cutoff of a vessel is diagnostic of an embolus. Indeterminate or nondiagnostic scans are reported when the filling defect is not visualized.
  • Catheter-based pulmonary angiography is more invasive and slightly less sensitive than CTPA and is usually reserved for patients where a concurrent therapeutic intervention is planned. Occasionally, echocardiography can be used when a rapid or presumptive diagnosis is needed in emergent circumstances but does not directly diagnose PE.
  • Pulmonary angiography, in which contrast is injected under fluoroscopy via a catheter introduced into the right heart, was the historical gold standard for the diagnosis of PE.
  • With the widespread emergence of CTPA, this procedure is infrequently used and reserved for rare circumstances in patients with a high clinical probability of PE, in whom CTPA or V/Q scanning is nondiagnostic and in whom a diagnosis determines an important clinical decision (e.g., an intervention).
  • Pulmonary angiography seems less accurate than CTPA, and its diagnostic performance is highly variable and dependent on the operator's experience (Thompson et al., 2019). Consequently, catheter-based pulmonary angiography is most often performed in patients with concurrent therapy since it can combine diagnosis with therapeutic interventions aimed at clot lysis (e.g., catheter-directed embolectomy or thrombolysis). Its use in this context is also dictated by local expertise.
  • As the historical gold standard, the sensitivity and specificity of catheter-based pulmonary angiography for the diagnosis of PE have not been formally evaluated. However, one retrospective analysis of 20 cases from PIOPED II suggested that it may be less sensitive than CTPA for detecting small emboli (Thompson et al., 2019). Nonetheless, in patients with a negative angiogram, the risk of subsequent symptomatic embolization is low (Thompson et al., 2019).
  • Although pulmonary angiography is generally well-tolerated in the presence of hemodynamic instability, the mortality of the procedure is approximately 2% but <1% for those who are hemodynamically stable (Thompson et al., 2019).
    • Morbidity occurs in approximately 5% of patients and is usually related to catheter insertion, contrast reactions, cardiac arrhythmias, or respiratory insufficiency (Thompson et al., 2019).
    • Radiation exposure depends upon the length and complexity of the procedure but is typically greater than that of CTPA (Thompson et al., 2019).
• Magnetic Resonance Pulmonary Angiography (MRPA)
  • MRPA may be an imaging option for diagnosing PE in patients in whom neither CTPA nor a V/Q scan can be performed.
  • Potential advantages of MRPA are that no ionizing radiation is involved, and the examination can be combined with magnetic resonance (MR) venography in the same sitting.
  • The patient is asked to lie in an MR scanner for >30 minutes, and IV gadolinium is administered.
  • Most importantly, to avoid a nondiagnostic result from inadequate image quality, MRPA should only be performed at sites with the necessary technology and expertise.
    • Technically inadequate images can result from patient motion, scanner technology, and the timing of the gadolinium contrast bolus (Thompson et al., 2019).
  • MRPA was studied prospectively in 371 adults with suspected PE.
    • Among the 75% of patients with technically adequate images, MRPA alone showed a sensitivity and specificity of 78% and 99%, respectively (Thompson et al., 2019). Among the 48% of patients with technically adequate images, MRPA and MR venography showed a sensitivity and specificity of 92% and 96%, respectively.
  • Two additional prospective studies reported a similarly poor sensitivity for MRPA alone (Thompson et al., 2019). Sensitivity was greater for emboli located in the main/lobar and segmental vessels compared with subsegmental vessels.
• Echocardiography
  • Echocardiography can diagnose PE when a thrombus is visualized in the proximal pulmonary arteries, although this is rare.
  • Echocardiography is rarely diagnostic of PE, but a presumptive diagnosis may be made in hemodynamically unstable patients so that life-saving therapy can be administered.
  • Although not definitive, the diagnosis of PE is supported by echocardiography by the presence of a clot in the right heart or new right heart strain. Demonstrating any clot or new strain in hemodynamically unstable patients with suspected PE may be useful if a rapid or presumptive diagnosis is required to justify the emergency use of thrombolytic therapy (Thompson et al., 2019).
  • However, in most cases, particularly those hemodynamically stable, echocardiography is generally considered insensitive (since abnormalities are frequently absent in patients with PE and nonspecific (since RV abnormalities can be seen in other conditions including chronic pulmonary disease, pulmonary hypertension, and RV infarction). Additionally, the demonstration of a new right heart strain may not be evident without a prior echocardiogram.
  • Although echocardiography has limited value diagnostically, it is most useful for prognostic purposes in patients with confirmed PE (e.g., new RV strain and RV thrombus are poor prognostic indicators).
  • Approximately 30% to 40% of patients with PE have echocardiographic abnormalities indicative of RV strain or pressure overload, and data suggest a direct correlation between the extent of RV dysfunction and the degree of perfusion defects on lung scans (Thompson et al., 2019). RV findings include:
    • Abnormal septal wall motion
    • Decreased RV function
    • Increased RV size
    • McConnell's sign
    • Tricuspid regurgitation
  • Regional wall motion abnormalities that spare the RV apex (McConnell's sign) are insensitive for the diagnosis of PE, but, in those who demonstrate this sign, it may be used to distinguish patients with RV strain from acute PE from those with pulmonary hypertension, who tend to have global RV dysfunction (Thompson et al., 2019). In general, RV strain is insensitive and nonspecific.
  • Additional echocardiographic findings suggestive of PE that are uncommon but more worrisome for PE include:
    • Pulmonary artery thrombus
      • Thrombus in the pulmonary arteries or main branches of the pulmonary arteries may be seen on transesophageal echocardiography but is rare.
    • RV thrombus
      • Among patients with intracardiac thrombus, one retrospective study reported that 35% had PE, while another registry-based study reported that among patients with known PE, approximately 4% have an RV thrombus (Thompson et al., 2019).

• Investigational
  • Dual Energy Computed Tomography (Dual Energy CT)
    • Dual-energy CT could reduce the amount of iodinated contrast needed to perform CTPA examinations and increase the sensitivity for PE by imaging an iodine map, which serves as a surrogate for lung perfusion (Thompson et al., 2019). Large cohort studies have not yet been reported.
  • Single Photon Emission CT (SPECT)
    • Technological advances in SPECT ventilation and perfusion imaging may allow for accurate diagnosis of PE without iodinated contrast administration. It may increase the detection of smaller pulmonary emboli. Preliminary studies suggest that SPECT is as sensitive as CTPA and more sensitive than V/Q scanning (Thompson et al., 2019).
  • Multiorgan Ultrasound
    • Multiorgan ultrasounds are being developed as imaging exams that could accurately and more safely diagnose PE.
    • Multiorgan ultrasonography (ultrasound of the heart, lung, and lower extremity) was prospectively examined in 357 patients suspected of having PE (Wells score >4) (Thompson et al., 2019). Sensitivity and a specificity of 90 and 86% were noted when CTPA was used as a reference standard. Rare case reports describe the demonstration of thrombus in central pulmonary arteries on endobronchial ultrasonography (Thompson et al., 2019).

More aggressive therapies than anticoagulation are suggested in patients with PE who are hemodynamically unstable or who become unstable due to recurrence despite anticoagulation. These include:

• Thrombolytic therapy provided there is no contraindication.
• Embolectomy in patients in whom thrombolysis is either contraindicated or unsuccessful (surgical or catheter-based).

Patients in this group are heterogeneous and have a wide range of presentations and a variable risk of recurrence and decompensation. This group includes those with submassive PE (moderate/intermediate risk) and minor PE (low risk).

The following approach is suggested for most hemodynamically stable (i.e., normotensive) patients with minor/low-risk PE:

• For those in whom the risk of bleeding is low, anticoagulant therapy is indicated.
• For those who have contraindications to anticoagulation or have an unacceptably high bleeding risk, an IVC filter should be placed.
• For those in whom the risk of bleeding is moderate or high, therapy should be individualized according to the assessed risk-benefit ratio and values and preferences of the patient.
  • For example, a patient >75 years old at risk of falling is not an ideal candidate for anticoagulation.
  • Anticoagulation may be considered if an IVC filter cannot be placed (e.g., inability to access the IVC due to extensive thrombus or tumor).
• For most hemodynamically stable patients, thrombolytic therapy is not recommended (e.g., low-risk patients).

In hemodynamically stable (i.e., normotensive) patients with intermediate-risk/submassive PE who are anticoagulated, close monitoring for deterioration should be ongoing. Thrombolysis or catheter-based therapies may be considered case-by-case when the clinician assesses the benefits to outweigh the risk of hemorrhage. Examples of such patients include those who have:

• A large clot burden
• High oxygen requirements
• Severe RV enlargement/dysfunction
• Severe tachycardia

Anticoagulant therapy is indicated for patients with PE in whom the risk of bleeding is low:

• Initial anticoagulation (0 to 10 days)
• Initial anticoagulant therapy is administered as soon as possible to achieve therapeutic anticoagulation quickly

The effects of thrombolytic therapy followed by anticoagulant therapy have been compared to those of anticoagulant therapy alone. The evidence consistently indicates that thrombolytic therapy leads to early hemodynamic improvement, but at the cost of increased major bleeding. Although thrombolytic therapy has been shown in one meta-analysis to improve mortality, methodologic flaws limited the analysis such that the specific population that may potentially derive benefit, as well as the optimal agent, dose, and delivery system (catheter-directed or systemic) remain unknown (Tapson & Weinberg, 2019).

• Mortality
  • Thrombolytic therapy has been shown in one meta-analysis of patients with acute PE to improve mortality, although the data was not robust for any specific patient population, nor was the optimal agent or dose identified.
    • This meta-analysis of 16 trials comprising 2,115 patients reported that compared to anticoagulation alone, thrombolytic therapy (mostly systemic agents) was associated with lower all-cause mortality (Tapson & Weinberg, 2019). The mortality benefit was maintained in a pre-specified analysis of the eight trials that enrolled only hemodynamically stable patients with RV dysfunction.
    • In contrast, the mortality benefit was insignificant in patients older than 65.
    • Importantly, any mortality benefit from thrombolysis came at the expense of an increased risk of major hemorrhage.
    • In order to put these opposing risks and benefits in context, 59 patients would need to be treated to prevent one death, while a major bleed occurs with every 18 patients treated, according to this analysis.
    • In addition, this meta-analysis was limited by the inclusion of different thrombolytic agents at varying doses and poor definitions of hemodynamic stability/instability and was unable to distinguish benefit from systemic versus catheter-directed therapy (Tapson & Weinberg, 2019).
    • Randomized trials that demonstrate a mortality benefit in select populations of patients with acute PE (other than high-risk PE) will be needed before thrombolytic therapy can be administered routinely.
• Recurrent thromboembolism
  • A meta-analysis of 16 trials reported reduced rates of recurrent thromboembolism with thrombolytic therapy compared to anticoagulation alone (Tapson & Weinberg, 2019). However, recurrence rates were assessed at varying time points, and the confidence intervals were wide, so the effect on recurrent thromboembolism remains in question.
• Bleeding
  • Systemic thrombolytic therapy increases the risk of major bleeding.
  • One meta-analysis of 16 trials compared bleeding rates with thrombolytic agents to that associated with anticoagulant therapy (usual heparin) (Tapson & Weinberg, 2019).
    • The use of thrombolytic agents was associated with greater overall rates of major bleeding and higher rates of intracranial hemorrhage.
    • In a subgroup analysis, the risk of thrombolysis-associated bleeding was three times greater in those older compared to those younger than 65 years of age. In this same analysis, older patients did not derive a mortality benefit from thrombolysis.
  • Few studies have sought to identify risk factors for bleeding during thrombolytic therapy.
    • In a retrospective analysis of 104 patients with acute PE who received IV rtPA (alteplase), 20 patients had significant bleeding (Tapson & Weinberg, 2019). The principal sites of bleeding were:
      • Unknown in nine patients (45%)
      • Gastrointestinal in six patients (30%)
      • Retroperitoneal in three patients (15%)
      • Intracranial in one patient (5%)
      • Splenic in one patient (5%)
    • Independent predictors of major hemorrhage were:
      • Administration of catecholamines for systemic arterial hypotension
      • Diabetes mellitus
      • Elevated INR
      • Malignancy
  • Bleeding during thrombolytic therapy occurs most commonly at sites of invasive procedures such as pulmonary arteriography or arterial puncture (Tapson & Weinberg, 2019).
    • Invasive procedures should be minimized when thrombolytic therapy is contemplated and while it is being administered.
    • Bleeding from vascular puncture sites should be controlled with manual compression followed by a pressure dressing.
  • Patients with significant or refractory bleeding are typically transfused ten units of cryoprecipitate and two units of fresh frozen plasma, then reassessed.
    • Additionally, protamine sulfate should be considered to reverse the effect of any heparin that may remain in the patient's plasma. When considering reversal, the relative severity of the bleeding and the thromboembolic process must be weighed in view of the potential to exacerbate the thromboembolic process.
  • Intracranial hemorrhage is the most devastating complication associated with systemic thrombolytic therapy (Tapson & Weinberg, 2019). Clinical trials suggest that this complication occurs in up to 3% of patients who receive thrombolytic therapy for acute PE, which is higher than the rate of intracranial hemorrhage reported after thrombolysis for acute coronary occlusion (Tapson & Weinberg, 2019).
    • If intracranial bleeding is suspected clinically, the infusion of the thrombolytic agent should be immediately discontinued. Following stabilization, a noncontrast-enhanced CT scan of the brain and emergent neurologic/neurosurgical consultation should be obtained.
• Hemodynamics
  • Thrombolytic therapy improves pulmonary arterial blood pressure, RV function, and pulmonary perfusion in the short term (Tapson & Weinberg, 2019). However, it is uncertain whether these beneficial effects persist because the data are contradictory. Two studies illustrated this best:
    • In a prospective, nonrandomized trial of 40 consecutive patients with acute PE, patients who received thrombolytic therapy had improved RV function 12 hours after the initiation of therapy compared to patients who received anticoagulation alone (Tapson & Weinberg, 2019). One week later, there was no difference in RV function, suggesting that either the improvement of RV function seen in patients who received thrombolytic therapy was transient and short-lived or that RV function improved later in patients who did not receive thrombolytic therapy. The latter seems more likely.
    • In another trial, 40 patients with acute PE were randomly assigned to receive thrombolysis or anticoagulation alone (Tapson & Weinberg, 2019). Follow-up two weeks and one year after the initiation of therapy demonstrated a complete resolution of emboli in the group that received thrombolytic therapy (determined by diffusing capacity and pulmonary capillary blood volume) (Tapson & Weinberg, 2019). Longer-term follow-up (an average of seven years) revealed that patients who had been treated with thrombolytic therapy had lower pulmonary artery pressure and pulmonary vascular resistance compared to patients who had received anticoagulant therapy alone, suggesting that the hemodynamic benefits of thrombolytic therapy were persistent (Tapson & Weinberg, 2019).

The prognosis from PE is variable. Accurate estimates have been limited by data that are mostly derived from earlier studies, registries, and hospital discharge records collected from heterogeneous populations of patients. For example:

• A patient with a single, asymptomatic SSPE likely has a different prognosis than a patient with massive PE and shock.
• However, if left untreated, PE is generally associated with an overall mortality of up to 30% compared with 2 to 11% in those treated with anticoagulation (Tapson & Weinberg, 2019).
• PE-related mortality may be decreasing, with reported rates falling from 3.3% (2001 to 2005) to 1.8% (2010 to 2013) in one study and from 17 to 10% in another study (Tapson & Weinberg, 2019).

Early outcomes are considered as those occurring within the first three months after the diagnosis of PE. The highest risk for events occurs within the first seven days. Death and morbidity during this period are most commonly due to shock and recurrent PE.

• Shock (i.e., hemodynamic collapse)
  • Shock can be the initial presentation or an early complication of PE.
  • Shock is the most common cause of early death, particularly in the first seven days, and when present, it is associated with a 30% to 50% risk of death (Tapson & Weinberg, 2019).
  • The high risk of death, which is greatest in the first two hours of presentation, is the rationale for considering reperfusion therapy (thrombolytics/embolectomy) rather than anticoagulation. The risk remains elevated for 72 hours or more, such that close observation of this population and those considered at risk of hemodynamic collapse (e.g., RV dysfunction) is prudent during hospitalization.
• Recurrence
  • The risk of recurrence (DVT and PE) is greatest in the first two weeks and declines afterward.
  • The cumulative proportion of patients with early recurrence while on anticoagulant therapy amounts to 2% at two weeks and 6% at three months (Tapson & Weinberg, 2019).
  • Factors including cancer and failure to rapidly achieve therapeutic levels of anticoagulation are major predictors of increased risk of recurrence during this period (Tapson & Weinberg, 2019).
• Pleuritic/alveolitis and pneumonia
  • In the one to two weeks following diagnosis, patients may deteriorate and develop worsening oxygenation, respiratory failure, hypotension, pain, or fever that suggests an evolving infarct or superimposed pneumonia.
  • Although CXR may reveal collapse, atelectasis, or a pleural effusion to support the presence of an evolving infarct or superimposed pneumonia, these patients should undergo repeat definitive imaging (preferably with the original diagnostic imaging modality) to distinguish these diagnoses from recurrent PE.
  • Patients without recurrence should be treated symptomatically with supplemental oxygen, analgesics, IV fluids, ventilation, vasopressors or antibiotics, as indicated.
• Stroke
  • Prospective and retrospective studies have suggested an increased risk of stroke, thought to be due to paradoxical embolism via a PFO, in patients with acute PE (Tapson & Weinberg, 2019).
  • Prevalence rates of stroke have ranged from 7% to 50% (averaging <17%), with higher rates in those with PE who also have a PFO (21% to 64%, averaging <33%).
  • Best illustrating this risk for stroke is a prospective study of 361 patients with acute PE who underwent contrast transthoracic echocardiography (TTE) and MRI of the brain (for silent or symptomatic stroke) within ten days after the diagnosis of PE (Tapson & Weinberg, 2019).
    • Stroke was diagnosed in 7.6% and PFO in 13% of patients with acute PE.
    • Rates of stroke were higher in those who had a PFO compared with those who did not have a PFO. However, nine patients were excluded from the analysis due to inconclusive TTE or MRI testing, and the rate of PFO was lower than that in the general population (approximately 25% to 30%), suggesting that these results are flawed (Tapson & Weinberg, 2019).
    • Further studies are recommended before a recommendation can be supported to routinely perform contrast echocardiography (transthoracic or transesophageal) or MRI imaging in patients with acute PE who have no stroke symptoms.
    • A symptom-directed approach is recommended where vigilant surveillance for neurologic symptoms is appropriate in those patients with acute PE and the presence of stroke and should prompt a search for a PFO.
      • Whether the discovery of a PFO with PE and stroke should prompt indefinite anticoagulation or PFO closure is also unknown such that a multidisciplinary approach with a pulmonologist, neurologist, and cardiologist is prudent.

At three months or later following a diagnosis of PE, the incidence of late events ranges from 9% to 32%, with increased mortality reported for as long as 30 years (Tapson & Weinberg, 2019). Late mortality is mostly due to predisposing comorbidities and less commonly due to recurrent thromboembolism or chronic thromboembolic pulmonary hypertension. As examples:

• Mortality
  • In one retrospective study of 1,023 patients with PE, the five-year cumulative mortality rate was 32% (Tapson & Weinberg, 2019).
    • Among those who died, only 5% were due to PE, 64% were due to non-cardiovascular causes (e.g., malignancy, sepsis), and 31% were due to cardiovascular causes other than PE (e.g., MI, heart failure, and stroke).
    • One-year follow-up of patients in the PIOPED cohort revealed similar findings (Tapson & Weinberg, 2019).
    • Another database analysis of over 128,000 patients with VTE reported a three-fold increase in mortality at 30 years in patients with PE compared to age and sex-matched controls who did not have PE during the same period (Tapson & Weinberg, 2019).
    • Combined data from two prospective studies of 748 patients with PE reported that those with SSPE had similar rates of mortality and recurrence at three months when compared with patients with proximal PE (Tapson & Weinberg, 2019).
      • Death in patients with SSPE was largely determined by comorbidities including malignancy, increasing age, male gender, chronic obstructive pulmonary disease, and heart failure.
• Recurrence
  • The cumulative rate of late recurrence has been reported to be 8% at six months, 13% at one year, 23% at five years, and 30% at 10 years (Tapson & Weinberg, 2019).
  • Rates of recurrence vary according to the population studied, with comparable rates reported in those with SSPE and proximal PE at three months (Tapson & Weinberg, 2019).
    • However, in general, the rate is lowered with therapeutic anticoagulation and increased by select risk factors (e.g., unprovoked PE, malignancy).
• CTEPH
  • CTEPH is an unusual complication of PE that typically presents with progressive dyspnea within two years of the initial event.
• Other
  • PE increases the risk of subsequent cardiovascular events and atrial fibrillation (Tapson & Weinberg, 2019).
  • For most patients with dyspnea, exercise capacity and quality of life improve over the first year.
  • Predictors of reduced improvement overtime in one prospective study of 100 patients with acute PE were:
    • Female sex
    • Higher body mass index
    • Higher systolic pulmonary artery pressure on day 10 echocardiography
    • Prior lung disease (Tapson & Weinberg, 2019)
  • The likelihood of complications and death from PE may differ depending on the presence or absence of provoking risk factors at the time of diagnosis.
    • A three-year observational study that followed 308 patients with PE found that patients with unprovoked PE were more likely to develop recurrence, CTEPH, malignancy, and cardiovascular events. In contrast, patients who had provoked PE had a higher risk of death over the seven-year study period (Tapson & Weinberg, 2019).

Poor prognostic factors in patients diagnosed with PE include:

• Shock and RV dysfunction
  • Several clinical, radiologic, and laboratory markers of RV dysfunction have been identified as poor prognosticators in patients with PE.
    • Clinical
      • Clinical shock, which is due to severe RV failure, consistently predicts death in patients diagnosed with PE.
    • Radiologic (echocardiography and CTPA)
      • RV dysfunction, assessed by echocardiography or CTPA, is associated with increased mortality (Tapson & Weinberg, 2019). It is believed that echocardiography is more reliable than CTPA.
        • One meta-analysis of seven studies that included 3,395 normotensive and hypotensive patients with PE reported that RV dysfunction was associated with a two-fold increase in PE-related in-hospital mortality (Tapson & Weinberg, 2019). However, a subgroup analysis of normotensive patients found that RV dysfunction on echocardiography or CT correlated poorly with mortality, suggesting that symptomatic RV dysfunction predicts death.
        • In a study of 1,950 patients diagnosed and treated with PE in a prospective multicenter trial, a larger pulmonary trunk diameter on CTPA was associated with higher mortality during the treatment period of 3 to 6 months and at one year (Tapson & Weinberg, 2019). An association with RV dysfunction was not observed.
      • RV dysfunction may also predict recurrent VTE.
        • In one prospective observational study of 301 patients with PE, those with persistent RV dysfunction on echocardiography at three months following diagnosis had a four-fold increased risk of recurrent VTE when compared with patients without RV dysfunction or with patients whose RV dysfunction resolved prior to discharge (Tapson & Weinberg, 2019).
    • Laboratory markers
      • Biochemical markers of RV dysfunction at diagnosis include elevated levels of the following:
        • BNP and NT-proBNP from RV strain.
        • Troponin-I and T levels due to RV-associated myocardial damage.
      • Elevated BNP, NT-proBNP, and troponin have consistently been associated with an increased risk of death or other adverse outcomes in patients with PE (Tapson & Weinberg, 2019). However, the optimal cut-off values for risk stratification are unknown.
        • In hemodynamically stable patients, these markers are poor predictors of death when elevated but consistently identify a benign clinical course when normal or low (Tapson & Weinberg, 2019).
• RV thrombus
  • Mobile right heart thrombi are seen in approximately 4% of patients with PE by either echocardiography or CT, and the proportion is higher among critically ill patients (up to 18%) (Tapson & Weinberg, 2019).
  • The presence of right heart thrombus has been shown in several studies to be associated with RV dysfunction and high early mortality (Tapson & Weinberg, 2019).
    • For example, data from an international registry of patients with PE reported that compared with patients without RV thrombus, patients with RV thrombus had higher 14-day mortality and three-month mortality (Tapson & Weinberg, 2019).
• Deep vein thrombosis
  • Patients with PE and a coexisting DVT are at increased risk for death.
    • For example, one prospective study of 707 patients with PE reported increased all-cause mortality and PE-specific mortality at three months in patients with concomitant DVT compared with those without concomitant DVT (Tapson & Weinberg, 2019).
• Other
  • Additional predictors of poor prognosis that require further validation include the following:
    • Hyponatremia (<130 mmol/L)
    • Indicators of renal dysfunction
    • Older age ≥65 years of age
    • Poor adherence to guidelines
    • Residual pulmonary vascular obstruction
    • Right heart thrombus
    • Serum lactate (>2 mmol/L)
    • White blood cell count (>12.6 x 109/L) (Tapson & Weinberg, 2019)

Subtherapeutic anticoagulation is the most common reason for recurrence. A detailed history and examination should be performed to identify factors contributing to subtherapeutic anticoagulation. These include:

• Altered dose requirement or pharmacokinetics for warfarin (e.g., dietary vitamin K), target-specific oral anticoagulants (e.g., drug interactions), or LMW heparin (e.g., weight gain)
• Discontinuation for an anticipated procedure
• High dose requirement for heparin (e.g., increased heparin-binding proteins, aprotinin)
• Incorrect dosing of medication
• Malabsorption (e.g., malabsorption syndromes, rivaroxaban should be taken with food)
• Poor compliance

Consulting a coagulation specialist may be warranted, especially when abnormal pharmacokinetics or noncompliance with medications that cannot be monitored easily (e.g., target-specific oral anticoagulants, LMW heparin) are suspected.

The dose should be increased for those subtherapeutic on UFH to achieve therapeutic levels rapidly. For patients on LMW heparin or factor Xa and direct thrombin inhibitors in whom subtherapeutic anticoagulation is suspected but unconfirmed, or for those subtherapeutic on warfarin, switching to a rapid-acting anticoagulant that can be followed (e.g., UFH) may be prudent while investigations are ongoing.

Because new direct thrombin and Xa inhibitors do not require monitoring, it is yet to be determined whether challenges will emerge with monitoring for therapeutic levels.

Therapeutic anticoagulation is the optimal therapy for VTE. Suboptimal therapies should be apparent to the investigating clinician, including IVC filters and embolectomy or thrombolysis not followed by anticoagulation. Resumption of therapeutic anticoagulation should be considered in such cases when feasible.

A search for conditions associated with high recurrence rates is recommended for patients who develop recurrence despite therapeutic anticoagulation. These include:

• Antiphospholipid syndrome
• Inherited thrombotic disorders (e.g., protein S, protein C, or antithrombin deficiency)
• Malignancy
• May-Thurner syndrome

In this population, therapeutic options are limited. An approach is suggested similar to that performed in patients with recurrent thrombosis with an underlying malignancy. These options include:

• Treatment with an LMW heparin for those on warfarin
• Escalation of the dose of LMW heparin for those already on LMW heparin
• Or the addition of an IVC filter

Recurrence may also be associated with conditions that promote thrombus propagation (e.g., mechanical obstruction of venous flow from pelvic masses or IVC filter) or thrombus dissociation (e.g., large RV4 or valvular thrombus). Treating the underlying cause or removing mobile thrombus may be appropriate when feasible in such patients.

Occasionally, tumor or fat emboli may radiographically mimic PE due to thrombus.

Mr. Williams, a 79-year-old Caucasian male, was transported to the Emergency Room via EMS on August 5, 2019, at 0700, accompanied by his wife. She states he has been experiencing midsternal chest pain, non-radiating with progressive difficulty breathing and intermittent coughing since 0500 this a.m. Cough non-productive.

Current Medical History:

• Alzheimer's disease
• COPD
• HTN
• Prostate cancer with metastases since 2018
• History of frequent falling over past 11 years: last fall, August 4, 2019, hitting head on bedside table (no LOC per wife)

Past Medical History:

• MI x 2: 2002, 2010 (two stents placed)
• Stroke: 2008

Past Surgical History:

• T@A: 1992
• Lower back surgery: 2002
• Radical prostatectomy: 2018 being currently treated with androgen deprivation therapy (ADT) and radiation therapy
• Right hip replacement: 2007

Current Medications:

• Coumadin 5mg PO qd-last taken 0800 August 4, 2019
• Diltiazem extended-release 120 mg PO qd-last taken August 4, 2019

Vital signs:

• BP right arm: 140/110
• Pulse oximetry: 75% on room air: placed on 2 L per nasal prongs
• Cardiac monitor shows atrial fibrillation with a ventricular rate of HR 140/min

IV access (left forearm): 1000ml 0.9 NS hung at 50 ml/hr.

Bloods drawn:

• CBC with differential
• Serum chemistry
• Liver function tests
• Serum troponin
• BNP
• D-dimer
• Coagulation studies
• ABGs

12-lead ECG done

CXR done

The emergency physician obtained an initial neurologic examination:

Neurologic:

• GCS was 10.
• Alert. Left facial droop.
• Appears unable to follow simple commands.
• Speech incomprehensible.
• PERRLA, EOMs intact.
• MAEs with right-sided weakness.
• Muscle strength 5/5 left upper and lower extremities.
• Muscle strength 4/5 right upper and lower extremities.
• No resting tremors, fasciculations or seizure activity was noted.
• Cerebellar testing is deferred at present.

Cardiac:

• HR irregular irregularity

Respiratory:

• Rales auscultated in RLL and LLL posteriorly.
• No wheezing.
• Rhonchi auscultated in LUL anteriorly.

GI/GU:

• Abdomen soft, non-tender with bowel sounds in all quadrants.
• Dry diaper on.

Extremities:

• +3 pitting edema of lower extremities.

ECG showed atrial fibrillation with ST depression.

CT of brain ordered stat.

Cardiology consult ordered stat.

Awaiting results of laboratory tests.

Mr. Williams was monitored in the ED, awaiting brain CT, cardiology recommendations and laboratory results.

Diagnoses: COPD, atrial fibrillation, CHF

Tentative diagnoses: r/o MI, r/o pulmonary embolism, r/o brain bleed.

Mr. Williams’s health history and physical examination were performed quickly with appropriate orders written. Appropriate interventions were initiated.