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Chapter 24
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Acute and Chronic Pulmonary Embolism:
Perspectives on Diagnosis and
Management
Avraham Unterman and Mordechai R. Kramer
Tel Aviv University, Tel Aviv, Israel
INTRODUCTION
Acute pulmonary embolism (PE) is a common and potentially fatal form of venous thromboembolism (VTE). In most
cases, it is preceded by deep vein throm bosis (DVT); thrombi originating from the deep veins, particularly those of the
lower limbs, become dislodged and migrate to the pulmonary arterial system.
The global annual incidence of VTE ranges from 75 to 269 cases per 100,000 persons [1,2]. The incidence gradually
increases with age [3], up to an annual incidence of 200e700 per 100,000 in individuals 70 years or older [1].
PE carries a significant risk of mortality, accounting for 50,000e100,000 deaths annually, in the United States [4].
Early diagnosis and treatment of PE can reduce mortality; however, the variable and nonspecific clinical presentation of PE
makes the diagnosis challenging.
This chapter will focus on the diagnosis and management of acute PE. We shall also discuss chronic thromboembolic
pulmonary hypertension (CTEPH), a serious and potentially curable complication occurring in a minority of patients who
survive acute PE.
PATHOGENESIS AND RISK FACTORS FOR VENOUS THROMBOEMBOLISM
The triad of venous stasis, hypercoagulability, and endothelial injury (Virchow’s triad) depicts the primary factors involved
in the pathogenesis of VTE (Fig. 24.1). VTE is considered to be a consequence of the interaction between patient-related
risk factors (e.g., hereditary thrombophilia) and setting-related risk factors (e.g., surgery) [2]. Risk factors for VTE can be
divided into hereditary thrombophilias (such as protein C or S deficiency, antithrombin III deficiency, factor V Leiden, or
prothrombin mutation) and acquired risk factors, whether surgical [5,6] or medical [6e8].
Major acquired risk factors include surgery, major trauma, pelvic or lower extremity fractures and joint repla cements,
acute paralytic stroke or spinal injury, and a past history of VTE [2,6]. Other acquired risk factors include malignancy [9],
prolonged general anesthesia, advancing age [3,6], cardiac disease [6], pregnancy and the postpartum state [10], estrogen
treatment [6,11], nephrotic syndrome [12], antiphospholipid syndrome, and prolonged immobilization [6]. Air travel is a
relatively modest risk facto r, with a doseeresponse relation to travel duration [13].
DIAGNOSIS OF ACUTE PULMONARY EMBOLISM
Clinical Presentation
The clinical symptoms and signs of PE, such as dyspnea (being the most common presenting symptom of PE) [14,15],
cough, chest pain, syncope, and hemoptysis, are nonspecific [2,14,15]. In addition, PE may be entirely asymptomatic, making
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Copyright © 2018 Elsevier Inc. All rights reserved.
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FIGURE 24.1 Virchow’s triad, depicting the primary factors involved in the pathogenesis of venous thromboembolism.
the diagnosis even more challenging [2]. Therefore, a high clinical index of suspicion is important in making a prompt
diagnosis of PE. A 2016 large prospective study further demonstrates this point [16]. This study examined the prevalence
of PE in patients hospitalized for a first episode of syncope; it found a surprisingly high prevalence (17.3%) of PE, with a
high prevalence (12.7%) even in patients with an alternative explanation for syncope [16].
The most common physical finding is tachypnea (respiratory rate >20/min) [15]. Additional physical findings include
tachycardia, hemoptysis, an increased pulmonic component of S2, and signs of DVT. With a more severe embolism, there
may be evidence of right-ventricular failure, such as jugular venous distension. Arterial hypotension and shock, although
less frequent, are important clinical presentations indicating massive PE, a condition associated with high mortality and
requiring different treatment strategies, including thrombolytics [17].
In patients with underlying cardiopulmonary diseases, the presenting symptoms and signs of PE may be obscured by
elements resembling the underlying disease, which may result in a missed diagnosis. For example, exacerbations of
chronic obstructive pulmonary disease (COPD) may be indistinguishable from acute PE. It thus presents a significant
diagnostic challenge, especially since it is estimated that 25% of patients hospitalized for an unexplained COPD exacerbation have PE [18,19].
In arterial blood gas samples, hypoxemia and hypocapnia are typical findings in acute PE, although not universal, and
thus cannot be used to exclude PE [20,21].
The chest X-ray may be either normal or abnormal. Although chest X-ray findings are usually nonspecific in PE, it is
useful for excluding other causes of dyspnea or chest pain [22].
Electrocardiographic changes indicative of right ventricle (RV) strain, such as inversion of T waves in leads V1eV4, a
QR pattern in V1, S1Q3T3 pattern, and incomplete or complete right bundle-branch block, may be helpful, although not
sensitive or specific, and are usually found in more severe cases of PE [2].
Assessing Pretest Probability
Despite the limited sensitivity and specificity of individual risk factors, symptoms, signs, and basic tests, combining these
into prediction rules allows for assessing the pretest probability of PE. This in turn corresponds to an increased prevalence
of confirmed PE in the definitive tests (e.g., computed tomographic angiography [CTA] or ventilationeperfusion [V/Q]
lung scan) and is an important step in the diagnostic algorithm for PE.
The most frequently used prediction rules are the Wells score [23] (Table 24.1) and the revised Geneva score [24],both
adequately validated [2]. Alternatively, the clinician can make a subjective (“gestalt”) assessment of the pretest probability of
PE, which apparently has sensitivity comparable to clinical prediction rules [25]. Nonetheless, using clinical prediction rules
is still preferred, since subjective clinical judgment lacks standardization and appears to have a lower specificity [2,25].
D-Dimer
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Acute and Chronic Pulmonary Embolism: Perspectives on Diagnosis and Management Chapter | 24 357
TABLE 24.1 Wells Score for Assessment of the Pretest
Probability of Pulmonary Embolism
Variable Points
Clinical signs of DVT 3.0
Alternative diagnosis less likely than PE 3.0
Heart rate >100 beats/min 1.5
Immobilization or surgery in the previous 4 weeks 1.5
Previous PE or DVT 1.5
Hemoptysis 1.0
Active cancer 1.0
A total score of 4.0 indicates that PE is unlikely, while a score of >4.0
indicates that PE is likely. DVT, deep vein thrombosis; PE, pulmonary embolism.
Adapted with permission from Wells PS, Anderson DR, Rodger M, et al.
Derivation of a simple clinical model to categorize patients probability of
pulmonary embolism: increasing the models utility with the SimpliRED
D-dimer. Thromb Haemost 2000;83:416e20.
The D-dimer is a marker of in vivo thrombin and plasmin activation [26] and is therefore elevated in VTE. The quantitative
enzyme-linked immunosorbent D-dimer assay has a high sensitivity and negative predictive value [2,27]. Studies have
demonstrated that a normal D-dimer result can safely exclude PE in patients with a low pretest probability, and therefore no
further tests are required [28e30].
An elevated D-dimer alone is insufficient for the diagnosis of PE, since it lacks specificity, thus requiring additional
confirmatory tests such as CTA or V/Q scan. D-dimer testing can produce a higher rate of false-positive results in certain
populations, such as hospitalized patients, cancer patients, pregnant women, patients with renal dysfunction, and
patients >50 years of age [2]. To improve the diagnostic yield in older patients, age-adjusted cutoff values (age 10 mg/
L above 50 years) were employed and tested in a large prospective study [31]. Compared with the standard fixed
D-dimercutoffof500mg/L, the combination of pretest clinical probability assessment with age-adjusted D-dimer cutoff
values resulted in a larger number of patients in whom PE could be safely excluded, without any additional falsenegative findings [31].
Definitive Diagnostic Modalities
Definitive modalities for PE diagnosis include multid etector CTA and V/Q scanning. Both are well-established techniques
[15,29,32e34], each with its own advantages and disadvantages.
Since the introduction of multidetector CTA, it has become the method of choice for imaging the pulmonary vasculature in patients with suspected PE [2,35]. Unlike V/Q scanning, CTA has the ability to directly visualize emboli
(Fig. 24.2), as well as detecting parenchymal abnormalities that may support an alternative diagnosis. Large prospective
studies have demonstrated its high sensitivity and specificity when combined with pretest probability assessment and
D-dimer testing [29,32e34].
On the other hand, V/Q scan delivers a lower radiation dose [36] and does not require the use of iodine-based contrast
medium, which is nephrotoxic and might cause an allergic reaction. Therefore, it may be the preferred imaging modality in
young patients (particularly females, since CTA delivers a greater radiation dose to the breast tissue) [36], in pregnancy, in
patients with a history of contrast medium-induced anaphylaxis, and in renal failure [37].
Performing only a perfusion scan (without a ventilation scan) is acceptable in patients with a normal chest X-ray; any
perfusion defect detected in this situation is considered a V/Q mismatch [38].
Advances in CTA have increased the frequency of subsegmental PE diagnosis from about 5% to about 10% of scans
[2,39] (Fig. 24.2). However, the clinical significance of isolated subsegmental PE on CTA is uncertain [2,39,40]. Recent
guidelines [39] suggest that clinical surveillance may be preferred over anticoagulation in patients with an isolated
subsegmental PE and no evidence of proximal DVT, who have a low risk for recurrent VTE. However, these guidelines are
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(A) (B)
(C)
FIGURE 24.2 (AeC) Computed tomographic angiography of an 81-year-old female with acute pulmonary embolism. (A) Nonobstructive eccentric
filling defect (arrow) in the left main pulmonary artery, extending to the left upper lobe artery, forming acute angles with the vessel wall typical of acute
embolism. (B) Partial filling defects surrounded by contrast material (“railway track” sign) in segmental arteries to right middle lobe and right lower lobe
(arrows) and in (C) subsegmental posterior basal pulmonary arteries (arrow). (D) Pulmonary infarction in the left lower lobe of a 22-year-old female who
presented with pleuritic chest pain following a trans-Atlantic flight; she was an active smoker on oral contraceptives and was later found to be heterozygous for both prothrombin and factor V Leiden mutations. A wedge-shaped peripheral consolidation (arrow) shows central foci of hypoattenuation. An
embolus was demonstrated on adjacent computed tomography sections. Courtesy of Dr. Osnat Moreh-Rahav, Department of Radiology, Rabin Medical
Center, Israel.
(D)
based on a low level of evidence, with no randomized trials to support them [39]. In any case, the decision whether to treat
should be made on an individual basis, taking into account the patient’s clinical probability for VTE, the cardiovascular
reserve, and the risk of bleeding [2,39,40].
Compression ultrasound (CUS) is a definitive modality for DVT (and thus VTE) diagnosis, and may be used as an
initial test in patients with suspected PE who have relative contraindications to perform CTA and/or V/Q scan
(e.g., during pregnancy). CUS detec ts DVT in 30%e50% of patients with PE [2,41]. In patients with suspected PE, a
finding of proximal DVT is highly predictive of PE and may be sufficient to warrant anticoagulant treatment without
further testing [42].
Echocardiography
Acute PE may increase pulmonary vascular resistance (PVR) through mechanical obstruction of the pulmonary vascular
bed, augmented by the release of pulmonary vasoconstrictive substances [43]. This in turn may lead to pressure overload
and dysfunction of the RV, a chamber ill-equipped to deal with an acute elevation in pressure load.
Echocardiography has the ability to detect signs of RV overload, such as RV dila tation (found in at least 25% of
patients with PE) or depressed contractility of the RV free wall (McConnell sign); however, owing to a low negative
predictive value it cannot be used to rule out PE [2,44]. Moreover, signs of RV overload or dysfunction may also be found
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in the absence of acute PE, reflecting other cardiac or respiratory diseases [44]. Currently, echocardiography is not
routinely recommended for all patients with suspected acute PE and is mainly used for the assessment and risk stratification
of hemodynamically compromised patients [2,39]. In these patients, the absence of echocardiographic signs of RV
overload essentially excludes PE as the cause of hemodynamic instability, and thus can further help in the differential
diagnosis of the cause of shock, by detecting pericardial tamponade, acute valvular dysfunction, left-ventricular
dysfunction, aortic dissection, or hypovolemia [2]. Moreover, in hemodynamically compromised patients, definitive
signs of RV pressure overl oad and dysfunction justify emergency reperfusion treatment for PE, if immediate CTA is not
feasible [2,39].
Diagnostic Algorithm
Many strategies and algorithms to confirm or exclude the diagnosis of PE, based on combinations of clinical assessment,
plasma D-dimer measurement, and imaging tests, have been investigated and validated [2,29,32,41]. A suggested
comprehensive and straightforward algorithm for PE diagnosis and treatment is presented in Fig. 24.3. One shoul d
remember, however, that the diagnostic approach to suspected PE may vary according to the clinical setting and the local
expertise or availability of diagnostic modalities. It may also differ in certain populations, such as pregnant women.
MANAGEMENT OF ACUTE PULMONARY EMBOLISM
The major principles of diagnosis and management of acute PE are depicted in Fig. 24.3. The first step in the management
of acute PE is risk stratification into low-risk PE and high-risk (or massive) PE according to hemodynamic instability,
FIGURE 24.3 Suggested algorithm for PE diagnosis and treatment (excluding pregnancy). Notes: (a) Not feasible: CTA not available or patient’s
condition so unstable that only bedside diagnostic tests are possible. (b) In patients with relative contraindications to CTA (e.g., severe renal impairment).
(c) Thrombolysis is the treatment of choice in most patients. Alternative options in selected patients are surgical embolectomy or catheter-directed
thrombolysis. CTA, computerized tomographic angiography; echo, echocardiography; PE, pulmonary embolism; RV, right ventricle; V/Q scan,
ventilationeperfusion scan.
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which is associated with early mortality risk [2,35]. High-risk PE is defined by the presence of shock or persistent arterial
hypotension, as a result of overt RV failure [2,35]. The large majority (>95%) of patients with acute PE, however, are
hemodynamically stable at presentation and are therefore not considered to be at high risk [45].
For high-risk (massive) PE patients, systemic thrombolysis is considered the treatment of choice [2]. Alternative
options include surgical embolectomy (indicated in patients with contraindications to thrombolysis or in those failing to
improve on thrombolytic treatment) or catheter-directed thrombolysis [2].
Intermediate-risk (submassive) PE patients present without hemodynamic compromise, but have echocardiographic or
computed tomographic evidence of RV dysfunction and a positive cardiac troponin test [2]. In a large prospective study in
such patients, thrombolytic therapy decreased the risk for hemodynamic decompensation; however, this benefit was
counterbalanced by an increased risk of major hemorrhage and stroke [46]. Therefore, routine thrombolysis is not recommended for intermediate-risk PE patients; instead, patients should be anticoagulated and monitored closely for at least
48e72 h, and rescue thrombolysis should be considered if hemodynamic decompensation appears [2,35].
Low-risk, hemodynamically stable PE patients (without evidence of significant RV dysfunction) require prolonged
systemic anticoagulation treatment; the duration of treatment is mainly influenced by the presence or absence of provoking
risk factors (such as orthopedic surgery) and the risk of bleeding [2,39]. For patients with PE provoked by surgery or by a
nonsurgical transient risk factor, anticoagulants should be given for 3 months and then stopped, provided that the transient
risk factor has resolved [2,39]. For patients with unprovoked PE, treatment duration should balance the risk of recurrent
VTE with the risk of bleeding; in patients without a high risk of bleeding, indefinite anticoagulation should be considered
[2,39]. The presence of hereditary thrombophilia, the antiphospholipid syndrome, or a second unprovoked VTE is usually
an indication for lifelong anticoagulation [2].
Vitamin K antagonists (VKAs) were commonly used to treat VTE. The newer, nonevitamin K-dependent oral anticoagulants (NOACs) dabigatran [47,48], apixaban [49], edoxaban [50], and rivaroxaban [51,52], all have shown efficacy in
large phase III studies for the treatment of VTE. A meta-analysis demonstrated that NOACs have similar efficacy compared
with VKAs, but are safer in terms of major bleeding (relative risk (RR) 0.61, 95% CI 0.45e0.83) [53]. As a result, several
guidelines recommend NOACs over VKAs for the treatment of VTE patients (without an associated cancer diagnosis) [2,39].
For patients with active cancer, low-molecular-weight heparin (LMWH) was shown to be more effective than VKAs in
reducing the risk of recurrent thromboembolism and is preferred over VKAs or NOACs for this population [2,39,54e56].
Although LMWH administration requires burdensome injections, it is more reliable in cancer patients, who often have
difficulties with oral thera py due to nausea and vomiting [35].
Inferior vena cava (IVC) filters may be used in patients with acute PE who have absolute contraindications to anticoagulation (e.g., intracranial bleeding) or in those who develop major bleeding events during the acute phase [2].
Complications of permanent IVC filters are common, although only rarely fatal [57], and include thrombotic occlusion of
the IVC, recurrent DVT, and the postthrombotic syndrome [2]. Retrievable (nonpermanent) IVC filters have been
developed to decrease the rate of these late complications; it is recommended that they be removed as soon as it is safe to
use anticoagulants [2]. Trial data and guidelines recommend against their use in patients who can be treated with anticoagulation [39,58].
Current areas of uncertainty and of ongoing research in PE management include the need for anticoagulation in
subsegmental PE, diagnosis and management of acute PE in pregnancy, use of NOACs in cancer-associated PE, duration
of anticoagulation for unprovoked PE patients, and the outpatient management of low-risk PE patients [35].
CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION
CTEPH is a debilitating and life-threatening disease, resulting from the chronic obstruction of the pulmonary vascular bed
by nonresolving thromboemboli [2,59e61].
It can arise in a minority of patients who survive acute or recurrent PE [59,62], and is potentially curable by surgery
[2,60]. Pathophysiologically, chronic occlusion of pulmonary arteries results in increased PVR, which subsequently leads
to progressive pulmonary hypertension (PH) and RV failure. In the nonoccluded vascular bed, a pulmonary arteriopathy
indistinguishable from pulmonary arterial hypertension (PAH) can develop and contribute to disease progression [59].
According to the Nice classification of PH, CTEPH is listed as a distinct subgroup of PH (group 4) [63].
The reported cumulative incidence of CTEPH following a symptomatic acute PE is in the range of 0.1%e9.1% within
2 years of the event [62,64]. Of note, a significant number of CTEPH cases (about 50%) have no history of acute PE, and
may originate from asymptomatic VTE [2,62,64]. Because of the low incidence of CTEPH after PE and the low yield of
echocardiography screening in this setting [65], routine screening for CTEPH in asymptomatic survivors of PE is not
recommended as of this writing [2,60,65].
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Diagnosis of CTEPH
According to a large international CTEPH registry, the disease affects both sexes equally and the median age of patients at
diagnosis is 63 years [59].
The early diagnosis of CTEPH is challenging, especially in the absence of an acute history of VTE, as symptoms and
signs are nonspecific or absent in early disease, and signs of RV failure appear only in advanced disease [60]. Diagnosis is
commonly delayed, with a median of 14 months passing from onset of symptoms until the diagnosis of CTEPH is finally
made [59]. Progressive dyspnea is a complaint common to all patients with CTEPH. Later in the course of the disease,
exertional chest pain, near-syncope or syncope, or lower extremity edema may develop.
CTEPH diagnosis requires certain physiological and imaging criteria, detected after at least 3 months of effective
anticoagulation (to differentiate this condition from subacute PE) [2,60,62]. These criteria are: (1) mean pulmonary artery
pressure 25 mm Hg with pulmonary arterial wedge pressure 15 mm Hg on right-heart catheterization (RHC) and (2) at
least one (segmental) perfusion defect detected by lung scan, or pulmonary artery filling defects seen by CTA, MRI, or
pulmonary angiography, such as ring-like stenoses, bands/webs, and pouch lesions (Fig. 24.4).
The diagnostic algorithm for CTEPH begins with a clinical suspicion, strengthened by signs of PH on echocardiography (Fig. 24.5). The next step is performing a V/Q scan, which is considered the first-line imaging modality for CTEPH,
as it carries a 96%e97% sensitivity (higher than that of CTA) and a 90%e95% specificity for the diagnosis [60,66]. If the
V/Q scan does not demonstrate mismatched perfusion defects, the diagnosis of CTEPH is ruled out; on the other hand, if it
does support the diagnosis of CTEPH (Fig. 24.5), the patient should be referred to a PH expert center and further
investigated with RHC and CTA (pulmonary angiography) [60].
(A) (B)
(C) (D)
FIGURE 24.4 Computed tomographic angiography images from patients with chronic thromboembolic disease, showing characteristic radiological
signs. (A) Pouch defect (asterisk); (B) residual band and intimal irregularities (arrow) in right lower lobe artery; (C) residual band (arrow) in the
left interlobar artery; (D) partially calcified thrombus in the right pulmonary artery forming obtuse angles with the vessel wall. Courtesy of Dr. Osnat
Moreh-Rahav, Department of Radiology, Rabin Medical Center, Israel.
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(A)
(C)
(B)
FIGURE 24.5 Perfusion lung scans of a 35-year-old female with CTEPH, (A) before and (B) after a successful pulmonary endarterectomy, showing
marked improvement in perfusion postsurgery. (C) A four-chamber echocardiographic view of the same patient prior to surgery showing an enlarged right
atrium (RA) and right ventricle (RV) with flattening of the intraventricular septum as signs of increased pressure in the right heart. Of note is a chronic,
partially calcified thrombus in the RA (arrow), connected by a stalk to the interatrial septum. This lesion resembles a cardiac myxoma, but was shown in a
subsequent cardiac MRI to be an organized thrombus. LA, left atrium; LV, left ventricle.
Treatment of CTEPH
Pulmonary endarterectomy (PEA) surgery is the treatment of choice for CTEPH and is the only potentially curative
treatment [60,67]. Following PEA, marked improvement (up to near normalization) can be achieved in most patients in RV
function, gas exchange, exercise capacity, and quality of life [67]. In-hospital mortality following PEA is less than 5% in
expert centers [67e69]. The surgical procedure involves bilateral pulmonary artery dissection to excise the organized
thromboembolic material down to the segmental arteries level (Fig. 24.6). It is performed under deep hypothermia and
circulatory arrest [60,69,70].
The operability assessment for PEA is done by an expert multidisciplinary team and is based upon four criteria: the
surgical accessibility of the thrombi (proximal disease in the main, lobar, or segmental arteries can be removed, while a
more distal/subsegmental disease may render the patient inoperable); the presence of hemodynamic and/or ventilatory
impairment; the patient’s comorbidities that increase the surgical risk; and the willingness of the patient to undergo surgery
[67,71]. The only absolute contraindication to PEA is the presence of a severe parenchymal lung disease, since the
procedure is unlikely to improve the patient’s condition [71]. Advanced age on its own is not a contraindication for surgery
[60,72]. Inoperable patients or those with persistent PH following PEA face a poor prognosis [60]. Lifelong anti-
coagulation is recommended in all patients with CTEPH, including after PEA [73], to prevent recurrent thromboembolism.
Medical therapy using pulmonary vasodilators that are used to treat PAH is not curative and its effects are relatively
modest; therefore, it is indicated only for inoperable patients or in those with persistent or recurrent PH after PEA [60,67].
Of these pulmonary vasodi lators, riociguat, a soluble guanylate cyclase stimulant, has shown efficacy in clinical trials
[74,75] and became the first agent approved for CTEPH [60,76]. Guidelines recommend its use in symptomatic patients
with inoperable CTEPH or those with persistent/recurrent PH after PEA [60]. In a randomized placebo-controlled phase 3
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FIGURE 24.6 Thromboembolic material taken out during pulmonary endarterectomy. Courtesy of Dr. David P Jenkins, Director of UK Pulmonary
Endarterectomy Service, Papworth Hospital NHS Foundation Trust, UK.
trial, patients on riociguat had an improved 6-min walking distance and PVR after 16 weeks, with a good safety profile
[75]. A follow-up long-term extension study reported that prolonged therapy for up to 2 years with riociguat resulted in a
similar efficacy and safety profile [61,74]. Bosentan, an endothelin receptor antagonist (ERA), has demonstrated a positive
treatment effect on PVR, but failed to meet the primary combined end point for the study [77]. Maci tentan, another ERA,
significantly improved PVR in patients with inoperable CTEPH in a recent phase 2 trial, meeting the study’s primary
endpoint [78].
Balloon pulmonary angioplasty (BPA) is an emerging treatment option for selected inoperable CTEPH patients with a
distal disease [79-82]. BPA involves repeated balloon dilatations in multiple occluded or stenosed distal pulmonary
arteries, to increase lung perfusion and improve the hemodynamic parameters. BPA is performed in a staged fashion over
multiple catheterization sessions, targeting only one lobe during each session, to reduce the risk of reperfusion pulmonary
edema, a serious complication of this procedure [60,80].
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