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Clinical Radiology xxx (2017) 1e14

Contents lists available at ScienceDirect

Clinical Radiology
journal homepage: www.clinicalradiologyonline.net

Review

Imaging of acute and chronic thromboembolic


disease: state of the art
A. Ruggiero, N.J. Screaton*
Department of Radiology, Papworth Hospital, Cambridge, UK

art icl e i nformat ion


Acute pulmonary embolism (PE) is a life-threatening condition that requires prompt diagnosis
Article history: and treatment. Recent advances in imaging allow acute and rapid recognition even by the non-
Received in revised form specialist radiologist. Most acute emboli resolve on anticoagulation without sequelae; how-
23 January 2017 ever, some emboli fail to fully resolve becoming endothelialised with the development of
chronic thromboembolic disease (CTED). Increased pulmonary vascular resistance arising from
CTED may lead to chronic thromboembolic pulmonary hypertension (CTEPH) a debilitating
disease affecting up to 5% of survivors of acute PE. Diagnostic evaluation is more complex in
CTEPH/CTED than acute PE with subtle imaging features often being overlooked or mis-
interpreted. Differentiation of acute from chronic PE and from other forms of pulmonary hy-
pertension has profound therapeutic implications. Diverse imaging techniques are available to
diagnose and monitor PEs both in the acute and chronic setting. Broadly they include tech-
niques that provide data on lung parenchymal perfusion (ventilationeperfusion [VQ] scin-
tigraphy), angiographic techniques (computed tomography [CT], magnetic resonance imaging
[MRI], and invasive angiography) or a combination of both (MR angiography and time-resolved
angiography or dual-energy CT angiography). This review aims to describe state of the art
imaging highlighting the strength and weaknesses of individual techniques in the diagnosis of
acute and chronic PE.
Crown Copyright Ó 2017 Published by Elsevier Ltd on behalf of The Royal College of
Radiologists. All rights reserved.

Introduction unnecessary treatment is associated with significant


morbidity.
Acute pulmonary embolism An overall annual incidence of 100e200 per 100,000
inhabitants for both DVT and acute PE has been reported2,3;
Pulmonary embolism (PE) is the third most common however, the epidemiology of acute PE is rather difficult to
acute cardiovascular disease after coronary artery disease determine as it may remain asymptomatic (in more than
and stroke.1 PE typically results from migration of deep vein two-thirds of patients)4,5 or it is an incidental finding,
thrombosis (DVT) from the lower limb. Rapid and accurate sometimes its first presentation can be sudden cardiac
diagnosis is crucial as untreated outcomes are poor and death. Clinical signs and symptoms of acute PE are non-
specific with imaging being key to establishing the
diagnosis.
Massive PE is characterised by systemic hypotension
* Guarantor and correspondent: N. J. Screaton, Department of Radiology,
Papworth Hospital, Cambridge, UK. Tel.: þ44 01480 364436. (systolic arterial pressure <90 mmHg or a drop in systolic
E-mail address: nicholas.screaton@papworth.nhs.uk (N.J. Screaton). arterial pressure of at least 40 mmHg for at least 15 minutes

http://dx.doi.org/10.1016/j.crad.2017.02.011
0009-9260/Crown Copyright Ó 2017 Published by Elsevier Ltd on behalf of The Royal College of Radiologists. All rights reserved.

Please cite this article in press as: Ruggiero A, Screaton NJ, Imaging of acute and chronic thromboembolic disease: state of the art, Clinical
Radiology (2017), http://dx.doi.org/10.1016/j.crad.2017.02.011
2 A. Ruggiero, N.J. Screaton / Clinical Radiology xxx (2017) 1e14

which is not due to new onset arrhythmias) or shock pulmonary hypertension and significantly lower pressures
(hypoxia, tissue hypoperfusion, altered level of conscious- without significant difference in rates of bleeding, recurrent
ness, oliguria) and angina chest pain. PE, and mortality18; however, a large multicentre trial of
Bedside tests such as the Wells6 and Geneva scores7 patients with PE and intermediate risk showed that ten-
enable assessment of clinical pre-test probability of acute ecteplase and heparin combination only reduced the pri-
PE. Electrocardiography (ECG), chest radiograph, and D- mary outcome of death or cardiovascular collapse at 7 days
dimer are the initial investigations. D-dimer, a plasmin- versus heparin, but increased major bleeding with no
derived degradation product elevated in acute venous overall benefit obtained from thrombolysis.19 Further
thromboembolism (VTE),8 is the most important laboratory studies are required to identify subgroups of intermediate
screening test carrying a high sensitivity and very high risk patients who will benefit from systemic thrombolytic
negative predictive value. A negative D-dimer, using a cut- therapy.17 Catheter-directed therapy (CDT) would allow
off value of 500 ng/ml in combination with a low or inter- lower doses of thrombolytic agent (due to direct infusion in
mediate clinical pre-test probability effectively excludes the the pulmonary artery) in patients at increased risk of
diagnosis of PE with the 3 month risk of VTE in untreated bleeding; however, systemic thrombolysis is recommended
patients being <1%.2,9 Recent evidence has shown that the over CDT in patients who are candidates for thrombolysis
specificity of D-dimer decreases with age to almost 10% in and additional studies are warranted for CDT approaches in
patients >80 years. Therefore an age-adjusted D-dimer cut- both high- and intermediate-risk patients.17
off (defined as age  10) in patients >50 years has been
proposed with a fivefold increase in the proportion of pa- Chronic thromboembolic disease
tients in whom PE could be ruled out without further im-
aging10; however, D-dimer is less useful in patients already Incomplete resolution and recanalisation of acute emboli
hospitalised as its values can be raised in pneumonia, results in chronic thromboembolic disease (CTED) with
myocardial infarction, sepsis, cancer, pregnancy, and in the organisation and endothelialisation of thromboembolic
postoperative state. material and formation of laminated thrombi, single bands
Although the ECG can be normal in patients with massive parallel to the vessel (shelves) or multiple bands in a com-
or sub-massive it may show typical features such as inver- plex web-like network as well as complete vascular occlu-
ted T waves in the precordial leads,11 right bundle branch sions. The pathophysiological basis underpinning the
block and the classic S1Q3T3 pattern suggestive of right transition from acute to chronic thromboembolism is un-
heart strain. The chest radiograph is performed to identify certain; however, failed thrombolysis, a localised inflam-
mimics of PE such as pneumonia, pneumothorax, or matory response and localised endothelial dysfunction,
congestive cardiac failure and can be normal in patients may be responsible.20 CTED can occur without or with
with massive PE. Ninety percent of PE arise from DVT in a chronic thromboembolic pulmonary hypertension (CTEPH).
lower limb12 with venous compression ultrasound (VCU) The evolution from acute PE to CTED and CTEPH is
carrying both a high sensitivity (>90%) and specificity (95%) incompletely understood, it may result from a single pul-
for symptomatic DVT.2,13 Therefore, if clinical and D-dimer monary embolic event or recurrent PEs.21 Patients with
evaluation is suggestive of PE in patients with signs and CTEPH often witness an initial “honeymoon period” with
symptoms of DVT VCU is indicated. This is of particular improvement in symptoms following acute PE, which is
value in the pregnant patient with suspected PE as it avoids followed by an insidious onset of progressive dyspnoea,
the need for ionising radiation. The utility of VCU screening chest pain, and right heart failure; however, not all patients
in patients with suspected DVT but no symptoms of DVT is who develop CTEPH describe prior VTE episodes. Interna-
controversial.14 In the context of suspected PE, VCU can be tional registry data confirmed prior observations and re-
limited to the assessment of the deep veins from the groin ported a history of acute PE in 74.8% and DVT in 56.1% of
to the popliteal fossa. The VCU diagnosis of DVT in patients CTEPH patients.22 Therefore, the absence of a previous acute
suspected of having PE is considered sufficient to start thromboembolic event does not exclude CTEPH. The cu-
anticoagulant treatment without additional testing.15 mulative incidence of CTEPH following PE is 1.3e5.1% after 1
Anticoagulant treatment alone is recommended over year23,24 and 0.8e3.8 after 2 years.25,26 This rather high
thrombolytic therapy in the majority of patients with acute margin of error is likely related to referral bias, absence of
DVT. The assessment of mortality risk in patients with acute early symptoms, and the difficulty in differentiating “true”
PE is used to define the treatment approach.2 High-risk PE is acute PE from an acute episode of PE on pre-existing
characterised by overt haemodynamic compromise (systolic CTEPH.2 Clinically, CTEPH is defined as mean pulmonary
blood pressure <90 mmHg) and warrants immediate ther- artery pressure (mPAP) 25 mmHg; pulmonary capillary
apy including systemic fibrinolysis. In low-risk PE standard wedge pressure (PCWP) <15 mmHg; persistence of multi-
anticoagulation is usually the standard treatment.16,17 Pa- ple organised thrombi in the lobar, segmental, or sub-
tients with acute right ventricular (RV) dysfunction without segmental pulmonary arteries after at least 3 months of
overt haemodynamic compromise are classified as inter- effective anticoagulation.26 The development of pulmonary
mediate risk and their treatment is rather controversial. The hypertension relates to a combination of proximal vascular
recent MOPETT trial reported that the combination group obstruction by the burden of chronic thromboemboli and a
(tissue type plasminogen activator plus heparin) compared distal arteriolar vasculopathy in non-obstructed areas.21 As
to the heparin alone group showed lower rates of such, in some cases the severity of pulmonary hypertension

Please cite this article in press as: Ruggiero A, Screaton NJ, Imaging of acute and chronic thromboembolic disease: state of the art, Clinical
Radiology (2017), http://dx.doi.org/10.1016/j.crad.2017.02.011
A. Ruggiero, N.J. Screaton / Clinical Radiology xxx (2017) 1e14 3

may be disproportionate to the severity of proximal and nosocomial pneumonia. Re-thrombosis of the endar-
vascular obstruction indicating a likely significant contri- terectomised vasculature is rare but may occur in patients
bution of distal vasculopathy and poor outcome from end- in whom anticoagulant treatment was discontinued or sub-
arterectomy. In CTEPH bronchial systemic blood flow therapeutic.34
markedly increases (up to 30% of total pulmonary blood After PEA with good clearance of the thromboembolic
flow) resulting from the development of systemic-to- burden, substantial improvement and often normalisation
pulmonary anastomoses to maintain pulmonary paren- of pulmonary haemodynamics, RV function, gas exchange,
chymal blood flow in presence of pulmonary arterial exercise capacity, and quality of life is typical.
obstruction. Due to increased pulmonary vascular resis- For patients not considered candidates for PEA due to
tance (PVR) and increased pressures RV hypertrophy, disease distribution or comorbidity or following unsuc-
dysfunction, and ultimately failure develops. The clinical cessful PEA balloon pulmonary angioplasty (BPA) is
symptoms of CTED/CTEPH are non-specific and often emerging as a feasible less invasive alternative in carefully
insidious in onset resulting in delay in diagnosis often of selected patients. The precise role of and target population
several years before they present with progressive exer- for BPA in CTEPH is still to be established but is the goal of
tional dyspnoea, atypical chest pain, and cor pulmonale. ongoing research. In those with more distal distribution of
Historically, the long-term prognosis of CTEPH has been CTEPH targeted vasodilator therapy can stabilise and
poor with 5-year survival rates as low as 10%.27 Therefore, improve pulmonary haemodynamics, albeit not to the same
there is a need to identify patients with acute PE who are at extent as primary PEA.
increased risk of developing CTED or CTEPH; however,
current imaging techniques fail to accurately determine the Imaging techniques in pulmonary
risk of developing chronic disease.28 Routine re-imaging of thromboembolic disease
patients following known acute PE is not routinely recom-
mended due to the concerns of radiation exposure29;
Different imaging techniques with various degrees of
however, if patients remain symptomatic following treat-
diagnostic performance are currently available to diagnose
ment for acute PE echocardiography to identify RV
and monitor the PE in the acute and chronic setting. Broadly
dysfunction is commonly performed and may lead to re-
they include techniques that provide data on lung paren-
evaluation of the pulmonary vasculature when positive.
chymal perfusion (e.g., ventilationeperfusion scintigraphy,
In CTED/CTEPH anticoagulant therapy is not effective in
V/QSCAN) and angiographic techniques (computed tomog-
clearing organised obstructive disease but long-term anti-
raphy [CT], magnetic resonance imaging [MRI], and invasive
coagulation is essential to avoid recurrent PE and in situ
angiography) or a combination of both (e.g., MR angiog-
thrombosis. The primary treatment for CTEPH is pulmonary
raphy and time and spatially resolved angiography or dual-
endarterectomy (PEA), which involves the careful surgical
energy CT angiography). The choice of modality is influ-
dissection of organised thrombotic material together with a
enced by a combination of institution experience, equip-
layer of pulmonary arterial media under deep hypothermic
ment availability, imaging expertise, referring physician
circulatory arrest. PEA is only suitable in carefully selected
preference, and patient suitability.
patients being considered in symptomatic patients with
haemodynamic impairment at rest or in selected patients CT
who have normal or near-normal pulmonary haemody-
namics at rest but who develop features of pulmonary hy- CT pulmonary angiography (CTPA) permits the direct
pertension during exercise.30 visualisation of emboli and the ancillary findings associated
The main determinant for PEA is the location and extent with acute PE (affecting therapy and prognosis) as well as
of chronic thromboembolic material, with proximal disease the diagnosis of alternative causes of symptoms. Given its
at lobar and proximal segmental level being considered low cost, wide availability, rapid acquisition, and interpre-
good targets.31 Good outcomes from PEA are associated tation, CTPA has become the method of choice for imaging
with bilateral lower-lobe web occlusions and at least eight suspected acute PE.2 The PIOPED II trial reported a sensi-
occluded segments.32 PVR is also considered in operability tivity of 83% and a specificity of 96% for (mainly four-
assessment as a disproportionately high PVR in the pres- detector) CT. The explosion in the CT technology since
ence of limited proximal obstructive disease implies a sig- PIOPED II with multisection detectors, rapid acquisition,
nificant contribution from a small vessel vasculopathy and and high contrast now being clinical routine, has further
therefore poor surgical outcome. As a guide the risk of enhanced image quality and diagnostic performance.
surgery is generally lower when the PVR is <1000 dyn/s/ Indeed it has been argued that modern CTPA, by enabling
cm5 and increases when the PVR is >1200 dyn/s/cm5.31 the visualisation of previously undetectable subsegmental
The mortality from PEA at experienced centres is <5%.33 emboli in 2e3 mm arteries, may result in “over-diagnosis”
Complications include transient reperfusion injury and possibly overtreatment.35 Morley et al.36 in a 10-year
(permeability oedema) in the reperfused areas, which oc- retrospective analysis demonstrated an increase in CTPA
curs to some extent in 10e15% typically within 48 hours of examinations performed by 325% and marked reduction in
surgery. Other rare complications include rupture of the the proportion of V/QSCAN studies (from 55% to 4% of studies
arteriotomy site, intrapulmonary bleeding, haemoptysis, for suspected PE). Over the same period, the number of

Please cite this article in press as: Ruggiero A, Screaton NJ, Imaging of acute and chronic thromboembolic disease: state of the art, Clinical
Radiology (2017), http://dx.doi.org/10.1016/j.crad.2017.02.011
4 A. Ruggiero, N.J. Screaton / Clinical Radiology xxx (2017) 1e14

imaging studies increased fourfold whilst the number of MRI


positive studies increased by a factor of 2.2; however,
despite the fourfold increase in the use of CTPA, there was Over the past decade, MRI has undergone significant
no significant change in the severity scores except those technical improvement with faster sequences, larger
with a modified Miller score of 1 (single-segment dis- coverage, and ability to perform functional studies, lung
ease).36 Although some advocate treatment of all emboli, perfusion imaging, and high-resolution MR pulmonary
others propose that small subsegmental emboli are part of angiography (MRPA). MRPA consists of a three-dimensional
normal physiology with one of the functions of the lungs (3D) heavily weighted T1 gradient echo MRI sequences
being to act as a sieve preventing them from reaching the acquired during first-pass perfusion (and during breath-
systemic arterial circulation.37 hold usually up to 5 seconds) following intravenous injec-
Given the increasing concern over radiation exposure, tion of gadolinium via an injector pump to visualise the
several strategies exist to reduce radiation dose such as pulmonary arteries. Non-contrast enhanced MRPA can be
lowering tube voltage, and high pitch acquisition. High pitch performed using SSFP free-breathing real-time imaging
acquisitions (80 kVp) with iterative reconstructions have technique with additional navigator-gating, which is used
been demonstrated to reduce radiation dose by approxi- to obtain the images in the same phase without the need for
mately 50% when compared to standard pitch 100 kVp CTPA breath-hold.46 MRI can be used to assess regional lung
with standard filtered back projections without degradation parenchymal perfusion; areas of reduced, delayed, or absent
of the image quality.38 The use of low voltage and high pitch blood flow suggest the presence of an obstruction.
also increases the photo-electric effect and the speed of The thorough and systematic analysis of the source im-
scanning allowing the reduction of the amount of iodinated ages together with the multiplanar reformations is crucial
contrast medium required, thus lowering the risk of contrast- for the precise assessment of the detailed morphologic
induced nephropathy. Diagnostic quality images can be findings. Maximum intensity projections and 3D refor-
generated by using as little as 20 ml contrast medium.38 matted images can be generated and provide an overview of
The introduction of dual-energy CT (DECT) permits the findings particularly for surgical planning. MRPA find-
functional data on lung perfusion (iodine distribution ings include non-occlusive features, such as dilatation of the
maps/lung perfusion blood volume [PBV] images) in addi- main pulmonary artery, proximal to distal tapering, calibre
tion to anatomical images. These are reader independent change with post-stenotic dilatation, intraluminal signal
and rapid tools to quantitatively assess regional iodine (secondary to thrombus) representing webs, and also
density, a surrogate for pulmonary perfusion, and correlate occlusive manifestations as complete absence of vessel
with V/QSCAN or single photon-emission computed tomog- enhancement.47,48
raphy (SPECT) V/QSCAN.39,40 Scoring systems for the In acute PE MRPA is not routinely used as CTPA is
assessment of iodine maps also correlate with the severity preferred due to its robustness, higher spatial resolution,
of PE.41 The diagnostic accuracy of iodine maps for occlusive speed of examination, safety, and costs; however, a sensi-
acute PE is high but this is not the case for non-occlusive tivity of 55% and a specificity of 99% was demonstrated for
disease.39,42 Although 96% accuracy for occlusive emboli is MRPA when compared to CTPA in the acute setting.49 The
described the overall accuracy including non-occlusive results from the multicentre prospective PIOPED III study
emboli was limited (58% sensitivity, 92% specificity).39 In demonstrated that technically adequate MRPA had a
CTED or CTEPH, vascular remodelling occurs with promi- sensitivity of 78% and a specificity of 99%, and when per-
nent bronchial collateral circulation sustaining paren- formed together with a MR venography had a sensitivity of
chymal perfusion distal to pulmonary arterial obstruction. 92% and a specificity of 96%; however, the study also
In CTEPH, there is a strong correlation between iodine maps showed that 52% of patients had technically inadequate
and mosaic attenuation pattern at both lobar and whole- results. Therefore, the study concluded that MRPA should be
lung level, but no statistically significant correlation be- considered only at centres that routinely perform it well
tween dual-energy CT perfusion and vascular obstructive and only for patients for whom standard tests are
index, mean pulmonary artery pressure, or PVR.43 Paren- contraindicated.50
chymal perfusion was demonstrated in 64% of the MRI is better suited for the diagnostic work-up and
completely occluded lobes, suggesting that blood supply follow-up of patients with CTEPH where it enables both an
was maintained via systemic collaterals.43 Pharmacody- assessment of the pulmonary arterial obstructive disease
namics of iodinated contrast media (which enhance both and detailed evaluation of RV function or alternative causes
the pulmonary and the systemic collateral circulation) and for pulmonary hypertension. There are only a few studies
perfusion scintigraphy tracers (trapped by the pulmonary exploring the accuracy MRPA in CTEPH.
capillary bed) differ significantly. It has been reported that In a comparison study of MRPA, DSA, and CTPA for non-
PBV maps obtained during the opacification of the pulmo- occlusive features in the central pulmonary arteries (main
nary arteries (pulmonary arterial phase) reflect lung pulmonary artery dilatation and pruned-tree sign) MRPA
perfusion solely by the pulmonary arteries although PBV showed high sensitivities (94e100%) but lower sensitivities
maps of a slightly delayed acquisition (systemic arterial for non-occlusive changes in the more peripheral vessels
phase) better depict the perfusion from systemic bronchial (57e89%). For occlusive features sensitivities were high for
collateral circulation.44,45 complete vessel occlusion and free-floating thrombi

Please cite this article in press as: Ruggiero A, Screaton NJ, Imaging of acute and chronic thromboembolic disease: state of the art, Clinical
Radiology (2017), http://dx.doi.org/10.1016/j.crad.2017.02.011
A. Ruggiero, N.J. Screaton / Clinical Radiology xxx (2017) 1e14 5

(83e96%), but lower for organised thrombi such as webs


and shelves (50e71%).51
Lung perfusion MRI has demonstrated a sensitivity
equivalent to V/QSCAN, with an overall sensitivity of 97%,
specificity 92%, compared with V/QSCAN (sensitivity 96%,
specificity 90%) and CTPA (sensitivity 94%, specificity
98%).52
Another study compared ECG-gated CTPA, MRPA, and
DSA and demonstrated sensitivity/specificity for CTEPH-
related changes at the main-lobar level and at segmental
level of 100%/100% and 100%/99% for CTPA; 83.1%/98.6% and
87.7%/98.1% for MRPA; 65.7%/100% and 75.8%/100% for
DSA.53
Magnetic resonance angiography has a longer acquisition
time than CTPA; therefore, selective pure arterial phase
enhancement cannot be always obtained. Consequently, both
the pulmonary arterial and venous systems are sometimes
visualised in some studies, which may complicate differen-
tiation between arteries and veins.54 Other limitations or
MRPA are claustrophobic and severely dyspnoeic patients
who may be unable to achieve the required breath-hold.
MRI allows an accurate and reproducible assessment of
the biventricular volumes and function, degree of myocar- Figure 1 DSPA allowing the direct visualisation of a complex web at
dial hypertrophy, valve disease with regurgitant fraction the origin of the anterior, posterior, and lateral basal segments of the
right lower lobe (arrow) with markedly reduced subsegmental opa-
and coexisting congenital heart diseases and interventric-
cification of the right lower lobe (arrowhead).
ular septal motion. Right ventricular fibrosis with late
gadolinium enhancement (LGE) can be assessed. A common
finding in patients with PH is the presence of LGE at the acute PE is limited to catheter-based intervention. The
insertion points of the inter-ventricular septum which is morbidity and mortality rates of invasive angiography are
related to the mechanical strain caused by elevated RV 3.5e6% and 0.2e0.5%, respectively.59,60
pressure and is a negative prognostic indicator.55 Right heart catheterisation (RHC) with or without se-
The blood flow in the pulmonary artery can be measured lective pulmonary angiography represents the reference
using phase contrast imaging with gradient echo imaging standard for the diagnosis of CTEPH but for assessment of
and velocity encoding gradients which allow haemody- the anatomical extent of disease cross-sectional angio-
namic measurements such as forward flow, retrograde flow, graphic techniques are increasingly utilised. The operator
average velocity and peak velocity.56 MR flow measure- dependency in radiographic interpretation remains a
ments have been shown to correlate with invasive mea- concern, a study of acute PE showed interobserver agree-
surements of pressure and resistance.57 MR measurements ment rates of 45e66%.61 RHC allows the measurements of
of RV parameters such as end-diastolic volume index and pulmonary artery pressure and PVR, which allows the
tricuspid regurgitant fraction shows higher inter- and intra- quantification of disease severity and the postoperative
observer agreement when compared to transthoracic prognosis.62
echocardiogram.58 Balloon pulmonary angioplasty is an emerging technique
which has been shown in early studies to be feasible and
Digital subtraction pulmonary angiography effective in CTEPH. Its precise role and target group for BPA
Pulmonary angiography and subsequently digital sub- are to be established and is an area of active research. In
traction pulmonary angiography (DSPA) enable direct vis- some practices it is reserved for inoperable CTEPH whether
ualisation of filling defects within the pulmonary arteries due to disease distribution or comorbidity while in others it
(Fig 1). DSPA provides excellent temporal and spatial reso- is being explored as a primary therapeutic option.63 The
lution allowing visualisation of all pulmonary arterial emergence of BPA as a feasible therapeutic option in CTEPH
branches, permitting the catheter-based measurement of may lead to increased utilisation of catheter selective
pulmonary haemodynamics and can potentially be used for angiography to more precisely delineate potential targets
therapeutic intervention. for angioplasty in patients not considered candidates for
Injection within the right or left pulmonary artery may surgical PEA.
permit all of the lobes of one lung to be opacified but more
selective injections (lobar or segmental) can enhance visu- Ventilationeperfusion scan
alisation of subtle lesions. For many years, ventilationeperfusion scan (V/QSCAN)
Catheter pulmonary angiography was historically was the primary imaging modality in patients with sus-
considered the reference standard for the diagnosis of acute pected acute PE. Perfusion scintigraphy is performed using
PE but this role has long since passed to CTPA and its use in 99m
Tc radiolabelled particles (macro-aggregated human

Please cite this article in press as: Ruggiero A, Screaton NJ, Imaging of acute and chronic thromboembolic disease: state of the art, Clinical
Radiology (2017), http://dx.doi.org/10.1016/j.crad.2017.02.011
6 A. Ruggiero, N.J. Screaton / Clinical Radiology xxx (2017) 1e14

albumin, 15e100 mm in size) which are injected into a pe- between V/Q SPECT and CTPA but has demonstrated that
ripheral vein and lodge in the pulmonary capillaries and planar V/QSCAN is inferior.74 The combination of V/Q SPECT
pre-capillary arterioles. In order to increase specificity and and low-dose CT could be even more accurate than V/Q
to map regional ventilation it is typically combined with a SPECT or CTPA, but more studies are warranted.75
ventilation scan performed following inhalation of radio- Although CTPA is the imaging of choice in acute PE, in-
labelled compounds. Given the conical conformation of the ternational guidelines still place V/Q as the first-line imag-
bronchopulmonary segments (which have their apex to- ing technique in CTEPH (Fig 2)2 to rule out chronic PE as a
wards the hilum), occlusive thrombi involving individual cause of pulmonary hypertension. Initial comparison
pulmonary arteries give characteristic lobar, segmental or studies showed better performances of V/Q in detecting
subsegmental peripheral wedge-shaped perfusion defects. chronic PE with a sensitivity of 96%e97.4% and a specificity
Ventilation is usually preserved in the segments affected by of 90%e95% compared with four- and eight-slice CTPA
PE therefore the pattern of preserved ventilation and studies, which showed a sensitivity of 51% and a specificity
regional absent perfusion defines the V/Q mismatch of of 99%76; however, more recent studies with newer gener-
underlying PE. Importantly, V/Q mismatch is not specific of ation CT systems (16 and 64 sections) showed similar
PE as it can be seen also in other disorders (congenital diagnostic performances for both techniques.77 Unmatched
pulmonary vascular abnormalities, veno-occlusive disease, segmental perfusion defects indicate PE, however, similar
vasculitis, lung cancer or tuberculous mediastinal findings have also been rarely seen in idiopathic pulmonary
adenopathy). artery hypertension (PAH) or pulmonary veno-occlusive
V/QSCAN can be performed using planar scintigraphy or disease (PVOD). Although V/Q remains of value for the
single photon emission computed tomography (SPECT). An screening of CTEPH patients, it may not be such a useful tool
occlusive clot in a segmental artery typically causes a to discriminate PVOD from PAH.78 Moreover, V/Q does not
perfusion defect large enough to be detected on the basis of allow detailed evaluation of the distribution and extent of
six to eight images on planar scintigraphy despite its low the disease and can be insensitive to web disease, and it is
resolution and motion artefacts.64 Perfusion defects within therefore not suited for the assessment of the surgical
the segments adjacent to the mediastinum are usually operability.
poorly visualised on the outer contour of the lung.
A perfusion scan only (QSCAN) performed with 100 MBq Echocardiography
of Tc-99m macro-aggregated albumin particles corresponds
to 1.1 mSv (average-sized adult) which is significantly lower Transthoracic echocardiography (TTE) is a valuable tool
than that of CTPA (2e6 mSv).65,66 Given this and the in both acute and chronic thromboembolism in the
absence of contrast medium V/Q is advocated in outpatients assessment of RV function and valve function. Also, it can
with low clinical probability and normal chest radiography, help screen for the presence of pulmonary hypertension (by
in young patients, in pregnancy, in severe renal impairment the estimation of the pulmonary artery systolic pressure
and in patients with history of contrast medium allergy. from peak Doppler velocity of tricuspid regurgitant jet). TTE
Probabilistic interpretation was introduced by the PIOPED I performed 6 weeks after PE has been suggested as a
study67 with assessment of high, intermediate, low proba- screening tool to identify patients with RV dysfunction and
bility V/QSCAN and indeterminate examinations. These persistent features of pulmonary hypertension. The further
terms have been further revised and a three-tier classifi- discussion of echocardiography is beyond the scope of this
cation: normal (excluding PE), high-probability (considered review.
diagnostic of PE consisting of ventilation/perfusion
mismatch of at least one segment or two sub-segments that Differentiating acute from chronic
conform to pulmonary vascular anatomy), and non- thromboemboli
diagnostic (Multiple V/P abnormalities not typical of spe-
cific diseases).68e70 PIOPED II demonstrated that, excluding Accurate differentiating of acute and chronic PE is
patients with intermediate or low probability, the sensi- essential as treatment options and outcomes differ signifi-
tivity of a high probability (PE present) scan was 77.4% while cantly. It is similarly important to recognise that both con-
the specificity of very low probability or normal (PE absent) ditions may co-exist. CT signs of acute and CTED are
scan was 97.7% confirming the effectiveness of a high- summarised in Table 1. Although the descriptions below
probability V/Q scan for diagnosing PE and of abnormal focus on the imaging features on CT, they apply equally to all
perfusion scan to exclude PE.71 angiographic techniques.
A randomised trial comparing V/Q with CT demonstrated
that it is safe to withhold anticoagulant therapy in patients Imaging features of acute PEs
with a normal perfusion scan.72 SPECT imaging (with or
without low-dose CT) improves the detection of sub- Direct (intravascular) features
segmental PE therefore reducing the frequency of non- CTPA directly demonstrates intravascular acute emboli
diagnostic scans, Reinartz et al.73 reported a sensitivity with complete or partial vascular obstruction. In complete
and specificity for V/Q planar scintigraphy of 76% and 85%, obstruction, the lumen is entirely occupied by low-density
respectively versus 97% and 91% for V/Q SPECT. A recent thromboembolic material. In contrast to chronic thrombo-
meta-analysis has shown no performance difference embolic obstruction vascular calibre at the level of

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Figure 2 Multiple perfusion defects (arrows) some of these with a clear wedge-shaped appearance in keeping with segmental perfusion defects
(arrows), which cannot be demonstrated on the ventilation scan (mismatched defect).

obstruction is typically preserved or slightly enlarged Although eccentric filling defects (Fig 4) may abut the
(Fig 3). Partial obstruction appears as a central or eccentric vascular wall, they form acute angles with the vessel wall
filling defect surrounded by high attenuation contrast me- both in short and long axis in contrast to chronic emboli.
dium. The morphology of emboli varies according to Semi-quantitative indices of PE burden have been
whether the vessel is imaged in short axis (“rim” or “polo developed such as the Qanadli and the Mastora score79,80;
mint” sign; Fig 4) or long axis (“railway track” sign). however, a recent meta-analysis showed that while overall

Table 1
Characteristics of acute and chronic pulmonary embolism.

Acute Chronic
Direct features Preserved calibre of the vessel Vessel narrowing
Central (“polo mint” or “railway track” Calibre change
sign) or eccentric filling defect Intimal irregularities
Laminated thrombus
Webs
Bands
Complete amputation of a vessel
Indirect feature Right ventricular enlargement (only in severe PE) Increased calibre of the main pulmonary artery (CTEPH)
Tricuspid regurgitation (only in severe PE) Right ventricular enlargement (CTEPH)
Right ventricular hypertrophy
Tricuspid regurgitation (CTEPH)
Prominence of bronchial collateral arteries
Parenchymal features Triangular subpleural consolidation or ground-glass Mosaic perfusion
opacity with fine reticular changes Subpleural scar/cavitation
Focal pleural thickening

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8 A. Ruggiero, N.J. Screaton / Clinical Radiology xxx (2017) 1e14

Figure 3 Acute PE located at the bifurcation of the main pulmonary


artery and extending into both pulmonary arteries (saddle). Figure 5 Complete obstruction in acute PE causes the complete loss
of perfusion with distal infarct that appears as (a) triangular sub-
pleural consolidation or ground-glass opacity with fine reticular
obstructive burden was not associated with increased 30- changes (arrow), note the large filling defect in the right interlobar
day mortality a central location of emboli was.81 Scoring artery (arrowhead). (b) One-year follow-up CT image after the acute
systems are also cumbersome (particularly for non- event shows a residual fibrotic band and a degree of pleura thick-
specialist radiologists) making their use unsuitable in the ening at the site of previous infarction (arrow).
emergency setting requiring rapid risk stratification.
Partial vascular obstruction causes a decrease in the flow
Indirect (parenchymal) features rate (oligaemia) which manifests as a nonuniform arterial
Complete obstruction causes the complete loss of perfusion of the lung parenchyma with decreased diameter
perfusion with distal infarct that appears as a triangular of the vessels and patchy areas of low attenuation on CT or
subpleural consolidation or ground-glass opacity with fine low signal on MR of the lung parenchyma (mosaic attenu-
reticular changes (Fig 5). ation pattern).

Figure 4 Acute PE. (aeb) Central and (ced) eccentric filling defects surrounded by high attenuation contrast medium: (a) “polo mint sign” and
(b) “railway track sign”. (ced) Eccentric filling defects abut the vascular wall forming acute angles with the vessel wall both in short and long
axis.

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A. Ruggiero, N.J. Screaton / Clinical Radiology xxx (2017) 1e14 9

Figure 6 (a) Chronic large pulmonary embolus involving both pulmonary arteries with a prominent calcification (arrowhead) and extending
into (b) the right lower lobe pulmonary artery and at segmental level, note the irregular contour of the intimal surface with obtuse angles with
the contrast column and appearing as a crescent-shaped filling defect. (c) Marked reduction in calibre of the anterior segmental pulmonary
artery of the right upper lobe due to retraction of the non-obstructive organised thrombus.

Indirect (cardiac) features reformatted four-chamber view. RV/LV ratio >1.0 (on
Obstruction to pulmonary arterial flow and the increase transverse CT images) or >0.9 (on four-chamber view) are
in PVR causes increase in the RV afterload with RV dilata- suggestive of RV dysfunction.83,84 Volumetric assessment of
tion, bowing of the interventricular septum, inferior/supe- LV/RV ratio is the most accurate, though clinically cumber-
rior vena cava and azygos vein dilatation and reflux of some, CT parameter for identifying patients with RV
contrast in the inferior vena cava and hepatic veins. dysfunction11 and is a predictor of early death in patients
Right ventricular dilatation assessed on CTPA is an in- with acute PE, independent of clinical risk factors and
dependent predictor for in-hospital death or clinical dete- comorbidities. Straightening of the interventricular septum
rioration in the overall population and in and inferior vena cava contrast reflux, and the RV/LV ratio
haemodynamically stable patients.82 RV/left ventricle (LV) on four chamber view was predictive of adverse outcomes,
ratio is commonly used to assess RV dilatation and can be whereas the RV/LV ratio measured on transverse images
measured either on axial images or using a multiplanar was not.85

Figure 7 (a) Obstructive chronic thrombus causing vessel amputation (arrowhead) of the right lower lobe pulmonary artery and a band or shelf
(arrow) in the left lower lobe pulmonary artery. Non-obstructive organised chronic thromboembolic material appears as (b) complex web at
distal segmental level in the anterior segment of the right upper lobe with subsegmental vascular attenuation (c) complex web at the trifurcation
in the left lower lobe and (d) thin laminated vessel wall abnormality with calcification (arrow).

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10 A. Ruggiero, N.J. Screaton / Clinical Radiology xxx (2017) 1e14

Imaging features of chronic PEs

Direct (intravascular) features


A complete obstructive filling defect leads to the absence
of contrast material distal to the obstruction and an abrupt
reduction in vessel diameter due to retraction of the
organised thrombus (vessel amputation). Incomplete
obstruction is associated with a small calibre and partially
opacified vessel (Fig 6) or possibly post-stenotic dilatation.
A systematic approach to the segmental anatomy is essen-
tial as complete absence of opacification in effected seg-
ments is easily overlooked (assess the paired segmental
bronchi and pulmonary arteries and look for the amputated
vessel). Non-obstructive organised chronic thromboem-
bolic material appears as vessel narrowing, intimal irregu-
larities, bands, and webs (Fig 7). Vessel attenuation results
from thrombus recanalisation and appears as an abrupt
reduction calibre.
Laminated thrombi represent organised, endothelialised,
thrombotic material along the vessel wall causing an
irregular contour of the intimal surface with obtuse angles
with the contrast column (in contrast to the acute angles
seen in acute emboli) and appearing as a crescent-shaped
filling defect in the transverse plane. Calcifications are
often seen within laminated thrombi (Figs 6 and 7).
Bands or shelves are fine linear structures attached at
both extremities to the vessel walls and are usually oriented
along the vessel long axis (Fig 7). Webs consist of a network
of multiple bands, which are commonly seen at vascular
bifurcations and typically associated with distal vascular
attenuation (Figs 6 and 7). Bands and webs are rarely seen in
the main pulmonary arteries and more often at distal lobar
or segmental level.

Indirect (intravascular) features


Increased vascular resistance related to the chronic
obstruction results in pulmonary hypertension and it is
associated with dilatation of the central pulmonary arteries.
The diameter of the main pulmonary artery is measured on
a transverse plane at the level of the bifurcation just later-
ally to the ascending aorta and usually values above 29 mm
(in men) and 27 mm (in women) are usually used as a
predictive cut-off of pulmonary hypertension86 however
others have suggested that a cut-off value of 31.6 mm is a
more robust to suggest pulmonary hypertension (sensi-
tivity, 47.3%, specificity, 93.3%).87 These measurements are
of limited utility in patients with interstitial lung disease.87 Figure 8 (a) Maximally intensity projection reconstructed image of a
Using the ascending aorta as an internal reference standard CTPA showing occlusive defects within the right pulmonary artery
and assessing the main pulmonary artery to the aorta (arrow) with marked enlargement of bronchial collateral vessels
arising from the aorta (arrowhead). (b) Marked dilatation of the RV
diameter ratio is both practical and reliable. An MPA:Aorta
cavity with prominent hypertrophy of the RV free wall (arrow). (c)
diameter of greater than 1:1 shows a strong correlation Mosaic attenuation of the lung parenchyma consisting of areas of
with increased pulmonary pressures with sensitivity, reduced attenuation (corresponding to the areas of perfusion defects)
specificity, positive and negative predictive values for with areas of increased attenuation (secondary to hyperperfusion of
determining PH of 70%, 92%, 96%, and 52%, respectively.88 the areas with patent vessels). Note that the calibre of the vessels is
In CTEPH the pulmonary arteries may appear rather increased in the areas of increased perfusion and reduced in the areas
tortuous and demonstrate vessel wall calcification. of decreased perfusion.
A segmental artery-to-bronchial diameter ratio >1:1 in
three or four lobes in the presence of a dilated (29 mm)

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A. Ruggiero, N.J. Screaton / Clinical Radiology xxx (2017) 1e14 11

Figure 9 (a) RV enlargement (ratio of the RVeLV diameters >1:1) with straightening of the interventricular septum (b) diastolic leftward
motion of the interventricular septum to cause the deformation of the LV, “D shape”, as a result of the pressure differential between LV and RV
chambers. (c) Late gadolinium enhancement at the inferior insertion point of the inter-ventricular septum, which is related to the mechanical
strain caused by elevated RV pressure and is a negative prognostic indicator.

main pulmonary artery and absence of significant structural MR demonstrates this dynamic diastolic leftward motion
lung disease has a specificity of 100% for the presence of of the interventricular septum to cause the deformation of
pulmonary hypertension89,90 but this sign is less reliable in the LV, “D shape”, as a result of the pressure differential
CTEPH due to distal attenuation of obstructed vessels. In between left and RV chambers. Beyar et al demonstrated in
CTEPH the bronchial circulation may appear markedly an animal model that interventricular septal bowing is
increased due to increased systemic-to-pulmonary shunts present when the pressure differential between the right
which help to maintain pulmonary blood flow (Fig 8). and left ventricle exceeds 5 mmHg and a strong association
The imaging appearances of CTED are similar in CTPA and between inter-ventricular septal curvature and the RVeLV
in MRPA, but laminated thrombus detection is more diffi- pressure gradient was demonstrated as RV pressure
cult in MRPA. The sensitivity of MRPA is lower than that of increases.96
digital subtraction angiography or CTPA for detection of Dilatation of the tricuspid valve annulus secondary to RV
subsegmental webs and bands. The main strength of MRPA enlargement results in a degree of tricuspid regurgitation
is related to the fact that it does not require the use of which can be manifest on CT as a column of contrast
ionising radiation or iodinated contrast medium.91 Overall, retrograde filling the inferior vena cava and the hepatic
CTPA remains superior because of the ease of use, short veins (though at high injection rates a degree of inferior
acquisition time and high spatial resolution.92,93 In CTEPH vena cava filling may be normal). MRI is helpful to visualise
abnormally enlarged bronchial and non-bronchial (inter- the tricuspid regurgitation and quantitatively characterise
costal arteries, internal mammary arteries, inferior phrenic this finding.
arteries) which are frequently present can account for 30% Slightly enlarged thoracic lymph nodes have also been
of systemic blood flow.94 CTPA provides a more accurate described in association with CTPEH97 correlating histo-
assessment of these collaterals vessels than DSPA or MRPA logically with vascular transformation of the sinus with a
but requires simultaneous opacification of the pulmonary degree of sclerosis.
and systemic circulation. Usually reformatted multiplanar
images and volume rendering technique allow a better Parenchymal features
understanding of the origin and course of the collateral A mosaic perfusion pattern reflects reduced perfusion in
vessels. MR allows to quantify the systemic to pulmonary areas subtended by occluded or stenosed vessels. It appears
collateral flow.95 on CT as sharply demarcated areas of low attenuation with
small vascular calibre contrasting with areas of increased
Indirect (cardiac) features attenuation with larger vessels representing the normal/
Increased pulmonary pressures result in RV hypertrophy hyper-perfused lung.
characterised by free wall thickness >4 mm (Fig 8). Over The mosaic pattern is non-specific as it can be seen in
time RV function deteriorates resulting in RV enlargement CTEPH as well as in small airway disease. Classically, in
defined as the ratio of the RVeLV diameters >1:1. patients with CTEPH there is a well-demarcated segmental
Straightening and often right-to-left bowing of the inter- or subsegmental distribution of the mosaicism due to the
ventricular septum is characteristic of right heart strain vascular distribution of the thromboemboli. In small air-
(Fig 9). ways disease the mosaic pattern has a more patchy

Please cite this article in press as: Ruggiero A, Screaton NJ, Imaging of acute and chronic thromboembolic disease: state of the art, Clinical
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12 A. Ruggiero, N.J. Screaton / Clinical Radiology xxx (2017) 1e14

pattern (Fig 10). Wedge unmatched perfusion defect can be


demonstrated on V/QSCAN both in the acute and chronic PE.

Conclusion

Acute thromboembolic disease is common with diag-


nostic pathways involving pretest probability assessment,
D-dimer, and imaging being widely advocated by interna-
tional guidelines. Chronic thromboembolic disease is
increasingly recognised as a not infrequent sequela of prior
acute emboli, which is often initially overlooked with
considerable delay in diagnosis. Among all imaging mo-
dalities, CTPA plays a key role both in the acute and chronic
setting of thromboembolic disease. Although the imaging
features of acute PE are easily recognised and enable
prompt the appropriate treatment, features of CTED or
CTEPH are more subtle and often difficult to diagnose. This
review has aimed to provide an up-to-date overview of the
diagnostic accuracy of all the available techniques as well as
the most common appearances to help identify and
describe the findings. The capabilities of dual-energy CTPA
have been exploited in the past few years and further
studies are required to justify its routine use in clinical
practice.

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Please cite this article in press as: Ruggiero A, Screaton NJ, Imaging of acute and chronic thromboembolic disease: state of the art, Clinical
Radiology (2017), http://dx.doi.org/10.1016/j.crad.2017.02.011