10.4081/btvb.2024.122
Acute pulmonary embolism (PE) is a common and potentially life-threatening disease characterized by the occlusion of arterial lung vasculature, typically due to thrombi traveling from a thrombotic vein in the lower limb. Several guidelines have been proposed worldwide to assist clinicians in its diagnosis, however, they are not consistent on the usage of diagnostic tools. This commentary reviews the literature and discusses the concordance/discordance between these international guidelines on PE diagnosis.
application/pdf
2785-5309
122
1
en
Gualtiero Palareti
https://creativecommons.org/licenses/by-nc/4.0
Bleeding, Thrombosis and Vascular Biology
guidelines
The diagnostic procedure for subjects with suspected pulmonary embolism. A recent comparison among the recommendations available from the international guidelines
Text.Serial.Journal
https://www.btvb.org/btvb
3
Commentaries
2024-03-19
2024-01-24
2024-03-01
2024-03-19
Bleed Thromb Vascul Biol
Gualtiero Palareti
2024/03/19
10.4081/btvb.2024.122
Arianna Anticoagulazione Foundation, Bologna
2785-5309
1
guidelines
en
Gibson NS, Sohne M, Kruip MJ, et al. Further validation and simplification of the Wells clinical decision rule in pulmonary embolism. Thromb Haemost 2008;99:229-34.
The diagnostic procedure for subjects with suspected pulmonary embolism. A recent comparison among the recommendations available from the international guidelines
https://www.btvb.org/btvb/article/download/122/100
3
                                                                                                                      COMMENTARY

The diagnostic procedure for subjects with suspected pulmonary embolism.
A recent comparison among the recommendations available
from the international guidelines
Gualtiero Palareti

Arianna Anticoagulazione Foundation, Bologna, Italy



ABSTRACT
    Acute pulmonary embolism (PE) is a common and potentially life-threatening disease characterized by the occlusion of arterial
lung vasculature, typically due to thrombi traveling from a thrombotic vein in the lower limb. Several guidelines have been proposed
worldwide to assist clinicians in its diagnosis, however, they are not consistent on the usage of diagnostic tools. This commentary
reviews the literature and discusses the concordance/discordance between these international guidelines on PE diagnosis.




                                                                                                ly
                                                                                        on
                                                                             the incidence of VTE is slightly higher in men than in women, at
Introduction                                                                 exception of women under 45 years of age, due to the risk related
                                                                             to estrogen therapy and pregnancy,4 and over 80 years in whom
    Acute pulmonary embolism (PE) is characterized by the oc-




                                                                                  e
                                                                             an excess of PE-related mortality has been reported.5
clusion of arterial lung vasculature typically due to thrombi trav-
eling from a thrombotic vein in the lower limb. It is a frequently
occurring and potentially life-threatening disease.1 The term ve-
                                                                            us    Clinical manifestations of PE may vary widely, ranging from
                                                                             entirely asymptomatic forms (as is the case of silent PE in 30-
                                                                             50% of patients with confirmed DVT),6-8 to extremely serious,
nous thromboembolism (VTE) encompasses PE and/or deep vein
                                                                            al
                                                                             and life-threatening illness. Between the two extremes lie most
thrombosis (DVT). The incidence of PE is approximately 1 in
                                                                             patients, who have symptomatic, non-high-risk PE. Common
                                                         ci

1000 persons per year;2 however, it increases sharply with age,
                                                                             symptoms of PE are fatigue, chest pain, short of breath, cough,
reaching 11.3 per 1000 people aged 80 years or older.3 Overall,
                                                       er


                                                                             hemoptysis, and syncope; more recently, even occurrence of dys-
                                                                             pnea on exertion was detected as potential symptom of PE.9 How-
                                                      m



                                                                             ever, the symptoms are non-specific for PE, and may be present
                                                                             in several different clinical conditions.
  Correspondence: Gualtiero Palareti, “Arianna Anticoagulazione”
                                          om




                                                                                  Clinical presentation of patients with suspected PE is there-
  Foundation, Via Paolo Fabbri 1/3, 40138, Bologna, Italy.
                                                                             fore highly variable. What is important is to tailor initial thera-
  Tel.: + 39.3282279868.
  E-mail: gualtiero.palareti@unibo.it                                        peutic and diagnostic management of patients according to the
                                    -c




                                                                             recommended classification of disease severity,10 which catego-
  Key words: pulmonary embolism, diagnosis, guidelines.                      rizes early mortality risks (in-hospital or 30 days) as: high, inter-
                           on




                                                                             mediate (high or low), and low. Anticoagulation with fast-acting
  Conflict of interest: the author declares no potential conflict of in-     drugs should be initiated in patients at high (hemodynamic insta-
  terest.                                                                    bility) or intermediate risk, even before diagnostic test results are
                     N




                                                                             known. A recent study (the COPE study),11 investigating a cohort
  Funding: none.
                                                                             of >5200 patients with acute PE, found an in-hospital mortality
  Received: 24 January 2024.                                                 of 3.4%, and a 30-day mortality of 4.8%, mostly due to associated
  Accepted: 5 March 2024.                                                    co-morbid conditions. Patients categorized at low severity risk
                                                                             may follow the diagnostic procedures without immediate antico-
  Publisher’s note: all claims expressed in this article are solely those    agulation.
  of the authors and do not necessarily represent those of their affili-          All patients with suspected PE need a diagnosis confirming
  ated organizations, or those of the publisher, the editors and the re-     the presence or not of the disease. This is necessary since a high
  viewers. Any product that may be evaluated in this article or claim        risk of early mortality has been reported when PE is left
  that may be made by its manufacturer is not guaranteed or endorsed         untreated.12 However, treating with anticoagulants subjects who
  by the publisher.                                                          do not have PE is associated with a significant and needless risk
  ©
   Copyright: the Author(s), 2024
                                                                             of bleeding and may delay the diagnosis of the real cause of symp-
  Licensee PAGEPress, Italy                                                  toms. Diagnostic management of hemodynamically stable patients
  Bleeding, Thrombosis and Vascular Biology 2024; 3:122                      with suspected PE (95-98% of all patients), aimed at ruling out
  doi:10.4081/btvb.2024.122                                                  the disease, does however present several challenges. The increas-
                                                                             ing awareness of the risks associated with PE, the wider availabil-
  This work is licensed under a Creative Commons Attribution-                ity of less-invasive imaging tests (computed tomography
  NonCommercial 4.0 International License (CC BY-NC 4.0).                    pulmonary angiography, CTPA), and the greater sensitivity of
                                                                             physicians towards PE are all factors favoring a larger recourse


                                             Bleeding, Thrombosis and Vascular Biology 2024; 3:122
12                                                                  G. Palareti




to diagnostic workup for PE, resulting in overutilization of imag-           guideline indications differ. The Wells rule is recommended by
ing tests and a lower rate proportion of PE diagnosis in suspected           all guidelines except for ACEP and JCS, while the revised Geneva
patients. As an example, a retrospective observational study, per-           score is recommended by 9 guidelines (UpToDate, ESC/ERS,
formed on 8449 patients who underwent CTPA, showed that more                 EANM, PERT, ACEP, ASH, ACP, SPAIN, BTS). While physician
than 99% of CTPA resulted negative.13 Inappropriate use of CTPA              gestalt has been shown to be useful in predicting pretest proba-
can be deleterious leading to adverse complications like contrast-           bility in suspected PE subjects,22 the use of clinical gestalt is rec-
induced allergic and non-allergic pathologies (especially contrast-          ommended by only 5 guidelines (UpToDate, ESC/ERS, ACP,
induced nephropathy) and increased healthcare costs.14,15                    JCS, and PIOPED II.
Furthermore, exposure to ionizing radiation and increased risk of                 The Pulmonary Embolism Rule out Criteria (PERC) has been
cancer due to radiation need to be taken into account.16                     recommended to reduce the need for further testing in subjects with
    An approach that combines different diagnostic tests accord-             low pretest probability of PE.23 PERC includes 8 items (Table 1)
ing to well validated algorithms is the only solution to the above-          and if none of them is present in subjects with low pretest proba-
mentioned diagnostic problems. Several international guideline               bility (<15%), then the probability of false negative results is so low
recommendations have been proposed to help clinicians in PE di-              (the predefined threshold is <1.8%) that further testing becomes un-
agnosis. Unfortunately, not all of them are always concordant on             necessary. Although PERC was subsequently validated by a larger,
how to use the various diagnostic tools.                                     prospective, multicenter clinical study,24 its inclusion to assess
    Falster et al.17 have recently published a comparison of inter-          pretest probability is recommended by only 8 of the guidelines.




                                                                                                         ly
national guideline recommendations regarding the diagnosis of
PE. In their extremely valuable work, the authors compared the




                                                                                                 on
content of 13 international guidelines (listed in Supplementary              Empirical treatment before pulmonary
Materials), authored by scientific medical societies or expert au-           embolism diagnosis
thor groups. The authors particularly focused on the assessment




                                                                                           e
of pretest probability, D-dimer testing interpretation, empirical                 As already said, to avoid early mortality and recurrent VTE
treatment before diagnosis, and diagnostic imaging. The authors
also provided an overview of the diagnostic pathways proposed
by each guideline.
                                                                                   us
                                                                             and death at three months,25 patients with suspected PE may need
                                                                             to start anticoagulant treatment before final diagnosis. Only some
                                                                             of the guidelines give recommendations on this issue. Furthermore,
                                                                            al
    The present commentary aims to go through the above-men-                 when reported, the recommendations present a high degree of het-
tioned article, highlighting the points of concordance/discordance           erogeneity with low levels of proof due to the general lack of sci-
                                                             ci

among the international guidelines on PE diagnosis.                          entific data on the matter. The initiation of anticoagulant treatment
                                                                             in all patients with suspected PE, irrespective of pretest probability,
                                                           er


                                                                             is recommended by 3 guidelines (with some differences in relation
Clinical presentation
                                                          m



                                                                             to Wells’ score and time needed for D-dimer results; NICE, EANM,
                                                                             and JCS). Four guidelines recommend treatment only in patients
                                                om




     The initial clinical evaluation of a patient with suspected PE          with high or intermediate probability (ESC/ERS, SPAIN, PIOPED
includes risk factor consideration, physical examination, blood              II, and BTS), one recommends treatment only in patients with high
tests, ECG monitoring and chest radiographs. These items are                 probability, though after having carefully considered bleeding risk
nonspecific for PE diagnosis, but the evaluation is of considerable
                                          -c




                                                                             (PERT) while 4 give no recommendation in this regard (THANZ,
value since it signals whether the patients may have an acute PE.            ACEP, ASH, and ACP). In conclusion, scientific data on empirical
                                  on




Furthermore, this first diagnostic approach is essential for identi-         treatment before PE diagnosis are lacking with only some guide-
fying subjects with suspected PE who are at high risk of early               lines providing recommendations on the matter (with light differ-
mortality (hemodynamic instability or right ventricular dysfunc-             ences). New clinical studies on this subject are warranted.
                            N




tion) and need fast diagnosis and therapy. Thankfully, most pa-
tients are not in this situation and, after suspected PE is confirmed,
should undergo pretest probability assessment.                               D-dimer testing
                                                                                  After assessment of pretest probability, D-dimer assay is
Assessment of pretest probability                                            largely used for the work up of VTE exclusion. A large variety of
                                                                             assays are available for clinical use. In most cases they have a sen-
     Assessment of PE probability before performing specific tests           sitivity above 95% and have been approved by the Food and Drug
may avoid unnecessary testing and is critical for interpretation of          Administration for VTE exclusion thanks to their high negative
test results. To this end, the use of validated clinical prediction          predictive value when the levels are below a certain validated
rules (summarized in Table 1) is recommended. The Wells rule                 threshold (then considered as negative D-dimer) in suspected sub-
consists of 7 variables,18 including a judgment of whether PE is             jects with low or unlikely pretest probability.26 D-dimer levels,
the most likely diagnosis. The revised Geneva score includes sim-            however, increase in all conditions associated with increased fibrin
ilar items except for a clinical subjective judgment on the likeli-          formation with non-specific positive results. The specificity of the
hood of PE.19 The presence of subjective clinical judgment in the            test, generally around 50%, may decrease further in many situa-
Wells rule is the main difference between the two tests and may              tions (as much as 10% in elderly subjects), resulting in a high rate
end up overemphasizing the role of subjective judgment when                  of false-positive results. This drawback is particularly important
using Wells. Though clinical studies and meta-analyses have re-              in the case of elderly subjects, a population with high prevalence
ported comparable predictive accuracies of the two tests,20,21               of suspected VTE.


                                          Bleeding, Thrombosis and Vascular Biology 2024; 3:122
                                                    Diagnostic procedure for suspected PE: a comparison                                         13



Table 1. Wells rule, original and simplified,18,44 revised Geneva score,19 and Pulmonary Embolism Rule out Criteria (PERC).23
                                                                             Wells rule
                                                                              Score
Items                                                                Original           Simplified
Previous PE or DVT                                                        1.5                         1
Heart rate >100                                                           1.5                         1
Recent surgery/immobilization                                             1.5                         1
Clinical signs of DVT                                                      3                          1
Alternative diagnosis less likely than PE                                  3                          1
Hemoptysis                                                                 1                          1
Cancer                                                                     1                          1
Total score (trichotomous)                                             *Estimated prevalence, %
<2 low probability                                                                     ≈6
2-6 intermediate                                                                       ≈23
>6 high                                                                                ≈49




                                                                                                                     ly
Total score (dichotomous)




                                                                                                           on
PE unlikely ≤4 or ≤ 1                                                                  ≈8
PE likely >4 or >1                                                                     ≈34




                                                                                                   e
Items
                                                                                          us
                                                                         Revised Geneva score
                                                                                                                                Score
                                                                                 al
Age >65 y                                                                                                                         1
Previous PE or DVT                                                                                                                3
                                                              ci

Surgery or fracture within 1 month                                                                                                2
                                                            er


Active malignancy                                                                                                                 2
Unilateral lower limb pain                                                                                                        3
                                                           m




Hemoptysis                                                                                                                        2
                                               om




Heart rate ≥75                                                                                                                    3
           ≥95                                                                                                                    5
Pain on lower limb palpation and unilateral edema                                                                                 4
                                       -c




Total score                                                                                                          *Estimated prevalence, %
<4 low probability                                                                                                               ≈9
                             on




4-10 intermediate                                                                                                                ≈26
>10 high                                                                                                                         ≈76
                       N




                                                                                    PERC
Items                                                                                                                           Score
Age ≥50 y                                                                                                                         1
Heart rate ≥100                                                                                                                   1
O2 saturation 95% without supplementary oxygen                                                                                   1
Unilateral leg swelling                                                                                                           1
Hemoptysis                                                                                                                        1
Surgery or trauma within 4 weekstreated in general anesthesia                                                                     1
Previous PE or DVT                                                                                                                1
OC, hormone replacement or estrogen hormone use                                                                                   1
Total score                                                                                                          *Estimated prevalence, %
0                                                                                                                                <2
≥1                                                                                                                               ≥2
PE, pulmonary embolism; DVT, deep vein thrombosis; OC, oral contraceptives.
*Values of estimated prevalence are obtained from the meta-analytic data by Ceriani et al.,21 as reported in Falster et al.17


                                                  Bleeding, Thrombosis and Vascular Biology 2024; 3:122
14                                                                   G. Palareti




     All guidelines, except for ACEP, recommend performing D-                 sons, the detection of DVT in subjects with suspected PE is ac-
dimer assay using predefined algorithm (after pretest probability             cepted as indicative of PE by 5 guidelines (ESC/ERS, PERT, ACP,
and after exclusion of other possible causes of positive results)             PIOPERD II, and BTS) which recommend stopping any further
to reduce as much as possible the number of false-positive re-                investigation after DVT diagnosis. Three other guidelines (UpTo-
sults. The guidelines generally agree on the need to perform D-               Date, ASH and SPAIN) recommend PE diagnosis be accepted in
dimer testing only in subjects with low or unlikely pretest                   the presence of DVT, but only if previous PE imaging tests are
probability to avoid possible false-negative results in subjects at           inconclusive.
high probability.
     Different diagnostic approaches have been proposed to in-
crease the usefulness of D-dimer testing in suspected PE sub-                 Diagnostic imaging
jects. According to the Age-Adjusted strategy,27 D-dimer cut-off
is calculated in relation to age: in patients aged 50 years or more                The guidelines generally agree that patients with suspected
the age-adjusted cut-off values are calculated by multiplying the             PE who i) are at low/intermediate clinical probability and have
age × 10. The YEARS strategy suggests assessing the presence                  altered D-dimer levels, or ii) have high clinical probability, should
of only three items:28 clinical signs of DVT, hemoptysis, and PE              undergo final diagnostic imaging. The quality of CT scanners has
as the most likely diagnosis. If none of these are present the D-             improved enormously in recent years and radiologists are now
dimer threshold is increased to 1000 ng/mL. Conversely, if one                better equipped to distinguish between contrast filling defects in
or more of the above items are present the conventional cut-off               the peripheral pulmonary vasculature that are real subsegmental




                                                                                                          ly
should be used (500 ng/mL). Finally, the Clinical Pretest Prob-               PE from flow artifacts that are not PE or that require anticoagula-




                                                                                                  on
ability-Adjusted strategy proposes using a D-dimer cut-off of                 tion.30 Guidelines differ on the need for VQ scan versus CTPA.
1000 ng/mL in subjects with a low pretest probability,29 whereas              Some guidelines (ESC/ESR) question reaching any clinical con-
in patients with moderate pretest probability, the conventional               clusion when CTPA is negative in subjects at high clinical prob-




                                                                                            e
cut-off (500 ng/mL) is used. These diagnostic approaches aim                  ability and recommend completing the investigation with VQ
to lower the number of CTPA needed, particularly in subjects at
low pretest probability, but clearly have an inherent risk of false-
negative results.
                                                                                    us
                                                                              scan. Conversely, other guidelines (PERT, THANZ, JCS, ACP
                                                                              and BTS) accept the exclusion of PE when CTPA is negative even
                                                                              in subjects at high clinical probability.
                                                                             al
     As expected, the guidelines differ on this issue. Of the nine
guidelines published after 2014, seven (NICE, ESC/ERS, EANM,
                                                              ci

PERT, ACEP, ASH, and ACP) recommend the adoption of the                       Conclusions
age-adjusted strategy; the THANZ does not give any recommen-
                                                            er


dation on D-dimer cutoff, whereas the UpToDate prefers the con-                    The diagnosis of PE is an extremely important clinical activity
ventional cutoff while also considering the age-adjusted cutoff,              because it involves an ever-increasing number of subjects in
                                                           m




but only in subjects with low pretest probability. The YEARS                  whom this disease is suspected. Since – in the end – many of them
                                                                              will not have the disease, the diagnostic procedure should be a
                                                 om




strategy is endorsed by ESC/ERS and PERT. All the guidelines
published before 2014 (SPAIN, JCS, PIOPED II, and BTS) rec-                   balancing act between keeping the use of imaging tests (not al-
ommend using the conventional cutoff.                                         ways without side-effects) as low as possible and recognizing the
                                                                              need to reach a definitive diagnosis. The serious and potentially
                                           -c




                                                                              fatal consequences of false negative decisions highlight the im-
                                  on




Diagnostic investigation                                                      portance of using standardized diagnostic approaches that have
                                                                              been proved to provide the best results in term of reducing useless
by echocardiography                                                           (and potentially harmful) tests and keeping clinical false negatives
                             N




     The utility of echocardiography in a hemodynamically stable              as low as possible. As such, all the currently available international
patient with suspected PE is controversial and signs of right ven-            guidelines recommend following a diagnostic procedure based on
tricular strain [including ventricular dilatation, septal deviation to-       i) assessment of pretest clinical probability using a validated score
wards the left ventricle (D-sign) and akinesia of the right                   [Wells score for PE or the revised Geneva score (low/intermediate
ventricular free wall (McConnell’s sign)] cannot be considered as             or high)] followed by ii) D-dimer testing but only in case of
indicative of PE. Only one guideline (ESC/ERS) considers the                  low/intermediate pretest clinical evaluation and finally, iii) the use
finding of a right heart thrombus as confirmation of PE diagnosis.            of CTPA in subjects with low/intermediate clinical probability,
Eight guidelines (UpToDate, ESC/ERS, EANM, PERT, SPAIN,                       who also have positive D-dimer results, and subjects with high
JCS, PIOPED II, and BTS) agree that echocardiography is useful                probability (without D-dimer assay). Furthermore, some strategies
in hemodynamically unstable suspected PE patients and that find-              have been proposed aimed at increasing the specificity of the
ing right ventricular strain in these patients supports fibrinolytic          assay, based on the use of higher D-dimer cutoff levels in relation
treatment.                                                                    to age (age-adjusted strategy), pretest probability (clinical pretest
                                                                              probability-adjusted strategy) and absence of three specific clin-
                                                                              ical signs (YEARS strategy). During this process, other issues may
Ultrasound diagnosis of deep vein thrombosis                                  emerge, such as the need for anticoagulation to protect patients
                                                                              before any final diagnosis is reached.
    DVT and PE are both VTE manifestations and generally re-                       As is to be expected, not all the international guidelines agree
quire identical treatment; furthermore, silent PE can be detected             on all the points and only the more recent one can be updated with
in a large number of DVT (especially proximal).6 For these rea-               the results of recent clinical studies.


                                           Bleeding, Thrombosis and Vascular Biology 2024; 3:122
                                           Diagnostic procedure for suspected PE: a comparison                                            15



    The article by Falster et al.17 is a cornerstone for comparing            embolism despite three different prophylaxis: a randomized
the currently available international guidelines on PE diagnostic             controlled trial. Acad Emerg Med 2016;23:1136-45.
procedure. The authors highlight the differences between the            16.   Brenner DJ, Elliston CD. Estimated radiation risks potentially
guidelines and provide a very useful visual summary of the testing            associated with full-body CT screening. Radiology 2004;
recommended by each guideline for subjects with suspected PE.                 232:735-8.
Furthermore, they analyze the important points still open to debate     17.   Falster C, Hellfritzsch M, Gaist TA, et al. Comparison of in-
and recommend future clinical studies be carried out in this regard.          ternational guideline recommendations for the diagnosis of
                                                                              pulmonary embolism. Lancet Haematol 2023;10:e922-35.
                                                                        18.   Wells PS, Anderson DR, Rodger M, et al. Excluding pul-
References                                                                    monary embolism at the bedside without diagnostic imag-
                                                                              ing: management of patients with suspected pulmonary
 1. Klemen ND, Feingold PL, Hashimoto B, et al. Mortality risk                embolism presenting to the emergency department by using
    associated with venous thromboembolism: a systematic review               a simple clinical model and D-dimer. Ann Intern Med 2001;
    and Bayesian meta-analysis. Lancet Haemaol 2020;7:e583-e93.               135:98-107.
 2. Lehnert P, Lange T, Moller CH, et al. Acute pulmonary em-           19.   LeGal G, Righini M, Roy PM, et al. Prediction of pulmonary
    bolism in a national danish cohort: increasing incidence and              embolism in the emergency department: the revised Geneva
    decreasing mortality. Thromb Haemost 2018;118:539-46.                     score. Ann Intern Med 2006;144:165-71.
 3. Duffett L, Castellucci LA, Forgie MA. Pulmonary embolism:           20.   Klok FA, Kruisman E, Spaan J, et al. Comparison of the re-




                                                                                            ly
    update on management and controversies. BMJ 2020;370:                     vised Geneva score with the Wells rule for assessing clinical




                                                                                    on
    m2177.                                                                    probability of pulmonary embolism. J Thromb Haemost
 4. Scheres LJJ, van Hylckama Vlieg A, Cannegieter SC. Sex-                   2008;6:40-4.
    specific aspects of venous thromboembolism: What is new             21.   Ceriani E, Combescure C, Le Gal G, al. Clinical prediction




                                                                              e
    and what is next? Res Pract Thromb Haemost 2022;6:e12722.                 rules for pulmonary embolism: a systematic review and meta-
 5. Barco S, Valerio L, Ageno W, et al. Age-sex specific pul-
    monary embolism-related mortality in the USA and Canada,
    2000-18: an analysis of the WHO Mortality Database and of
                                                                       us
                                                                        22.
                                                                              analysis. J Thromb Haemost 2010;8:957-70.
                                                                              Penaloza A, Verschuren F, Meyer G, al. Comparison of the
                                                                              unstructured clinician gestalt, the wells score, and the revised
                                                                  al
    the CDC Multiple Cause of Death database. Lancet Respir                   Geneva score to estimate pretest probability for suspected pul-
    Med 2021;9:33-42.                                                         monary embolism. Ann Emerg Med 2013;62:117-24.
                                                   ci

 6. Stein PD, Matta F, Musani MH, Diaczok B. Silent pulmonary           23.   Kline JA, Mitchell AM, Kabrhel C, et al. Clinical criteria to
    embolism in patients with deep venous thrombosis: a system-               prevent unnecessary diagnostic testing in emergency depart-
                                                 er


    atic review. Am J Med 2010;123:426-31.                                    ment patients with suspected pulmonary embolism. J Thromb
 7. Jimenez D, Aujesky D, Diaz G, et al. Prognostic significance              Haemost 2004;2:1247-55.
                                                m




    of deep vein thrombosis in patients presenting with acute           24.   Kline JA, Courtney DM, Kabrhel C, et al. Prospective multi-
    symptomatic pulmonary embolism. Am J Respir Crit Care
                                      om




                                                                              center evaluation of the pulmonary embolism rule-out criteria.
    Med 2010;181:983-91.                                                      J Thromb Haemost 2008;6:772-80.
 8. Tzoran I, Saharov G, Brenner B, et al. Silent pulmonary em-         25.   Roy PM, Meyer G, Vielle B, et al. Appropriateness of diag-
    bolism in patients with proximal deep vein thrombosis in the              nostic management and outcomes of suspected pulmonary
                                -c




    lower limbs. J Thromb Haemost 2012;10:564-71.                             embolism. Ann Intern Med 2006;144:157-64.
                        on




 9. Prandoni P, Lensing AWA, Prins MH, et al. Prevalence of pul-        26.   Riley RS, Gilbert AR, Dalton JB, et al. Widely used types
    monary embolism among patients with recent onset of dysp-                 and clinical applications of D-Dimer assay. Lab Med 2016;
    nea on exertion. A cross-sectional study. J Thromb Haemost                47:90-102.
                   N




    2023;21:68-75.                                                      27.   Righini M, Van Es J, Den Exter PL, et al. Age-adjusted D-
10. Konstantinides SV, Meyer G. The 2019 ESC guidelines on                    dimer cutoff levels to rule out pulmonary embolism: the AD-
    the diagnosis and management of acute pulmonary embolism.                 JUST-PE study. JAMA 2014;311:1117-24.
    Eur Heart J 2019;40:3453-5.                                         28.   van der Hulle T, Cheung WY, Kooij S, et al. Simplified diag-
11. Becattini C, Agnelli G, Maggioni AP, et al. Contemporary                  nostic management of suspected pulmonary embolism (the
    management and clinical course of acute pulmonary em-                     YEARS study): a prospective, multicentre, cohort study.
    bolism: the COPE study. Thromb Haemost 2023;123:613-26.                   Lancet 2017;390:289-97.
12. Kearon C. Natural history of venous thromboembolism. Cir-           29.   Kearon C, de Wit K, Parpia S, et al. Diagnosis of pulmonary
    culation 2003;107:122-30.                                                 embolism with D-Dimer adjusted to clinical probability. N
13. Dhakal P, Iftikhar MH, Wang L, et al. Overutilisation of im-              Engl J Med 2019;381:2125-34.
    aging studies for diagnosis of pulmonary embolism: are we           30.   Wiener RS, Schwartz LM, Woloshin S. When a test is too
    following the guidelines? Postgrad Med J 2019;95:420-4.                   good: how CT pulmonary angiograms find pulmonary emboli
14. Mitchell AM, Jones AE, Tumlin JA, Kline JA. Prospective                   that do not need to be found. BMJ 2013;347:f3368.
    study of the incidence of contrast-induced nephropathy              31.   Thompson BT KC, Pena C, Zachrison KS, et al. Clinical pres-
    among patients evaluated for pulmonary embolism by con-                   entation, evaluation,and diagnosis of the nonpregnant adult
    trast-enhanced computed tomography. Acad Emerg Med                        with suspected pulmonary embolism. 2022. Available from:
    2012;19:618-25.                                                           https://wwwuptodatecom/contents/clinical-presentation-eval-
15. Turedi S, Erdem E, Karaca Y, et al. The high risk of contrast-            uation-and-diagnosis-of-the-nonpregnant-adult-with-sus-
    induced nephropathy in patients with suspected pulmonary                  pected-acute-pulmonary-embolism.


                                         Bleeding, Thrombosis and Vascular Biology 2024; 3:122
16                                                                      G. Palareti




32. NICE G. Venous thromboembolic diseases: diagnosis, man-                             thromboembolism: diagnosis of venous thromboembolism.
    agement and thrombophilia testing (NG158). NICE Guid-                               Blood Adv 2018;2:3226-56.
    ance2020. Available from: https://www.nice.org.uk/guidance/                   39.   Raja AS, Greenberg JO, Qaseem A, et al. Evaluation of patients
    ng158.                                                                              with suspected acute pulmonary embolism: best practice advice
33. Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC                            from the Clinical Guidelines Committee of the American Col-
    guidelines for the diagnosis and management of acute pul-                           lege of Physicians. Ann Intern Med 2015;163: 701-11.
    monary embolism developed in collaboration with the Euro-                     40.   Uresandi F, Monreal M, Garcia-Bragado F, et al. National
    pean Respiratory Society (ERS). Eur Heart J 2020;41:                                Consensus on the Diagnosis, Risk Stratification and Treat-
    543-603.                                                                            ment of Patients with Pulmonary Embolism. Spanish Soci-
34. Bajc M, Schumichen C, Gruning T, et al. EANM guideline                              ety of Pneumology and Thoracic Surgery (SEPAR). Society
    for ventilation/perfusion single-photon emission computed                           Espanola Internal Medicine (SEMI). Spanish Society of
    tomography (SPECT) for diagnosis of pulmonary em-                                   Thrombosis and Haemostasis (SETH). Spanish Society of
    bolism and beyond. Eur J Nucl Med Mol Imaging 2019;46:                              Cardiology (ESC). Spanish Society of Medicine Accident
    2429-51.                                                                            and Emergency (SEMES). Spanish Society of Angiology
35. Rivera-Lebron B, McDaniel M, Ahrar K, et al. Diagnosis,                             and Surgery Vascular (SEACV). Arch Bronconeumol
    treatment and follow up of acute pulmonary embolism: con-                           2013;49:534-47.
    sensus practice from the PERT consortium. Clin Appl Thromb                    41.   Guidelines for the diagnosis, treatment and prevention of pul-
    Hemost 2019;25:1076029619853037.                                                    monary thromboembolism and deep vein thrombosis (JCS




                                                                                                               ly
36. Tran HA, Gibbs H, Merriman E, et al. New guidelines from                            2009). Circ J 2011;75:1258-81.




                                                                                                        on
    the Thrombosis and Haemostasis Society of Australia and                       42.   Stein PD, Woodard PK, Weg JG, et al. Diagnostic pathways
    New Zealand for the diagnosis and management of venous                              in acute pulmonary embolism: Recommendations of the PI-
    thromboembolism. Med J Aust 2019;210:227-35.                                        OPED II investigators. Radiology 2007;242:15-21.




                                                                                                 e
37. Wolf SJ, Hahn SA, Nentwich LM, et al. Clinical policy: crit-                  43.   British Thoracic Society Standards of Care Committee Pul-
    ical issues in the evaluation and management of adult patients                      monary Embolism Guideline Development G. British Tho-
    presenting to the emergency department with suspected acute
    venous thromboembolic disease. Ann Emerg Med 2018;71:
                                                                                         us
                                                                                        racic Society guidelines for the management of suspected
                                                                                        acute pulmonary embolism. Thorax 2003;58:470-83.
    e59-e109.                                                                     44.   Gibson NS, Sohne M, Kruip MJ, et al. Further validation and
                                                                                 al
38. Lim W, Le Gal G, Bates SM, et al. American Society of                               simplification of the Wells clinical decision rule in pulmonary
                                                                 ci

    Hematology 2018 guidelines for management of venous                                 embolism. Thromb Haemost 2008;99:229-34.
                                                               er
                                                              m
                                                   om
                                            -c
                                    on
                              N




Online supplementary material:
List of compared international guidelines (the more recent first) with references, the acronyms in brackets.


                                             Bleeding, Thrombosis and Vascular Biology 2024; 3:122
