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Residual pulmonary thromboemboli after acute pulmonary embolism
European Journal of Internal Medicine 23 (2012) 379–383
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Original article
Residual pulmonary thromboemboli after acute pulmonary embolism José Luis Alonso-Martínez a, Francisco Javier Anniccherico-Sánchez a, Miren Aránzazu Urbieta-Echezarreta a, José Luis García-Sanchotena b,⁎, Helena Gómez Herrero b a b
Departments of Internal Medicine A, Hospital Complex of Navarra, Irunlarrea 6, 31008 Pamplona, Navarra, Spain Department of Radiology, Hospital Complex of Navarra, Irunlarrea 6, 31008 Pamplona, Navarra, Spain
a r t i c l e
i n f o
Article history: Received 5 April 2011 Received in revised form 12 August 2011 Accepted 17 August 2011 Available online 10 September 2011 Keywords: Thrombosis Residual pulmonary thromboemboli Pulmonary embolism Venous thromboembolic disease
a b s t r a c t Background: After an acute pulmonary embolism (PE), the complete resolution of thromboemboli may not be routinely achieved. The rate of persistence may depend on the time and the diagnostic technique used for evaluation. Patients and methods: Patients were diagnosed with acute PE by means of computed tomography angiography (CTA). While they were receiving anticoagulant therapy, a second CTA was used to explore the rate of persistence of residual thromboemboli. During the initial episode, the plasma levels of Troponin I and natriuretic peptide, patient demographics, and hemodynamic and gas exchange data were evaluated as risk factors for persistence of pulmonary thromboemboli. Results: In this study 166 patients were diagnosed. A second CTA was not made in 46 (28%) patients for different reasons. In 120 (72%) patients a second CTA was made 4.5 [SD2.34] months after the initial episode (range 2–12 months). Complete clearance of thrombi occurred in 89 (74%, 95% CI 65–81) patients. Residual thrombi remained in 31 (26%, 95% CI 18–34) patients. In 6%, 13% and 81% of the patients the size of the residual thrombi was greater, similar to and smaller than initially diagnosed, respectively. The risk factors for residual thrombi included the thrombotic burden (OR 1.95), the alveolar to arterial difference of oxygen (OR 1.64), and the clinical antecedents of venous thromboembolic disease (OR 0.65). Conclusions: After 4.5 months of anticoagulant therapy, residual pulmonary thromboemboli persisted in 26% of the patients. The risk factors for residual thromboemboli include a greater initial thrombotic burden, a deeper gas exchange disturbation and a history of previous venous thromboembolism. © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Traditionally the study of normalized pulmonary perfusion after an acute pulmonary embolism has been evaluated in prospective studies using lung scintigraphy. These studies demonstrated that pulmonary circulation normalized in 34–43% of patients at a variable times, ranging between 3 and 6 months after the acute episode [1,2]. Currently, pulmonary circulation can be evaluated with helical computed tomography [3] (CT), and a few studies have addressed the subject of repermeabilization after an acute occlusion of the pulmonary arterial tree. In a study with 62 consecutive patients, after a mean of 11 months after the acute episode, a follow-up CT scan was performed. Complete resolution of pulmonary thrombi was found in 48% of patients [4]. In another study with 19 consecutive patients, helical CT was used to check the evolution of thrombi 6 weeks after an acute pulmonary embolism, and a resolution rate of 32% was observed [5]. A systematic analysis of studies [6] evaluating pulmonary reperfusion, some of them with scintigraphy and others with helical CT scan,
revealed that a complete resolution of pulmonary embolism is not routinely achieved, and that depending on the time of evaluation, more than 50% of patients show persistent perfusion defects in pulmonary circulation 6 months after an acute pulmonary embolism. However, the number of patients included in these studies has been small, particularly in studies using CT angiography (CTA). Patients with acute pulmonary embolism are at risk for recurrent venous thromboembolic events [7,8]. The rate of relapsing pulmonary embolism can be as high as 10% after a discontinuation of anticoagulant therapy, particularly in cases of unprovoked pulmonary embolism, and the clinical presentation can be nonspecific; thus, it can be difficult to determine whether new defects of perfusion are actually new or whether these defects are thrombi from a previous pulmonary embolism. For this reason, studying the repermeabilisation of the pulmonary arterial tree can be useful. Thus, we studied consecutive patients with a second CTA and analyzed the possible factors that are associated with the persistence of thrombi in the pulmonary arterial tree. 2. Patients and methods
⁎ Corresponding author. Tel.: + 34 848422135; fax: + 34 847 498 5460. E-mail address: [email protected] (J.L. García-Sanchotena).
To evaluate the rate of vascular repermeabilization after an acute pulmonary embolism, all consecutive patients diagnosed with acute
0953-6205/$ – see front matter © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2011.08.018
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pulmonary embolism using CTA were admitted to an area of internal medicine that included 12 beds to diagnose and treat patients. After their discharge, the patients were evaluated in the polyclinic as outpatients with a second CTA. The aim was to observe the disappearance or the persistence of thromboemboli in the pulmonary arterial tree. 2.1. Study design and methods During the index hospitalization we recorded demographic data, the delay in diagnosis of the pulmonary embolism (measured from the beginning of symptoms or signs to the unequivocal diagnosis), clinical antecedents of venous thromboembolic disease, systolic blood pressure, heart rate, shock index (the ratio of heart rate to systolic blood pressure), respiratory rate and coexistent deep venous thrombosis. Within the first 24 h of the index hospitalization we recorded the value of plasma Troponin I (Access AccuTnI, analyzer Beckman Coulter Chaska, MN 55318 USA), B-type brain natriuretic peptide (Pro-BNP) (Elecsys Roche Diagnostics, Mannheim, Germany), arterial gases and D-dimer (HemosIL, D-Dimer HS 500, Instrumentation Laboratory, CO USA). Alveolar to arterial gradient of oxygen (A-aO2) was calculated as follows: Fi O2 ðPb −47Þ−PA CO2 =R þ Fi O2 =Rð1 RÞðPa CO2 =RÞ−Pa O2 where FiO2 is the inspiratory fraction, Pb is the barometric pressure, and PA CO2 is alveolar CO2 pressure assumed to be equal to the arterial CO2 pressure (PaCO2), PaO2 is arterial oxygen and R is the respiratory exchange ratio, which was set to be 0.8. CT angiographies were made by means of a 64-detector row CT (General Electric Medical Systems, Milwaukee, WI). The protocol for multidetector-row CT consisted of evaluating of pulmonary arteries up to the subsegmental arteries after the intravenous injection of contrast material. A clot was considered present if contrast material outlined an intraluminal defect or if an artery was completely occluded. Scanning was made with 1 to 1.3 mm per sections and images were reconstructed at 0.8 mm intervals. CT angiographies were usually interpreted by radiologists who were not aware of the purpose of the study. Thrombotic burden was calculated with the formula for the CT obstruction index [9,10] applied to the initial CT angiography, which was diagnostic of pulmonary embolism. Each lung is considered to have 10 arteries, 2 in the upper lobe, 2 in the middle lobe and lingula and 5 in the lower lobe. The presence of embolus in a segmental artery is scored as 1 point, and emboli in the most proximal arterial level was scored as the value equal to the number of segmental arteries arising distally. A weight factor was assigned depending on the degree of vascular obstruction: 1 point when the thrombus was partially occlusive, and 2 points with total occlusion. Therefore, the maximal CT obstruction index is 40 points. The percentage of vascular pulmonary obstruction was calculated as follows: n · d/40 × 100 where n is the value of the proximal thrombus in the pulmonary arterial tree equal to the number of segmental branches arising distally and d is the degree of obstruction. The quantification of the degree of pulmonary obstruction was calculated by the clinicians who were caring for the patients, represented with each of the authors belonging to internal medicine. We scored 2 points for the artery to where the irrigated territory of a pulmonary infarction was seen and when contrast was not observed distal to the thrombus. The rest of the cases were scored 1 point. Every patient was treated with enoxaparin at a dose of 1 mg/kg of body weight, twice daily and then also with coumarin for an overlapping period until two INR of prothrombin N2 were observed. Some patients were considered appropriate for long-term anticoagulant therapy with low molecular weight heparin. These patients were discharged with ambulatory controls of INR of prothrombin. One patient was
treated with fibrinolysis, and no one required a cava filter. A second CTA was obtained with the specific purpose of evaluating the repermeabilisation of the pulmonary arterial tree. All patients evaluated with the second CTA were kept under anticoagulant therapy. Each patient approved and signed the informed consent for radiologic contrast administration in each exploration. In addition patients were informed of the purpose of the study and signed the informed consent form. 2.2. Statistical analysis All quantitative variables were tested for normal distribution with the Kolmogorov–Smirnov test. Qualitative variables are expressed as percentages. Continuous variables normally distributed are expressed as mean ± standard deviation [SD], and variables without normal distribution are expressed as the median and its interquartile range [IQR]. Comparisons of the means were performed using the Mann– Whitney U test for non-Gaussian variables and the t test for normally distributed variables. The chi-square test and Fisher exact test were used for proportional comparisons. The log rank test was used to compare the times when the second CTA was made in patients with persistent and resolved thrombi. The independence of the degree of occlusion of the pulmonary arterial tree, Pro BNP, Troponin I, shock index, A-aO2 and clinical history of previous venous thromboembolic disease were performed with logistic regression. We used the standardized b coefficient because of the wide variability in measurement units. All statistical tests were 2-tailed and a p value of b.05 was considered statistically significant. 3. Results Overall, during a period of 5 years from January 2006 to December 2010, 166 patients (male 85 [51%]) were admitted with a diagnosis of acute pulmonary embolism made by mean of CTA, with a median age of 74 [IQR 17] years. In 46 (28%) patients (male 25 [54%]), a second CTA could not be performed for different reasons (Table 1). The mean age of these patients was 75 [SD 12] years old, (p b .001 with respect to patients with repeated second CTA). A second CTA was obtained in 120 (72%) patients with a mean time of 4.5 [SD 2.34] months after the initial episode. The median age of the patients was 73 [IQR 17] years old, and 65 of the patients were male (53%). Because of particularities of our polyclinic, the second CTA was not made at a fixed time. Among the 19 (16%) patients for which the second CTA was performed between 2 and 3 months, 6 patients had residual thrombi. Among in 27 (22.5%) patients with scans performed between 3 and 4 months, 7 had residual thrombi. Among the 17 (14%) patients with scans between 4 and 5 months, 2 had residual thrombi. Among the 18 (15%) patients with scans between 5 and 6 months, 3 had residual thrombi. Among the 6 (5%) patients with scans between 6 and 7 months, 2 had residual thrombi. Among the 3 (2.5%) patients
Table 1 Causes of non-repeated CT angiography. Causes
N (%)
Cognitive impairment Mobility impairment Renal failure Death Living out of our community Pregnancy Rejection
5 (11) 17 (37) 4 (9) 9 (19) 6 (13) 1 (2) 4 (9)
J.L. Alonso-Martínez et al. / European Journal of Internal Medicine 23 (2012) 379–383
with scans between 7 and 8 months, no patients had residual thrombi. Among the 8 (7%) patients with scans between 8 and 12 months, 3 had persistent thrombi. The time when the second CTA was made was not different between patients with residual or clearance of thrombi (Fig. 1). The initial pulmonary embolism was caused by an identified event in 43 (36%) patients and was unprovoked in 77 (64%) patients. The provoking events were as follow: orthopedic surgery, 3; transitory immobilization by joint or muscular strains and fractures, 15; estrogens, 6; long haul travel, 2; recent hospitalization due to medical causes, 5; and usual reduced mobility because of multifactor causes, 12 patients. On admission, 38 (32%) patients showed signs of deep venous thrombosis in the lower limbs, although angiographic examination of the limbs was not routinely made since patients already had a diagnosis of venous thromboembolic disease, and the therapy would not be substantially modified. Thirty (25%) patients had clinical antecedents of venous thromboembolic disease, 14 (47%) as isolated deep venous thrombosis and 16 (53%) as pulmonary embolism. Pulmonary embolism affected the main pulmonary arteries in 57 (47.5%) patients and it affected segmental or sub-segmental arteries in 63 (52.5%) patients. The median thrombotic burden was 32.5 [IQR 30] per patient. Complete clearance of thrombi occurred in 89 (74%, 95%CI 65–81) patients and persistent thrombi were observed in 31 (26%, 95%CI 18– 34) patients. Residual thrombi were greater than initially in 2 (6%), similar in 4 (13%) and smaller in 25 (81%) patients. The main pulmonary arteries remained with thrombotic material in 5 (16%) patients (Fig. 2). When the second CTA was performed, 109 (91%) patients followed treatment with vitamin K antagonists and 11 (9%) patients followed treatment with low molecular weight heparin. Table 2 presents the data for several parameters measured from the initial episode of pulmonary embolism, separated into those patients with complete resolution of the thrombi and those who had residual thrombus. The estimation of thrombi burden, plasma levels of Pro-BNP and Troponin I, the A-aO2 and shock index, all of which were measured in initial episode, were examined using bivariant statistical analysis and where shown to be different between those patients with complete clearance of pulmonary thrombi and those patients with residual thrombi in their pulmonary circulation. Table 3 presents other clinical data and their relationship with resolution or persistent residual thrombi, all of which were evaluated during the initial episode. Thus, thrombotic material seen in the main pulmonary arteries and a history of previous venous thromboembolic disease were associated with residual thrombi in the second CTA. In addition, patients with complete resolution were more frequently in NYHA class I than patients in whom residual thrombi were seen. Using an analysis of logistic regression (Table 4), only the thrombotic burden estimated in the initial pulmonary embolism episode,
cumulative probability %
Log rank of time of realization of 2nd CT angiography 120
P=.12
100 clearence of thrombi
80 60
persistence of thrombi
40 20 0 2
3
4
5
6
7
8
9 10 12
Months Fig. 1. Log rank of time of realization of 2nd CT angiography.
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a greater A-aO2 and a history of previous venous thromboembolic disease were demonstrated to be independent predictors of residual thrombi in pulmonary arteries seen in second CTA, which was performed 4 months after the initial episode. Although shock index may seem to be an independent predictor of persistence of residual thrombi, the wide confidence interval suggests that it is not independent factor. 4. Discussion The development of multidetector CT [3] has enabled the facile visualization of pulmonary arteries up to subsegmental levels. An additional advantage is that it allows the evaluation of other intrathoracic structures, the existence of lung infarction, the relationship of right to left ventricle as a sign of right ventricular overload [10] and the coexistence of other pathological processes with relatively few deleterious effects. Studies made with lung scintigraphy have demonstrated that patients with persistent perfusion defects could be at risk of thromboembolic pulmonary hypertension [11]. There are few studies made with CTA about the fate of pulmonary thrombi after an acute pulmonary embolism has occurred, but the rate of persistent occlusion could be high. Despite some suggestion of the development of thromboembolic pulmonary arterial hypertension in cases of persistent endovascular abnormalities, whether pulmonary hypertension is more frequent or not is predominantly unknown. In patients who underwent pulmonary thromboendarterectomy [12], the absence of central thrombi in the CTA was a risk factor for inadequate hemodynamic improvement. However, the importance of persistence or resolution of pulmonary thrombi has to be determined in future studies. On the other hand, since the prevalence of pulmonary embolism is growing as the average age of patients increases, and because elderly patients often are affected with diseases with dyspnea as its main symptom [13], determining whether a new pulmonary embolism has occurred has important implications for the therapy. In our patients, complete resolution of occlusion in the pulmonary arterial tree measured at 4.5 months after the acute episode, was achieved in 74% of patients. A second CTA was made while patients were undergoing treatment with anticoagulant therapy, most of them with vitamin K antagonists. We consider this fact important because it minimizes the possibility that unnoticed pulmonary embolism has occurred and because it confers a credible rate of 26% persistent occlusion. It seems appropriate to think that the time when the pulmonary arterial tree is evaluated after the initial episode could influence the rate of disappearance of residual thrombi. However, in our patients, the persistence of residual thrombi was independent of the time when the second CTA was made, since the analysis of curves of time was similar between both groups. The age, gender or delay in diagnosis did not influence the persistence of thrombi. The initial thrombotic load was greater in patients with residual thrombi than in patients who cleared them. This factor is an important and independent risk factor for persistence of thrombotic material into pulmonary circulation. Those patients who achieved the complete resolution of pulmonary thrombi had a better functional status and it is more probable that they had a lower degree of dyspnea as measured with the NYHA class. Several biomarkers of ventricular dysfunction are prognostically useful for the setting of acute pulmonary embolism. The measure of plasma ProBNP levels during hospitalization for pulmonary embolism has proved to be a predictor of acute deterioration of the clinical condition, the burden of pulmonary embolism and early death [14–16]. However, the evaluation of different sorts of troponin as a biomarker of risk gave contradictory results, being useful in some studies [17] but not in others [18,19]. During the initial episode of hospitalization,
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74%
Greater occlusion Similar occlusion Smaller occlusion 3% 2%
21%
Complete clearance
Fig. 2. Percentage and size of residual pulmonary thrombi. Greater, similar and smaller occlusion mean bigger, same and lesser size of pulmonary thrombi respectively as seen in second computed tomography.
patients in the present study with residual thrombi had higher levels of ProBNP and Troponin I, greater changes in hemodynamic status and deeper alterations in gas exchange than patients who cleared the thrombi. Nevertheless, ProBNP or Troponin I were not independent factors in explaining the residual thrombi; instead, they were associated with acute strain to the right ventricle as an index of a greater load of thrombotic material. The percentage of INR of prothrombin higher than 2 was similar between both groups of patients, suggesting that ongoing activation of coagulation system does not play a central role in the persistence of thrombotic material. A defective fibrinolytic system of plasminogen–plasmin could be implicated in the persistence of thrombi; however we did not explore this circumstance. Future directions to investigate could include the possible connection between fibrinolysis and inflammation and the role of plasminogen activator inhibitor 1 and 2 in the persistence of residual thrombi [20]. The concept of organ-specific hemostasis [21] as a unique interplay between hemostatic and vascular processes has recently gained importance. In studies of mouse brains diseased by thromboembolism, a phenomenon of extravasation of the emboli has been shown to occur 2 h after embolisation. Although it is not well understood yet, the clearance process depends on the size and quantity of embolised objects. If a similar phenomenon occurs in pulmonary circulation is at present unknown. Hypoxemia is associated with the slowing-down of pulmonary circulation and arterial pulmonary hypertension [22]. This event
Table 2 Results of biochemical, gas exchange and hemodynamic parameters measured on admission of pulmonary embolism and their relationship with resolution or persistence.
Age (years) Gender (F/M) Thrombotic burden (%) Months of second CTA Pro-BNP (ng/L) Troponin I (μg/L) D-dimer (ng/ml) Delay in diagnosis (days) % of INR of Prothrombin ≥ 2 PaO2 mm Hg PaCO2 mm Hg A-a O2 mm Hg SBP mm Hg Heart rate Shock index Respiratory rate
Complete resolution
Residual thrombi
p
73 [IQR17] 41/48 27 [IQR 32.5] 4.7 [SD 2.30] 446.5 [IQR 1806] 0.03 [IQR 0.049] 2413.8 [SD 1577] 6 [IQR 8] 78 [IQR 3.34] 64.68 [SD 12.19] 36.13 [SD 6.45] 40.17 [SD 12.67] 131.96 [SD 19.08] 87.04 [SD19.03] 0.67 [SD 0.19] 20.96 [SD 6.52]
74 [IQR 24] 15/16 50 [IQR 25] 3.93 [SD2.3] 1069 [IQR 2737] 0.065 [IQR 0.19] 2354.9 [SD1795] 7 [IQR 12] 75 [IQR 37] 62 [SD 11.63] 33.19 [SD 4.56] 46.66 [SD 14.59] 125.16 [SD18.57] 95.06 [SD 20.16] 0.77 [SD 0.20] 21.81 [SD7.46]
.25 .29 .0013 .23 .015 .00012 .73 .11 .20 .055 .010 .02 .08 .04 .019 .44
M: male. F: female. CTA: computed tomography angiography. Pro-BNP: B-type brain natriuretic peptide. INR: international normalized ratio. A-aO2: alveolar to arterial difference of oxygen. SBP: systolic blood pressure. SD: Standard deviation. IQL: Interquartile range.
could trigger the molecular and cellular mechanism implicated in pulmonary hypertension favoring the persistence of thrombi. In addition, there is evidence of the interplay between hypoxia and inflammation [23] with hypoxia triggering an increase in proinflammatory cytokines and fluid leakage from capillary. This fact could additionally operate in persistent thrombosis. In our study patients with deeper gas exchange alterations had a higher rate of residual thrombi in pulmonary circulation. Thus, a greater alveolar to arterial difference in oxygen, through the process discussed above, may be considered an independent risk factor of residual thrombi. Another independent factor for the persistence of residual thrombi was the antecedent of venous thromboembolic disease. A previous venous thromboembolism is considered the most important risk factor for predicting recurrence of the condition, particularly if the previous episode has been unprovoked or the patient has cancer. But whether the changes in vascular endothelium caused by a thromboembolic phenomenon predispose a patient to a persistence of thrombi is at present essentially unknown. Limitations to this report include the fact that the samples were drawn from a single center with a limited number of patients. In addition, a second CTA was not performed in 28% of patients for various reasons. It is unknown whether a greater sample would have yielded different results in the prevalence of residual pulmonary thromboemboli; however, this should be evaluated in future studies with higher numbers of patients. Another limitation of this study is that the second CTA was not obtained at a fixed time after the acute pulmonary embolism, though the time of achievement did not show differences between the clearance and the persistence of thromboemboli. In our study, a cause of concern was the CTA related X-ray radiation exposure. CT related X-ray doses are large enough to slightly increase cancer risk, particularly in children [24]. Breasts, particularly those that are fattier, might accumulate enough radiation to have an
Table 3 Data related to resolution of thrombi according to trigger factors, affectation of main pulmonary arteries, the existence of previous venous thromboembolic disease and degree of dyspnea evaluated with class of NYHA.
Unprovoked PE DVT evident Thrombi in main arteries Previous VTED NYHA class I NYHA class II NYHA class III or IV
Complete resolution
Residual thrombi
95% CI
p
56 (73%) 59 (66%) 35 (39%) 17 (19%) 64 (72%) 20 (22%) 5 (6%)
21 (29%) 22 (71%) 22 (71%) 13 (42%) 14 (45%) 13(42%) 4 (13%)
0.28 to 0.54 − 0.25 to 0.16 − 0.52 to−0.10 − 0.44 to − 0.01 0.04–0.48 − 0.41 to 0.02 − 0.22 to 0.07
.001 .62 .0010 0.019 .008 0.04 .25
PE: Pulmonary embolism. DVT: Deep venous thrombosis. VTED: Venous thromboembolic disease. NYHA: New York Heart Association for graduation of dyspnea. CI: Confidence interval.
J.L. Alonso-Martínez et al. / European Journal of Internal Medicine 23 (2012) 379–383 Table 4 Logistic regression for evaluation of independence of risk factors predicting residual pulmonary thrombi.
Thrombotic burden (%) Pro BNP (ng/L) Troponin I (μg/L) A-aO2 (mm Hg) Shock Index (HR/SBP ∙ 100) Previous VTED
β
p
Odds ratio (95%CI)
0.67 0.29 0.08 0.49 0.47 − 0.42
.002 0.16 0.68 0.03 0.02 0.03
1.95 1.34 1.08 1.64 1.60 0.65
(1.01–1.06) (0.99–1.002) (0.43–3.51) (1.003–1.07) (1.36–76.28) (0.15–0.91)
Pro-BNP: B-type brain natriuretic peptide. A-aO2: alveolar to arterial difference of oxygen. VTED: venous thromboembolic disease. HR: heart rate, SBP: systolic blood pressure.
increased risk of future breast cancer [25,26]. Nevertheless, the patients of this study are mostly elderly and very elderly patients; thus, their life expectancy may not be long enough so to develop radiation related cancer. On the other hand, taking into account the high accuracy of CTA in the diagnosis of pulmonary embolism, and the frequent ambiguity of ventilation–perfusion lung scan results, which also delivers radiation, we think that the benefits of knowing the pulmonary thromboembolic fate may be greater than the radiation related risks. In conclusion, after acute pulmonary thromboembolism, emboli remain lodged in pulmonary circulation in a quarter of patients. Predicting factors of persistent thromboemboli were a greater initial greater thrombotic burden, a deeper gas exchange alteration and previous episodes of venous thromboembolism. Learning points • In the setting of acute pulmonary embolism, the initial thrombotic burden, the deeper gas exchange alteration and a previous history of venous thromboembolism predict the persistence of thrombotic material in pulmonary arteries. • Mapping pulmonary arteries is important in order to determine the etiology of new episodes of dyspnea in patients with clinical antecedents of pulmonary embolism. • The sort and the length of antithrombotic therapy could be influenced by the persistence of pulmonary thrombi. Whether the residual thrombosis has implication in pulmonary hypertension or not remain to be explored. Conflict of interest This manuscript is the result of independent investigation and authors has not any conflict of interest. Acknowledgment We thank Professor Miguel Andériz for his invaluable advice and review of statistical methods.
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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original article
Residual pulmonary thromboemboli after acute pulmonary embolism José Luis Alonso-Martínez a, Francisco Javier Anniccherico-Sánchez a, Miren Aránzazu Urbieta-Echezarreta a, José Luis García-Sanchotena b,⁎, Helena Gómez Herrero b a b
Departments of Internal Medicine A, Hospital Complex of Navarra, Irunlarrea 6, 31008 Pamplona, Navarra, Spain Department of Radiology, Hospital Complex of Navarra, Irunlarrea 6, 31008 Pamplona, Navarra, Spain
a r t i c l e
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Article history: Received 5 April 2011 Received in revised form 12 August 2011 Accepted 17 August 2011 Available online 10 September 2011 Keywords: Thrombosis Residual pulmonary thromboemboli Pulmonary embolism Venous thromboembolic disease
a b s t r a c t Background: After an acute pulmonary embolism (PE), the complete resolution of thromboemboli may not be routinely achieved. The rate of persistence may depend on the time and the diagnostic technique used for evaluation. Patients and methods: Patients were diagnosed with acute PE by means of computed tomography angiography (CTA). While they were receiving anticoagulant therapy, a second CTA was used to explore the rate of persistence of residual thromboemboli. During the initial episode, the plasma levels of Troponin I and natriuretic peptide, patient demographics, and hemodynamic and gas exchange data were evaluated as risk factors for persistence of pulmonary thromboemboli. Results: In this study 166 patients were diagnosed. A second CTA was not made in 46 (28%) patients for different reasons. In 120 (72%) patients a second CTA was made 4.5 [SD2.34] months after the initial episode (range 2–12 months). Complete clearance of thrombi occurred in 89 (74%, 95% CI 65–81) patients. Residual thrombi remained in 31 (26%, 95% CI 18–34) patients. In 6%, 13% and 81% of the patients the size of the residual thrombi was greater, similar to and smaller than initially diagnosed, respectively. The risk factors for residual thrombi included the thrombotic burden (OR 1.95), the alveolar to arterial difference of oxygen (OR 1.64), and the clinical antecedents of venous thromboembolic disease (OR 0.65). Conclusions: After 4.5 months of anticoagulant therapy, residual pulmonary thromboemboli persisted in 26% of the patients. The risk factors for residual thromboemboli include a greater initial thrombotic burden, a deeper gas exchange disturbation and a history of previous venous thromboembolism. © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Traditionally the study of normalized pulmonary perfusion after an acute pulmonary embolism has been evaluated in prospective studies using lung scintigraphy. These studies demonstrated that pulmonary circulation normalized in 34–43% of patients at a variable times, ranging between 3 and 6 months after the acute episode [1,2]. Currently, pulmonary circulation can be evaluated with helical computed tomography [3] (CT), and a few studies have addressed the subject of repermeabilization after an acute occlusion of the pulmonary arterial tree. In a study with 62 consecutive patients, after a mean of 11 months after the acute episode, a follow-up CT scan was performed. Complete resolution of pulmonary thrombi was found in 48% of patients [4]. In another study with 19 consecutive patients, helical CT was used to check the evolution of thrombi 6 weeks after an acute pulmonary embolism, and a resolution rate of 32% was observed [5]. A systematic analysis of studies [6] evaluating pulmonary reperfusion, some of them with scintigraphy and others with helical CT scan,
revealed that a complete resolution of pulmonary embolism is not routinely achieved, and that depending on the time of evaluation, more than 50% of patients show persistent perfusion defects in pulmonary circulation 6 months after an acute pulmonary embolism. However, the number of patients included in these studies has been small, particularly in studies using CT angiography (CTA). Patients with acute pulmonary embolism are at risk for recurrent venous thromboembolic events [7,8]. The rate of relapsing pulmonary embolism can be as high as 10% after a discontinuation of anticoagulant therapy, particularly in cases of unprovoked pulmonary embolism, and the clinical presentation can be nonspecific; thus, it can be difficult to determine whether new defects of perfusion are actually new or whether these defects are thrombi from a previous pulmonary embolism. For this reason, studying the repermeabilisation of the pulmonary arterial tree can be useful. Thus, we studied consecutive patients with a second CTA and analyzed the possible factors that are associated with the persistence of thrombi in the pulmonary arterial tree. 2. Patients and methods
⁎ Corresponding author. Tel.: + 34 848422135; fax: + 34 847 498 5460. E-mail address: [email protected] (J.L. García-Sanchotena).
To evaluate the rate of vascular repermeabilization after an acute pulmonary embolism, all consecutive patients diagnosed with acute
0953-6205/$ – see front matter © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2011.08.018
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pulmonary embolism using CTA were admitted to an area of internal medicine that included 12 beds to diagnose and treat patients. After their discharge, the patients were evaluated in the polyclinic as outpatients with a second CTA. The aim was to observe the disappearance or the persistence of thromboemboli in the pulmonary arterial tree. 2.1. Study design and methods During the index hospitalization we recorded demographic data, the delay in diagnosis of the pulmonary embolism (measured from the beginning of symptoms or signs to the unequivocal diagnosis), clinical antecedents of venous thromboembolic disease, systolic blood pressure, heart rate, shock index (the ratio of heart rate to systolic blood pressure), respiratory rate and coexistent deep venous thrombosis. Within the first 24 h of the index hospitalization we recorded the value of plasma Troponin I (Access AccuTnI, analyzer Beckman Coulter Chaska, MN 55318 USA), B-type brain natriuretic peptide (Pro-BNP) (Elecsys Roche Diagnostics, Mannheim, Germany), arterial gases and D-dimer (HemosIL, D-Dimer HS 500, Instrumentation Laboratory, CO USA). Alveolar to arterial gradient of oxygen (A-aO2) was calculated as follows: Fi O2 ðPb −47Þ−PA CO2 =R þ Fi O2 =Rð1 RÞðPa CO2 =RÞ−Pa O2 where FiO2 is the inspiratory fraction, Pb is the barometric pressure, and PA CO2 is alveolar CO2 pressure assumed to be equal to the arterial CO2 pressure (PaCO2), PaO2 is arterial oxygen and R is the respiratory exchange ratio, which was set to be 0.8. CT angiographies were made by means of a 64-detector row CT (General Electric Medical Systems, Milwaukee, WI). The protocol for multidetector-row CT consisted of evaluating of pulmonary arteries up to the subsegmental arteries after the intravenous injection of contrast material. A clot was considered present if contrast material outlined an intraluminal defect or if an artery was completely occluded. Scanning was made with 1 to 1.3 mm per sections and images were reconstructed at 0.8 mm intervals. CT angiographies were usually interpreted by radiologists who were not aware of the purpose of the study. Thrombotic burden was calculated with the formula for the CT obstruction index [9,10] applied to the initial CT angiography, which was diagnostic of pulmonary embolism. Each lung is considered to have 10 arteries, 2 in the upper lobe, 2 in the middle lobe and lingula and 5 in the lower lobe. The presence of embolus in a segmental artery is scored as 1 point, and emboli in the most proximal arterial level was scored as the value equal to the number of segmental arteries arising distally. A weight factor was assigned depending on the degree of vascular obstruction: 1 point when the thrombus was partially occlusive, and 2 points with total occlusion. Therefore, the maximal CT obstruction index is 40 points. The percentage of vascular pulmonary obstruction was calculated as follows: n · d/40 × 100 where n is the value of the proximal thrombus in the pulmonary arterial tree equal to the number of segmental branches arising distally and d is the degree of obstruction. The quantification of the degree of pulmonary obstruction was calculated by the clinicians who were caring for the patients, represented with each of the authors belonging to internal medicine. We scored 2 points for the artery to where the irrigated territory of a pulmonary infarction was seen and when contrast was not observed distal to the thrombus. The rest of the cases were scored 1 point. Every patient was treated with enoxaparin at a dose of 1 mg/kg of body weight, twice daily and then also with coumarin for an overlapping period until two INR of prothrombin N2 were observed. Some patients were considered appropriate for long-term anticoagulant therapy with low molecular weight heparin. These patients were discharged with ambulatory controls of INR of prothrombin. One patient was
treated with fibrinolysis, and no one required a cava filter. A second CTA was obtained with the specific purpose of evaluating the repermeabilisation of the pulmonary arterial tree. All patients evaluated with the second CTA were kept under anticoagulant therapy. Each patient approved and signed the informed consent for radiologic contrast administration in each exploration. In addition patients were informed of the purpose of the study and signed the informed consent form. 2.2. Statistical analysis All quantitative variables were tested for normal distribution with the Kolmogorov–Smirnov test. Qualitative variables are expressed as percentages. Continuous variables normally distributed are expressed as mean ± standard deviation [SD], and variables without normal distribution are expressed as the median and its interquartile range [IQR]. Comparisons of the means were performed using the Mann– Whitney U test for non-Gaussian variables and the t test for normally distributed variables. The chi-square test and Fisher exact test were used for proportional comparisons. The log rank test was used to compare the times when the second CTA was made in patients with persistent and resolved thrombi. The independence of the degree of occlusion of the pulmonary arterial tree, Pro BNP, Troponin I, shock index, A-aO2 and clinical history of previous venous thromboembolic disease were performed with logistic regression. We used the standardized b coefficient because of the wide variability in measurement units. All statistical tests were 2-tailed and a p value of b.05 was considered statistically significant. 3. Results Overall, during a period of 5 years from January 2006 to December 2010, 166 patients (male 85 [51%]) were admitted with a diagnosis of acute pulmonary embolism made by mean of CTA, with a median age of 74 [IQR 17] years. In 46 (28%) patients (male 25 [54%]), a second CTA could not be performed for different reasons (Table 1). The mean age of these patients was 75 [SD 12] years old, (p b .001 with respect to patients with repeated second CTA). A second CTA was obtained in 120 (72%) patients with a mean time of 4.5 [SD 2.34] months after the initial episode. The median age of the patients was 73 [IQR 17] years old, and 65 of the patients were male (53%). Because of particularities of our polyclinic, the second CTA was not made at a fixed time. Among the 19 (16%) patients for which the second CTA was performed between 2 and 3 months, 6 patients had residual thrombi. Among in 27 (22.5%) patients with scans performed between 3 and 4 months, 7 had residual thrombi. Among the 17 (14%) patients with scans between 4 and 5 months, 2 had residual thrombi. Among the 18 (15%) patients with scans between 5 and 6 months, 3 had residual thrombi. Among the 6 (5%) patients with scans between 6 and 7 months, 2 had residual thrombi. Among the 3 (2.5%) patients
Table 1 Causes of non-repeated CT angiography. Causes
N (%)
Cognitive impairment Mobility impairment Renal failure Death Living out of our community Pregnancy Rejection
5 (11) 17 (37) 4 (9) 9 (19) 6 (13) 1 (2) 4 (9)
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with scans between 7 and 8 months, no patients had residual thrombi. Among the 8 (7%) patients with scans between 8 and 12 months, 3 had persistent thrombi. The time when the second CTA was made was not different between patients with residual or clearance of thrombi (Fig. 1). The initial pulmonary embolism was caused by an identified event in 43 (36%) patients and was unprovoked in 77 (64%) patients. The provoking events were as follow: orthopedic surgery, 3; transitory immobilization by joint or muscular strains and fractures, 15; estrogens, 6; long haul travel, 2; recent hospitalization due to medical causes, 5; and usual reduced mobility because of multifactor causes, 12 patients. On admission, 38 (32%) patients showed signs of deep venous thrombosis in the lower limbs, although angiographic examination of the limbs was not routinely made since patients already had a diagnosis of venous thromboembolic disease, and the therapy would not be substantially modified. Thirty (25%) patients had clinical antecedents of venous thromboembolic disease, 14 (47%) as isolated deep venous thrombosis and 16 (53%) as pulmonary embolism. Pulmonary embolism affected the main pulmonary arteries in 57 (47.5%) patients and it affected segmental or sub-segmental arteries in 63 (52.5%) patients. The median thrombotic burden was 32.5 [IQR 30] per patient. Complete clearance of thrombi occurred in 89 (74%, 95%CI 65–81) patients and persistent thrombi were observed in 31 (26%, 95%CI 18– 34) patients. Residual thrombi were greater than initially in 2 (6%), similar in 4 (13%) and smaller in 25 (81%) patients. The main pulmonary arteries remained with thrombotic material in 5 (16%) patients (Fig. 2). When the second CTA was performed, 109 (91%) patients followed treatment with vitamin K antagonists and 11 (9%) patients followed treatment with low molecular weight heparin. Table 2 presents the data for several parameters measured from the initial episode of pulmonary embolism, separated into those patients with complete resolution of the thrombi and those who had residual thrombus. The estimation of thrombi burden, plasma levels of Pro-BNP and Troponin I, the A-aO2 and shock index, all of which were measured in initial episode, were examined using bivariant statistical analysis and where shown to be different between those patients with complete clearance of pulmonary thrombi and those patients with residual thrombi in their pulmonary circulation. Table 3 presents other clinical data and their relationship with resolution or persistent residual thrombi, all of which were evaluated during the initial episode. Thus, thrombotic material seen in the main pulmonary arteries and a history of previous venous thromboembolic disease were associated with residual thrombi in the second CTA. In addition, patients with complete resolution were more frequently in NYHA class I than patients in whom residual thrombi were seen. Using an analysis of logistic regression (Table 4), only the thrombotic burden estimated in the initial pulmonary embolism episode,
cumulative probability %
Log rank of time of realization of 2nd CT angiography 120
P=.12
100 clearence of thrombi
80 60
persistence of thrombi
40 20 0 2
3
4
5
6
7
8
9 10 12
Months Fig. 1. Log rank of time of realization of 2nd CT angiography.
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a greater A-aO2 and a history of previous venous thromboembolic disease were demonstrated to be independent predictors of residual thrombi in pulmonary arteries seen in second CTA, which was performed 4 months after the initial episode. Although shock index may seem to be an independent predictor of persistence of residual thrombi, the wide confidence interval suggests that it is not independent factor. 4. Discussion The development of multidetector CT [3] has enabled the facile visualization of pulmonary arteries up to subsegmental levels. An additional advantage is that it allows the evaluation of other intrathoracic structures, the existence of lung infarction, the relationship of right to left ventricle as a sign of right ventricular overload [10] and the coexistence of other pathological processes with relatively few deleterious effects. Studies made with lung scintigraphy have demonstrated that patients with persistent perfusion defects could be at risk of thromboembolic pulmonary hypertension [11]. There are few studies made with CTA about the fate of pulmonary thrombi after an acute pulmonary embolism has occurred, but the rate of persistent occlusion could be high. Despite some suggestion of the development of thromboembolic pulmonary arterial hypertension in cases of persistent endovascular abnormalities, whether pulmonary hypertension is more frequent or not is predominantly unknown. In patients who underwent pulmonary thromboendarterectomy [12], the absence of central thrombi in the CTA was a risk factor for inadequate hemodynamic improvement. However, the importance of persistence or resolution of pulmonary thrombi has to be determined in future studies. On the other hand, since the prevalence of pulmonary embolism is growing as the average age of patients increases, and because elderly patients often are affected with diseases with dyspnea as its main symptom [13], determining whether a new pulmonary embolism has occurred has important implications for the therapy. In our patients, complete resolution of occlusion in the pulmonary arterial tree measured at 4.5 months after the acute episode, was achieved in 74% of patients. A second CTA was made while patients were undergoing treatment with anticoagulant therapy, most of them with vitamin K antagonists. We consider this fact important because it minimizes the possibility that unnoticed pulmonary embolism has occurred and because it confers a credible rate of 26% persistent occlusion. It seems appropriate to think that the time when the pulmonary arterial tree is evaluated after the initial episode could influence the rate of disappearance of residual thrombi. However, in our patients, the persistence of residual thrombi was independent of the time when the second CTA was made, since the analysis of curves of time was similar between both groups. The age, gender or delay in diagnosis did not influence the persistence of thrombi. The initial thrombotic load was greater in patients with residual thrombi than in patients who cleared them. This factor is an important and independent risk factor for persistence of thrombotic material into pulmonary circulation. Those patients who achieved the complete resolution of pulmonary thrombi had a better functional status and it is more probable that they had a lower degree of dyspnea as measured with the NYHA class. Several biomarkers of ventricular dysfunction are prognostically useful for the setting of acute pulmonary embolism. The measure of plasma ProBNP levels during hospitalization for pulmonary embolism has proved to be a predictor of acute deterioration of the clinical condition, the burden of pulmonary embolism and early death [14–16]. However, the evaluation of different sorts of troponin as a biomarker of risk gave contradictory results, being useful in some studies [17] but not in others [18,19]. During the initial episode of hospitalization,
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74%
Greater occlusion Similar occlusion Smaller occlusion 3% 2%
21%
Complete clearance
Fig. 2. Percentage and size of residual pulmonary thrombi. Greater, similar and smaller occlusion mean bigger, same and lesser size of pulmonary thrombi respectively as seen in second computed tomography.
patients in the present study with residual thrombi had higher levels of ProBNP and Troponin I, greater changes in hemodynamic status and deeper alterations in gas exchange than patients who cleared the thrombi. Nevertheless, ProBNP or Troponin I were not independent factors in explaining the residual thrombi; instead, they were associated with acute strain to the right ventricle as an index of a greater load of thrombotic material. The percentage of INR of prothrombin higher than 2 was similar between both groups of patients, suggesting that ongoing activation of coagulation system does not play a central role in the persistence of thrombotic material. A defective fibrinolytic system of plasminogen–plasmin could be implicated in the persistence of thrombi; however we did not explore this circumstance. Future directions to investigate could include the possible connection between fibrinolysis and inflammation and the role of plasminogen activator inhibitor 1 and 2 in the persistence of residual thrombi [20]. The concept of organ-specific hemostasis [21] as a unique interplay between hemostatic and vascular processes has recently gained importance. In studies of mouse brains diseased by thromboembolism, a phenomenon of extravasation of the emboli has been shown to occur 2 h after embolisation. Although it is not well understood yet, the clearance process depends on the size and quantity of embolised objects. If a similar phenomenon occurs in pulmonary circulation is at present unknown. Hypoxemia is associated with the slowing-down of pulmonary circulation and arterial pulmonary hypertension [22]. This event
Table 2 Results of biochemical, gas exchange and hemodynamic parameters measured on admission of pulmonary embolism and their relationship with resolution or persistence.
Age (years) Gender (F/M) Thrombotic burden (%) Months of second CTA Pro-BNP (ng/L) Troponin I (μg/L) D-dimer (ng/ml) Delay in diagnosis (days) % of INR of Prothrombin ≥ 2 PaO2 mm Hg PaCO2 mm Hg A-a O2 mm Hg SBP mm Hg Heart rate Shock index Respiratory rate
Complete resolution
Residual thrombi
p
73 [IQR17] 41/48 27 [IQR 32.5] 4.7 [SD 2.30] 446.5 [IQR 1806] 0.03 [IQR 0.049] 2413.8 [SD 1577] 6 [IQR 8] 78 [IQR 3.34] 64.68 [SD 12.19] 36.13 [SD 6.45] 40.17 [SD 12.67] 131.96 [SD 19.08] 87.04 [SD19.03] 0.67 [SD 0.19] 20.96 [SD 6.52]
74 [IQR 24] 15/16 50 [IQR 25] 3.93 [SD2.3] 1069 [IQR 2737] 0.065 [IQR 0.19] 2354.9 [SD1795] 7 [IQR 12] 75 [IQR 37] 62 [SD 11.63] 33.19 [SD 4.56] 46.66 [SD 14.59] 125.16 [SD18.57] 95.06 [SD 20.16] 0.77 [SD 0.20] 21.81 [SD7.46]
.25 .29 .0013 .23 .015 .00012 .73 .11 .20 .055 .010 .02 .08 .04 .019 .44
M: male. F: female. CTA: computed tomography angiography. Pro-BNP: B-type brain natriuretic peptide. INR: international normalized ratio. A-aO2: alveolar to arterial difference of oxygen. SBP: systolic blood pressure. SD: Standard deviation. IQL: Interquartile range.
could trigger the molecular and cellular mechanism implicated in pulmonary hypertension favoring the persistence of thrombi. In addition, there is evidence of the interplay between hypoxia and inflammation [23] with hypoxia triggering an increase in proinflammatory cytokines and fluid leakage from capillary. This fact could additionally operate in persistent thrombosis. In our study patients with deeper gas exchange alterations had a higher rate of residual thrombi in pulmonary circulation. Thus, a greater alveolar to arterial difference in oxygen, through the process discussed above, may be considered an independent risk factor of residual thrombi. Another independent factor for the persistence of residual thrombi was the antecedent of venous thromboembolic disease. A previous venous thromboembolism is considered the most important risk factor for predicting recurrence of the condition, particularly if the previous episode has been unprovoked or the patient has cancer. But whether the changes in vascular endothelium caused by a thromboembolic phenomenon predispose a patient to a persistence of thrombi is at present essentially unknown. Limitations to this report include the fact that the samples were drawn from a single center with a limited number of patients. In addition, a second CTA was not performed in 28% of patients for various reasons. It is unknown whether a greater sample would have yielded different results in the prevalence of residual pulmonary thromboemboli; however, this should be evaluated in future studies with higher numbers of patients. Another limitation of this study is that the second CTA was not obtained at a fixed time after the acute pulmonary embolism, though the time of achievement did not show differences between the clearance and the persistence of thromboemboli. In our study, a cause of concern was the CTA related X-ray radiation exposure. CT related X-ray doses are large enough to slightly increase cancer risk, particularly in children [24]. Breasts, particularly those that are fattier, might accumulate enough radiation to have an
Table 3 Data related to resolution of thrombi according to trigger factors, affectation of main pulmonary arteries, the existence of previous venous thromboembolic disease and degree of dyspnea evaluated with class of NYHA.
Unprovoked PE DVT evident Thrombi in main arteries Previous VTED NYHA class I NYHA class II NYHA class III or IV
Complete resolution
Residual thrombi
95% CI
p
56 (73%) 59 (66%) 35 (39%) 17 (19%) 64 (72%) 20 (22%) 5 (6%)
21 (29%) 22 (71%) 22 (71%) 13 (42%) 14 (45%) 13(42%) 4 (13%)
0.28 to 0.54 − 0.25 to 0.16 − 0.52 to−0.10 − 0.44 to − 0.01 0.04–0.48 − 0.41 to 0.02 − 0.22 to 0.07
.001 .62 .0010 0.019 .008 0.04 .25
PE: Pulmonary embolism. DVT: Deep venous thrombosis. VTED: Venous thromboembolic disease. NYHA: New York Heart Association for graduation of dyspnea. CI: Confidence interval.
J.L. Alonso-Martínez et al. / European Journal of Internal Medicine 23 (2012) 379–383 Table 4 Logistic regression for evaluation of independence of risk factors predicting residual pulmonary thrombi.
Thrombotic burden (%) Pro BNP (ng/L) Troponin I (μg/L) A-aO2 (mm Hg) Shock Index (HR/SBP ∙ 100) Previous VTED
β
p
Odds ratio (95%CI)
0.67 0.29 0.08 0.49 0.47 − 0.42
.002 0.16 0.68 0.03 0.02 0.03
1.95 1.34 1.08 1.64 1.60 0.65
(1.01–1.06) (0.99–1.002) (0.43–3.51) (1.003–1.07) (1.36–76.28) (0.15–0.91)
Pro-BNP: B-type brain natriuretic peptide. A-aO2: alveolar to arterial difference of oxygen. VTED: venous thromboembolic disease. HR: heart rate, SBP: systolic blood pressure.
increased risk of future breast cancer [25,26]. Nevertheless, the patients of this study are mostly elderly and very elderly patients; thus, their life expectancy may not be long enough so to develop radiation related cancer. On the other hand, taking into account the high accuracy of CTA in the diagnosis of pulmonary embolism, and the frequent ambiguity of ventilation–perfusion lung scan results, which also delivers radiation, we think that the benefits of knowing the pulmonary thromboembolic fate may be greater than the radiation related risks. In conclusion, after acute pulmonary thromboembolism, emboli remain lodged in pulmonary circulation in a quarter of patients. Predicting factors of persistent thromboemboli were a greater initial greater thrombotic burden, a deeper gas exchange alteration and previous episodes of venous thromboembolism. Learning points • In the setting of acute pulmonary embolism, the initial thrombotic burden, the deeper gas exchange alteration and a previous history of venous thromboembolism predict the persistence of thrombotic material in pulmonary arteries. • Mapping pulmonary arteries is important in order to determine the etiology of new episodes of dyspnea in patients with clinical antecedents of pulmonary embolism. • The sort and the length of antithrombotic therapy could be influenced by the persistence of pulmonary thrombi. Whether the residual thrombosis has implication in pulmonary hypertension or not remain to be explored. Conflict of interest This manuscript is the result of independent investigation and authors has not any conflict of interest. Acknowledgment We thank Professor Miguel Andériz for his invaluable advice and review of statistical methods.
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