Introduction: In patients presenting with pulmonary embolism (PE), a concomitant deep venous thrombosis (DVT) is relatively common even without clinical symptoms of DVT.

Objectives: To determine the percentage of PE patients with concomitant DVT and to identify risk factors that increases the likelihood of (asymptomatic) DVT.

Patients and methods: Patients with acute PE at Rijnstate Hospital (Arnhem, the Netherlands) were retrospectively analysed after evaluation with whole leg duplex ultrasound. Patients with confirmed DVT were treated with compression therapy and compression stockings. To determine risk factors for concomitant DVT in PE patients, we performed a multivariate analysis. Results: An ultrasound was performed in 505 patients. Concomitant DVT was diagnosed in 299 patients (59.2%), of which 195 (65.2%) had limited DVT and 101 (33.8%) had extended DVT. Clinical complaints and edema were present in 40.5% and 40.4% of patients with DVT respectively. DVT was significantly more often diagnosed in patients with central PE and clinical manifestations (92.9%; 95%-confidence interval 84.1-97.6). Clinical complaints (multivariate odds ratio 12.3) and central PE (multivariate odds ratio 8.0) were found to be the strongest predicting factors for concomitant DVT in patients with PE. Adversely, no characteristics could be identified that could safely exclude DVT.

Conclusion: Concomitant DVT is common in PE patients, even without the presence of clinical symptoms. Since DVT cannot be excluded based on clinical characteristics alone, a duplex ultrasound should be performed in all PE patients to ensure adequate DVT treatment and to prevent long-term complications such as PTS.

Essentials

• Pulmonary embolism (PE) patients have a high chance of concomitant deep venous thrombosis (DVT).

• The incidence of, clinical manifestations of and risk factors for DVT were determined in PE patients.

• DVT was seen more often in patients with central PE and clinical manifestations.

• Risk factors that can safely exclude DVT could not be identified.

•    Duplex ultrasonography
•    Post-thrombotic syndrome
•    Pulmonary embolism
•    Risk factors
•    Venous thrombosis

Visch MB, Valke LLFG, Hazelaar G, Hovens MMC (2021) Patients with Pulmonary Embolism: Clinical Examination Is Insufficient to Rule Out Deep Venous Thrombosis. Ann Vasc Med Res 8(3): 1132.

Deep venous thrombosis (DVT) and pulmonary embolism (PE) represent two clinical characteristics of venous thromboembolism (VTE). VTE is a major global burden since it is the third leading vascular disease after acute myocardial infarction and stroke [1,2]. Moreover, the incidence of VTE is steadily increasing due to population ageing and the increasing occurrence of comorbidities associated with VTE, such as cancer, obesity and heart failure.

VTE is associated with high rates of morbidity and mortality. Long-term VTE is a chronic disease with recurrence in 30% of patients within 10 years [3,4]. PE is associated with chronic thromboembolic pulmonary hypertension, which occurs in 0.1- 4.0% of PE patients [5]. Post-thrombotic syndrome (PTS), which develops in 20-50% of patients with DVT, further complicates DVT [6]. PTS has a significant impact on a person’s quality of life and healthcare resources [7]. Long-term sequelae are often underestimated in the acute phase of VTE. Pulmonary embolism medical care in particular is focused on survival rather than the recurrence of disease and complications. Several studies have shown that a significant percentage of patients presenting with PE have concomitant DVT, with percentages ranging between 45.4 and 75.5, of which most patients have proximal DVT [7-11]. A recent meta-analysis of 7,868 patients showed that concomitant DVT is found in 56% of patients with PE [12], reflecting the fact that DVT of the leg is the most important source of the pulmonary embolism [4]. Although, in some cases a thrombosis in the leg cannot be demonstrated. A thrombus originating from another place such as the pelvic region may otherwise be the cause. Pelvic thrombosis can be missed because the pelvic region is often not evaluated in duplex ultrasound imaging when screening for DVT. Even though evidence shows a high percentage of concomitant DVT in PE patients, performing an ultrasound is not advised in guidelines on routine investigations [13]. The primary reason for this might be because the diagnosis of DVT does not have the direct consequence of administering therapy with anticoagulants. DVT, however, is a an independent risk factor for PE mortality rates and the burden of long term complication PTS still seems to be underestimated. Besides, the recognition of DVT is limited in the acute phase due to its asymptomatic presentation and the more acute and distracting symptoms of PE. Since no compression therapy is started without a diagnosis of DVT, patients presenting with PE that have concomitant DVT are often undertreated. Although recent studies have shown different results, proper compression therapy in the initial phase of DVT is still thought to be the cornerstone of treatment for DVT and the prevention of PTS [14]. There is no consensus on the recommended duration of compression therapy. Currently, at least half a year or longer is advised. Several studies that do not support the importance of compression therapy use either the Villalta score or Ginsberg score to indicate the presence of PTS, while objectivation by ultrasound is often not used [15,16].

The goal of this study is to identify the incidence of DVT in patients with PE in a Dutch regional hospital and to evaluate whether the location of DVT, the presence of clinical symptoms and the extent of thrombosis are related to the type of PE. Moreover, we investigated whether clinical symptoms and patient characteristics could predict the presence of DVT in patients with PE.

During the study period, between January 2012 and January 2016, all patients with proven pulmonary embolism (PE) at Rijnstate Hospital (Arnhem, the Netherlands) were referred for duplex ultrasound of both legs as a part of the local PE protocol. Pulmonary embolism was diagnosed using computed tomography angiography of the pulmonary arteries (Philips CT scan ICT 128 and Brilliance 40) and is defined as a filling defect in one or multiple pulmonary arteries. Trained chest radiologists judged the extent of PE and assigned each incidence to one of four categories. Central PE is defined as an embolism in the central, right or left main pulmonary artery. Lobular PE is defined as a PE in the interlobar or lobar pulmonary artery. Segmental PE is defined as a PE in a segmental artery, and sub-segmental PE is defined as a PE in a sub-segmental or smaller artery. The radiologists were unaware of any DVT diagnosis.

All patients who underwent a whole leg (no pelvic) ultrasound within 72 hours after receiving the diagnosis of PE (either during clinical observation for PE or in the outpatient setting) were included in this study. Whole leg ultrasounds with colour flow duplex ultrasound imaging (Philips IU22) were performed while a patient was in a supine position and done by trained vascular ultrasound technicians.

The vascular technicians were aware of the PE diagnosis. We defined DVT as the non-compressibility of the veins in a transverse mode and consider that they are generated by the presence of new clots. Based on the ultrasound imaging results, a patient’s DVT was classified based on the location of the thrombus and the extent of thrombosis. The classification consists of 5 categories that range from 1 to 5, see Figure 1 [17].

All patients with proven VTE were treated with anticoagulant therapy according to local guidelines (mostly low-molecular weight heparin (LMWH) and vitamin-K antagonists) as well as additional bandaging and/or elastic stockings. Patients with DVT and edema were treated by dermatologists, conform hospital protocol.

Patient demographics and clinical characteristics at the moment of presentation were collected retrospectively. Variables that were collected included: gender, age, survival, cause of death (if applicable), signs and symptoms of DVT at presentation, such as complaints of pain and edema, localization of the PE and the occurrence of a follow-up ultrasound (see below). Edema was defined as the objective swelling of the leg as recorded by the treating physician and complaints such as pain or muscle cramps were considered clinical symptoms. Symptomatic DVT was defined as subjective complaints of the ipsilateral leg and/or objective edema of the leg. Distal DVT was defined as occlusion of only 1 or 2 distal segments, while proximal DVT was defined as 3 or more occluded segments. Patients with an old DVT were registered as non-DVT.

As the standard use of duplex ultrasound imaging was included in the local PE protocol and clinical characteristics were obtained retrospectively, patients were not required to sign informed consent. All patients were followed for at least one year after their diagnosis of PE. In a group of patients, selected by their treating dermatologist, ultrasound imaging was also performed one year after their PE diagnosis to evaluate post-thrombotic abnormalities.

Statistical analysis

Demographics and clinical characteristics are presented using descriptive statistics. Continuous data are presented as mean ± standard deviation (SD). Categorical data are presented as frequencies and percentages. Differences between groups were tested using the student’s t-test or the Pearson chi-squared test. To correlate risk factors with outcomes and to determine the odds for concomitant DVT in PE patients, a multivariate logistic regression analysis was performed. Two-sided p-values < 0.05 were considered statistically significant. All analyses were performed with the SPSS IBM Software version 25.0.

During the study period, a total number of 601 patients were identified with CT findings of a pulmonary embolism. In 505 patients (84%), ultrasound imaging was performed. Ultrasound imaging was primarily performed in the inpatient clinic setting and otherwise in the outpatient clinic setting if a patient had a shorter or no clinical admission. In patients that were very ill and not able to stand in an upright position, no ultrasound was performed. The overall rate of DVT in these 505 patients with PE was 299 (59.2%). A flow diagram of the patients included in the study is provided in Figure 2. DVT was found 156 times in the left leg, 119 times in right leg. In 24 patients both legs were affected. The demographics and clinical characteristics of patients are shown in Table 1. By the time of the follow-up, 60 patients had died. The most common cause of death was the progression of malignancy. Concomitant DVT was found in 37 (61.7%) patients that had died and 262 (58.9%) patients that survived until the end of the follow-up. Distal DVT was seen in 195 (65.2%) patients, while proximal DVT was diagnosed in 101 (33.8%) patients. In 3 (1%) patients the number of occluded segments was unknown because the ultrasound was performed in another hospital.

Clinical manifestations and DVT

Complaints of pain and edema occurred significantly more often in patients with DVT compared with patients without DVT (Table 1).

No clinical manifestations of DVT were found in 55.9% of the patients with a distal thrombosis and in 27.6% of patients with a proximal thrombosis. Clinical complaints or edema was seen only in 28.5% of the patients with an extensive DVT, compared with 25.5% of the patients with a limited DVT.

The combination of experiencing complaints and edema was seen in 43.9% of patients with proximal DVT and 18.6% of patients with distal DVT. Patients with a central PE were the most likely to have a DVT (119/150; 79.3%). The odds of concomitant DVT diminish to a chance of 28.1% in patients with a subsegmental PE. Patients with central PE and clinical manifestations of DVT (edema and clinical complaints) were significantly more often diagnosed with DVT (92.9%; 95%-confidence interval 84.1-97.6) compared with patients without clinical manifestations and non-central PE (37.6%; 95%- confidence interval 30.6%- 44.9%). Irrespective of the presence of complaints, DVT was present in 79.3% of patients with a central PE. Table 2 shows the risk factors for the presence of concomitant DVT in patients with PE.

The strongest predictor, with a multivariate odds ratio (OR) of 12.3 (p < 0.001), is the presence of clinical complaints. Moreover, central PE was associated with a higher chance of concomitant DVT (OR 8.0). In contrast, there was no group of patients in which clinical manifestations and/or characteristics of PE could exclude DVT. Therefore, there is no group of patients with PE in which ultrasound screening can be safely omitted from a clinical work-up. Follow-up ultrasound In 106 patients, which were selected by their treating dermatologist, a follow-up ultrasound was performed between 12-24 months after PE presentation. The main reason for performing a follow-up ultrasound was to obtain information on post-thrombotic abnormalities after the discontinuation of anticoagulant therapy as a baseline situation in the case of recurrent thrombosis. Ultrasound screening showed that most patients suffered from persisting thrombotic abnormalities despite earlier anticoagulant therapy, bandaging and use of compressive stockings. In only 32 patients (30.2%) no postthrombotic abnormalities were seen. 66 patients (62.3%) had mild thrombotic abnormalities. Eight patients developed severe PTS (7.5%), from which six had extended thrombotic lesions and two patients had venous reflux. In the patients with severe PTS, the number of affected segments was three in six patients, five in one patient and two in one patient. Of the eight patients with severe PTS, six patients (75%) had no complaints or clinical abnormalities of the legs when duplex was performed at the presentation of PE, and only two patients had clinical manifestations of DVT at the time, as shown in Table 2. No Villalta or Ginsberg scores were used.

The goal of this study was to identify the percentage of PE patients with concomitant DVT. DVT might be a risk factor for fatal prognosis of PE; it does not change management of acute PE, but can be a life time burden for patients. Therefore, we were interested whether clinical characteristics have predictive value for the presence of DVT in PE patients and if the extent of a DVT is associated with the localization of PE.

In this study, 59% of patients with PE had a concomitant DVT (38.6% distal, 20% proximal and 0.6% unknown) that was often asymptomatic. This incidence of DVT is comparable to results from other studies [9-12]. Most of these studies show more often proximal DVT, while in our study a distal DVT was seen more often than a proximal DVT. A reason for the high number of distal DVT’s might be a result that in several studies US was only performed in proximal part of the legs.

A recent meta-analysis of the 7,868 patients showed concomitant DVT in 56% of the patients [12]. The incidence of concomitant DVT in our study might have been higher if all patients were screened with ultrasound imaging. Also, a negative ultrasound of the lower limb does not exclude the incidence of DVT. In this case, a thrombosis of the pelvic vein can be considered [18]. Further investigations with CT venography might have obtained a higher incidence of DVT. As this is an invasive procedure and is not a part of our regular prototocol this investigation was not performed.

As shown before, the presence of symptoms predicts the presence of DVT.[11] This was true for only half of the patients. The absence of clinical manifestations on the other hand does not rule out DVT since a large proportion of patients (40.8%) did not have edema or clinical complaints. Patients with a proximal DVT had a higher chance of having clinical manifestations of DVT.

However, 25% of the patients with a proximal thrombosis did not have any clinical manifestations. Furthermore, in line with the available literature, 56% of the patients with a confirmed distal DVT in this study did not have any clinical manifestations. Most importantly, of the patients with severe signs of PTS after 12 to 24 months of follow-up, 75% did not have clinical manifestations of DVT at presentation. Moreover, central and lobar PE is most likely to be associated with the occurrence of concomitant DVT, especially when combined with clinical manifestations of DVT. However, the absence of one of these influencing factors cannot rule out the presence of concomitant DVT. Therefore, clinical manifestations alone are insufficient to exclude concomitant DVT in PE patients.

A late complication of DVT is PTS, which develops in 20-50% of symptomatic DVT patients.[6] Both a more extended DVT (i.e. more affected segments) and proximal located DVT results in an increased risk of developing PTS. PTS is a debilitating syndrome that has a significant impact on a person’s quality of life. It is defined as a chronic venous insufficiency of the lower extremity previously affected by one or more DVTs [7,19]. There is no gold standard for the diagnosis of PTS. It can be diagnosed by identifying ultrasound abnormalities (insufficiency or obstruction) and/or clinical symptoms using the Villalta score or Ginsberg criteria [20]. PTS causes increased medical costs [12], especially since it is associated with a higher prevalence of venous leg ulcers in 1-5% of the patients with PTS [21]. The importance and especially the duration of compression therapy for the treatment of DVT are debated, but compression therapy still seems to be the most important factor in the risk reduction of PTS [14]. If patients with a PE are not screened for a concomitant DVT, they may have a higher risk of developing PTS as a longterm complication due to the lack of appropriate treatment for DVT. Almost all patients with severe PTS in our study did not have clinical symptoms at presentation, although most of them had extended thrombosis. Even in the case of asymptomatic DVT, patients are at risk for developing PTS. This relation is illustrated by the observation that after joint arthroplasty, patients have a higher risk to develop PTS after the incidence of an asymptomatic DVT with a relative risk of 1.58 [22].

Compression stockings are usually prescribed for a period of one or two years [14]. Recently, a study that was performed by Ten Cate et al., showed that the cumulative incidence of PTS for patients with DVT was highest within the first six months after presentation [16]. The group of patients that stopped wearing compression stockings after six months showed an increase compared to the group that used compression stockings for 24 months, suggesting that duration of compression therapy is based on individual criteria and should be tailor made. For all patients with DVT, immediate compression is recommended in order to reduce the risk of PTS and to relieve symptomatic swelling [16]. All our patients were prescribed compression stockings for two years. For the group of 106 patients in which an ultrasound was performed after 12-24 months, most ultrasounds (69.8%) still showed post-thrombotic abnormalities. Most of these abnormalities were obstruction and fibrotic changes. Since we did not use the Villalta score at that time, we are unable to state the incidence of PTS in our population. In our opinion the use of a clinical score in combination with ultrasound imaging is the best way to screen for the presence of PTS. This screening method would be an interesting topic for further research. Unmentioned until now is the increased risk of recurrent DVT for patients with symptomatic DVT [23]. If patients with PE are not aware that they have a concomitant DVT, they (or their doctors) may be less aware of recurrent DVT, which can cause a more extended DVT and an increased risk of PTS. Also, if a concomitant DVT is not diagnosed at the presentation of PE, a possible recurrent DVT is harder to diagnose because the distinction of a fresh thrombosis from a residual thrombotic abnormality can be difficult [24]. Furthermore, a recent meta-analysis indicated that patients with PE and concomitant DVT have a higher risk of death compared to patients without concomitant DVT [12]. In our study, no higher risk of death was seen within the group of patients with concomitant DVT.

Taken together, we strongly recommend screening all patients with PE for DVT with duplex ultrasound. Ultrasound imaging should not only be performed on the leg but ideally of the pelvic region as well. If no DVT can be objectivated, it remains unclear what the cause of PE may be.

This study has several limitations. First, adherence to a protocol on how to perform an ultrasound in all patients with PE was not followed by clinicians in all cases (16%). This inconsistency could have influenced the results of this study as patients with a lower or higher risk for concomitant DVT were possibly missed. In our study, ultrasound imaging was often not performed on hospitalized or very ill patients in order to diminish the diagnostic burden for these patients. One reason that these patients are more affected by PE is that they have a higher chance of central PE. Furthermore, our results show that they more often have concomitant DVT.

Second, clinical characteristics were recorded retrospectively. Since we were only interested in characteristics that were recorded in a standardized way, this procedure did not influence our results, except that we did not identify the number of patients with cancer systematically. We used whole leg ultrasound imaging to show the presence of DVT. The absolute number of DVT cannot be determined as iliac thrombosis is not considered. In future research, further techniques like CT venography may be considered if ultrasound results are negative so that the definitive incidence of concomitant DVT in PE patients can be determined. Patients that undergo follow-up ultrasounds were selected by their treating physician after the discontinuation of anticoagulation. Therefore, we are unable to reliably estimate the prevalence of lasting thrombotic abnormalities after DVT. Lastly, during follow-up we did not use the Villalta score systematically. Hence, we were unable to make any statements about the incidence of PTS after asymptomatic DVT.

In the future, new studies should investigate the incidence of concomitant DVT and whether compression therapy for the purpose of reducing the burden of PTS is a necessary treatment in all PE patients. A systematic evaluation involving a follow-up that includes ultrasound imaging and Villalta score of all patients should be performed to estimate the real incidence of PTS after PE.

This study shows that even without the presence of clinical symptoms, a high percentage of patients with PE has concomitant DVT. This finding highlights the importance of performing ultrasound screening in all patients with PE for DVT. Screening for DVT is necessary to optimize the treatment of DVT since compression therapy is important in preventing PTS. Moreover, screening is important for risk estimation for other complications in patients with PE, which gives more insight into the chances of and a possible diagnosis of DVT recurrences. In our study, severe PTS was mainly seen in patients without symptoms or leg complaints. Since no good clinical predictors are available to exclude the presence of DVT, universal ultrasound screening among PE patients should be performed to identify more asymptomatic DVT patients.

1. Raskob GE, Angchaisuksiri P, Blanco AN, H Buller, A Gallus, B J Hunt, et al. Thrombosis: a major contributor to global disease burden. Arterioscler Thromb Vasc Biol. 2014; 34: 2363-2371.

2. Di Nisio M, van Es N, Buller HR. Deep vein thrombosis and pulmonary embolism. Lancet. 2016; 388: 3060-3073.

3. Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol. 2015; 12: 464-474.

4. Kearon C. Natural history of venous thromboembolism. Circulation. 2003; 107: I22-30.

5. Hoeper MM, Madani MM, Nakanishi N, Meyer B, Cebotari S, Rubin LJ. Chronic thromboembolic pulmonary hypertension. Lancet Respir Med. 2014; 2: 573-582.

6. Kahn SR, Comerota AJ, Cushman M, Natalie S Evans, Jeffrey S Ginsberg, Neil A Goldenberg, et al. The postthrombotic syndrome: evidencebased prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation. 2014; 130: 1636-1661.

7. Bergqvist D, Jendteg S, Johansen L, Persson U, Odegaard K. Cost of long-term complications of deep venous thrombosis of the lower extremities: an analysis of a defined patient population in Sweden. Ann Intern Med. 1997; 126: 454-457.

8. Perrier A, Bounameaux H. Cost-effective diagnosis of deep vein thrombosis and pulmonary embolism. Thromb Haemost. 2001; 86: 475-487.

9. Lee JS, Moon T, Kim TH, Se Young Kim, Jun Young Choi, Kyung Bok Lee, et al. Deep Vein Thrombosis in Patients with Pulmonary Embolism: Prevalance, Clinical Significance and Outcome. Vasc Specialist Int. 2016; 32: 166-174.

10. Girard P, Musset D, Parent F, Maitre S, Phlippoteau C, Simonneau G. High prevalence of detectable deep venous thrombosis in patients with acute pulmonary embolism. Chest. 1999; 116: 903-908.

11. Pomero F, Brignone C, Serraino C, Sergio Panzone, Christian Bracco, Elena Migliore, et al. Venous lower-limb evaluation in patients with acute pulmonary embolism. South Med J. 2011; 104: 405-411.

12. Becattini C, Cohen AT, Agnelli G, et al. Risk Stratification of Patients With Acute Symptomatic Pulmonary Embolism Based on Presence or Absence of Lower Extremity DVT: Systematic Review and Metaanalysis. Chest. 2016; 149: 192-200.

13. Kearon C, Akl EA, Ornelas J, Allen Blaivas, David Jimenez, Henri Bounameaux, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016; 149: 315-352.

14. Brandjes DP, Buller HR, Heijboer H, M V Huisman, M de Rijk, H Jagt, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet. 1997; 349: 759- 762.

15. Kahn SR, Shapiro S, Wells PS, Marc A Rodger, Michael J Kovacs, David R Anderson, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014; 383: 880-888.

16. Ten Cate-Hoek AJ, Amin EE, Bouman AC, Karina Meijer, Lidwine W Tick, Saskia Middeldorp, et al. Individualised versus standard duration of elastic compression therapy for prevention of post-thrombotic syndrome (IDEAL DVT): a multicentre, randomised, single-blind, allocation-concealed, non-inferiority trial. Lancet Haematol. 2018; 5: e25-e33.

17. De Maeseneer MG, Bochanen N, van Rooijen G, Neglen P. Analysis of 1,338 Patients with Acute Lower Limb Deep Venous Thrombosis (DVT) Supports the Inadequacy of the Term “Proximal DVT”. Eur J Vasc Endovasc Surg. 2016; 51: 415-420.

18. Gary T, Steidl K, Belaj K, F Hafner, H Froehlich, H Deutschmann, et al. Unusual deep vein thrombosis sites: magnetic resonance venography in patients with negative compression ultrasound and symptomatic pulmonary embolism. Phlebology. 2014; 29: 25-29.

19. Aschwanden M, Jeanneret C, Koller MT, Thalhammer C, Bucher HC, Jaeger KA. Effect of prolonged treatment with compression stockings to prevent post-thrombotic sequelae: a randomized controlled trial. J Vasc Surg. 2008; 47: 1015-1021.

20. Villalta S BP, Piccioli A, Lensing AW, Prins MH, Prandoni P. Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome (abstract). Haemostasis. 2014; 24: 158a.

21. Pengo V, Lensing AW, Prins MH, Antonio Marchiori, Bruce L Davidson, Francesca Tiozzo, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004; 350: 2257-2264.

22. Wille-Jorgensen P, Jorgensen LN, Crawford M. Asymptomatic postoperative deep vein thrombosis and the development of postthrombotic syndrome. A systematic review and meta-analysis. Thromb Haemost. 2005; 93: 236-241.

23. Beyth RJ, Cohen AM, Landefeld CS. Long-term outcomes of deep-vein thrombosis. Arch Intern Med. 1995; 155: 1031-1037.

24. Le Gal G, Kovacs MJ, Carrier M, K Do, SR Kahn, PS Wells, et al. Validation of a diagnostic approach to exclude recurrent venous thromboembolism. J Thromb Haemost. 2009; 7: 752-759.