• clinical decision rule;
  • D-dimer;
  • deep vein thrombosis;
  • diagnostic management;
  • imaging;
  • pulmonary embolism;
  • venous thromboembolism


  1. Top of page
  2. Summary
  3. Clinical probability assessment and D-dimer tests
  4. Imaging tests for clinically suspected DVT
  5. Imaging test for clinically suspected PE
  6. Diagnostic algorithms for acute VTE
  7. Conclusions
  8. Disclosure of Conflict of Interests
  9. References

Acute deep vein thrombosis (DVT) and pulmonary embolism (PE) represent two expressions of a similar clinical pathological process, often referred to as venous throm-boembolism (VTE). It has long been recognized that, as clinical signs and symptoms of PE and DVT are not specific for the diagnosis, objective diagnosis in both patients presenting with leg symptoms and those with chest symptoms is mandatory. Since the last review on this subject in this journal in 2009, several large trials have been performed that shed new light on all aspects of the diagnostic management of suspected VTE, especially in the field of simplified clinical decision rules, age-dependent D-dimer cut-offs and magnetic resonance imaging. A literature search covering the period 2007–2012 was performed using the Medline/PubMed database to identify all relevant papers regarding the diagnostic management of acute PE and DVT. Established concepts and the latest evidence on this subject will be the main focus of this review.

Clinical probability assessment and D-dimer tests

  1. Top of page
  2. Summary
  3. Clinical probability assessment and D-dimer tests
  4. Imaging tests for clinically suspected DVT
  5. Imaging test for clinically suspected PE
  6. Diagnostic algorithms for acute VTE
  7. Conclusions
  8. Disclosure of Conflict of Interests
  9. References

A certain diagnosis of acute PE or DVT can only be established by means of imaging [1]. On the other hand, ruling out acute VTE can be safely achieved by using a standardized clinical probability assessment and a D-Dimer blood test. The main advantage of such an approach is a reduction in the required number of imaging tests, which are in general time consuming, costly and associated with radiation exposure and other complications.


Fibrin D-dimer is the final product of the plasmin-mediated degradation of cross-linked fibrin. Its plasma concentration is dependent on fibrin generation and subsequent degradation by the endogenous fibrinolytic system [2]. D-dimer levels are typically elevated in patients with acute venous thrombosis. Accordingly, the sensitivity of an elevated D-dimer concentration for VTE is very high [3]. In contrast, as D-dimer levels can be elevated in other clinical conditions that are associated with enhanced fibrin (e.g. malignancy, trauma, increased age, disseminated intravascular coagulation, inflammation, infection, sepsis, postoperative states and pre-eclampsia), the specificity for acute thrombosis is rather poor [3]. Thus the diagnostic strength of D-dimer tests lies in ruling out DVT or PE.

A large variety of assays are available for D-dimer measurement, and they are all based on the use of monoclonal antibodies that recognize epitopes of the D-dimer fragment that are not present on fibrinogen or non-crossed fragments of fibrin [4]. From numerous accuracy and management studies, it has been demonstrated that the sensitivities of the D-dimer enzyme-linked immunofluorescence assay (ELFA) (DVT 96%; PE 97%), microplate enzyme-linked immunosorbent assay (ELISA) (DVT 94%; PE 95%) and latex quantitative assay (DVT 93%; PE 95%) are superior to those of the whole-blood D-dimer assay (DVT 83%; PE 87%), latex semiquantitative assay (DVT 85%; PE 88%) and latex qualitative assay (DVT 69%; PE 75%), and have virtually no interobserver variability. The latex qualitative (DVT 99%, PE 99%) and whole-blood D-dimer assays (DVT 71%; PE 69%) have the highest specificities and are more operator dependent [3, 4]. Higher sensitivity yields a higher negative predictive value and thus less concern regarding false-negative test results. As no D-dimer assay has a perfect 100% sensitivity, the use of the D-dimer test should be restricted to patients with a non-high clinical probability.

In general, the D-dimer threshold for a normal test result is 500 μg L−1. In non-thrombotic clinical conditions associated with increased fibrin formation or decreased D-dimer clearance, the specificity of D-dimer testing with this particular cut-off is unquestionably decreased. For instance, in patients with active malignancy, the specificity was 16%, compared with 41% in patients without cancer, with a comparable sensitivity of 100% [5]. Analogous numbers were reported in elderly patients, patients with renal function impairment and those with a high inflammatory state [6-8]. Hence, it is likely that in such cases a higher cut-off results in higher specificity without a relevant fall in sensitivity. Indeed, the results of a retrospective analysis of two cohorts with suspected PE totalling 1331 patients aged over 50 years old suggests that an age dependent cut-off defined as patient's age × 10 μg L−1 is safe for use in clinical practice [6]. Acute PE could be excluded in 42% with the new cut-off value in combination with an unlikely clinical probability, compared to 36% with the standard cut-off value (< 500 μg L−1), without radiological imaging. A second and third post-hoc analysis in different patient populations provided further validation of the use of such an age-dependent D-dimer threshold [9, 10]. No large studies evaluating other corrections for clinical circumstances associated with elevated D-dimer concentrations have been performed. A recent study, in which doubling of the threshold for a positive D-dimer to 1000 μg L−1 was evaluated in 678 consecutive patients with an unlikely clinical probability for PE, independent of other co-morbid conditions or age, indicated that the number of patients in whom PE could be ruled out without the need for a CT scan as well as the rate of false-negative D-dimer tests, roughly doubled [11]. The failure rate of the combination of an unlikely clinical probability and a D-dimer of < 1000 μg L−1 was 5.3% (11 of 208 patients). Of note, 10 of 11 missed PEs were subsegmental. Nonetheless, the safe use of an age-dependent or other altered D-dimer threshold should be confirmed in a prospective management study before it can be implemented in daily clinical care, both for PE and DVT.

Clinical decision rules

The introduction of clinical decision rules has led to a standardized evaluation of the clinical pre-test probability in patients with suspected PE or DVT. For DVT, several decision rules are available [12]. Nonetheless, the first published one by Wells and colleagues is the most widely validated and used [12, 13]. It utilizes information from medical history and physical examination and consists of nine items. One point is given for each item and two points are deducted when an alternative diagnosis is considered more likely than DVT (Table 1). The decision rule initially categorized patients into low (0 points; 4.0–8.0% risk), intermediate (1–2 points, 13–23% risk) and high pre-test probability (≥ 3 points, 44–61% risk), and was later dichotomized into a low risk (< 2 points, 3.8–7.6% risk) or high risk category (≥ 2 points, 24–32% risk) for practical purposes [13, 14]. Notably, because of suggested disadvantages of the Wells rule, for example the lack of complete objectiveness due to the subjective element of considering an alternative diagnosis and lack of validation in selected cohorts including pregnant patients and the elderly, several alternative rules have been proposed [12]. Nonetheless, the reported inter-observer variability of the Wells score is good (κ = 0.85), and it has been shown that assessing the score is independent of the physicians' experience [13, 15]. Moreover, as alternative decision rules have not been validated in prospective management studies as extensively as the Wells rule, we recommend using the Wells rule for DVT. As stated before, because DVT cannot be ruled out by either a D-dimer test or clinical probability assessment alone, both tests should be used in conjunction. Approximately 40% of patients will have the combination of an unlikely probability (Wells score ≤ 2 points) and a normal D-dimer test result, yielding a negative likelihood ratio of 0.08 for the presence of DVT, in which case it is safe to withhold anticoagulant therapy without further testing [16].

Table 1. Wells rule for DVT
Active cancer1
Calf swelling ≥ 3 cm compared with asymptomatic calf1
Swollen unilateral superficial veins1
Unilateral pitting edema1
Previous documented DVT or PE1
Swelling of entire leg1
Localized tenderness along the deep venous system1
Recently bedridden ≥ 3 days or major surgery1
Alternative diagnosis at least as likely as DVT−2
Clinical probability
 High> 2
 PE unlikely≤ 1
 PE likely> 1

Regarding decision rules for acute PE, two are extensively validated in several outcome studies, the Wells rule for PE and the revised Geneva score. The first one consists of seven variables (Table 2), including a judgement on whether PE is the most likely diagnosis [17]. As with the Wells rule for DVT, this latter subjective item is the one that is most criticized, not least because it carries a major weight in the score. Using this rule, patients are classified as low (< 2 points; 2.0–5.9% risk), intermediate (2–6 points, 17–24% risk) or high pre-test probability (≥ 6 points, 54–78% risk), or alternatively as PE unlikely (≤ 4 points, 2.3–9.4% risk) or PE likely (> 4 points, 28–52% risk) [17]. The Christopher investigators showed that the combination of an unlikely clinical probability and a normal quantitative D-dimer test safely ruled out the presence of PE with a low 3-month VTE recurrence rate of 0.49% [18]. A meta-analysis including all high-quality prospective studies investigating the safety of ruling out PE based on a normal D-dimer blood test result and an unlikely clinical probability according to the Wells rule, confirmed this very low risk in 1660 consecutive patients with a pooled negative predictive value of 99.7% (95% CI, 99.0–99.9) and a very low PE-related mortality risk of 0.06% (95% CI, 0.0017–0.46) [19]. In contrast, patients with a likely clinical probability should undergo further testing regardless of the D-dimer test outcome as venous thromboembolism can be diagnosed in 9.3% (95% CI, 4.8–17) of patients with a negative D-dimer test result in this population [1]. Several attempts to construct a more objective decision rule were made. Of these, the revised Geneva score is the best validated rule and contains nearly the same items (Table 2), except for a clinical judgement of the likelihood of PE [20, 21]. This rule also has both a three- and a two-level outcome: low (< 3 points; 6.6–13% risk), intermediate (3–11 points, 24–31% risk) or high pre-test probability (≥ 11 points, 58–82% risk), and PE unlikely (≤ 2 points, 13–19% risk) or PE likely (> 2 points, 28–35% risk) [20-22]. In combination with a normal D-dimer test result, acute PE can be ruled out with high certainty in patients with a non-high (0% PE; 95% CI, 0.0–2.2) or less likely probability (0.54% PE; 95% CI, 0.0–3.0) according to the revised Geneva score [21, 22].

Table 2. Clinical decision rules for PE
Wells ruleRevised Geneva score
Previous PE or DVT1.51Previous DVT or PE31
Heart rate > 100/min1.51Heart rate 75–94/min31
   Heart rate ≥ 95/min52
Surgery or immobilization < 4 weeks1.51Surgery or fracture within 1 month21
Active malignancy11Active malignancy21
Clinical signs of DVT31Unilateral lower limb pain31
Alternative diagnosis less likely than PE31Pain on lower limb deep vein palpation and unilateral edema41
   Age > 65 years11
Clinical probabilityClinical probability
 Low< 2  Low0–3 
 Intermediate2–6  Intermediate4–10 
 High> 6  High≥ 11 
 PE unlikely≤ 4≤ 1 PE unlikely≤ 5≤ 2
 PE likely> 4> 1 PE likely> 5> 2

For practical purposes, both rules have been simplified by assigning only one point to each item (Table 2), without a resulting decrease in diagnostic accuracy [23, 24]. Several recent meta-analyses regarding the clinical utility of the above-discussed clinical decision rules in the management of acute PE have been published [19, 25-27]. They all conclude that the available decision rules show similar accuracy. However, a formal prospective management study comparing the (simplified) Wells rule and (simplified) revised Geneva score was lacking until recently. In the Prometheus study, both the original and the simplified Wells rule and revised Geneva score were directly compared in 807 consecutive patients [22]. The four decision rules showed similar performance for exclusion of acute PE in combination with D-dimer testing. The 3-month venous thromboembolic recurrence rates of all four scores ranged between 0.5% and 0.6%, while 30% of patients could be managed without the need for imaging. Therefore, the authors concluded that either the simplified or original Wells and Geneva decision scores can be used in clinical practice with equal safety and clinical utility. The specific rule that is used should depend on local preference.

In summary, the initial diagnostic work-up of acute thrombosis is dependent on several non-invasive diagnostic tests that should be used sequentially, always starting with probability assessment using a validated clinical decision rule, followed by a quantitative D-dimer test in case of an unlikely or non-high pre-test probability. D-dimer testing in patients with a likely or high probability is redundant for diagnostic purposes. Acute DVT or PE can be ruled out in patients with the combination of a non-high or unlikely clinical probability and normal D-dimer test result. All other patients should be referred to a radiologist for an imaging test. As use of such a validated diagnostic algorithm is associated with lower healthcare costs and a decreased complication risk, we recommend implementation of such a standardized approach. Regrettably and despite clear international guidelines [28, 29] in addition to overwhelming evidence, adherence to guidelines in the real world of clinical practice is poor [30-32]. For instance, in a random record review of Canadian patients in whom a D-dimer test was ordered because of a suspected acute venous thrombosis, pre-test assessment was not documented in 64% of the cases [30]. In the case of a positive d-dimer result, further imaging was not performed in 25–42% of patients, independent of clinical probability [30, 31]. In a large nationwide German assessment of the utilization of diagnostic methods for suspected DVT, almost every patient received an imagining examination, whereas clinical pre-test estimation was not used at all. Lastly, D-dimer tests were used as an adjunct to imaging rather than as a tool for exclusion of the disease without imaging [32].

Imaging tests for clinically suspected DVT

  1. Top of page
  2. Summary
  3. Clinical probability assessment and D-dimer tests
  4. Imaging tests for clinically suspected DVT
  5. Imaging test for clinically suspected PE
  6. Diagnostic algorithms for acute VTE
  7. Conclusions
  8. Disclosure of Conflict of Interests
  9. References

Contrast venography

In the past, contrast venography has been the reference method for diagnosing DVT. The diagnosis of DVT is established when, upon injection of contrast material, a constant intraluminal filling defect on at least two views is observed. Treatment can be safely withheld safely when a venogram doesn't show acute DVT, as only 1.3% (95% CI, 0.4–5.4) of 160 patients with a normal venogram developed DVT during 6 months follow-up [33]. However, venography is invasive, involves the injection of contrast and it is an expensive test. Therefore, contrast venography is nowadays seldom used.

Compression ultrasonography

In daily clinical practice, compression ultrasonography (CUS) has become the first-line accepted imaging method in the diagnostic procedure for patients with clinically suspected DVT. With this technique, the femoral and popliteal vein are directly visualized and subsequently assessed for their compressibility in the transverse plane, so-called two-point CUS. Non-compressibility of either the femoral or popliteal vein, or both, is diagnostic for a first episode of acute proximal DVT in patients suspected of having clinically manifest DVT, with a sensitivity of 94% (95% CI, 92–95) and specificity of 98% (95% CI, 97–98) [34]. The interobserver agreement of CUS is excellent, with a kappa of 1 for proximal DVT of the leg [35, 36]. As an alternative to the two-point strategy, extended CUS of the proximal deep venous system can be applied. Starting at the common femoral vein, subsequent stepwise compression is applied approximately every 1 cm along the course of the femoral and popliteal vein. An extended CUS examination could hypothetically lead to identification of more thrombosis. Cogo and colleagues showed by evaluating the distribution of DVT, that all proximal DVTs were located as follows: in the popliteal vein only (10%); popliteal and superficial femoral vein (42%); popliteal, superficial and common femoral vein (5%); entire proximal venous system (35%); and common femoral and superficial vein or iliac vein (8%) [37]. Notably, no isolated superficial femoral vein thrombosis was detected. Based on his study, the two-point CUS method is the preferred one, as it is time-efficient because it limits the examination of the proximal veins to the common femoral vein and popliteal vein. In summary, CUS is a simple, accurate and non-invasive diagnostic tool and serves as a first choice of imaging modality in the diagnostic work-up of patients with a first episode of clinically suspected DVT of the lower extremities.

In contrast to proximal DVT of the leg, distal DVT has been less well examined. Regardless of the method of US, accuracy is substantially lower compared with proximal DVT. CUS was reported to have sensitivities that were just over 70% (73%; 95% CI, 54–93) [38]. In addition, there is a high chance of false-positive findings due to the different and variable distal veins.

Complete compression ultrasonography

Complete compression ultrasonography (CCUS) is a combination of the extended CUS of the proximal deep veins and CUS of the distal deep veins of the leg. CCUS was introduced to avoid the need for a repeat US in patients that had an initially normal CUS [39]. This second CUS is necessary to avoid a distal DVT propagating over days into the proximal (popliteal vein and above) system without being detected (see section on 'Diagnostic algorithms for acute VTE'). Importantly, no study has been performed in which CCUS has been compared with the reference method contrast venography. Therefore the true sensitivity and specificity of CCUS are unknown. The main advantage of the use of CCUS is the lack of necessity for a repeat US after 1 week. However, the technique is time consuming (additional imaging time varies between 4 and 30 min) and imaging may be inadequate in up to 32% and 55% of cases [40, 41]. Finally, as around 50% of DVTs diagnosed by CCUS are isolated distal DVTs, these distal DVTs can consist of either true-positive small distal DVTs that may resolve spontaneously or false-positive distal DVTs [42, 43]. ]. In a randomized study, serial two-point US plus D-dimer has been compared with CCUS. Both strategies performed similarly, with 3-month VTE after normal tests of 0.9% (95% CI, 0.3–1.8) for the two-point strategy and 1.2% (95% CI, 0.5–2.2) for the whole leg strategy [44]. In conclusion, although CCUS is efficient (1 day testing) and can be performed adequately by experienced operators, there are many disadvantages to this technique. These include time-inefficiency, potential for over-diagnosing and over-treating patients with a distal DVT and a high rate of inadequate examinations. In routine practice the use of CCUS as an established test in DVT diagnosis cannot be recommended yet.

Computed tomography and magnetic resonance imaging

Computed tomography (CT) and magnetic resonance imaging (MRI) may serve as an alternative or complementary imaging tool to US. However, compared with US, both modalities are less well evaluated. In a recent meta-analysis, a pooled sensitivity for CT venography was 96% (95% CI, 93–98), with a pooled specificity of 95% (95% CI, 94–97) [45]. Of note, different techniques and different diagnostic criteria were used for the diagnosis of proximal DVT. Furthermore, most studies were performed in patients with suspected pulmonary embolism without symptoms or signs of thrombosis of the legs, for whom the CT scan was subsequently extended to the legs MR venography can be performed with or without intravenously administered gadolinium and both techniques have been evaluated for their accuracy. The pooled sensitivity and specificity of MR venography were reported to be 92% (95% CI, 88–95) and 94.8% (95% CI, 93–97), respectively [46]. In conclusion, although the sensitivity and specificity of CT venography and MR venography are within the range of US, the safety of withholding anticoagulant treatment on the basis of a normal CT venography or normal MR venography has not been studied and therefore these modalities cannot be recommended as first-line imaging approaches. CT venography or MR venography could be useful in patients with a suspected DVT in whom US cannot be performed or is less reliable, such as patients with morbid obesity or casts and patients with a suspected deep vein thrombosis in the iliac or inferior cava vein or suspected venous anomaly.

Imaging tests in the diagnosis of recurrent DVT

While CUS is the preferred test for a first episode of DVT, the diagnosis of ipsilateral recurrent DVT by CUS poses a problem because persistent CUS abnormalities are present in approximately 80% and 50% of patients at 3 months and 1 year, respectively, after a proximal DVT [47-49]. Therefore, when a patient with suspected recurrence has a non-compressible venous segment, it can be difficult to determine whether this represents new disease or a residual abnormality from previous DVT with an inherent risk of false-positive US results. Recurrent DVT is diagnosed by CUS when a new vein segment has become non-compressible or a previously normalized vein segment has become non-compressible [50]. An increase in thrombus diameter of at least 4 mm in a previously affected segment can also be considered diagnostic of recurrent DVT. It should be noted that interobserver agreement of this thrombus diameter measurement is poor [51]. CUS is only accurate when ipsilateral recurrent DVT occurs in a different venous segment to that at the time of the first DVT or when a previously normal venous segment is abnormal. As an alternative, 99mTC-recombinant tissue plasminogen activator (rt-PA) scintigraphy imaging has been evaluated. Although this technique can potentially distinguish between an old and new thrombus, 99mTC-rt-PA is not widely available and suffers from high interobserver variability [52]. Magnetic resonance direct thrombus imaging (MRDTI) is based upon the paramagnetic properties of methaemoglobin, which gives a high signal on T1 weighted images. The intensity of this signal correlates with the amount of methaemoglobin. In a feasibility study, after 6 months the abnormal MR signal of the acute DVT event had vanished in all 39 study patients, while in 12 patients the CUS examination was still abnormal. This indicates that MRDTI may potentially be an accurate method to distinguish a new recurrent event from an old thrombus in patients with acute suspected recurrent DVT [53]. In a very recent study in 41 patients with suspected recurrent DVT, MRI direct thrombus imaging showed a sensitivity of 93% and specificity of 100% with an excellent kappa of 0.96 [54]. A management outcome study is needed before MR direct thrombus imaging can be used to safely exclude recurrent DVT.

Imaging test for clinically suspected PE

  1. Top of page
  2. Summary
  3. Clinical probability assessment and D-dimer tests
  4. Imaging tests for clinically suspected DVT
  5. Imaging test for clinically suspected PE
  6. Diagnostic algorithms for acute VTE
  7. Conclusions
  8. Disclosure of Conflict of Interests
  9. References

Pulmonary angiography

Pulmonary angiography (PA) is the historical reference standard imaging technique for PE [55]. However, this method is invasive due to the need for right heart catheterization and injection of contrast media. Also, it requires expertise, which is less available nowadays. Of note, the 3-month incidence of recurrent venous thromboembolism (VTE) after normal pulmonary angiogram is 1.7% (95% CI, 1.0–2.7), with fatal PE occurring in 0.3% (95% CI, 0.02–0.7) of the patients [56]. As computed tomography pulmonary angiography (CTPA) has excellent accuracy characteristics, this method is now considered to have replaced PA as the reference in the diagnosis of PE [57]. PA is only used nowadays in special situations where CTPA is inadequate and in patients suspected of chronic thromboembolic hypertension [58].

Computed tomographic pulmonary angiography

Multi-row computed tomographic pulmonary angiography (CTPA) is nowadays the imaging test of choice in patients with clinically suspected acute PE and it is readily available in most hospitals. After injection of intravenous contrast material, CTPA can be performed within 4–6 s, and PE can be diagnosed in the case of the presence of intraluminal filling defects in the pulmonary arteries. With the first-generation single-slice CT scanners sensitivity and specificity were 76 and 89%, respectively, based on pooled data from accuracy studies [59]. The sensitivity proved to be dependent on the location of the embolus in the pulmonary arterial tree: for the main, lobar or segmental pulmonary artery branches the sensitivity was 89%, while for distal PE a sensitivity of only 21% was obtained [60]. A significant improvement in sensitivity was seen with the introduction of multi-detector row CT scanners. CTPA studies using the multi-detector row technique showed a high sensitivity (96–100%) and specificity (97–98%) and several cohort follow-up studies have demonstrated that it is safe to withhold anticoagulant treatment if CTPA has excluded acute PE [1, 29, 56, 57]. In only 1.3% of patients with a high pre-test probability of PE but a negative CTPA, was a VTE diagnosed during 3-month follow-up [18]. The safety of using MD-CTPA as a single imaging test has been established by a randomized, non-inferiority trial, in which performing compression ultrasonography (CUS) in addition to MD-CTPA did not lead to better results in excluding PE [61]. In a meta-analysis these results were confirmed and showed a high negative predictive value of a normal CTPA result (99%; 95% CI, 98–99) [62]. In one study CTPA was randomly compared with V-Q scintigraphy and revealed a prevalence of PE of 14–19% and a 0.6–1.0% incidence of recurrent VTE after normal V-Q scan during 3-month follow-up [63].

The most important advantage of CTPA over V-Q scintigraphy is the low number of inconclusive test results (0.9–3.0 vs. 28–46%) and the possibility to provide an alternative diagnosis, explaining the complaints of the patients, including pneumonia, malignancy or aortic dissection. There are also disadvantages associated with widespread use of CTPA. With the development of the CTPA technique and the low threshold for using this technique at the Emergency Department, more and smaller, symptomatic subsegmental emboli may become visualized. Although observational research suggests that treated as well as untreated patients have a good prognosis, the true clinical relevance of these emboli is yet uncertain [64-66]. In fact, a cohort study has started recently to evaluate the safety of withholding anticoagulant treatment in patients with a subsegmental PE on CTPA and normal ultrasound of the leg veins [67]. Further disadvantages of CTPA are the contraindications in patients with allergy to iodinated contrast material and in patients with severely impaired renal function. Finally, the radiation dose of a single CTPA ranges from 3 to 5 mSv, with an estimated cancer risk of 150 excess cancer deaths per million resulting from exposure to a single CT scan for suspected PE [68]. The cancer risk is especially of interest to the younger, female patient during reproductive age.

Ventilation-perfusion lung scan

Ventilation-perfusion (V-Q) lung scanning involves the simultaneous scintigraphic imaging of thrombo-emboli in the pulmonary arteries and airways. After a normal perfusion lung scan, the 3-month VTE failure rate is 0.9% (upper 95%CI, 2.3%) [69]. In contrast, a so called ‘high-probability’ lung scan (i.e. a lung scan showing at least a segmental perfusion defect combined with a normal ventilation scan) has a 85–90% predictive value for PE [70, 71]. Finally, 28–46% of patients may have a non-diagnostic test result and the prevalence of PE in these patients is 10–30%. Further investigation by imaging is thus needed in many patients with prior lung scan. One way to limit the number of non-diagnostic lung scans is to perform lung scanning only in patients with a normal chest X-ray. This combination of perfusion scintigraphy and chest X-ray, without adding ventilation lung scanning, led to sensitivities of 80–85% and specificities of 93–97%, comparable to the diagnostic accuracy of V-Q scintigraphy in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) II study [72, 73]. Importantly, this combination also has lower costs and a lower radiation dose compared with CTPA [72]. This technique could be an alternative to the current imaging modalities, especially in young women, due to the increased risk of breast cancer from radiation and because of the low amount of co-morbidity in this specific group of patients. Also, three-dimensional images acquired by single-photon emission computed tomography (SPECT) using a gamma-emitting radioisotope may improve the accuracy and inadequate readings of V/Q scintigraphy and has a lower radiation dose. It has been reported to have a low rate (3%) of non-diagnostic test results, but formal outcome studies in acute PE are lacking for both X-Q scanning and SPECT [74].

Magnetic resonance angiography

In patients with suspected PE, in whom radiation should be avoided, or who are allergic to iodine contrast agents, magnetic resonance pulmonary angiography (MRPA) has potential as an alternative to CTPA [75-78]. In earlier studies in limited numbers of patients, sensitivities of 77–100% and specificities of 95–98% were observed [37]. The PIOPED III investigators performed a large prospective study to evaluate the performance of MRA, with or without magnetic resonance venography, using various accepted diagnostic tests as reference standard, including CTPA and VQ scan. While in this study the sensitivity of MRA was 78% and specificity was 99%, a disturbing 25% inadequacy rate of MRPA was observed [76]. Poor arterial opacification of segmental or subsegmental branches (67%) and motion artefacts (36%) were the most prevalent reasons for a non-interpretable MRA [77]. Very recently, Sanchez et al. studied MRI performance in acute PE diagnosis by reference to 64-detector CTPA in 300 patients and demonstrated a high specificity (99–100%) with a sensitivity of 79–85% for conclusive MR results [78]. However, as in the BIOPED III study, 28–30% of the included patients had an inconclusive MR result. Sensitivity was higher in proximal (98–100%) than in segmental (68–91%) and subsegmental PE (21–33%). Most importantly, there are no outcome studies in patients with normal MRPA. Therefore, MRPA is not yet an optimal alternative in the diagnostic process for suspected PE [79].

Diagnosis of recurrent PE

Diagnosing recurrent PE is more challenging than diagnosing a first episode of PE for several reasons. First, the sensitivity of D-dimer tests in patients with recurrent thrombotic disease is decreased compared with a first episode [80]. Second, recurrent emboli may be radiographically difficult to differentiate from residual emboli, which may be identified in up to 50% of patients diagnosed with PE [81]. Studies regarding whether a control CTPA at the end of anticoagulant treatment will facilitate the clinical decision process in patients with suspected recurrent PE remain to be performed. In a multicenter clinical outcome study, the performance of a diagnostic strategy including the Wells score, D-dimer testing and CTPA was determined in a specific subset of 516 patients with suspected recurrent PE [82]. The combination of an unlikely Wells clinical probability and a normal D-dimer level was safe to exclude PE, with a 3-month VTE rate of 0% (95% CI, 0–3.3). Recurrent VTE was diagnosed during 3 months of follow-up in 3.2% (95% CI, 1.5–5.9) of patients with a negative CTPA result, compared with 1.2% in a population with mostly first PE [62].

Diagnostic algorithms for acute VTE

  1. Top of page
  2. Summary
  3. Clinical probability assessment and D-dimer tests
  4. Imaging tests for clinically suspected DVT
  5. Imaging test for clinically suspected PE
  6. Diagnostic algorithms for acute VTE
  7. Conclusions
  8. Disclosure of Conflict of Interests
  9. References

Diagnostic algorithms for clinically suspected DVT

Several diagnostic algorithms can be applied in patients with a first episode of clinically suspected acute DVT, of which the most widely used are the serial two-point CUS and a combination of clinical decision rule, D-dimer test and CUS.

The first algorithm implies serial two-point CUS of both the popliteal and inguinal region in all patients. In the case of an initial normal CUS, a second CUS is performed after 1 week. The cumulative VTE failure rate using this approach was 0.7% (95% CI, 0.3–1.2) after 3 months follow-up. The mean number of additional hospital visits and US tests required per initially referred patient was 0.8 using this algorithm (DVT algorithm 1) [83]. A combination of CUS with a D-dimer test can lower the number of ultrasound tests (DVT algorithm 2). In patients with a normal US, a D-dimer test is performed, and if normal, DVT is excluded. In the case of an abnormal D-dimer test, repeat CUS is performed after 1 week. With this strategy, the cumulative 3-month VTE failure rate in patients with normal CUS and D-dimer test was 0.4% (95% CI, 0.0–0.9), with a low mean number of 0.1 extra hospital visits and additional US tests required per initially referred patient [84]. In the third algorithm, a clinical decision rule is combined with a D-dimer test and CUS (DVT algorithm 3, Fig. 1). The combination of a low clinical probability and normal D-dimer showed a 3-month VTE failure rate of 0.9% (95% CI, 0.1–3.3) [85]. None of the patients with either high D-dimer but normal CUS or high clinical probability normal CUS and normal D-dimer had recurrent VTE at 3 months follow-up (upper 95% CI, 2.0%). As the addition of a clinical decision rule renders the diagnosis of DVT structured and fewer (repeat) US examinations are needed to establish the diagnosis of a first episode DVT, this algorithm is the preferred one.


Figure 1. Preferred diagnostic algorithm for clinically suspected DVT. DVT, deep vein thrombosis; CDR, clinical decision rule; CUS, compression ultrasonography.

Download figure to PowerPoint

Alternatively, a single CCUS can be used and anticoagulant treatment withheld in patients with a normal CCUS (DVT algorithm 4). With this approach the 3-month VTE risk varied between 0.5% (95% CI, 0.1–1.8) and 0.3% (95% CI, 0.1–0.8) [39, 86]. As mentioned above, although the use of the CCUS seems promising, the risk of over-diagnosing distal DVT is substantial and data supporting anticoagulation for distal DVT are limited. Therefore an algorithm using CCUS is not recommended as a first-line imaging algorithm in DVT.

Diagnostic algorithms for clinically suspected PE

In a large meta-analysis pooling 23 studies and a total of 4657 patients, it has been shown that patients with suspected PE all can be managed by multi-row detector CTPA alone (PE algorithm 1). The 3-month rate of subsequent VTE after CT as a single test is 1.4% (95% CI, 1.1–1.8), and the 3-month fatal VTE rate 0.51% (95% CI, 0.33–0.76) [87]. However, such a strategy may lead to a very high rate (> 90%) of negative CT results and logistic availability problems. We recommend a strategy including a clinical decision rule, a sensitive D-dimer test and multi-row detector CTPA (PE algorithm 2, Fig. 2). As stated earlier, the combination of an unlikely clinical probability and a normal D-dimer blood test result safely rules out PE [19, 25]. In the remaining patients, a negative CTPA has a 3-month incidence of subsequent venous thrombosis of 1.2% (95% CI, 0.8–1.8) with a very low VTE-related mortality risk (0.6%; 95% CI, 0.4–1.1) [62]. The yield of additional CUS in patients with normal multi-row detector CTPA is very low (0.9–1.4%) and therefore unnecessary [63, 88]. Using this algorithm, CT scanning can be avoided in 30% of patients with suspected acute PE and a management decision can be made in 98% of patients.


Figure 2. Preferred diagnostic algorithm for clinically suspected PE. PE, pulmonary embolism; CDR, clinical decision rule; HS, high sensitive; MD-CTPA, multi-row detector computed tomography pulmonary angiography.

Download figure to PowerPoint

If V-Q scanning is used as the initial imaging method after clinical probability and, if indicated, D-dimer assessment, PE can be ruled out by a normal V-Q scan and established by a high probability V-Q scan result (PE algorithm 3). Patients with an intermediate probability V-Q result still require CTPA for a final diagnosis. Of note, this strategy needs a proper prospective validation before it can be generally applied.


  1. Top of page
  2. Summary
  3. Clinical probability assessment and D-dimer tests
  4. Imaging tests for clinically suspected DVT
  5. Imaging test for clinically suspected PE
  6. Diagnostic algorithms for acute VTE
  7. Conclusions
  8. Disclosure of Conflict of Interests
  9. References

The pillars of the diagnostic management of patients with suspected VTE are clinical decision rules, D-dimer assays and imaging tests. Numerous studies support a standardized strategy consisting of these three diagnostic modalities to optimize safety and cost-effectiveness. In the near future, most progress in this field can be expected in improved imaging possibilities with, for instance, MR applications for recurrent DVT.


  1. Top of page
  2. Summary
  3. Clinical probability assessment and D-dimer tests
  4. Imaging tests for clinically suspected DVT
  5. Imaging test for clinically suspected PE
  6. Diagnostic algorithms for acute VTE
  7. Conclusions
  8. Disclosure of Conflict of Interests
  9. References
  • 1
    Huisman MV, Klok FA. Diagnostic management of clinically suspected acute pulmonary embolism. J Thromb Haemost 2009; 7(Suppl. 1): 3127.
  • 2
    Prisco D, Grifoni E. The role of D-dimer testing in patients with suspected venous thromboembolism. Semin Thromb Hemost 2009; 35: 509.
  • 3
    Righini M, Perrier A, De Moerloose P, Bounameaux H. D-Dimer for venous thromboembolism diagnosis: 20 years later. J Thromb Haemost 2008a; 6: 105971.
  • 4
    Di Nisio M, Squizzato A, Rutjes AW, Büller HR, Zwinderman AH, Bossuyt PM. Diagnostic accuracy of D-dimer test for exclusion of venous thromboembolism: a systematic review. J Thromb Haemost 2007; 5: 296304.
  • 5
    Righini M, Le Gal G, De Lucia S, Roy PM, Meyer G, Aujesky D, Bounameaux H, Perrier A. Clinical usefulness of D-dimer testing in cancer patients with suspected pulmonary embolism. Thromb Haemost 2006; 95: 7159.
  • 6
    Douma RA, le Gal G, Söhne M, Righini M, Kamphuisen PW, Perrier A, Kruip MJ, Bounameaux H, Büller HR, Roy PM. Potential of an age adjusted D-dimer cut-off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts. BMJ 2010; 30: 340.
  • 7
    Karami-Djurabi R, Klok FA, Kooiman J, Velthuis SI, Nijkeuter M, Huisman MV. D-dimer testing in patients with suspected pulmonary embolism and impaired renal function. Am J Med 2009; 122: 10503.
  • 8
    Klok FA, Karamidjurabi R, Velthuis SI, Nijkeuter M, Huisman MV. Utility of D-dimer testing in patients with clinically suspected pulmonary embolism and elevated C-reactive protein levels. Thromb Haemost 2008a; 99: 9724.
  • 9
    Jaffrelot M, Le Ven F, Le Roux PY, Tissot V, Rame E, Salaun PY, Le Gal G. External validation of a D-dimer age-adjusted cut-off for the exclusion of pulmonary embolism. Thromb Haemost 2012; 107: 10057.
  • 10
    van Es J, Mos I, Douma R, Erkens P, Durian M, Nizet T, van Houten A, Hofstee H, ten Cate H, Ullmann E, Büller H, Huisman M, Kamphuisen PW. The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded. Thromb Haemost 2012; 107: 16771.
  • 11
    Kline JA, Hogg MM, Courtney DM, Miller CD, Jones AE, Smithline HA. D-dimer threshold increase with pretest probability unlikely for pulmonary embolism to decrease unnecessary computerized tomographic pulmonary angiography. J Thromb Haemost 2012; 10: 57281.
  • 12
    Tan M, van Rooden CJ, Westerbeek RE, Huisman MV. Diagnostic management of clinically suspected acute deep vein thrombosis. Br J Haematol 2009; 146: 34760.
  • 13
    Wells PS, Hirsh J, Anderson DR, Lensing AW, Foster G, Kearon C, Weitz J, D'Ovidio R, Cogo A, Prandoni P. Accuracy of clinical assessment of deep-vein thrombosis. Lancet 1995; 345: 132630.
  • 14
    Wells PS, Owen C, Doucette S, Fergusson D, Tran H. Does this patient have deep vein thrombosis? JAMA 2006; 295: 199207.
  • 15
    Cornuz J, Ghali WA, Hayoz D, Stoianov R, Depairon M, Yersin B. Clinical prediction of deep venous thrombosis using two risk assessment methods in combination with rapid quantitative D-dimer testing. Am J Med 2002; 112: 198203.
  • 16
    Wells PS. Integrated strategies for the diagnosis of venous thromboembolism. J Thromb Haemost 2007; 5(Suppl. 1): 4150.
  • 17
    Wells PS, Anderson DR, Rodger M, Ginsberg JS, Kearon C, Gent M, Turpie AG, Bormanis J, Weitz J, Chamberlain M, Bowie D, Barnes D, Hirsh J. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 2000; 83: 41620.
  • 18
    van Belle A, Büller HR, Huisman MV, Huisman PM, Kaasjager K, Kamphuisen PW, Kramer MH, Kruip MJ, Kwakkel-van Erp JM, Leebeek FW, Nijkeuter M, Prins MH, Sohne M, Tick LW, Christopher Study Investigators. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006; 295: 1729.
  • 19
    Pasha SM, Klok FA, Snoep JD, Mos IC, Goekoop RJ, Rodger MA, Huisman MV. Safety of excluding acute pulmonary embolism based on an unlikely clinical probability by the Wells rule and normal D-dimer concentration: a meta-analysis. Thromb Res 2010; 125: e1237.
  • 20
    Le Gal G, Righini M, Roy PM, Sanchez O, Aujesky D, Bounameaux H, Perrier A. Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med 2006a; 144: 16571.
  • 21
    Klok FA, Kruisman E, Spaan J, Nijkeuter M, Righini M, Aujesky D, Roy PM, Perrier A, Le Gal G, Huisman MV. Comparison of the revised Geneva score with the Wells rule for assessing clinical probability of pulmonary embolism. J Thromb Haemost 2008b; 6: 404.
  • 22
    Douma RA, Mos IC, Erkens PM, Nizet TA, Durian MF, Hovens MM, van Houten AA, Hofstee HM, Klok FA, ten Cate H, Ullmann EF, Büller HR, Kamphuisen PW, Huisman MV, Prometheus Study Group. Performance of 4 clinical decision rules in the diagnostic management of acute pulmonary embolism: a prospective cohort study. Ann Intern Med 2011; 154: 70918.
  • 23
    Klok FA, Mos IC, Nijkeuter M, Righini M, Perrier A, Le Gal G, Huisman MV. Simplification of the revised Geneva score for assessing clinical probability of pulmonary embolism. Arch Intern Med 2008c; 168: 21316.
  • 24
    Gibson NS, Sohne M, Kruip MJ, Tick LW, Gerdes VE, Bossuyt PM, Wells PS, Buller HR, Christopher study investigators. Further validation and simplification of the Wells clinical decision rule in pulmonary embolism. Thromb Haemost 2008; 99: 22934.
  • 25
    Lucassen W, Geersing GJ, Erkens PM, Reitsma JB, Moons KG, Büller H, van Weert HC. Clinical decision rules for excluding pulmonary embolism: a meta-analysis. Ann Intern Med 2011; 155: 44860.
  • 26
    Ceriani E, Combescure C, Le Gal G, Nendaz M, Perneger T, Bounameaux H, Perrier A, Righini M. Clinical prediction rules for pulmonary embolism: a systematic review and meta-analysis. J Thromb Haemost 2010; 8: 95770.
  • 27
    Carrier M, Righini M, Djurabi RK, Huisman MV, Perrier A, Wells PS, Rodger M, Wuillemin WA, Le Gal G. VIDAS D-dimer in combination with clinical pre-test probability to rule out pulmonary embolism. A systematic review of management outcome studies. Thromb Haemost 2009; 101: 88692.
  • 28
    Bates SM, Jaeschke R, Stevens SM, Goodacre S, Wells PS, Stevenson MD, Kearon C, Schunemann HJ, Crowther M, Pauker SG, Makdissi R, Guyatt GH, American College of Chest Physicians. Diagnosis of DVT: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2012; 141(Suppl. 2): e351S418S.
  • 29
    Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP, ESC Committee for Practice Guidelines (CPG). Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008; 29: 2276315.
  • 30
    Smith C, Mensah A, Mal S, Worster A. Is pretest probability assessment on emergency department patients with suspected venous thromboembolism documented before SimpliRED D-dimer testing? CJEM 2008; 10: 51923.
  • 31
    Corwin MT, Donohoo JH, Partridge R, Egglin TK, Mayo-Smith WW. Do emergency physicians use serum D-dimer effectively to determine the need for CT when evaluating patients for pulmonary embolism? Review of 5,344 consecutive patients AJR Am J Roentgenol 2009; 192: 131923.
  • 32
    Schellong SM, Gerlach H, Hach-Wunderle V, Rabe E, Riess H, Carnarius H, Eberle S, Bauersachs R. Diagnosis of deep-vein thrombosis: adherence to guidelines and outcomes in real-world health care. Thromb Haemost 2009; 102: 123440.
  • 33
    Hull R, Hirsh J, Sackett DL, Taylor DW, Carter C, Turpie AG, Powers P, Gent M. Clinical validity of a negative venogram in patients with clinically suspected venous thrombosis. Circulation 1981; 64: 6225.
  • 34
    Goodacre S, Sampson F, Thomas S, van Beek E, Sutton A. Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis. BMC Med Imaging 2005; 5: 6.
  • 35
    Lensing AW, Prandoni P, Brandjes D, Huisman PM, Vigo M, Tomasella G, Krekt J, Wouter Ten Cate J, Huisman MV, Büller HR. Detection of deep-vein thrombosis by real-time B-mode ultrasonography. N Engl J Med 1989; 320: 3425.
  • 36
    Schwarz T, Schmidt B, Schmidt B, Schellong SM. Interobserver agreement of complete compression ultrasound for clinically suspected deep vein thrombosis. Clin Appl Thromb Hemost 2002; 8: 459.
  • 37
    Cogo A, Lensing AW, Prandoni P, Hirsh J. Distribution of thrombosis in patients with symptomatic deep vein thrombosis. Implications for simplifying the diagnostic process with compression ultrasound. Arch Intern Med 1993; 153: 277780.
  • 38
    Kearon C, Julian JA, Newman TE, Ginsberg JS. Noninvasive diagnosis of deep venous thrombosis. McMaster Diagnostic Imaging Practice Guidelines Initiative. Ann Intern Med 1998; 128: 66377.
  • 39
    Elias A, Mallard L, Elias M, Alquier C, Guidolin F, Gauthier B, Viard A, Mahouin P, Vinel A, Boccalon H. A single complete ultrasound investigation of the venous network for the diagnostic management of patients with a clinically suspected first episode of deep venous thrombosis of the lower limbs. Thromb Haemost 2003; 89: 2217.
  • 40
    Forbes K, Stevenson AJ. The use of power Doppler ultrasound in the diagnosis of isolated deep venous thrombosis of the calf. Clin Radiol 1998; 53: 7524.
  • 41
    Gottlieb RH, Widjaja J, Tian L, Rubens DJ, Voci SL. Calf sonography for detecting deep venous thrombosis in symptomatic patients: experience and review of the literature. J Clin Ultrasound 1999; 27: 41520.
  • 42
    Righini M. Is it worth diagnosing and treating distal deep vein thrombosis? No J Thromb Haemost 2007; 5(Suppl. 1): 559.
  • 43
    El Kheir D, Büller H. One-time comprehensive ultrasonography to diagnose deep venous thrombosis: is that the solution? Ann Intern Med 2004; 140: 10523.
  • 44
    Bernardi E, Camporese G, Büller HR, Siragusa S, Imberti D, Berchio A, Ghirarduzzi A, Verlato F, Anastasio R, Prati C, Piccioli A, Pesavento R, Bova C, Maltempi P, Zanatta N, Cogo A, Cappelli R, Bucherini E, Cuppini S, Noventa F, et al., Erasmus Study Group. Serial 2-point ultrasonography plus D-dimer vs whole-leg color-coded Doppler ultrasonography for diagnosing suspected symptomatic deep vein thrombosis: a randomized controlled trial. JAMA 2008; 300: 16539.
  • 45
    Thomas SM, Goodacre SW, Sampson FC, van Beek EJ. Diagnostic value of CT for deep vein thrombosis: results of a systematic review and meta-analysis. Clin Radiol 2008; 63: 299304.
  • 46
    Sampson FC, Goodacre SW, Thomas SM, van Beek EJ. The accuracy of MRI in diagnosis of suspected deep vein thrombosis: systematic review and meta-analysis. Eur Radiol 2007; 17: 17581.
  • 47
    Murphy TP, Cronan JJ. Evolution of deep venous thrombosis: a prospective evaluation with US. Radiology 1990; 177: 5438.
  • 48
    Piovella F, Crippa L, Barone M, Viganò D'Angelo S, Serafini S, Galli L, Beltrametti C, D'Angelo A. Normalization rates of compression ultrasonography in patients with a first episode of deep vein thrombosis of the lower limbs: association with recurrence and new thrombosis. Haematologica 2002; 87: 51522.
  • 49
    Heijboer H, Jongbloets LM, Büller HR, Lensing AW, ten Cate JW. Clinical utility of real-time compression ultrasonography for diagnostic management of patients with recurrent venous thrombosis. Acta Radiol 1992; 33: 297300.
  • 50
    Prandoni P, Cogo A, Bernardi E, Villalta S, Polistena P, Simioni P, Noventa F, Benedetti L, Girolami A. A simple ultrasound approach for detection of recurrent proximal-vein thrombosis. Circulation 1993; 88: 17305.
  • 51
    Linkins LA, Stretton R, Probyn L, Kearon C. Interobserver agreement on ultrasound measurements of residual vein diameter, thrombus echogenicity and Doppler venous flow in patients with previous venous thrombosis. Thromb Res 2006; 117: 2417.
  • 52
    Brighton T, Janssen J, Butler SP. Aging of acute deep vein thrombosis measured by radiolabeled 99mTc-rt-PA. J Nucl Med 2007; 48: 8738.
  • 53
    Westerbeek RE, van Rooden CJ, Tan M, van Gils AP, Kok S, de Bats MJ, de Roos A, Huisman MV. Magnetic resonance direct thrombus imaging of the evolution of acute deep vein thrombosis of the leg. J Thromb Haemost 2008; 6: 108792.
  • 54
    Tan M, Mol GC, van de Ree MA, van Rooden CJ, Westerbeek RE, Iglesias de Sol A, de Roos A, Huisman MV. Accuracy of Magnetic Resonance Direct Thrombus Imaging (MRDTI) As a Novel Tool in the Diagnosis of Acute Ipsilateral Recurrent Deep Vein Thrombosis. ASH 2012 abstract 395.
  • 55
    Stein PD, Athanasoulis C, Alavi A, Greenspan RH, Hales CA, Saltzman HA, Vreim CE, Terrin ML, Weg JG. Complications and validity of pulmonary angiography in acute pulmonary embolism. Circulation 1992; 85: 4628.
  • 56
    van Beek EJ, Brouwerst EM, Song B, Stein PD, Oudkerk M. Clinical validity of a normal pulmonary angiogram in patients with suspected pulmonary embolism-a critical review. Clin Radiol 2001; 56: 83842.
  • 57
    Remy-Jardin M, Pistolesi M, Goodman LR, Gefter WB, Gottschalk A, Mayo JR, Sostman HD. Management of suspected acute pulmonary embolism in the era of CT angiography: a statement from the Fleischner Society. Radiology 2007a; 245: 31529.
  • 58
    Klok FA, Huisman MV. Epidemiology and management of chronic thromboembolic pulmonary hypertension. Neth J Med 2010; 68: 34751.
  • 59
    Rathbun SW, Raskob G, Whitsett TL. Sensitivity and specificity of helical computed tomography in the diagnosis of pulmonary embolism: a systematic review. Ann Intern Med 2000; 132: 22732.
  • 60
    van Strijen MJ, De Monye W, Kieft GJ, Pattynama PM, Prins MH, Huisman MV. Accuracy of single-detector spiral CT in the diagnosis of pulmonary embolism: a prospective multicenter cohort study of consecutive patients with abnormal perfusion scintigraphy. J Thromb Haemost 2005; 3: 1725.
  • 61
    Righini M, Le Gal G, Aujesky D, Roy PM, Sanchez O, Verschuren F, Rutschmann O, Nonent M, Cornuz J, Thys F, Le Manach CP, Revel MP, Poletti PA, Meyer G, Mottier D, Perneger T, Bounameaux H, Perrier A. Diagnosis of pulmonary embolism by multidetector CT alone or combined with venous ultrasonography of the leg: a randomised non-inferiority trial. Lancet 2008b; 371: 134352.
  • 62
    Mos IC, Klok FA, Kroft LJ, De Roos A, Dekkers OM, Huisman MV. Safety of ruling out acute pulmonary embolism by normal computed tomography pulmonary angiography in patients with an indication for computed tomography: systematic review and meta-analysis. J Thromb Haemost 2009; 7: 14918.
  • 63
    Anderson DR, Kahn SR, Rodger MA, Kovacs MJ, Morris T, Hirsch A, Lang E, Stiell I, Kovacs G, Dreyer J, Dennie C, Cartier Y, Barnes D, Burton E, Pleasance S, Skedgel C, O'Rouke K, Wells PS. Computed tomographic pulmonary angiography vs ventilation-perfusion lung scanning in patients with suspected pulmonary embolism: a randomized controlled trial. JAMA 2007; 298: 274353.
  • 64
    Carrier M, Righini M, Wells PS, Perrier A, Anderson DR, Rodger MA, Pleasance S, Le Gal G. Subsegmental pulmonary embolism diagnosed by computed tomography: incidence and clinical implications A systematic review and meta-analysis of the management outcome studies. J Thromb Haemost 2010; 8: 171622.
  • 65
    Le Gal G, Righini M, Parent F, van Strijen M, Couturaud F. Diagnosis and management of subsegmental pulmonary embolism. J Thromb Haemost 2006b; 4: 72431.
  • 66
    Donato AA, Khoche S, Santora J, Wagner B. Clinical outcomes in patients with isolated subsegmental pulmonary emboli diagnosed by multidetector CT pulmonary angiography. Thromb Res 2010; 126: e266e270.
  • 67
    Carrier M. A Study to Evaluate the Safety of Withholding Anticoagulation in Patients With Subsegmental PE Who Have a Negative Serial Bilateral Lower Extremity Ultrasound (SSPE). GovTrials number NCT01455818 ( Accessed 12 December 2012.
  • 68
    Remy-Jardin M, Pistolesi M, Goodman LR, Gefter WB, Gottschalk A, Mayo JR, Sostman HD. Management of suspected acute pulmonary embolism in the era of CT angiography: a statement from the Fleischner Society. Radiology 2007b; 245: 31529.
  • 69
    Kruip MJ, Leclercq MG, van der Heul C, Prins MH, Büller HR. Diagnostic strategies for excluding pulmonary embolism in clinical outcome studies. A systematic review. Ann Intern Med 2003; 138: 94151.
  • 70
    The PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 1990; 263: 27539.
  • 71
    Hull RD, Hirsh J, Carter CJ, Jay RM, Dodd PE, Ockelford PA, Coates G, Gill GJ, Turpie AG, Doyle DJ, Buller HR, Raskob GE. Pulmonary angiography, ventilation lung scanning, and venography for clinically suspected pulmonary embolismwith abnormal perfusion lung scan. Ann Intern Med 1983; 98: 8919.
  • 72
    Sostman HD, Miniati M, Gottschalk A, Matta F, Stein PD, Pistolesi M. Sensitivity and specificity of perfusion scintigraphy combined with chest radiography for acute pulmonary embolism in PIOPED II. J Nucl Med 2008; 49: 17418.
  • 73
    Miniati M, Sostman HD, Gottschalk A, Monti S, Pistolesi M. Perfusion lung scintigraphy for the diagnosis of pulmonary embolism: a reappraisal and review of the prospective investigative study of acute pulmonary embolism diagnosis methods. Semin Nucl Med 2008; 38: 45061.
  • 74
    Stein PD, Freeman LM, Sostman HD, Goodman LR, Woodard PK, Naidich DP, Gottschalk A, Bailey DL, Matta F, Yaekoub AY, Hales CA, Hull RD, Leeper KV Jr, Tapson VF, Weg JG. SPECT in acute pulmonary embolism. J Nucl Med 2009; 50: 19992007.
  • 75
    Oudkerk M, van Beek EJ, Wielopolski P, van Ooijen PM, Brouwers-Kuyper EM, Bongaerts AH, Berghout A. Comparison of contrast-enhanced magnetic resonance angiography and conventional pulmonary angiography for the diagnosis of pulmonary embolism: a prospective study. Lancet 2002; 359: 16437.
  • 76
    Stein PD, Chenevert TL, Fowler SE, Goodman LR, Gottschalk A, Hales CA, Hull RD, Jablonski KA, Leeper KV Jr, Naidich DP, Sak DJ, Sostman HD, Tapson VF, Weg JG, Woodard PK. PIOPED III (Prospective Investigation of Pulmonary Embolism Diagnosis III) Investigators. Gadolinium-enhanced magnetic resonance angiography for pulmonary embolism: a multicenter prospective study (PIOPED III). Ann Intern Med 2010; 152: 43443.
  • 77
    Sostman HD, Jablonski KA, Woodard PK, Stein PD, Naidich DP, Chenevert TL, Weg JG, Hales CA, Hull RD, Goodman LR, Tapson VF. Factors in the technical quality of gadolinium enhanced magnetic resonance angiography for pulmonary embolism in PIOPED III. Int J Cardiovasc Imaging 2012; 28: 30312.
  • 78
    Revel MP, Sanchez O, Couchon S, Planquette B, Hernigou A, Niarra R, Meyer G, Chatellier G. Diagnostic accuracy of magnetic resonance imaging for an acute pulmonary embolism: results of the ‘IRM-EP’ study. J Thromb Haemost 2012; 10: 74350.
  • 79
    Huisman MV, Klok FA. Magnetic resonance imaging for diagnosis of acute pulmonary embolism: not yet a suitable alternative to CT-PA. J Thromb Haemost 2012; 10: 7412.
  • 80
    Le Gal G, Righini M, Roy PM, Sanchez O, Aujesky D, Perrier A, Bounameaux H. Value of D-dimer testing for the exclusion of pulmonary embolism in patients with previous venous thromboembolism. Arch Intern Med 2006c; 166: 17680.
  • 81
    Klok FA, Mos IC, van Kralingen KW, Vahl JE, Huisman MV. Chronic pulmonary embolism and pulmonary hypertension. Semin Respir Crit Care Med 2012; 33: 199204.
  • 82
    Mos ICM, Douma RA, Erkens PMG, Nizet TAC, Durian MF, Hovens MM, van Houten AA, Hofstee HMA, Kooiman J, Klok FA, ten Cate H, Ullmann EF, Büller HR, Kamphuisen PW, Huisman MV. High false negative CTPA rate in patients with clinically suspected recurrent pulmonary embolism managed with a structured algorithm using a clinical decision rule, D-dimer and CT scan – the Repead study. ISTH 2012, abstract 304.
  • 83
    Cogo A, Lensing AW, Koopman MM, Piovella F, Siragusa S, Wells PS, Villalta S, Büller HR, Turpie AG, Prandoni P. Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ 1998; 316: 1720.
  • 84
    Bernardi E, Prandoni P, Lensing AW, Agnelli G, Guazzaloca G, Scannapieco G, Piovella F, Verlato F, Tomasi C, Moia M, Scarano L, Girolami A. D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ 1998; 317: 103740.
  • 85
    Wells PS, Anderson DR, Rodger M, Forgie M, Kearon C, Dreyer J, Kovacs G, Mitchell M, Lewandowski B, Kovacs MJ. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003; 349: 122735.
  • 86
    Schellong SM, Schwarz T, Halbritter K, Beyer J, Siegert G, Oettler W, Schmidt B, Schroeder HE. Complete compression ultrasonography of the leg veins as a single test for the diagnosis of deep vein thrombosis. Thromb Haemost 2003; 89: 22834.
  • 87
    Moores LK, Jackson WL Jr, Shorr AF, Jackson JL. Meta-analysis: outcomes in patients with suspected pulmonary embolism managed with computed tomographic pulmonary angiography. Ann Intern Med 2004; 141: 86674.
  • 88
    Perrier A, Roy PM, Sanchez O, Le Gal G, Meyer G, Gourdier AL, Furber A, Revel MP, Howarth N, Davido A, Bounameaux H. Multidetector-row computed tomography in suspected pulmonary embolism. N Engl J Med 2005; 352: 17608.