Incidence and distribution of lower extremity deep venous thrombosis at indirect computed tomography venography in patients suspected of pulmonary embolism

Indirect computed tomography (CT) venography reportedly provides high accuracy for detection of venous thrombosis in patients suspected of pulmonary embolism (PE). Nevertheless, the extent of the scanning range for lower limb and abdominal veins remains to be determined. It was the objective of this study to investigate the distribution of venous thrombosis in order to identify the most appropriate extent of scanning range when using CT venography. We reviewed 1,408 combined CT pulmonary angiographies (CTPA) and indirect CT venographies of the lower limbs, performed in patients suspected of PE. Percentage of venous thromboembolism (VTE), which includes PE and/or venous thrombosis was calculated. Location and the upper end of clots were recorded in 37 venous segments per patient from calf to diaphragm. PE, venous thrombosis and VTE, were found respectively in 272 (19.3%), 259 (18.4%) and 329 (23.4%) patients. Addition of CT venography to CTPA increased depiction of VTE in 17.3%. The upper end of venous thrombosis was located below the knee in 48%, between knee and inguinal ligament in 36% of the patients, and above the inguinal ligament in 15%. Ninety-six patients had thrombosis in a single vein, of which none occurred above the iliac crests in a patient without PE at CTPA. In conclusion, when added to CTPA, optimal scanning of CT venography should extent from calves to the iliac crests in patients suspected of VTE.     

Diagnostic performance of complete lower limb venous ultrasound in patients with clinically suspected acute pulmonary embolism

A limited ultrasound (US) confined to the popliteal and femoral veins is usually performed to detect deep vein thrombosis (DVT) in patients with clinically suspected acute pulmonary embolism (PE). Our objective was to assess the diagnostic accuracy of complete lower limb US examining both the proximal and distal veins in this setting. In this prospective study, 210 consecutive patients were included. Complete US was performed by independent operators and compared blindly with a reference strategy combining clinical probability, ventilation perfusion scan and pulmonary angiography to a three-month clinical follow-up. Simultaneously, VIDAS D-dimer (DD) assay and helical computed tomography (HCT) of the lungs were assessed independently and blindly. PE was present in 74 patients (35%). Complete US detected DVT in 91 patients (43%), proximal in 51 and distal in 40. Sensitivity and specificity with a 0.95 confidence interval were respectively 0.93 [0.85 - 0.97] and 0.84 [0.77 - 0.89]. Limited US detected DVT in only 46 patients (22%). Sensitivity and specificity were respectively 0.55 [0.44 - 0.66] and 0.96 [0.92 - 0.98]. For DD they were 0.92 [0.83 - 0.96] and 0.24 [0.17 - 0.32] and for HCT 0.84 [0.73 - 0.90] and 0.87 [0.80 - 0.92]. Complete lower limb US has higher sensitivity and capacity to exclude PE than limited US, but a slightly lower specificity. Complete US results also compared favourably with those of HCT and DD. The utility of including this method in diagnostic strategies for PE needs to be assessed in cost-effectiveness analysis and in outcome studies.     

Effect of age on the performance of single detector helical computed tomography in suspected pulmonary embolism

The prevalence of pulmonary embolism increases with age, but reduces the diagnostic yield of ventilation-perfusion lung scan age. Helical computed tomography (hCT) is widely used to diagnose pulmonary embolism, and should be less susceptible to the influence of age. We studied the influence of age on the performance of hCT to verify that hypothesis. We analyzed a database of 299 consecutive outpatients suspected of pulmonary embolism, in whom pulmonary embolism was diagnosed according to accepted criteria, and who were all submitted to a helical CT. We divided the patient population into tertiles, corresponding to the following age categories: less than 59 years (group 1), 60 to 75 years (group 2), and over 75 years (group 3). Sensitivity and specificity of hCT were calculated in each age category. Overall sensitivity was 70% (95% CI: 62 to 78) and specificity was 91% (95% CI: 86 to 95). Sensitivity was 81% (95% CI: 64 to 93) in group 1, 63% (95% CI: 46 to 78) in group 2, and 67 % (95% CI: 52 to 80) in group 3. The corresponding values for specificity were 92% (95% CI: 82 to 97) in group 1, 86% (95% CI: 75 to 94) in group 2 and 96% (95% CI: 87 to 100) in group 3. Positive predictive values ranged from 75% to 94% and negative predictive values from 77% to 94%. Our data suggest that age does not have a marked influence on the diagnostic performances of hCT in clinically suspected pulmonary embolism.     

Spiral computed tomography for the diagnosis of acute pulmonary embolism

The accuracy of computed tomography (CT) imaging for the diagnosis of acute pulmonary embolism (PE) was reviewed. Single detector CT, based on pooled data, showed a sensitivity of 73% and multidetector CT, mostly 4-slice, showed a sensitivity of 83%. Respective specificities were 87% and 96%. Among patients with suspected PE evaluated with single slice CT, 20% of patients found to have venous thromboembolic disease were diagnosed on the basis of a positive CT venous phase venogram. With multislice CT, 14% were diagnosed on the basis of a positive CT venogram. The positive likelihood ratio with single detector CT was 5.7 and with multidetector CT it was 19.6. Respective negative likelihood ratios were 0.31 and 0.18. Calculations of post-test probability using pretest probability and likelihood ratios according to Bayes' theorem showed that even with multidetector CT, false positive and false negative images are not uncommon when clinical assessment is discordant with the CT interpretation. Outcome studies showed recurrent PE in only 1.7% or fewer untreated patients with negative CT pulmonary angiograms.     

Diagnostic management of pulmonary embolism using clinical assessment, plasma D-dimer assay, complete lower limb venous ultrasound and helical computed tomography of pulmonary arteries. A multicentre clinical outcome study

The objective of the study was to assess the clinical validity of a non-invasive diagnostic strategy for acute pulmonary embolism using clinical assessment combined with both ELISA D-dimer and complete lower limb ultrasound (US) examination of proximal and distal veins, before single-detector helical computed tomography (CT) of pulmonary arteries. We expected the strategy to have a high diagnostic exclusion power and to safely decrease the number of CT scans. This prospective, multicenter outcome study included 274 consecutive outpatients. All underwent a priori clinical probability, D-dimer and bilateral complete lower limb US assessments. Only patients with a high clinical probability and both tests negative, or positive D-dimer and negative US assessments, underwent CT. This was deemed necessary in 114 patients (42%). At baseline, venous thromboembolism (VTE) was detected in 110 patients (40%), either by US showing proximal (n=65) or distal (n=36) thrombosis, or by CT (n=9). Anticoagulant was withheld in the remaining patients with negative results in both D-dimer and US but a non-high clinical probability (n=59), or in both US and CT (n=90), or with negative US (n=6) and inadequate CT (n=9). All patients underwent a three-month clinical follow-up. VTE occurred in one patient with inadequate CT, yielding an incidence of 0.6% [95% confidence interval: 0.1-3.4]. No patient died from VTE or had major bleeding. Using clinical probability, ELISA D-dimer and complete US before helical CT is a safe strategy resulting in a substantial reduction in CT scans.     

The value of 64-detector row computed tomography for the exclusion of pulmonary embolism

Identification of patients at high risk of recurrence after a first event of venous thromboembolism (VTE) remains difficult. Resistance to activated protein C (APC) is a known risk factor for VTE, but data on the risk of recurrence is controversial. We wanted to investigate whether APC resistance in the absence of factor V Leiden, determined with global coagulation test such as the thrombin generation assay, could be used as a marker for increased risk of recurrent VTE among women 18-65 years old after a first event of VTE. In a cohort of 243 women with a first event of VTE, plasma was collected after discontinuation of anticoagulant treatment and the patients were followed up for 46 months (median). Thrombin generation was measured via calibrated automated thrombography, at 1 pM and 10 pM of tissue factor (TF). In women without factor V Leiden (n=117), samples were analysed in the absence and in the presence of APC. Increase in ETP (endogenous thrombin potential) and peak height analysed in the presence of APC correlated significantly with higher risk of recurrence. At 1 pM, peak height correlated with increased risk of recurrence. In conclusion, high thrombin generation in the presence of APC, in women after a first event of VTE is indicative for an increased risk of a recurrence. We also found that thrombin generation at low TF (1 pM) is correlated with the risk of recurrence. Our data suggest that APC resistance in the absence of factor V Leiden is a risk factor for recurrent VTE.     

Clinical usefulness of D-dimer testing in cancer patients with suspected pulmonary embolism

Limited data are available about the diagnostic value of D-dimer testing in cancer patients with clinically suspected pulmonary embolism (PE). Therefore, we evaluated i) the safety and clinical usefulness of an ELISA D-dimer test to rule out PE in cancer patients compared with non-cancer patients and ii) whether adopting a higher D-dimer cut-off value might increase the usefulness of D-dimer in cancer patients. We analysed data from two outcome studies which enrolled 1,721 consecutive patients presenting in the emergency department with clinically suspected PE. Presence of an active malignancy was abstracted from the database. All patients underwent a sequential diagnostic work-up including an ELISA D-dimer test and a 3-month followup. Sensitivity and predictive value (NPV) were 100% in both cancer and non-cancer patients. PE was ruled out by a negative D-dimer test in 494/1,554 (32%) patients without cancer, and in 18/164 (11%) patients with a malignancy. At cut-off values varying from 500 to 900 microg/l, the sensitivity was unchanged (100%, 95% CI: 93% to 100%) and the specificity increased from 16% (95% CI: 11% to 24%) to 30% (95% CI: 22% to 39%). The 3-month thromboembolic risk was 0% (95% CI: 0% to 18%) in cancer patients with a negative D-dimer test. ELISA D-dimer appears safe to rule out pulmonary embolism in cancer patients but it is negative in only one of ten patients at the usual cut-off value. Increasing the cut-off value of D-dimer in cancer patients might increase the test's clinical usefulness.     

The diagnostic value of compression ultrasonography in patients with suspected recurrent deep vein thrombosis

Diagnosis of recurrent deep-vein thrombosis (DVT) is difficult because of limitations in distinguishing acute from old thrombi. In the past, an ultrasound method for diagnosis of recurrent ipsilateral DVT was developed, which relies on repeated measurements of the diameters of the common femoral and popliteal veins. To assess the safety of withholding anticoagulation from patients with improved or stable compression vein diameters, 205 consecutive patients presenting with suspected recurrent ipsilateral DVT were evaluated. The vein diameter was measured under compression with the transducer and compared with earlier ultrasound results. Patients with stable or improved ultrasound findings had repeat ultrasound assessments after 2 (+/- 1) and 7 (+/- 1) days. Patients with repeatedly normal ultrasound results were followed-up for six months to determine the incidence of symptomatic recurrent venous thromboembolism. Of the 205 patients, 153 had stable or improved ultrasound findings. Repeat ultrasound assessment became abnormal in 3, and recurrence was confirmed by venography in all. A six months follow-up was done in the remaining 150 patients with repeatedly normal ultrasound tests and showed 2 (1.3%; 95% CI, 0.02 to 4.7%) confirmed non-fatal venous thromboembolic complications. The positive predictive value of a stable or improved ultrasound was 90% (95% CI, 77 to 97%). In conclusion, it is safe to withhold anticoagulant treatment from patients with suspected recurrent ipsilateral DVT in whom compression ultrasonography showed improved or stable vein diameters.     

The interobserver reliability of pretest probability assessment in patients with suspected pulmonary embolism

INTRODUCTION: Pretest probability assessment and objective testing are combined to appropriately manage patients with suspected pulmonary embolism (PE). However, the interobserver reliability of pretest probability assessment has not been investigated. We sought to determine (for patients with suspected PE) the interobserver reliability of pretest probability assessment (by overall impression (gestalt) versus an explicit clinical model). MATERIALS AND METHODS: A prospective cohort study was conducted at an urban university hospital. For patients referred for ventilation and perfusion (V/Q) scanning for suspected PE, structured assessments (11 history and 4 physical examination parameters) were performed by a referring physician and a designated thrombosis physician. The referring and thrombosis physicians also assigned a pretest probability for PE (low, moderate, or high) by gestalt. An explicit seven-point clinical model for suspected PE was later applied to each structured assessment to determine the pretest probability. Assessments were performed independently and prior to diagnostic test results. Interobserver reliability (two rater unweighted Kappa (kappa) statistic) was determined for each parameter on the structured assessment and the pretest probability assessments (gestalt vs. explicit clinical model). RESULTS: One hundred and ten patients with suspected PE received duplicate assessments. Historical features demonstrated substantial to almost perfect interobserver reliability (kappa=0.60-0.95). For the physical findings, only heart rate had substantial interobserver reliability (kappa=0.60). Pretest probability assessment was not reliable when using physician's gestalt (kappa=0.33), but produced substantial interobserver reliability using the explicit clinical model (kappa=0.62). CONCLUSIONS: Given the inadequate interobserver reliability of pretest probability assessment by overall impression (or gestalt), physicians should use explicit clinical models in the diagnostic management of patients with suspected pulmonary embolism.     

Observer dependency of the SimpliRed D-dimer assay in 81 consecutive patients with suspected pulmonary embolism

The SimpliRed D-dimer assay is a whole blood agglutination test for the exclusion of pulmonary embolism (PE) and has been advocated as a reliable rapid bedside alternative to more time-consuming quantitative assays. However, widely differing negative predictive values (77-100%) are reported. This study assessed the intra- and interobserver variability as a possible cause for this wide accuracy range and evaluated the accuracy of the SimpliRed test in 81 consecutive patients with clinically suspected PE. Absolute D-dimer concentration was measured using the Tinaquant (Roche Diagnostics GmbH, Mannheim, Germany) assay. Every assay was immediately scored by one observer and then photographed. Photos were randomised and read twice by two other independent observers. The intraobserver reproducibility was good: kappa=0.81 and 0.73. However, we found poor interobserver reproducibility with kappa=0.47. This seems due to the fact that the SimpliRed test proved difficult to interpret in the 0.3-1.3 microg/mL plasma concentration D-dimer range, which contained 32/81 (40%) patients, 8 of whom had PE. Using pulmonary angiograms and ventilation perfusion lung scans with a concurrent spiral computed tomography scan as a gold standard (25 patients had PE), SimpliRed's accuracy to exclude PE was moderate, with negative predictive values of 0.78 and 0.84. In particular, the two observers scored the SimpliRed test as normal in 12 of 25 and 5 of 25 patients with proven PE. We conclude that SimpliRed is strongly observer-dependent. This explains the varying sensitivities for the detection of venous thromboembolism as reported in previous studies.     

Improvements in the diagnostic approach for patients with suspected deep vein thrombosis or pulmonary embolism

Recent advances in the management of patients with suspected VTE have resulted in improvements in the diagnostic testing accuracy and the development of management algorithms that are safer and more accessible. Ongoing clinical trials are evaluating whether these diagnostic management strategies can be made even simpler and less expensive. Diagnostic procedures for VTE continue to be refined, and modalities, such as magnetic resonance imaging and spiral CT, have the potential to further increase the accuracy of the investigation approach. There is still need to improve management strategies for the diagnosis of recurrent venous thrombosis and to determine whether diagnostic testing results may be correlated with long-term patient treatment needs.     

Plasma levels of microparticle-associated tissue factor activity in patients with clinically suspected pulmonary embolism

Introduction

Microparticles (MPs) carrying active tissue factor (TF) have been detected in the plasma of cancer patients in particular in those presenting with acute deep vein thrombosis (DVT) or pulmonary embolism (PE). Experimental studies in mice have revealed that circulating MPs carrying TF contribute to thrombus formation.

Aim

To study whether unselected patients with an acute confirmed PE have elevated TF activity in the MP fraction (MP-TF activity).

Materials and Methods

Plasma MP-TF activity was measured in 159 non-selected patients with clinically suspected PE and in 48 healthy controls as previously described. Blood was collected at time of inclusion. The diagnosis of acute PE was confirmed in 54 patients and excluded in 105 patients.

Results

Median MP-TF activity in 159 patients with clinically suspected PE was 72 fM Xa/min [range 32-6657] fM Xa/min and higher than in healthy controls (66 [range 28-183] fM Xa/min; P < 0.05). There was no significant difference (P = 0.169) in MP-TF activity between patients with confirmed PE (median 84.5 fM Xa/min [range 36-2149]) and patients without PE (72 fM Xa/min [range 32-6657]) fM Xa/min). In the 159 patients with clinically suspected PE we observed in an exploratory analysis higher MP-TF activity levels in patients with active cancer (median 137 fM Xa/min [range 36-6657]) and cardiovascular disease (median 131.5 fM Xa/min [range 45-2149]) than in patients without these disorders (P = 0.0004 and P = 0.014, respectively).

Conclusion

In patients presenting with clinically suspected PE plasma MP-TF activity was not associated with confirmed PE.     

The predictive value of heart-type fatty acid-binding protein is independent from symptom duration in normotensive patients with pulmonary embolism

Background

Heart-type fatty acid-binding protein (H-FABP) is a useful biomarker for risk stratification of patients with pulmonary embolism (PE). In patients with acute myocardial infarction, H-FABP plasma concentrations rise after 30 minutes and return to normal within 20-24 hours. We tested whether the predictive value of H-FABP is affected by the duration of symptoms prior to diagnosis in patients with PE.

Material and Methods

We prospectively studied 257 consecutive normotensive patients with confirmed symptomatic PE.

Results

Patients with acute (< 24 hours; n = 150) symptom onset presented more often with syncope (28.7% vs. 6.5%; p < 0.001) compared to patients with symptoms ≥ 24 hours (n = 107); other baseline characteristics, comorbidities, and risk factors were distributed equally. Patients with an adverse 30-day outcome (6.6%) had higher H-FABP levels (11.84 [3.57-19.62] ng/ml) compared to patients with a favorable course (3.42 [1.92-5.42] ng/ml; p < 0.001). However, the proportion of patients with H-FABP levels ≥ 6 ng/ml did not differ among patients with acute symptom onset and late presentation (p = 0.104). Only tachycardia and elevation of H-FABP were associated with an increased risk of an adverse 30-day outcome both in patients with acute symptom onset (H-FABP: OR, 5.8; 95% CI, 1.4-24.5; p = 0.016; tachycardia: 7.0 [1.4-36.0]; p = 0.018) and late presentation (H-FABP: 9.3 [2.0-43.2]; p = 0.004 and tachycardia: 12.3 [1.5-103.6]; p = 0.021). The prognostic value could further be improved by the use of a simple H-FABP-based clinical prediction score.

Conclusions

Our findings indicate that H-FABP is a useful biomarker for risk stratification of normotensive patients with PE regardless of symptom duration prior to diagnosis.     

Prognostic implications of computed tomographic right ventricular dilation in patients with acute pulmonary embolism

Introduction

Whether right ventricular (RV) dilation on computerized tomography (RVD-CT) is a useful predictor for clinical outcomes of acute pulmonary embolism (PE) remains debatable. Furthermore, data regarding the best combination of prognostic markers for predicting the adverse outcome of PE are limited.

Materials and Methods

The authors retrospectively reviewed 657 consecutive patients hospitalized at a tertiary referral center with a diagnosis of PE based on multi-detector row CT scan.

Results

Patients were allocated into an adverse outcome group (11% [n = 69]) or a low risk group (89% [n = 588]). Multivariate analysis showed that RVD-CT (RV/left ventricle [LV] diameter ratio ≥ 1), high pulmonary embolism severity index (PESI) score (class IV-V), high N-terminal-pro-B-type natriuretic peptide (NT-proBNP,≥1,136 pg/ml), and elevated troponin I (≥ 0.05 ng/ml) significantly predicted an adverse outcome (odds ratio [OR] 6.26, 95% confidence interval [CI] 2.74-14.31, p < 0.001; OR 4.71, 95% CI 2.00-11.07, p < 0.001; OR 2.71, 95% CI 1.15-6.39, p = 0.023; and OR 3.00, 95% CI 1.27-7.07, p = 0.012, respectively). The addition of RVD-CT to PESI, NT-proBNP, troponin I or their combinations enhanced the positive predictive values and positive likelihood ratios of an adverse outcome.

Conclusions

RVD-CT could be an independent prognostic factor of adverse outcomes in patients with acute PE, and provides additional prognostic value when combined with other prognostic factors.     

The performance of two rapid quantitative D-dimer assays in 287 patients with clinically suspected pulmonary embolism

Context: Objective tests are necessary for the diagnosis of pulmonary embolism (PE). D-dimer assays have been suggested as useful screening tests to exclude this diagnosis. Objective: To compare the diagnostic accuracy of two rapid quantitative D-dimers in patients with suspected pulmonary embolism. Design: Plasma D-dimer levels were measured using two commercially available assays (Tinaquant® and Vidas®). A strict imaging protocol was used to arrive at a final diagnosis of PE or deep venous thrombosis (DVT). Setting: Multicenter study in six Dutch referral centers. Patients: A total of 287 in- and outpatients with clinically suspected pulmonary embolism. Main outcome measures: Diagnostic accuracy indices for the two assays were calculated and additional receiver-operated characteristics (ROC) analysis was performed. Results: Using the manufacturer's advised cutoff values, the sensitivity and specificity were 88% and 52% for Vidas and 82% and 61% for Tinaquant, respectively. These differences were statistically significant (McNemar, P<0.0001). However, no statistical differences were found between the two assays using ROC analysis (AUC=0.78 for both assays). Conclusions: Both quantitative D-dimer tests had similar diagnostic accuracy; however, at the manufacturer's advised cutoff level, Vidas performed significantly better. Nevertheless, to safely exclude pulmonary embolism, D-dimer assays should be combined with other diagnostic tests.