Search

Clinical probability and D-dimer measurement play an essential role in the non-invasive diagnostic strategies for pulmonary embolism (PE). PE can be ruled out without further imaging in patients with non-high clinical probability and negative D-dimer. D-dimer level is increased in patients with renal impairment. Whether its diagnostic usefulness is maintained in these patients is not well determined. We aimed to evaluate the effects of renal impairment on diagnostic performances of D-dimer in patients with suspected PE. A retrospective analysis of 1,625 patients with suspected PE included in a multicentre prospective study was performed. D-dimer levels and percentages of patients with a negative D-dimer were compared between three subgroups according to glomerular filtration rate (GFR) estimated by the MDRD formula: ≥90 ml/min (normal renal function), 60-89 ml/min (mild renal impairment), 30-59 ml/min (moderate renal impairment). D-dimer levels increased and the proportion of negative D-dimer decreased significantly according to renal status: 46% negative D-dimer in patients with normal GFR, 31% in patients with mild renal impairment, 11% in those with moderate renal impairment, corresponding to number of patients needed to test to obtain one negative test of 2.2, 3.2 and 9, respectively. In conclusion, the clinical usefulness of D-dimer decreases with renal impairment. However, PE can still be ruled out by negative D-dimer in a substantial proportion of patients with non-high clinical probability, avoiding exposure to contrast media.

Importance: D-dimer measurement is an important step in the diagnostic strategy of clinically suspected acute pulmonary embolism (PE), but its clinical usefulness is limited in elderly patients., Objective: To prospectively validate whether an age-adjusted D-dimer cutoff, defined as age × 10 in patients 50 years or older, is associated with an increased diagnostic yield of D-dimer in elderly patients with suspected PE., Design, Settings, and Patients: A multicenter, multinational, prospective management outcome study in 19 centers in Belgium, France, the Netherlands, and Switzerland between January 1, 2010, and February 28, 2013., Interventions: All consecutive outpatients who presented to the emergency department with clinically suspected PE were assessed by a sequential diagnostic strategy based on the clinical probability assessed using either the simplified, revised Geneva score or the 2-level Wells score for PE; highly sensitive D-dimer measurement; and computed tomography pulmonary angiography (CTPA). Patients with a D-dimer value between the conventional cutoff of 500 µg/L and their age-adjusted cutoff did not undergo CTPA and were left untreated and formally followed-up for a 3-month period., Main Outcomes and Measures: The primary outcome was the failure rate of the diagnostic strategy, defined as adjudicated thromboembolic events during the 3-month follow-up period among patients not treated with anticoagulants on the basis of a negative age-adjusted D-dimer cutoff result., Results: Of the 3346 patients with suspected PE included, the prevalence of PE was 19%. Among the 2898 patients with a nonhigh or an unlikely clinical probability, 817 patients (28.2%) had a D-dimer level lower than 500 µg/L (95% CI, 26.6%-29.9%) and 337 patients (11.6%) had a D-dimer between 500 µg/L and their age-adjusted cutoff (95% CI, 10.5%-12.9%). The 3-month failure rate in patients with a D-dimer level higher than 500 µg/L but below the age-adjusted cutoff was 1 of 331 patients (0.3% [95% CI, 0.1%-1.7%]). Among the 766 patients 75 years or older, of whom 673 had a nonhigh clinical probability, using the age-adjusted cutoff instead of the 500 µg/L cutoff increased the proportion of patients in whom PE could be excluded on the basis of D-dimer from 43 of 673 patients (6.4% [95% CI, 4.8%-8.5%) to 200 of 673 patients (29.7% [95% CI, 26.4%-33.3%), without any additional false-negative findings., Conclusions and Relevance: Compared with a fixed D-dimer cutoff of 500 µg/L, the combination of pretest clinical probability assessment with age-adjusted D-dimer cutoff was associated with a larger number of patients in whom PE could be considered ruled out with a low likelihood of subsequent clinical venous thromboembolism., Trial Registration: clinicaltrials.gov Identifier: NCT01134068.

Background: D-dimer testing to rule out deep vein thrombosis is less useful in older patients because of a lower specificity. An age-adjusted D-dimer cut-off value increased the proportion of older patients (>50 years) in whom pulmonary embolism could be excluded. We retrospectively validated the efficacy of this cut-off combined with clinical probability for the exclusion of deep vein thrombosis., Design and Methods: Five management study cohorts of 2818 consecutive outpatients with suspected deep vein thrombosis were used. Patients with non-high or unlikely probability of deep vein thrombosis were included in the analysis; four different D-dimer tests were used. The proportion of patients with a normal D-dimer test and the failure rates were calculated using the conventional (500 μg/L) and the age-adjusted D-dimer cut-off (patient's age x 10 μg/L in patients >50 years)., Results: In 1672 patients with non-high probability, deep vein thrombosis could be excluded in 850 (51%) patients with the age-adjusted cut-off value versus 707 (42%) patients with the conventional cut-off value. The failure rates were 7 (0.8; 95% confidence interval 0.3-1.7%) for the age-adjusted cut-off value and 5 (0.7%, 0.2-1.6%) for the conventional cut-off value. The absolute increase in patients in whom deep vein thrombosis could be ruled out using the age-adjusted cut-off value was largest in patients >70 years: 19% among patients with non-high probability., Conclusions: The age-adjusted cut-off of the D-dimer combined with clinical probability greatly increases the proportion of older patients in whom deep vein thrombosis can be safely excluded.

The diagnosis of venous thromboembolism has evolved considerably with the development of standardized diagnostic algorithms that include clinical probability assessment, D-dimer measurement and the use of non-invasive imaging modalities such as compression ultrasonography and computed tomography angiography. The implementation of these strategies aims to improve resource allocation and patient outcome. The judicious use of these diagnostic tools requires a thorough knowledge of the appropriate clinical setting in which every test and strategy is efficient and can be used safely. For this purpose, D-dimer measurement and compression ultrasonography are complementary: the former is mainly used to exclude VTE in selected patients, while the latter is used to confirm the presence of an underlying DVT. This review provides an appraisal of the features and use of D-dimer and compression ultrasonography in the context of suspected venous thromboembolism.

Objectives: In older patients, the the D-dimer test for pulmonary embolism has reduced specificity and is therefore less useful. In this study a new, age dependent cut-off value for the test was devised and its usefulness with older patients assessed., Design: Retrospective multicentre cohort study., Setting: General and teaching hospitals in Belgium, France, the Netherlands, and Switzerland. Patients 5132 consecutive patients with clinically suspected pulmonary embolism., Intervention: Development of a new D-dimer cut-off point in patients aged >50 years in a derivation set (data from two multicentre cohort studies), based on receiver operating characteristics (ROC) curves. This cut-off value was then validated with two independent validation datasets., Main Outcome Measures: The proportion of patients in the validation cohorts with a negative D-dimer test, the proportion in whom pulmonary embolism could be excluded, and the false negative rates., Results: The new D-dimer cut-off value was defined as (patient's agex10) microg/l in patients aged >50. In 1331 patients in the derivation set with an "unlikely" score from clinical probability assessment, pulmonary embolism could be excluded in 42% with the new cut-off value versus 36% with the old cut-off value (<500 microg/l). In the two validation sets, the increase in the proportion of patients with a D-dimer below the new cut-off value compared with the old value was 5% and 6%. This absolute increase was largest among patients aged >70 years, ranging from 13% to 16% in the three datasets. The failure rates (all ages) were 0.2% (95% CI 0% to 1.0%) in the derivation set and 0.6% (0.3% to 1.3%) and 0.3% (0.1% to 1.1%) in the two validation sets., Conclusions: The age adjusted D-dimer cut-off point, combined with clinical probability, greatly increased the proportion of older patients in whom pulmonary embolism could be safely excluded.

Twenty years after its first use in the diagnostic workup of suspected venous thromboembolism (VTE), fibrin D-dimer (DD) testing has gained wide acceptance for ruling out this disease. The test is particularly useful in the outpatient population referred to the emergency department because of suspected deep vein thrombosis (DVT) or pulmonary embolism (PE), in which the ruling out capacity concerns every third patient clinically suspected of having the disease. This usefulness is based on the high sensitivity of the test to the presence of VTE, at least for some assays. Due to its poor specificity precluding its use for ruling in VTE, DD testing must be integrated in comprehensive, sequential diagnostic strategies that include clinical probability assessment and imaging techniques such as lower limb venous compression ultrasonography for suspected DVT or multi-slice helical computed tomography for suspected PE. The present narrative review updates the data available on the use of the various commercially available DD assays in the diagnostic approach of clinically suspected VTE in distinct patient populations or situations, including outpatients and inpatients, patients with cancer, older age, pregnancy, a suspected recurrent event, limited thrombus burden, and patients already on anticoagulant treatment.

Background: Multislice CT (MSCT) combined with D-dimer measurement can safely exclude pulmonary embolism in patients with a low or intermediate clinical probability of this disease. We compared this combination with a strategy in which both a negative venous ultrasonography of the leg and MSCT were needed to exclude pulmonary embolism., Methods: We included 1819 consecutive outpatients with clinically suspected pulmonary embolism in a multicentre non-inferiority randomised controlled trial comparing two strategies: clinical probability assessment and either D-dimer measurement and MSCT (DD-CT strategy [n=903]) or D-dimer measurement, venous compression ultrasonography of the leg, and MSCT (DD-US-CT strategy [n=916]). Randomisation was by computer-generated blocks with stratification according to centre. Patients with a high clinical probability according to the revised Geneva score and a negative work-up for pulmonary embolism were further investigated in both groups. The primary outcome was the 3-month thromboembolic risk in patients who were left untreated on the basis of the exclusion of pulmonary embolism by diagnostic strategy. Clinicians assessing outcome were blinded to group assignment. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00117169., Findings: The prevalence of pulmonary embolism was 20.6% in both groups (189 cases in DD-US-CT group and 186 in DD-CT group). We analysed 855 patients in the DD-US-CT group and 838 in the DD-CT group per protocol. The 3-month thromboembolic risk was 0.3% (95% CI 0.1-1.1) in the DD-US-CT group and 0.3% (0.1-1.2) in the DD-CT group (difference 0.0% [-0.9 to 0.8]). In the DD-US-CT group, ultrasonography showed a deep-venous thrombosis in 53 (9% [7-12]) of 574 patients, and thus MSCT was not undertaken., Interpretation: The strategy combining D-dimer and MSCT is as safe as the strategy using D-dimer followed by venous compression ultrasonography of the leg and MSCT for exclusion of pulmonary embolism. An ultrasound could be of use in patients with a contraindication to CT.

Purpose of Review: To discuss reports published in 2005 on the diagnosis of clinically suspected nonmassive pulmonary embolism., Recent Findings: Progress has been made in assessing the clinical probability of pulmonary embolism, in addressing diagnosis in the elderly, in evaluating the diagnostic performance of single-detector and multidetector row helical computed tomography, and in the role of D-dimer measurement and lower limb venous compression ultrasonography in the diagnostic work-up of pulmonary embolism., Summary: Diagnosing venous thromboembolism depends mainly on noninvasive diagnostic tools that are used sequentially. In most patients, a noninvasive work-up is feasible and the diagnostic algorithms are becoming simpler. This review focuses on developments in clinical probability assessment, pulmonary embolism in the elderly, potential new uses of D-dimer measurement, advent of multidetector row helical computed tomography, and utility of ultrasonography in detecting deep vein thrombosis in patients with suspected pulmonary embolism. With the development of potentially more sensitive diagnostic tests for pulmonary embolism, physicians are now facing the risk of overdiagnosis and hence overtreatment. The issue will no longer be just to detect clots but to identify patients who must be treated using anticoagulants, a complicated question.

Background: Elevated plasma D-dimer and factor VIII coagulant activity (FVIIIc) may be associated with the risk of recurrent venous thromboembolism (VTE)., Objectives: To evaluate D-dimer and FVIIIc as risk factors for recurrent VTE and assess the efficacy of extended low-intensity warfarin (target International Normalized Ratio 1.5-2.0) in preventing recurrence by biomarker level., Patients and Methods: In the Prevention of Recurrent Venous Thromboembolism trial, 508 idiopathic VTE patients treated for > or = 3 months with full-intensity warfarin, and who had stopped warfarin for 7 weeks on average, were randomized to low-intensity warfarin or placebo and followed for 2.1 years for recurrent VTE. Prerandomization blood samples were analysed for D-dimer and FVIIIc., Results: One-third of participants had elevated baseline D-dimer (> or = 500 ng mL(-1)) and one-fourth, elevated FVIIIc (> or = 150 IU dL(-1)). Adjusting for other risk factors, the hazard ratios (HRs) for recurrent VTE with elevated D-dimer or FVIIIc were 2.0 [95% confidence interval (CI) 1.2-3.4] and 1.5 (95% CI 0.8-2.8), respectively. The association of elevated D-dimer with recurrence was larger among patients with one prior VTE (HR 3.2, 95% CI 1.3-8.0) than in patients with more than one event (HR 1.4, 95% CI 0.7-2.2). For patients with one prior VTE on placebo, the annual recurrence incidence was 10.9% with elevated D-dimer and 2.9% with normal values. Low-intensity warfarin was equally effective in recurrence risk reduction in those with normal or elevated biomarkers., Conclusions: Among patients with idiopathic VTE, measurement of D-dimer, but not FVIIIc, might be useful for risk stratification. The efficacy of extended low-intensity warfarin therapy did not vary by biomarker level.

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.

Background: D-dimer levels remain elevated in many patients after completion of a 6-month anticoagulant drug course for a first episode of venous thromboembolism (VTE), which may limit the clinical usefulness of D-dimer testing for ruling out a possible recurrence., Methods: We assessed the safety and usefulness of D-dimer testing in patients with suspected pulmonary embolism (PE) who had experienced a previous VTE. We analyzed data from 2 outcome studies that enrolled 1721 consecutive emergency department patients with clinically suspected PE. Information on the existence of a previous episode of VTE was abstracted from the database. All the patients underwent a sequential diagnostic workup, including an enzyme-linked immunosorbent assay D-dimer test and a 3-month follow-up., Results: The proportion of confirmed PE was 24.1% (415/1719); PE was ruled out by a negative D-dimer test result in 32.7% (462/1411) of the patients without previous VTE but in only 15.9% (49/308) of the patients with previous VTE (P<.001). The 3-month thromboembolic risk was 0% (95% confidence interval, 0.0%-7.9%) in patients with previous VTE and a negative D-dimer test result. The 2-fold lower chance of a negative D-dimer test result in patients with previous VTE was independent of older age, active malignancy, fever, and recent surgery., Conclusions: In patients with suspected PE and previous VTE, a negative D-dimer test result seems to allow safely ruling out a recurrent event. However, the proportion of negative results is lower in such patients, definitely reducing the clinical usefulness of the D-dimer test in that subgroup.

Background: Single-detector-row computed tomography (CT) has a low sensitivity for pulmonary embolism and must be combined with venous-compression ultrasonography of the lower limbs. We evaluated whether the use of D-dimer measurement and multidetector-row CT, without lower-limb ultrasonography, might safely rule out pulmonary embolism., Methods: We included 756 consecutive patients with clinically suspected pulmonary embolism from the emergency departments of three teaching hospitals and managed their cases according to a standardized sequential diagnostic strategy. All patients were followed for three months., Results: Pulmonary embolism was detected in 194 of the 756 patients (26 percent). Among the 82 patients with a high clinical probability of pulmonary embolism, multidetector-row CT showed pulmonary embolism in 78, and 1 patient had proximal deep venous thrombosis and a CT scan that was negative for pulmonary embolism. Of the 674 patients without a high probability of pulmonary embolism, 232 (34 percent) had a negative D-dimer assay and an uneventful follow-up; CT showed pulmonary embolism in 109 patients. CT and ultrasonography were negative in 318 patients, of whom 3 had a definite thromboembolic event and 2 died of possible pulmonary embolism during follow-up (three-month risk of thromboembolism, 1.7 percent; 95 percent confidence interval, 0.7 to 3.9). Two patients had proximal deep venous thrombosis and a negative CT scan (risk, 0.6 percent; 95 percent confidence interval, 0.2 to 2.2). The overall three-month risk of thromboembolism in patients without pulmonary embolism would have been 1.5 percent (95 percent confidence interval, 0.8 to 3.0) if the D-dimer assay and multidetector-row CT had been the only tests used to rule out pulmonary embolism and ultrasonography had not been performed., Conclusions: Our data indicate the potential clinical use of a diagnostic strategy for ruling out pulmonary embolism on the basis of D-dimer testing and multidetector-row CT without lower-limb ultrasonography. A larger outcome study is needed before this approach can be adopted., (Copyright 2005 Massachusetts Medical Society.)

Background: We evaluated whether a highly sensitive D-dimer test is clinically useful and safe for ruling out pulmonary embolism (PE) in patients with a high clinical probability and whether adopting different cutoff values according to the clinical probability category might increase the proportion of patients in whom PE is ruled out., Methods: We retrospectively analyzed the databases of 2 outcome studies on the diagnosis of PE with a 3-month follow-up that included 1409 patients. We evaluated the usefulness of D-dimer testing by calculating the number needed to test to rule out one PE, and its safety by measuring the 3-month thromboembolic risk in patients not treated by anticoagulant agents based on a normal D-dimer level., Results: The sensitivity of D-dimer was 100% in all clinical probability categories, but the number needed to test increased with increasing clinical probability of PE. The 95% confidence interval (0%-23%) of the 3-month thromboembolic risk (0%) among 13 of 121 patients with a normal D-dimer level and a high clinical probability of PE was wide. Increasing the cutoff value to 700 mug/L in patients with a low clinical probability would rule out PE in an additional 5% of the entire patient cohort at the expense of a lower sensitivity (93% [95% confidence interval, 83%-97%])., Conclusions: The safety of D-dimer testing in patients with a high clinical probability of PE is not established, and testing results are rarely negative in such patients. Increasing the enzyme-linked immunosorbent assay D-dimer cutoff value only marginally increased the test's usefulness.

To evaluate the performances of a new D-dimer assay, Stratus CS D-dimer (Dade Behring, Newark, Delaware, USA), for the exclusion of venous thromboembolism and to determine the best cut-off values. This test relies on a sandwich enzyme-linked immunosorbent assay with a fluorogenic substrate in a radial partition immunoassay system in a dedicated device. It does not require laboratory staff and the results are available within 18 min. Two hundred and ninety-one frozen samples from patients suspected of either deep venous thrombosis (n = 137) or pulmonary embolism (n = 154) were measured and the results compared with the VIDAS D-dimer New assay. There were 37 deep venous thrombosis (27%) and 49 pulmonary embolism (32%) samples. Receiver-operating characteristic curve analysis indicated that the cut-off value could be set at either 300 or 400 ng/ml Fibrinogen Equivalent Units (FEU). The coefficient of variation determined with a lyophilized low-level control plasma (305 ng/ml FEU) was 6%. With a cut-off at 300 ng/ml FEU, the sensitivity, the specificity and the negative predictive value were 100% [95% confidence interval (CI), 95.8-100], 33.1% (95% CI, 26.8-40) and 100% (95% CI, 94.7-100), respectively. Raising the cut-off to 400 ng/ml FEU, the corresponding figures were 96.5% (95% CI, 90.1-99.3), 46.3% (95% CI, 39.4-53.2) and 96.9% (95% CI, 91.3-99.4), respectively. At 400 ng/ml, three results were false-negative, one with both devices and two with the Stratus D-dimer only. Stratus D-dimer appears to be suitable for the exclusion of venous thromboembolism in the emergency room setting., (Copyright 2004 Lippincott Williams and Wilkins)

Purpose: To evaluate a diagnostic strategy for pulmonary embolism that combined clinical assessment, plasma D-dimer measurement, lower limb venous ultrasonography, and helical computed tomography (CT)., Methods: A cohort of 965 consecutive patients presenting to the emergency departments of three general and teaching hospitals with clinically suspected pulmonary embolism underwent sequential noninvasive testing. Clinical probability was assessed by a prediction rule combined with implicit judgment. All patients were followed for 3 months., Results: A normal D-dimer level (<500 microg/L by a rapid enzyme-linked immunosorbent assay) ruled out venous thromboembolism in 280 patients (29%), and finding a deep vein thrombosis by ultrasonography established the diagnosis in 92 patients (9.5%). Helical CT was required in only 593 patients (61%) and showed pulmonary embolism in 124 patients (12.8%). Pulmonary embolism was considered ruled out in the 450 patients (46.6%) with a negative ultrasound and CT scan and a low-to-intermediate clinical probability. The 8 patients with a negative ultrasound and CT scan despite a high clinical probability proceeded to pulmonary angiography (positive: 2; negative: 6). Helical CT was inconclusive in 11 patients (pulmonary embolism: 4; no pulmonary embolism: 7). The overall prevalence of pulmonary embolism was 23%. Patients classified as not having pulmonary embolism were not anticoagulated during follow-up and had a 3-month thromboembolic risk of 1.0% (95% confidence interval: 0.5% to 2.1%)., Conclusion: A noninvasive diagnostic strategy combining clinical assessment, D-dimer measurement, ultrasonography, and helical CT yielded a diagnosis in 99% of outpatients suspected of pulmonary embolism, and appeared to be safe, provided that CT was combined with ultrasonography to rule out the disease.

The performances for thromboembolic disease exclusion of a new microlatex-enhanced D-dimer immunoassay have been evaluated. Advanced D-dimer (Dade-Behring, Marburg, Germany) was tested with two automated analyzers, namely BCS and CA-1500. Precision studies yielded coefficients of variation (within-run and run-to-run) of 3% and 6.3% at D-dimer levels near the cut-off value, for BCS and CA-1500 respectively. Frozen samples from 294 consecutive symptomatic outpatients suspected of either deep venous thrombosis (140) or pulmonary embolism (154) from a previous management study were tested with both analyzers, as well as with the VIDAS New assay (BioMerieux, Marcy-l'Etoile, France). For BCS, sensitivity and specificity were 96.6% (95% CI, 90.5, 99.3) and 42% (35.1, 49.0) respectively at a cut-off value of 1.35 microg/ml. For CA-1500, the corresponding figures were 95.5% (88.9, 98.8) and 47.8% (40.8, 54.9) at a cutt-off value of 1.1 microg/ml. This assay appears promising and should be validated in clinical practise to assess its place in the work-up schemes of thromboembolism.

FIBRIN BREAKDOWN PRODUCTS: D-dimers are protein substances resulting from the action of 3 enzymes, thrombin, factor XIII and plasmin, on the fibrinogen molecules. In the case of thrombosis, all these enzymatic reactions are activated, explaining the increase in D-dimer levels induced. The notion of a threshold is only significant for a given test; the 500 micrograms/L threshold is widely used for tests relying on ELISA methods (enzyme-linked immunosorbent assay). FROM A TECHNICAL POINT OF VIEW: The use of D-dimer ELISA in excluding pulmonary embolism is now well established. New quantitative tests with latex, based on a turbidimetric method, also appear interesting in this context. The latter is reliable, rapid, inexpensive, remarkably sensitive (97 to 100%) and widely available., Interest: Performed in the initial stages of diagnosis in an out-patient population with a 20-25% prevalence of the disease, it excludes the diagnosis in around 30% of patients. Decisional analysis models have shown that this method is economically profitable. However, in elderly hospitalised patients, its clinical utility is lesser because of its low specificity in this population. The association of high clinical probability of pulmonary embolism and normal D-dimer leves is rare and has a weaker negative predictive value, even when the ELISA technique is used.

Pulmonary embolism (PE) may encompass a wide spectrum of severity. To determine whether clinical findings, D-dimer (DD) concentration, and deep vein thrombosis (DVT) shown by lower-limb venous compression ultrasonography (US) might predict the scintigraphic extent of PE, we studied 104 hemodynamically stable consecutive outpatients with acute PE diagnosed by a high-probability ventilation-perfusion lung scan. Scintigraphic extent of PE was classified into three categories: perfusion defects corresponding to <30%, 30-50%, or >50% of the total lung area. Median respiratory and heart rates were found to be significantly related to the extent of PE. Higher median alveolar-arterial oxygen difference values were observed as the proportion of lung perfusion defects increased (>50% vs. <30%, 6.3 vs. 3.6 kPa, P <.0001). Median plasma DD concentration was 7950 microg/L in patients with >50% perfusion defects compared to 2731 microg/L in those with <30% defects (P = .0001). DD levels above 4000 microg/L were associated to more extensive perfusion defects (>50% vs. <30% defects, OR 30; 95% CI 5.8-155). Finally, a proximal DVT was more likely among patients with larger perfusion defects (>50% vs. <30% defects, OR 4.5; 95% CI 1.5-13.6). In conclusion, clinical signs such as tachypnea and tachycardia, alveolar-arterial oxygen difference, plasma DD concentration, and presence of DVT on US are predictors of a larger PE, as assessed by the extent of perfusion defects on high probability lung scans.

The performance of a new latex-enhanced turbidimetric assay, D-Dimer PLUS, has been evaluated with two analyzers performing various coagulation assays: the BCS Analyzer and the BCT Analyzer. A precision study showed total coefficients of variation ranging from 2.7 to 11.1% with the BCS Analyzer and from 2.5 to 6.6% with the BCT Analyzer. We investigated the ability of D-Dimer PLUS to exclude venous thromboembolism in 312 outpatients suspected of either pulmonary embolism or deep venous thrombosis. Three months follow-up was available for all patients. With the BCS Analyzer, we determined a cut-off value of 190 ng/ml, which gave a sensitivity of 97.9% [95% confidence interval (CI), 92.6-99.7%], a specificity of 37.9% (95% CI, 30.9-43.8%) and a negative predictive value of 97.6% (95% CI, 91.7-99.7%). With the BCT Analyzer, at a cut-off value of 130 ng/ml, sensitivity was 96.8% (95% CI, 91.0-99.3%), specificity was 45.2% (95% CI, 38.5-51.2%) and the negative predictive value was 97% (95% CI, 91.6-99.4). This new assay is fast and fully automated, and its performance is suitable to exclude venous thromboembolism. Management studies should be performed to assess its utility.

Purpose: Four strategies for the diagnosis of deep vein thrombosis have been validated recently. The strategies use various combinations of assessment of a patient's clinical probability of having deep venous thrombosis, serial lower limb venous compression ultrasonography, and measurement of plasma D-dimer levels. We compared the cost-effectiveness of these diagnostic strategies., Materials and Methods: We performed a formal cost-effectiveness analysis using a decision-analysis model. Outcomes considered were costs per patient, 3-month quality-adjusted survival, number of lives saved per 1,000 patients, and incremental costs per quality-adjusted life-year (QALY) gained., Results: Under baseline conditions, with a 24% prevalence of deep vein thrombosis in tested patients, the effectiveness of all strategies was similar (4.6 to 4.8 lives saved per 1,000 patients managed). The most expensive strategy was serial ultrasound (repeat ultrasound on day 7 in all patients with a normal initial ultrasound) at a cost-effectiveness of $10,716 per additional QALY. Performing a repeat ultrasound only in patients with an elevated D-dimer level (serial ultrasound with D-dimer) was somewhat less expensive at $10,281 per additional QALY. Taking clinical probability into account by repeating ultrasound only in patients with an intermediate clinical probability of deep vein thrombosis (risk-based serial ultrasound) yielded further savings and cost $10,090 per additional QALY. The least expensive and most cost-effective option was to perform D-dimer as the initial test, followed by a single ultrasound if the D-dimer level was abnormal, and by phlebography in patients with a normal ultrasound and a high clinical probability of deep vein thrombosis (D-dimer with risk-based single ultrasound) at $8,897 per additional QALY. This strategy allowed a 17% reduction in incremental costs compared with the most expensive algorithm and reduced resource consumption (70 ultrasound procedures per 100 patients managed vs 130 to 170 with the other diagnostic strategies)., Conclusions: Combining clinical probability and D-dimer with a single ultrasound in the diagnostic workup of patients with possible deep vein thrombosis is highly cost-effective, allowing a reduction in costs and resource use without any substantial increase in mortality. Serial ultrasonography is less cost-effective.

Plasma D-dimer, a highly sensitive marker of venous thromboembolism, was measured using an enzyme-linked immunosorbent assay pre-operatively, on the third postoperative day, and at the time of phlebography in 118 patients undergoing elective total knee arthroplasty. Deep venous thrombosis (DVT) was detected using systematic bilateral phlebography between the eighth and 12th postoperative day in 47 (39.8%) patients. D-dimer plasma concentrations did not differ between patients who had DVT and those who had no DVT, either pre-operatively (n = 118, P = 0.63) or at the time of phlebography (n = 111, P = 0.70). On the third postoperative day, D-dimer concentration was significantly higher (P < 0.01) in the patients who had DVT (median 3270 microg/l, range 1156-9996, n = 47) than in those who did not (2287 microg/l, 685-7062, n = 64). However, receiver operating characteristics curve analysis did not provide any useful cutoff values that would allow individual diagnoses to be made. In conclusion, the results of the present study suggest that plasma measurement of D-dimer concentration is of no value for predicting, diagnosing or ruling out DVT in patients undergoing total knee arthroplasty.

The presence of D-dimers in the serum reflects fibrin formation and lysis. If the serum D-dimer level is lower than a threshold level which depends on the assay technique (usually 500 micrograms/l), pulmonary embolism can be excluded with a predictive value of 95%. This makes D-dimer assay an ideal screening tool for ambulatory patients with suspected pulmonary embolism. Screening costs can be reduced in about one-third of the cases as other tests are not required. For routine practice, only ELISA tests have been validated for this indication, the sensitivity of latex tests being too low. D-dimer assay would be of little benefit for patients hospitalized for more than 24 for reasons other than suspected pulmonary embolism as specificity is very low in this population.

When a patient is suspected of having pulmonary embolism (PE), the first procedure performed in most institutions is lung scintigraphy. Here we propose an alternative diagnostic strategy based on the following sequential combination of procedures: clinical assessment, D-dimer measurement, ultrasonography of lower limbs, and lung scan. This integrated approach may rule out PE in the majority of outpatients suspected of PE and permits district hospitals without lung-scan facilities to manage approximately 50% of outpatients without referral. D-dimer alone will exclude PE in about 30% of patients at low cost. This stepwise strategy is especially useful because only 20-35% of patients suspected of PE really have the disease. Thus, in the majority of patients, ruling out the disease has replaced ruling in the disease.

The plasma level of D-dimer, a fibrin degradation product (FDP), is nearly always increased in the presence of acute pulmonary embolism (PE). Hence, a normal D-dimer level (below a cutoff value of 500 micrograms/L by enzyme-linked immunosorbent assay [ELISA]) may allow the exclusion of PE. To assess the negative predictive value of a D-dimer concentration below 500 micrograms/L in outpatients with suspected PE, and the safety of withholding anticoagulant treatment from such patients, we performed D-dimer assays, lower limb venous compression ultrasonography, and lung scans in 671 consecutive outpatients presenting in the Emergency Center of the Geneva University Hospital with suspected PE. Pulmonary angiography was reserved for patients with an inconclusive noninvasive workup. Patients with a normal D-dimer concentration were discharged without anticoagulant treatment and followed for 3 mo. The prevalence of PE was 29%, and D-dimer (using a cutoff of 500 micrograms/L) had a diagnostic sensitivity for PE of 99.5%. Overall diagnostic specificity of D-dimer was 41%, but it was lower among older patients. Of the 198 patients with a D-dimer concentration below the cutoff value, 196 were free of PE, one had a PE, and one had incomplete information because of loss to follow-up. Thus, the negative predictive value of D-dimer concentration fell between 197 of 198 and 196 of 198 cases of PE (99% [95% CI: 96.4 to 99.9]). Using a cutoff value of 4,000 micrograms/L, the overall specificity of D-dimer concentration for PE was 93.1%. In conclusion, a plasma D-dimer concentration below 500 micrograms/L allows the exclusion of PE in 29% of outpatients suspected of having PE. Withholding anticoagulation from such patients is associated with a conservative 1% risk of thromboembolic events during follow-up.

The presence of D-dimers in the bloodstream is secondary to fibrin formation and lysis. Because fibrin is the main component of a thrombus, deep vein thrombosis and/or pulmonary embolism may be excluded with a predictive value of more than 95%, provided D-dimer plasma concentration is below a critical, assay-dependent cutoff. The D-dimer test is thus an ideal screening step in outpatients clinically suspected of venous thromboembolism. Only ELISA tests have been validated in clinical practice at present time for this indication, sensitivity of latex assays being insufficient.

Background: Assessment of the clinical probability of pulmonary emboli sm, plasma D-dimer measurement, and lower-limb venous compression ultrasonography have all been advocated in the workup of suspected pulmonary embolism, to minimize the requirement for pulmonary angiography in patients with nondiagnostic lung scans. However, their contribution has not been assessed prospectively., Methods: Three hundred eight consecutive patients who came to the emergency department with suspected pulmonary embolism were managed according to a diagnostic protocol that included clinical probability assessment, lung scan, and sequential noninvasive tests: plasma D-dimer measurement by enzyme-linked immunosorbent assay (a concentration <500 microgram/L ruled out pulmonary embolism) and lower-limb B-mode venous compression ultrasonography (a positive finding was diagnostic of venous thromboembolism). Patients without pulmonary embolism according to the diagnostic workup did not receive anticoagulant treatment. The safety of this approach was assessed by a 6-month follow-up., Results: of the 308 patients, 106 (34%) had a diagnostic lung scan (normal in 43 and high probability in 63). For the remaining 202 patients, noninvasive workup was diagnostic in 125 (62%). Pulmonary embolism was ruled out by a low clinical probability and a nondiagnostic scan in 48 patients and a D-dimer level less than 500 microgram/L in 53; pulmonary embolism was established by a high clinical probability and a nondiagnostic scan in seven patients and by a finding of a deep vein thrombosis on ultrasonography in 17. Therefore, only 77 of these 202 patients underwent pulmonary angiography (negative in 55; positive in 22). At 6-month follow-up (completed for 99.4% of the study population), only two of the 199 patients in whom the diagnostic protocol had ruled out pulmonary embolism (1.0% [95% confidence interval, 0.1 to 3.6]) had a thromboembolic event (pulmonary embolism, one; deep vein thrombosis, one)., Conclusions: This decision analysis strategy yielded a definitive noninvasive diagnosis in 62% of patients with a nondiagnostic scan and appears to be safe.

The performance of a new automated ELISA for a rapid, individual and quantitative measurement of plasma D-dimer (VIDAS D-dimer) has been evaluated. First, a study of 100 patients was performed in order to choose the best couple of antibodies in comparison with an already clinically validated ELISA. Then the results were certified in a prospective study including 195 consecutive patients suspected of pulmonary embolism (PE). For a cut-off level of 500 ng/ml VIDAS D-dimer showed a sensitivity of 100% (95% confidence interval 92-100), a specificity of 37.6%, a negative predictive value of 100% (95% CI 93.3-100) and a positive predictive value of 33.1%. During a 6 months' follow-up no patient (95% CI 0-6.4) with D-dimer < 500 ng/ml presented a new suspicion of venous thromboembolic disease. These results suggest that this rapid and single-dose ELISA provides a very useful tool for the clinician to exclude on a day-to-day basis the diagnosis of PE.

The diagnostic strategy of pulmonary embolism is based firstly on pulmonary scintigraphy, a non-invasive investigation which provides a definitive diagnosis in about 30% of patients, and then on pulmonary angiography, which remains the investigation of reference. However, new diagnostic methods have been introduced in order to reduce the number of angiographies. Measurement of plasma D-dimer, a fibrin degradation product, enables exclusion of the diagnosis in 20-50% of patients without pulmonary embolism when the result is normal on ELISA (< 500 micrograms/l with the commercialized Stago test). This is due to the very high sensitivity of D-dimer: in a compilation of recent series with a total of 1,159 patients suspected of having pulmonary embolism, their concentration was over the threshold of 500 micrograms/l in 96% (CI 95%, 93-98) of patients with pulmonary embolism. On the other hand, their low specificity makes them useless for a positive diagnosis of the condition. Lower limb venous compression ultrasonography enables detection of proximal deep venous thrombosis in about 57% (CI 95%, 52-62) of patients with pulmonary embolism, posing the indication for anticoagulation without further investigations because of its high specificity (98%) (CI 95%, 97-99). When venous ultrasonography is normal, however, pulmonary embolism cannot be excluded. A diagnostic strategy associating these two investigations and pulmonary scintigraphy reduces the number of diagnostic angiographies by 30 to 50% according to whether D-dimer and ultrasonography are performed before or after scintigraphy respectively. More extensive use of D-dimer in clinical practice requires more rapid and equally reliable unitary tests as the ELISA.

The performance of a new membrane ELISA for semi-quantitative determination of plasma D-dimer has been evaluated. Its cut-off is about 500 ng/ml FEU and this single test is completed within 10 min. D-dimer was measured in 301 patients suspected of pulmonary embolism by conventional microplate and membrane ELISA. For the latter, readings were made by eye and some differences were noticed between the readers for reactions in the grey zone. Sensitivity and negative predictive values were similar for the two ELISA (higher than 90%). The 95% confidence intervals of sensitivity and negative predictive values obtained with this membrane ELISA suggest that this new test may be used as a diagnostic tool to exclude the presence of pulmonary embolism.

D-dimer (DD), when measured by a quantitative enzyme-linked immunosorbent assay (ELISA), is a valuable test to exclude venous thromboembolism (VTE). However, DD ELISA technique is not appropriate for emergency use and the available agglutination latex assays are not sensitive enough to be used as an alternative to rule out the diagnosis of VTE. Latex assays could still be used as screening tests. We tested this hypothesis by comparing DD levels measured by ELISA and latex assays in 334 patients suspected of pulmonary embolism. All but one patient with a positive (DD > or = 500 ng/ml) latex assay had DD levels higher than 500 ng/ml with the ELISA assay. Accordingly, ELISA technique could be restricted to patients with a negative result in latex assay. This two-step approach would have spared about 50% of ELISA in our cohort. In conclusion, our data indicate that a latex test can be used as a first diagnostic step to rule out pulmonary embolism provided a negative result is confirmed by ELISA and the performance of the latex assay used has been assessed properly.

The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study has shown that clinical evaluation and lung scanning may substantiate or exclude pulmonary embolism with reasonable probability in approximately half of the patients in whom it is suspected; for the remainder, pulmonary angiography is considered the gold standard diagnostic test. We performed a decision analysis to assess the potential of two noninvasive tests, D-dimer plasma measurement and lower-limb B-mode venous ultrasound, for reducing the number of pulmonary angiograms necessary to diagnose pulmonary embolism. Our decision model addresses hypothetical patients in the emergency ward with suspected pulmonary embolism and abnormal lung scan results. Results show that D-dimer measurements of less than 500 micrograms/L could be used reliably to exclude pulmonary embolism in patients with an abnormal but not high-probability (inconclusive) lung scan. D-dimer measurements of greater than 500 micrograms/L have no positive predictive value for pulmonary embolism and should be followed by ultrasound, which may replace pulmonary angiography when it discloses deep venous thrombosis. Pulmonary angiography should be performed when ultrasound is negative because of its presumably low sensitivity for deep venous thrombosis in patients with pulmonary embolism. A D-dimer measurement of less than 500 mu/L does not exclude pulmonary embolism in patients with a high clinical suspicion of pulmonary embolism. On the basis of the results of the PIOPED study, we calculated that the combination of D-dimer measurement and ultrasound might reduce the requirement for pulmonary angiography by one third among patients with inconclusive scan results and intermediate clinical probability of pulmonary embolism.