Clinical Chemistry AACC Online Job Center
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Clinical Chemistry 49: 1483-1490, 2003; 10.1373/49.9.1483
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit an electronic Letter to
the Editor about this paper
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (24)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schrecengost, J. E.
Right arrow Articles by Bruns, D. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schrecengost, J. E.
Right arrow Articles by Bruns, D. E.
Related Collections
Right arrow Clinical Immunology
Right arrow Evidence Based Laboratory Medicine and Test Utilization
Right arrow Hemostasis and Thrombosis
Right arrow Hematology
(Clinical Chemistry. 2003;49:1483-1490.)
© 2003 American Association for Clinical Chemistry, Inc.

Hemostasis and Thrombosis

Comparison of Diagnostic Accuracies in Outpatients and Hospitalized Patients of D-Dimer Testing for the Evaluation of Suspected Pulmonary Embolism

John E. Schrecengost1, Robin D. LeGallo1, James C. Boyd1,a, Karel G.M. Moons4, Steven L. Gonias1,2, C. Edward Rose, Jr3 and David E. Bruns1

Departments of
1 Pathology,
2 Biochemistry and Molecular Biology, and
3 Internal Medicine, University of Virginia Health System, Charlottesville, VA 22908.
4 Julius Center for Health Sciences and Primary Care, University Medical Center, 3508TA Utrecht, The Netherlands.

aAddress correspondence to this author at: Department of Pathology, PO Box 800214, University of Virginia Medical School, Charlottesville, VA 22908. Fax 434-243-5930; e-mail jboyd{at}virginia.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: The ability of various D-dimer assays to exclude the diagnosis of thromboembolic diseases is controversial. We examined the diagnostic accuracy of two D-dimer methods in hospitalized patients and outpatients.

Methods: We studied consecutive patients for whom D-dimer testing was ordered for investigation of suspected pulmonary embolism. We measured D-dimer by an ELISA (VIDAS D-dimer) and an enhanced microlatex immunoassay method (Diagnostica Stago STA Liatest D-di). Patient diagnoses were based on imaging studies or, when these were not performed, on follow-up by review of medical records 3 months later.

Results: We examined 233 hospitalized patients and 234 outpatients with a mean age of 58 years (range, 1–92 years) and a female-to-male ratio of 1.4 to 1. Thromboembolism was present in 8% of outpatients and 12% of hospitalized patients. In outpatients, the negative predictive values were 98% [95% confidence interval (CI), 93–100%] and 99% (94–100%) for the microlatex and ELISA methods, respectively, at the recommended cutoffs. Areas under the ROC curves were similar for the two methods [0.77 (95% CI, 0.67–0.87) and 0.81 (0.73–0.89), respectively]. By contrast, in hospitalized patients, the confidence intervals for the areas under the ROC curves included 0.5 [0.60 (95% CI, 0.50–0.71) and 0.56 (0.44–0.67)].

Conclusions: For hospitalized patients, in contrast to outpatients, the diagnostic accuracy of D-dimer testing for pulmonary embolism is poor in a tertiary care setting, presumably reflecting thrombosis and comorbidities, other than pulmonary embolism, that increase the D-dimer concentrations in these patients. The patient population studied appears more important than assay method in studies of the diagnostic accuracy of D-dimer testing.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
D-Dimer testing has been used to aid in the diagnosis of disseminated intravascular coagulation (1)(2)(3). Recently, however, these tests have been studied for the exclusion of thromboembolic disease in patients suspected of having pulmonary embolism (PE)1 or deep vein thrombosis (DVT) (4)(5)(6). In these conditions, D-dimer, an end-stage product of fibrin degradation by plasmin, is increased as a result of fibrinolysis, but it does not result from fibrinogenolysis. When plasma D-dimer is low, venous thromboembolism (VTE) is likely to be absent (4)(5)(6).

Because the 3-month mortality rate of untreated PE can be as high as 17.5% (7), the cost of missing the diagnosis is high. The cutpoint for D-dimer must be low if the test is to be used to exclude PE. False-positive results are thus frequent and are particularly common among individuals who have experienced recent trauma and those with pregnancy or malignancy. These states may be associated with accelerated coagulation and fibrinolysis without true large vessel thrombosis (1)(8)(9)(10). Because the prevalence of these conditions is high among hospitalized patients, D-dimer testing may be of limited utility in hospitals. Moreover, false-positive results are seen in patients with a variety of other serious medical conditions that lead to hospitalization and can affect D-dimer metabolism, e.g., by decreasing its clearance from the circulation. Patients with false-positive D-dimer tests are commonly referred for additional expensive imaging tests; thus, high false-positive rates can increase healthcare costs (11). Nonetheless, in our health center, we observed that the D-dimer assay was used to investigate suspected VTE in hospitalized patients as often as it was used for ambulatory outpatients, in whom the test is less likely to be affected by comorbidities.

To compare the potential utility of D-dimer testing in outpatients and inpatients, we studied its diagnostic accuracy in these groups separately. Because no consensus exists on which D-dimer assay to use, we used two methods that represent the two classes of D-dimer assays that have been reported to achieve high negative predictive values [see, for examples, Refs. (4)(5)(12)].


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
patients
We included all patients seen between May and December 2001 in whom there was a clinical suspicion of PE (which consisted mainly of shortness of breath, chest pain, or syncopal episode) and for whom D-dimer testing was requested to investigate possible VTE. An ELISA D-dimer method was offered, as part of routine testing, in this medical center specifically for the investigation of suspected VTE. Medical records were reviewed to determine the suspicion of PE and the indication for the test. All treating physicians had available to them a clinical probability algorithm to guide their requests for further diagnostic testing, including D-dimer assays, in each patient (13). This algorithm dictates use of the D-dimer assay when clinical suspicion is sufficient to warrant further investigation but is not high enough to warrant immediate use of emergent diagnostic imaging studies. We did not attempt to document use of the clinical probability algorithm. For all ELISA tests during the study period, a portion of the sample was used for simultaneous testing by a comparison microlatex method (see below).

The study population comprised emergency room patients, patients from outpatient clinics, and hospitalized patients. Patients were excluded from the present analysis when either the ELISA or the microlatex agglutination result was not available, when the diagnosis of VTE was made despite negative imaging, and when the clinical presentation indicated the presence of DVT only (e.g., patients with a swollen extremity only). The requesting clinician received the result of only the ELISA assay during the patient evaluation, and not the microlatex assay result. The examined population included patients who were potentially on anticoagulation therapy for various conditions, including atrial fibrillation, cardiac valve replacement, or recent/remote history of PE or DVT (see below).

Clinical data were collected retrospectively by review of electronic medical records. We tabulated each patient’s age, sex, presenting symptoms and signs, significant medical history, and information on the final diagnosis, including the presence or absence of thromboembolic disease (see "Reference Standard" below). The results of the two D-dimer tests were retained in the laboratory and were added to the data collection form. The elapsed time between D-dimer testing and reference testing was <48 h in all cases. This study was approved by the Institutional Review Board (Human Investigation Committee) at the University of Virginia Health System.

The sponsor was not involved in the study design, data collection or analysis, or the decision to submit the manuscript for publication.

d-dimer testing
The same blood sample of each referred patient was used for the ELISA and for the microlatex method. Blood samples for D-dimer determinations were collected in plastic tubes containing 0.109 mol/L trisodium citrate at a ratio of nine parts blood to one part sodium citrate and were centrifuged for 10 min at 2000g. For any one sample, the same registered laboratory technologist performed both tests within 15 min of centrifugation of the sample. All D-dimer testing was performed by one of three technologists without knowledge of the other test result or the patient’s clinical outcomes or pretest clinical probability. D-Dimer was then assayed by the VIDAS (bioMerieux, Inc.) and LiaTest D-di (Diagnostica Stago) methods.

The VIDAS D-dimer ELISA assay, an enzyme-linked immunofluorescence assay, has been described elsewhere (14)(15)(16). D-Dimer results were reported in mg/L of fibrinogen equivalent units (FEU). Results above 1.0 mg/L were reported as >1.0 mg/L. The assay was recalibrated for each new lot of reagents and at least every 2 weeks. Control samples were tested every 8 h or with each instrument run if the time between runs exceeded 8 h. The imprecision (CV) of the assay was 5.8% at a mean concentration of 0.42 mg/L and 6.5% at a mean concentration of 0.69 mg/L.

The STA Liatest DS-di assay is an automated microlatex immunoassay performed on the Stago Star analyzer. The details of the method have been described previously (17)(18). The results were reported as mg/L of FEU; values above 4.0 mg/L were initially reported by the instrument as >4.0 mg/L, but a repeat test with a 1:5 dilution extended the reportable range to 20 mg/L. Higher results were reported as >20 mg/L. Precalibrated reagent lots (barcoded) were used, and a new calibration curve was provided with each new lot of reagents. Controls were analyzed every 8 h or with each instrument run if the time between runs exceeded 8 h. The imprecision (CV) of the assay was 5.0% at a mean concentration of 2.8 mg/L and 14% at a mean concentration of 0.31 mg/L.

Because the microlatex assay provided a wider range of reportable values than the ELISA, the microlatex assay had the potential to produce a misleading larger area under the ROC curve. To adjust for this potential artifact, we used Passing–Bablok regression analysis on the data set for ELISA values up to 0.999 mg/L to determine the approximate value of the microlatex method that corresponded to the upper reporting limit (1.000 mg/L) for the ELISA method. The regression analysis used 243 pairs of results. From the calculated slope and intercept, the microlatex value that corresponded to an ELISA result of 1.000 mg/L was 1.06 mg/L; thus, all higher results from the microlatex method were assigned a value of 1.06 mg/L for ROC analysis. Because the clinical cutoff values for these assays (~0.5 mg/L) were well below this value, the calculation appeared acceptable for all data analyses performed here.

reference standard
A final diagnosis of VTE, i.e., a pulmonary embolus or DVT, in these patients, all of whom had symptoms suggestive of PE, required a positive result for VTE by one of the following executed imaging procedures, as documented in the electronic medical record: ventilation-perfusion scan of high probability (19); positive findings on either pulmonary angiogram or computed tomography angiogram (20); or the presence of a DVT on compression ultrasound studies of the extremities (21). In the absence of a positive result (e.g., negative or low-probability result), patients were classified as "negative", i.e., VTE absent. For those patients who did not undergo one of the above procedures or who underwent only lower extremity ultrasound, a 3-month follow-up examination of the medical record was used to determine whether they experienced VTE as indicated by follow-up visits or autopsy results or as suggested by patient death. The pathologist who reviewed the medical records had access to the D-dimer results.

statistical analysis
We plotted ROC curves and estimated the areas under the curves (ROC area) and their 95% confidence intervals (95% CIs). All analyses were performed with SPSS, Ver. 11.0. The ROC area was used to provide an overall estimate of the tests’ diagnostic performance in differentiating between patients with and without VTE in the setting of suspected PE. Differences in diagnostic accuracy between the two test methods were estimated by use of the difference in ROC area, taking into account the correlation between the two test methods as they were based on the same individuals (22)(23)(24)(25). Because the ROC area provides only an overall estimate of test diagnostic accuracy and does not directly indicate the performance of the test as used or perceived by physicians (26), we also tabulated the absolute number of correctly and incorrectly classified patients, calculating negative predictive value, positive predictive value, sensitivity, and specificity (and their corresponding 95% CIs) for each test at recommended cutoffs. We used cutoff values that were recommended in the corresponding manufacturer’s product literature and the references therein; these thresholds were 0.5 mg/L FEU for the ELISA and 0.5 mg/L FEU for the microlatex assay.

Discordant results (microlatex-positive, ELISA-negative, or vice versa) were also analyzed over the entire patient population. This analysis was carried out using simple statistics to evaluate the possible introduction of verification bias into the study as a result of physicians’ access to the ELISA, but not microlatex, results.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Of 504 patients enrolled in the study, we excluded 15 patients who had no microlatex result, 20 who had a clinical presentation of DVT with no evidence of PE, and 2 who were clinically diagnosed as having thromboembolic disease despite negative results by diagnostic testing (Fig. 1 ). The remainder of the patients had both D-dimer tests (Fig. 1 ). The mean age of the 467 patients included in the study (195 males and 272 females) was 58 years (range, 1–92 years). Review of the 3-month follow-ups in patients who had not undergone imaging studies revealed no deaths or evidence of PE at return visits.



View larger version (28K):
[in this window]
[in a new window]
  		Figure 1. Flow diagram for participants in the study.

Reference imaging indicates pulmonary angiogram, ventilation perfusion scan, and/or computed tomography angiogram. LEUS, lower extremity ultrasound only.

Of the 467 patients, 48 (10%) had VTE (Table 1 ). Considering all 467 patients together, the ROC areas were 0.66 (95% CI, 0.58–0.74) for the microlatex method and 0.70 (0.63–0.77) for the ELISA method. These areas were not statistically significantly different. As shown in Table 2 , the sensitivity, specificity, and predictive values were also statistically indistinguishable for the ELISA and microlatex methods. The total numbers of true-negative results at the recommended cutoff values were 149 (32%) for the ELISA method and 143 (31%) for the microlatex method. A total of six falsely negative results were identified by the microlatex method and four falsely negative results by the ELISA method.


View this table:
[in this window]
[in a new window]
  		Table 1. Thromboembolic conditions detected in 467 patients.


View this table:
[in this window]
[in a new window]
  		Table 2. Sensitivity, specificity, and predictive values of D-dimer in 467 test patients.1

Because concurrent anticoagulant therapy can decrease D-dimer concentrations, we reviewed the patients’ medical histories to identify those patients whose results may have been affected by anticoagulant use. Because medical records may fail to capture prescription histories, we also identified all patients who had conditions that made them candidates for anticoagulation before the time that the D-dimer samples were collected. The conditions identified included atrial fibrillation, status post cardiac valve replacement, and a history of prior PE and/or DVT.

Records of anticoagulant use or indications for anticoagulation were found in 45 patients (10% of the patients studied). Of these 45 patients, D-dimer was <0.5 mg/L in 13 patients, including 2 of the 4 patients noted above with PE and falsely negative ELISA results. The microlatex results in both patients also were negative. One of these two patients was in the hospital on chronic warfarin therapy for atrial fibrillation; the other had been sent from another emergency department and had received heparin before arrival at our emergency department. If these two patients were to be excluded as inappropriate for testing, the negative predictive values of ELISA and microlatex tests would be 99% and 97%, respectively. If all 45 patients were excluded, the negative predictive values would be 99% and 97%.

The outpatient group consisted of 234 patients from the emergency room and outpatient clinics. Their mean age was 54 years (range, 15–90 years), with a female-to-male ratio of 1.98 to 1. The VTE prevalence in this group was 8%. The areas under the ROC curves (Fig. 2A ) were 0.81 (95% CI, 0.73–0.89) for the ELISA and 0.77 (0.67–0.87) for the microlatex test, which were not statistically different. As shown in the 2 x 2 contingency table (Table 3B ), one ELISA result was falsely negative, as were two microlatex assay results at the usually recommended cutpoint of 0.5 mg/L. A total of 109 (47%) patients were correctly "ruled-out" (negative D-dimer and absence of VTE) by the ELISA method and 103 (44%) by the microlatex method. The sensitivity, specificity, and predictive values for the two assays were not significantly different (Table 3A ).



View larger version (12K):
[in this window]
[in a new window]
  		Figure 2. ROC curves for outpatients (n = 234; A) and inpatients (n = 233; B).

Dotted line, ELISA; dashed line, microlatex; solid line, sensitivity = (1 - specificity); •, cutoff values (0.5 mg/L FEU).


View this table:
[in this window]
[in a new window]
  		Table 3. Sensitivity, specificity, and predictive values of D-dimer in hospitalized patients and outpatients (A) and 2 x 2 contingency table (B).1

The group of 233 hospitalized patients included individuals on medical and surgical floors, as well as intensive care unit patients. Their mean age was 62 years (range, 1–92 years), and the female-to-male ratio was 1.02 to 1. The prevalence of thromboembolic disease in the hospitalized patient group was 12%. The 95% CI for the area under the ROC curve for each of the two test methods (Fig. 2BUp ) included 0.5 [0.60 (95% CI, 0.50–0.71) for the ELISA and 0.56 (95% CI, 0.44–0.67) for the microlatex]. The areas under the ROC curves were recalculated after the exclusion of two patients who were <1 year of age. This exclusion did not alter the areas under the curves, nor did it alter the CIs. As shown in the 2 x 2 contingency table (Table 3BUp ), at the usually recommended cutpoint of 0.5 mg/L for each assay, three patients were falsely negative for the ELISA and microlatex tests. The sensitivity, specificity, and predictive values for the hospitalized patients (Table 3AUp ) were similar for the two methods. The false-positive rate was ~80% for each assay method.

analysis of discordant results
Among the 467 examined patients, the ELISA and microlatex results were discordant in 42 patients, with 19 ELISA-positive/microlatex-negative data pairs and 23 ELISA-negative/microlatex-positive results. Of the first group (ELISA-positive), 17 of 19 (89%) went on to reference imaging, whereas only 7 of the 23 (30%) with a negative ELISA received reference imaging, suggesting that positive ELISA results (which were seen by the physicians) prompted further testing. Positive microlatex results were not seen by the physicians and thus could not have this effect. As a result, the study was potentially biased against the microlatex test. Two of the 17 ELISA-positive patients in whom imaging tests were performed had positive imaging results; none of the 7 patients in the microlatex-positive group who went on to imaging had positive results. This difference was not statistically significant (Fisher exact test).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The value of the D-dimer assay in the evaluation of thromboembolic disease lies in its high negative predictive value and high sensitivity, which provide the possibility to avoid expensive or invasive tests for PE, such as ventilation-perfusion lung scanning and angiography, in patients with negative D-dimer test results (4)(5)(16)(26). High sensitivity and high negative predictive values are critical to minimize the possibility of missing the diagnosis of PE because the mortality of untreated PE approaches 26% (7). On the other hand, the high false-positive rate that has been noted for D-dimer testing may serve only to increase the number of patients evaluated for VTE, leading to increased morbidity and expense of clinical testing (27).

Recently, several enhanced microlatex agglutination assays have become available commercially, and results of several studies of these assays appear promising (e.g., (12)(17)(18). Our study is one of the few to compare the diagnostic performance of the new Stago microlatex assay with ELISA D-dimer testing for inpatients and outpatients with suspected PE. We conclude that differences, if any, between the two assays are numerically small in both inpatients and outpatients.

In this study, both D-dimer assays had high negative predictive values and sensitivities in the outpatient population, with relatively low false-positive rates. By contrast, there seems to be little justification for the use of the D-dimer assay in the hospitalized population, as indicated by the poor performance of these assays in this group compared with the outpatient group. The difference in the utility of the D-dimer test to rule out PE in inpatients vs patients presenting in the emergency room probably reflects the typical presentation of these patient populations. D-Dimer may be increased equally in PE or in DVT without embolism. Patients with extensive inflammation and wound healing or malignancy also may have increased plasma D-dimer concentrations (28)(29)(30). Furthermore, because D-dimer is cleared principally in the liver, patients with liver disease may have an increased D-dimer concentration (30)(31). In our hospital population, patients with suspected PE are frequently those who are at high risk for venous thrombosis, including postoperative patients and other immobilized individuals (data not shown), and they are more likely than outpatients to have comorbidities that increase D-dimer. Because of these comorbid disorders, which may affect the D-dimer concentration, the usefulness of this clinical test in this patient population is limited.

Physicians ordering the ELISA on inpatients were from several medical and surgical services, and we found little evidence that these physicians followed a standard testing pathway. Testing may have been performed on patients who had very high or very low clinical probability of having VTE. This may have led to the low rule-out rate, with exclusion of only 40 (17%) of the 233 inpatients evaluated, giving a false-positive rate >80%. Such a high false-positive rate and low rate of excluding the diagnosis may lead to increased and unnecessary use of expensive imaging tests as has been described elsewhere (11).

A potential threat to the validity of this study is verification bias. The study was based on routinely documented medical data, which commonly carries the potential of verification bias (27)(32)(33)(34)(35)(36). This bias commonly leads to an overestimation of the sensitivity and positive predictive value and underestimation of the specificity and negative predictive value. In addition, the ELISA result was available to the clinicians during the patient evaluation in our study, but the microlatex assay result was not. Our analysis of the discordant test results indicated that patients with positive ELISA results were three times as likely to undergo one or more of the reference tests as were those with a negative ELISA result and a positive microlatex result (94% vs 30%). This additional source of verification bias may have led to the underdiagnosis of VTE in the ELISA-negative group, falsely underestimating the number of both false and true negatives (37). Consequently, the relative diagnostic accuracy of the ELISA test may have been overestimated compared with that of the microlatex test.

It does not appear likely that verification bias obscured a significant difference in accuracy between the two assays. Statistical modeling (not shown) suggests that correction for verification bias might narrow the difference between the tests further. Verification bias may, however, explain why the specificities and negative predictive values in our study are somewhat lower than those reported in previous studies (5)(12)(15)(17)(38). Selective D-dimer testing in only the low clinical probability group could have artificially increased the exclusion rates. Nonetheless, the potential effects of both patient selection and verification bias were similar for both tests, and they do not affect our conclusion that the tests behave similarly.

A further, potential source of bias is that not all patients underwent objective reference testing or underwent only lower extremity ultrasound, and we were forced to rely on clinical follow-up to set the final diagnosis. Although small numbers of patients may have been misclassified through our use of clinical follow-up information, there is no reason to assume that this misclassification differed between the two assays. Because differential verification commonly leads to overestimation of the diagnostic accuracy, this threat to validity would not be expected to change our conclusion that D-dimer testing has low diagnostic accuracy in inpatients. Moreover, outcome-based standards have been considered appropriate for this type of evaluation, and a 3-month follow-up period has been suggested to be a "valid outcome measure" in studies of PE in an emergency department (39)(40).

Anticoagulation therapy is a known confounder of D-dimer assay results, producing lower D-dimer concentrations, and the use of D-dimer testing in the anticoagulated population remains a point of continued controversy. Mean plasma D-dimer concentrations of untreated patients with chronic atrial fibrillation are higher than those of control individuals and decrease to concentrations similar to those of the controls on anticoagulation therapy (41)(42). The D-dimer assay appears to retain utility in select patient groups, but the results need to be more carefully considered (43)(44). Although anticoagulation can lower D-dimer concentrations, in 32 of 45 of our anticoagulation group patients, D-dimer was >0.5 mg/L. A higher result would not have changed their classification. Of the 13 patients with negative D-dimer results, 2 had evidence of VTE. Exclusion of these 2 patients or of all 45 patients in the anticoagulant group only slightly changed assay sensitivity and negative predictive value.

In summary, we conclude that the diagnostic accuracies of the ELISA and microlatex methods were statistically indistinguishable for inpatients, outpatients, and all patients combined in this study. Not surprisingly, we observed greater numbers of patients with false-positive D-dimer tests in the inpatient group, likely because of an increased prevalence of comorbid disease in these patients and of inconspicuous thromboses without PE. In contrast, the outpatient group had fewer patients with false-positive results, suggesting that outpatients are more suitable for D-dimer testing to exclude PE. However, in both inpatients and outpatients, we observed a small number of negative D-dimer results in patients with VTE, with four patients having falsely negative results by both methods. Thus, even with the suggestion of superior D-dimer performance in outpatients when used to screen for VTE, there must continue to be consideration that a negative D-dimer result does not exclude the possibility of VTE.


   Acknowledgments
 
Supported, in part, by a grant from Stago. We gratefully acknowledge the technical assistance of Gary Manuel.


   Footnotes
 
1 Nonstandard abbreviations: PE, pulmonary embolism; DVT, deep vein thrombosis; VTE, venous thromboembolism; FEU, fibrinogen equivalent unit(s); and 95% CI, 95% confidence interval.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Carey MJ, Rodgers GM. Disseminated intravascular coagulation: clinical and laboratory aspects. Am J Hematol 1998;59:65-73.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  2. Mammen EF. Disseminated intravascular coagulation (DIC). Clin Lab Sci 2000;13:239-245.[Medline] [Order article via Infotrieve]
  3. Yu M, Nardella A, Pechet L. Screening tests of disseminated intravascular coagulation: guidelines for rapid and specific laboratory diagnosis. Crit Care Med 2000;28:1777-1780.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  4. Anderson DR, Wells PS. D-Dimer for the diagnosis of venous thromboembolism. Curr Opin Hematol 2000;7:296-301.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  5. Perrier A, Desmarais S, Goehring C, de Moerloose P, Morabia A, Unger PF, et al. D-Dimer testing for suspected pulmonary embolism in outpatients. Am J Respir Crit Care Med 1997;156:492-496.[Abstract/Free Full Text]
  6. Perrier A, Desmarais S, Miron MJ, de Moerloose P, Lepage R, Slosman D, et al. Non-invasive diagnosis of venous thromboembolism in outpatients. Lancet 1999;353:190-195.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  7. Goldhaber SZ. Pulmonary embolism. N Engl J Med 1998;339:93-104.[Free Full Text]
  8. Giavarina D, Mezzena G, Dorizzi RM, Soffiati G. Reference interval of D-dimer in pregnant women. Clin Biochem 2001;34:331-333.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  9. Owings JT, Gosselin RC, Anderson JT, Battistella FD, Bagley M, Larkin EC. Practical utility of the D-dimer assay for excluding thromboembolism in severely injured trauma patients. J Trauma 2001;51:425-429.[ISI][Medline] [Order article via Infotrieve]
  10. Schutgens RE, Esseboom EU, Haas FJ, Nieuwenhuis HK, Biesma DH. Usefulness of a semiquantitative D-dimer test for the exclusion of deep venous thrombosis in outpatients. Am J Med 2002;112:617-621.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  11. Goldstein NM, Kollef MH, Ward S, Gage BF. The impact of the introduction of a rapid D-dimer assay on the diagnostic evaluation of suspected pulmonary embolism. Arch Intern Med 2001;161:567-571.[Abstract/Free Full Text]
  12. Quinn DA, Fogel RB, Smith CD, Laposata M, Taylor Thompson B, Johnson SM, et al. D-Dimers in the diagnosis of pulmonary embolism. Am J Respir Crit Care Med 1999;159:1445-1449.[Abstract/Free Full Text]
  13. Wicki J, Perneger TV, Junod AF, Bounameaux H, Perrier A. Assessing clinical probability of pulmonary embolism in the emergency ward. Arch Intern Med 2001;161:92-97.[Abstract/Free Full Text]
  14. Pittet JL, De Moerloose P, Reber G, Durand C, Villard C, Piga N, et al. VIDAS D-dimer: fast quantitative ELISA for measuring D-dimer in plasma. Clin Chem 1996;42:410-415.[Abstract/Free Full Text]
  15. de Moerloose P, Desmarais S, Bounameaux H, Reber G, Perrier A, Dupuy G, et al. Contribution of a new, rapid, individual and quantitative automated D-dimer ELISA to exclude pulmonary embolism. Thromb Haemost 1996;75:11-13.[ISI][Medline] [Order article via Infotrieve]
  16. van der Graaf F, van den Borne H, van der Kolk M, de Wild PJ, Janssen GW, van Uum SH. Exclusion of deep venous thrombosis with D-dimer testing—comparison of 13 D-dimer methods in 99 outpatients suspected of deep venous thrombosis using venography as reference standard. Thromb Haemost 2000;83:191-198.[ISI][Medline] [Order article via Infotrieve]
  17. Oger E, Leroyer C, Bressollette L, Nonent M, Le Moigne E, Bizais Y, et al. Evaluation of a new, rapid, and quantitative D-dimer test in patients with suspected pulmonary embolism. Am J Respir Crit Care Med 1998;158:65-70.
  18. Escoffre-Barbe M, Oger E, Leroyer C, Grimaux M, Le Moigne E, Nonent M, et al. Evaluation of a new rapid D-dimer assay for clinically suspected deep venous thrombosis (Liatest D-dimer). Am J Clin Pathol 1998;109:748-753.[ISI][Medline] [Order article via Infotrieve]
  19. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). The PIOPED Investigators. JAMA 1990;263:2753-2759.[Abstract]
  20. Remy-Jardin M, Remy J, Deschildre F, Artaud D, Beregi JP, Hossein-Foucher C, et al. Diagnosis of pulmonary embolism with spiral CT: comparison with pulmonary angiography and scintigraphy. Radiology 1996;200:699-706.[Abstract/Free Full Text]
  21. Lensing AW, Prandoni P, Brandjes D, Huisman PM, Vigo M, Tomasella G, et al. Detection of deep-vein thrombosis by real-time B-mode ultrasonography. N Engl J Med 1989;320:342-345.[Abstract]
  22. Hanley JA, McNeil BJ. A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology 1983;148:839-843.[Abstract/Free Full Text]
  23. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 1982;143:29-36.[Abstract/Free Full Text]
  24. Delong ER, Delong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a non-parametric approach. Biometrics 1988;44:837-845.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  25. Moons KG, van Es GA, Deckers JW, Habbema JD, Grobbee DE. Limitations of sensitivity, specificity, likelihood ratio and Bayes’ theorem in assessing diagnostic probabilities: a clinical example. Epidemiology 1997;8:12-17.[ISI][Medline] [Order article via Infotrieve]
  26. Wells PS, Anderson DR, Rodger M, Stiell I, Dreyer JF, Barnes D, et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and D-dimer. Ann Intern Med 2001;135:98-107.[Abstract/Free Full Text]
  27. van der Schouw YT, van Dijk R, Verbeek ALM. Problems in selecting the adequate patient population from existing data files for assessment of new diagnostic tests. J Clin Epidemiol 1995;48:417-422.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  28. Wallberg-Jonsson S, Cvetkovic JT, Sundqvist KG, Lefvert AK, Rantapaa-Dahlqvist S. Activation of the immune system and inflammatory activity in relation to markers of atherothrombotic disease and atherosclerosis in rheumatoid arthritis. J. Rheumatol 2002;29:875-882.
  29. Walston J, McBurnie MA, Newman A, Tracy RP, Kop WJ, Hirsch CH, et al. Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study. Arch Intern Med 2002;162:2333-2341.[Abstract/Free Full Text]
  30. Wilde JT, Kitchen S, Kinsey S, Greaves M, Preston FE. Plasma D-dimer levels and their relationship to serum fibrinogen/fibrin degradation products in hypercoagulable states. Br J Haematol 1989;71:65-70.[ISI][Medline] [Order article via Infotrieve]
  31. Pizzo SV, Pasqua JJ. The clearance of human fibrinogen fragments D1, D2, D3 and fibrin fragment D1 dimer in mice. Biochim Biophys Acta 1982;718:177-184.[Medline] [Order article via Infotrieve]
  32. Knottnerus JA. The effects of disease verification and referral on the relationship between symptoms and diseases. Med Decis Making 1987;7:139-148.
  33. Knottnerus JA, Leffers JP. The influence of referral patterns on the characteristics of diagnostic tests. J Clin Epidemiol 1992;45:1143-1154.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  34. Begg CB, Greenes RA. Assessment of diagnostic tests when disease verification is subject to selection bias. Biometrics 1983;39:207-215.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  35. Ransohoff DF, Feinstein AR. Problems of spectrum and bias in evaluating the efficiency of diagnostic tests. N Engl J Med 1978;299:926-930.[Abstract]
  36. Moons KGM, Stijnen T, Michel BC, Buller HR, van Es GA, Grobbee DE, et al. Application of treatment thresholds to diagnostic-test evaluation: an alternative to the comparison of areas under receiver operating characteristic curves. Med Decis Making 1997;17:447-454.[Abstract/Free Full Text]
  37. Bossuyt PM, Lijmer JG, Mol BW. Randomized comparisons of medical tests: sometimes invalid, not always efficient. Lancet 2000;356:1844-1847.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  38. Duet M, Benelhadj S, Kedra W, Vilain D, Ajzenberg C, Elkharrat D, et al. A new quantitative D-dimer assay appropriate in emergency: reliability of the assay for pulmonary embolism exclusion diagnosis. Thromb Res 1998;91:1-5.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  39. Brown MD, Rowe BH, Reeves MJ, Bermingham JM, Goldhaber SZ. The accuracy of the enzyme-linked immunosorbent assay D-dimer test in the diagnosis of pulmonary embolism: a meta-analysis. Ann Emerg Med 2002;40:133-144.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  40. Wolfe TR, Hartsell SC. Pulmonary embolism: making sense of the diagnostic evaluation. Ann Emerg Med 2001;37:504-514.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  41. Lip GYH, Lip PL, Zarifis J, Watson RDS, Bareford D, Lowe GD, et al. Fibrin D-dimer and B-thromboglobulin as markers of thrombogenesis and platelet activation in atrial fibrillation. Circulation 1996;94:425-431.[Abstract/Free Full Text]
  42. Li-Saw-Hee FL, Blann AD, Lip GY. Effects of fixed low-dose warfarin, aspirin-warfarin combination therapy, and dose-adjusted warfarin on thrombogenesis in chronic atrial fibrillation. Stroke 2000;31:828-833.[Abstract/Free Full Text]
  43. Roussi J, Bentolila S, Boudaoud L, Casadevall N, Vallee C, Carlier R, et al. Contribution of D-dimer determination in the exclusion of deep venous thrombosis in spinal cord injury patients. Spinal Cord 1999;37:548-552.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  44. Couturaud F, Kearon C, Bates SM, Ginsberg JS. Decrease in sensitivity of D-dimer for acute venous thromboembolism after starting anticoagulant therapy. Blood Coagul Fibrinolysis 2002;13:241-246.[CrossRef][ISI][Medline] [Order article via Infotrieve]



The following articles in journals at HighWire Press have cited this article:


Home page
 Eur Respir JHome page
S. Jouveshomme, I. Bohn, and A. Cazaban
Diagnosis of pulmonary embolism in hospitalised patients: retrospective survey of an institutional standard
Eur. Respir. J., December 1, 2007; 30(6): 1117 - 1123.
[Abstract] [Full Text] [PDF]

Home page
 AJGPHome page
K. Aschbacher, R. von Kanel, J. E. Dimsdale, T. L. Patterson, P. J. Mills, B. T. Mausbach, M. A. Allison, S. Ancoli-Israel, and I. Grant
Dementia Severity of the Care Receiver Predicts Procoagulant Response in Alzheimer Caregivers
Am J Geriatr Psychiatry, August 1, 2006; 14(8): 694 - 703.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
M. D. Brown, J. Lau, R. D. Nelson, and J. A. Kline
Turbidimetric D-Dimer Test in the Diagnosis of Pulmonary Embolism: A Metaanalysis
Clin. Chem., November 1, 2003; 49(11): 1846 - 1853.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit an electronic Letter to
the Editor about this paper
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (24)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schrecengost, J. E.
Right arrow Articles by Bruns, D. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schrecengost, J. E.
Right arrow Articles by Bruns, D. E.
Related Collections
Right arrow Clinical Immunology
Right arrow Evidence Based Laboratory Medicine and Test Utilization
Right arrow Hemostasis and Thrombosis
Right arrow Hematology

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS