Negative D-dimers and peripheral pulmonary embolism

The measurement of D-dimers is a recent addition to the diagnostic strategy of pulmonary embolism and has been shown to be a valuable tool with excellent sensitivity. However, there have been rare reports of patients with pulmonary embolism but negative D-dimer tests. The object of this study was to study patients with pulmonary embolism but negative D-dimers and to compare them with a population of patients with pulmonary embolism and raised D-dimers. One hundred and fifty consecutive patients admitted for pulmonary embolism were included in this study. All underwent measurement of D-dimers (normal <500 ng/ml) by an ELISA technique. The data of clinical examination and complementary investigations were analysed with respect to the D-dimers result. The sensitivity of raised D-dimers for pulmonary embolism was 96% (6 patients had results <500 ng/ml). The finding of chest pain was statistically greater in the group with negative D-dimers (p=0.01). In these cases, the emboli were all distal (p=0.0003), the average Miller index was significantly lower than in patients with high D-dimers (p=0.04) and the diagnostic value of ultrasound investigations (echocardiography, ultrasonography of lower limb veins) was less (p<0.0001). The authors conclude that measurement of D-dimers by the ELISA method may be non-diagnostic in distal pulmonary embolism and one explanation could be the less extensive thromboembolic process. In cases with negative D-dimers, a strong clinical suspicion of pulmonary embolism should lead to the request for further investigations.     

Plasma D-dimers in the diagnosis of venous thromboembolism

Clinical suspicion for venous thromboembolism (VTE) mandates objective testing to confirm or exclude the diagnosis. However, current imaging modalities are imperfect because of a small but important risk of complications with invasive techniques or limited sensitivity with noninvasive ones. A diagnostic tool for VTE is needed that is noninvasive and highly accurate, allowing immediate treatment decisions to be made in most cases. Plasma D-dimers (D-ds), specific cross-linked fibrin derivatives, partially fulfill these criteria in that they are sensitive markers for thrombosis but lack specificity. They therefore cannot be used to make a positive diagnosis of VTE; however, they generally have high negative predictive value and are useful as an exclusionary test, a potentially important role given that VTE is eventually ruled out in most patients investigated. Clinical management studies are clarifying the role of D-ds in the diagnostic paradigm of VTE: negative ultrasound and D-d findings obviate the need for serial imaging in suspected deep vein thrombosis, and anticoagulant therapy can be safely withheld in patients with non-high clinical suspicion for pulmonary embolism and non-high probability ventilation perfusion scan if D-d test results are negative. More recently, the combination of a negative SimpliRED (AGEN Biomedical Ltd, Brisbane, Australia) D-d result and low clinical suspicion derived using a formal scoring system has been shown to exclude deep vein thrombosis and pulmonary embolism and to obviate the need for imaging. Several different D-d assays are now available, and clinicians should be aware of the performance characteristics of the test used before incorporation into diagnostic algorithms as these will differ between assays, and the results of clinical management studies cannot necessarily be safely extrapolated to assays other than those specifically evaluated. If alternative assays are to be substituted, these should consistently have been shown to possess equivalent or greater sensitivity.     

D-dimers in the diagnosis of deep venous thrombosis

D-dimers (D-d) are degeneration products of fibrin. According to some recommendations (Lee et al., Ann Rev Med, 2002; 53: 15-33) the vein thromboembolism may be excluded by the determination of D-dimers level especially when the probability of diagnosis of deep vein thrombosis is less strong. The determination of D-dimers with made possible was the development of monoclonal antibodies and their detection is based on the determination using the principle of ELISA or agglutination techniques. An increased D-d level is not completely specific for venous thrombo-embolism; it may be enhanced during tumorous diseases, infections, kidney failure etc. In contrast, a negative result of the test is highly sensitive for exclusion of deep vein thrombosis or pulmonary embolism (sensitivity 90% to 100%). The authors also present their own results of a prospective study on the dynamism of D-dimer level in plasma of patients with deep vein thrombosis demonstrated by sonography at the time of start and in the course of the anticoagulant therapy. D-dimers were determined by two methods, the quantitative agglutination latex method and the rapid VIDAS ELISA method. At the time of admission, an increased level was established in up to 80% of patients using the VIDAS method and in 70% using the latex method. In the period of five to seven days after the beginning of treatment the proportions were 75% and 60%, respectively, according to the method used. After six weeks, a slightly elevated level above normal may be expected in 1/3 of patients and less than in 1/5 of patients in the later months.     

Value of the plasma measurement of D-dimers in the diagnosis of venous thromboembolism

Plasma measurement of D-dimers (DD), which are fibrin-specific degradation products, progressively replaces the cumbersome dosage of fibrinogen degradation products (FDP's) in serum for diagnosis and follow-up of consumption coagulopathies, for diagnosis of prethrombotic states and, potentially, for the control of the efficacy of antithrombotic therapies. Moreover, when the ELISA technique is used, this measurement may be very useful in the diagnosis approach of venous thromboembolic disease. In the present review, data are presented which strongly support the view that a low level of plasma D-dimers (less than 500 micrograms/L when using the ELISA from Stago) allows to exclude the diagnosis of deep venous thrombosis or pulmonary embolism with predictive values of 94 % and 100 % respectively. It is suggested that such a diagnostic potential might be very useful in the group of patients with inconclusive perfusion-ventilation scintigraphy (low or indeterminate probability of pulmonary embolism) which represent about 50 % of the patients with suspected pulmonary embolism.     

D-dimer assays for the exclusion of venous thromboembolism

Many assay systems for D-dimer measurement are available. Their intended use is mainly the exclusion of venous thromboembolism (VTE). Despite standardization attempts, an important variability in assay results is observed, and therefore data obtained by use of one assay cannot be extrapolated to another assay. As a consequence, each assay must be validated in appropriate clinical trials to determine its cut-off value for VTE exclusion. The differences observed can be explained by the heterogeneity of fibrin degradation products present in patient samples, by the reactivity of the various antibodies and their combinations, and by the differences in calibrators and in the format of assays. Among the different assay systems available, the use of automated, observer-independent tests having good analytical sensitivity is highly recommended. The assay should also exhibit a high sensitivity for VTE exclusion to be used as the first step of any diagnostic strategy.     

Negative predictive value of d-dimer for diagnosis of venous thromboembolism

The d-dimer levels are considered to be useful for the diagnosis of thrombosis, and they can be clinically used as a negative predictive value (NPV). However, evidence for the efficacy of diagnosing thrombosis based on the d-dimer levels is still not well established. The present study was designed to evaluate the cut-off values of d-dimer levels as a negative predictor for thrombosis. The plasma concentrations of d-dimer were measured in inpatients suspected of having thrombosis, and then the findings were evaluated to assess the correlation with the diagnosis of thrombosis. In healthy volunteers, the median value of VIDAS-d-dimer was 0.12 μg/ml, and the 95% confidence interval was from 0.05 to 0.38 μg/ml. However, the plasma d-dimer levels were significantly higher in patients with thrombosis than in those without thrombosis; there was no significant difference in d-dimer levels among various thromboses such as pulmonary embolism (PE), deep vein thrombosis (DVT), and disseminated intravascular coagulation (DIC). The NPV for venous thromboembolism was 100% in patients with 0.5 μg/ml VIDAS-d-dimer and 1.2 μg/ml LPIA-d-dimer levels. Elevated d-dimer levels might indicate a high risk of thrombosis, especially DVT/PE, and they are thus considered to be useful as a negative predictor for thrombosis.     

Combined D-dimer and clinical probability are useful for exclusion of recurrent deep venous thrombosis

It is estimated that up to one-third of patients with a history of deep venous thrombosis (DVT) present with symptoms of recurrent DVT. Our objective was to investigate both the diagnostic value of D-dimer (DD) and safety of a standard diagnostic algorithm including clinical assessment, plasma DD levels, and compression venous ultrasound as diagnostic tools in outpatients presenting with clinically suspected acute recurrent DVT of the lower limbs. We have enrolled 105 outpatients with a previous history of confirmed DVT and clinically suspected recurrent DVT. A 3-month follow-up period was carried out for patients in whom DVT was initially excluded. Prevalence of DVT in our study population was 44.8% (47/105). DD was negative in 17.1% of cases (18/105) and DVT could be ruled out in 15.2% of patients evaluated (16/105) on the basis of an unlikely clinical probability and a negative DD result. Only one false negative DD result in a patient scored as likely for DVT was found. Sensitivity, specificity, positive and negative predictive value of DD for the diagnosis of DVT were 97.9% (95% CI 88.9-99.6%), 29.3% (95% CI 19.2-42.0%), 52.9% (95% CI 42.5-63.0) and 94.4% (95% CI 74.2%-99.0), respectively. Sensitivity was 100% (95% CI 75.7-100) in the group of patients in whom DVT was considered unlikely. A diagnostic strategy combining clinical evaluation and DD has proved to be useful for the exclusion of DVT in subjects with clinically suspected recurrent DVT, especially in patients included in the lower clinical pretest probability group.     

D-dimers measurement to predict the risk of thromboembolic recurrence

PURPOSE: The optimal duration of anticoagulant therapy after a first episode of venous thromboembolism (VTE) is still matter of debate. Currently, the duration of anticoagulation is recommended on the basis of the clinical characteristics of the index event. In particular, the seventh ACCP conference on antithrombotic and thrombolytic therapy suggests that events secondary to a reversible risk factor should anticoagulated for shorter period of time than idiopathic VTE. Recently, D-dimer measurement has been used to predict the risk of recurrence and to tailor anticoagulant therapy on an individual basis. CURRENT KNOWLEDGE AND KEY POINTS: Four studies used various D-dimer tests at various cut-off to predict the risk of recurrence after a first VTE event. Overall, these studies confirmed that D-dimer measurement has a high negative predictive value (>92%) to predict the risk of a recurrent VTE event. One intervention randomized study confirmed that in patients who stopped anticoagulation, the adjusted hazard ratio for a recurrent event among those with an abnormal D-dimer test, as compared with those with a normal test was of 2.27 (95% CI:1.15-4.46). FUTURE PROSPECTS AND PROJECTS: The missing gap remains to find a test able to detect patients at high risk of recurrence in whom maintaining anticoagulation would be beneficial. The limited positive predictive value of D-dimer reported in all studies suggests that the D-dimer test will have limited value in this field. Moreover, standardization of the cut-off and of the time of blood sampling in relation to cessation of anticoagulation is warranted.     

Performances of a new, automated latex assay for the exclusion of venous thromboembolism.

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.     

犬实验性肺血栓栓塞症后血清乳酸脱氢酶同工酶3和血浆D-二聚体的动态研究

目的　动态监测犬肺血栓栓塞症 (PTE)后血清乳酸脱氢酶同工酶 3(L DH3)与血浆 D-二聚体的变化 ,探讨两者在急性 PTE诊断中的价值。方法　采用健康杂种犬 18只 ,随机分为三组。栓塞 组采用自体血加凝血酶及人纤维蛋白原制备的自体血栓 ,由股静脉输入建立急性 PTE模型。栓塞 组不加人纤维蛋白原 ,余同栓塞 组。对照组由股静脉输入生理盐水加人纤维蛋白原。三组均于栓塞前后做肺动脉造影及螺旋 CT血管造影 ,栓塞前及栓塞后多时点留取血样测 L DH3及血浆 D-二聚体浓度。结果　肺动脉造影及螺旋 CT血管造影均证实犬 PTE模型制备成功。栓塞 组血浆 D-二聚体于栓塞后 30 m in明显上升 ,2 4 h后明显下降 ,自身前后比较及与栓塞 组、对照组比较 ,差异有显著性 (P<0 .0 5 )。栓塞 ( 、 )组栓塞后 2 h至 4 d L DH3明显升高 ,与栓塞前及对照组比较差异有显著性 (P<0 .0 5 )。结论　血浆 D-二聚体、L DH3在急性 PTE早期有一个相对特征性的动态变化过程 ,联合检测 D-二聚体、L DH3有助于急性 PTE的早期诊断。     

Usefulness of a semiquantitative D-dimer test for the exclusion of deep venous thrombosis in outpatients

PURPOSE: The D-dimer test is used commonly in diagnostic strategies to reduce the need for ultrasonography in patients suspected of having deep venous thrombosis. We studied several clinical and laboratory variables that might limit the accuracy of a semiquantitative D-dimer test. SUBJECTS AND METHODS: In this retrospective cohort study, 704 outpatients suspected of having deep venous thrombosis underwent a semiquantitative D-dimer test and ultrasonography. The performance of the D-dimer test was calculated in patients using anticoagulants (n =61), patients with previous thrombosis (n =127), and patients with malignancy (n =47), including 39 patients with more than one of these characteristics. The 508 remaining patients were considered to be the reference group. RESULTS: A total of 254 patients (36%) had evidence of deep venous thrombosis. The D-dimer test had a sensitivity of 99% (174/176; 95% confidence interval [CI]: 96% to 100%) and a negative predictive value of 98% (98/100; 95% CI: 93% to 100%) in the reference group. The sensitivity of the D-dimer test in patients using oral anticoagulants was 75% (6/8; 95% CI: 35% to 97%; P =0.01 compared with the reference group). Test sensitivity was 96% (51/53; 95% CI: 87% to 100%) in patients with previous thrombosis, and 100% (29/29; 95% CI: 88% to 100%) in patients with cancer. However, 553 (79%) of all patients, including 43 of the cancer patients (91%), had an abnormal D-dimer test. CONCLUSION: The semiquantitative D-dimer test in this study has a high sensitivity and negative predictive value in the exclusion of deep venous thrombosis, except perhaps among patients using oral anticoagulants. D-dimer tests in patients with cancer and in patients over 70 years old may not be worthwhile, because the tests are usually positive.