Comparison of the diagnostic performance of three soluble fibrin monomer tests and a D-dimer assay in patients with clinically suspected deep vein thrombosis of the lower limbs

We assessed three soluble fibrin monomer (SFM) assays in 231 in and out-patients with clinically suspected deep-vein thrombosis. Thrombosis was confirmed or excluded by complete lower-limb ultrasound. SFM assay were less accurate than VIDAS D-dimer and in patients with small thrombosis or under anticoagulation. Specificity was lower for a similar sensitivity.     

Diagnostic management of clinically suspected acute deep vein thrombosis

Deep vein thrombosis (DVT) is a common disease that may lead to potentially fatal complications, such as pulmonary embolism. In the past decades several diagnostic tools and algorithms for DVT have been studied. Currently the combination of a clinical decision rule, D-dimer testing and compression ultrasonography has proved to be safe and effective for the diagnosis of DVT in the lower extremities. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) can be useful as additional or secondary imaging modalities. This review will discuss the elements currently used in making the clinical diagnosis of DVT. These elements include clinical decision rules and D-dimer testing, different imaging investigations and the appropriate use of these within diagnostic algorithms in patients with clinically suspected DVT. Although current knowledge of the options available to diagnose DVT of the lower extremities is well established, there are still unresolved issues, including the optimal diagnosis of recurrent DVT and distal DVT. Furthermore, the diagnosis of DVT of the upper extremities will be discussed, including the different imaging modalities and the limitations of these techniques.     

Simplification of the diagnostic management of suspected deep vein thrombosis

BACKGROUND: The standard diagnostic approach in patients with suspected deep vein thrombosis is to repeat the compression ultrasonography after 1 week in all patients with an initial normal result. We hypothesized that a normal finding of a D-dimer assay safely obviates the need for repeated ultrasonography. In addition, we evaluated the potential value of a pretest probability assessment for this purpose. METHODS: At presentation, consecutive outpatients with suspected thrombosis underwent independent assessment by means of ultrasonography of the proximal veins, a whole-blood D-dimer assay, and a pretest clinical model. Patients with normal ultrasonographic findings and an abnormal D-dimer assay result were scheduled for repeated ultrasonography. We evaluated the incidence of symptomatic venous thromboembolic complications during a 3-month follow-up, and the value of clinical pretest probability with ultrasonography or D-dimer assay in scenario analyses. RESULTS: We studied 1756 patients with prevalence of thrombosis of 22%. At entry, results of the D-dimer assay and ultrasonography were normal in 828 patients (47%). Of these, 6 returned with confirmed symptomatic venous thromboembolism (complication rate, 0.7%; 95% confidence interval [CI], 0.3%-1.6%). Repeated ultrasonography was avoided in 61% of the patients with an initial normal test result. Scenario analyses disclosed that the complication rate was 1.6% (95% CI, 0.8%-2.6%) in those with a low clinical pretest probability and a normal result of ultrasonography at referral, whereas this figure was 1.8% (95% CI, 0.9%-3.3%) in patients with a low clinical probability result and a normal result of the D-dimer assay at referral. CONCLUSIONS: It is safe to withhold repeated ultrasonography in patients with suspected deep vein thrombosis who have normal results of ultrasonograpy and the SimpliRED D-dimer assay at presentation. The combination of a low clinical pretest probability with a normal result of compression ultrasonography or the D-dimer assay appears to be equally safe in refuting the diagnosis of deep vein thrombosis.     

Failure of soluble fibrin polymers in the diagnosis of clinically suspected deep venous thrombosis.

A new diagnostic test has recently become available which is highly specific for plasma soluble fibrin polymers, the thrombus precursor protein (TpP) enzyme immunoassay. In order to evaluate the diagnostic accuracy of this test and that of a new rapid and automated test for the determination of D-dimers, the BC D-dimer test, in patients with clinically suspected deep vein thrombosis (DVT), 70 consecutive symptomatic patients underwent laboratory analysis with both tests and with the classic enzyme-linked immunosorbent assay (ELISA) D-dimer test, followed by the execution of a compression ultrasound (CUS) test of the affected limb. Patients with a positive CUS test were considered to have DVT (20 of 70), whereas those with a serially negative test and an uneventful 3-month follow-up test were regarded as not having DVT (50 of 70). The sensitivity of the TpP test (45.0%) was significantly lower than that of both the BC D-dimer test (80.0%; P = 0.02) and the classic ELISA test (90.0%; P = 0.002). The specificity of the TpP test (66.0%) did not differ from that of either D-dimer test (60.0 and 64.0%, respectively). The negative predictive value of the TpP test (75.0%) was significantly lower than that of the classic ELISA D-dimer test (94.1%; P = 0.02), which in turn did not differ from that of the BC D-dimer test (88.2%). The positive predictive value was similarly low for each investigated test (34.6, 44.4, and 50.0%, respectively). In conclusion, the TpP test can neither be used to detect a DVT nor to exclude its development in patients with the clinical suspicion of this disease. By contrast, the BC D-dimer might safely replace the classic ELISA test for excluding DVT in symptomatic patients.     

Integrated diagnostic approach to suspected deep vein thrombosis and pulmonary embolism

Diagnosing deep vein thrombosis and pulmonary embolism has become definitely easier and more reliable over the past fifteen years, especially thanks the development of lower limbs venous compression ultrasonography and fibrin D-Dimer measurement. These tests allowed reducing the requirement for venography and pulmonary angiography to a small minority of patients. Simultaneously, ventilation/perfusion lung scan criteria have been standardized, and the performance of spiral computed tomography has been analyzed in an appropriate way. New sequential, mainly noninvasive strategies could be developed that proved to be safe in large-scale prospective cohort studies with prolonged follow-up. They should now be implemented in daily practice according to cost-effectiveness analyses as well as local facilities and expertise.     

The diagnostic evaluation of deep vein thrombosis

Due to the morbidity and mortality associated with either untreated disease or inappropriate anticoagulant therapy, accurate diagnosis of venous thromboembolism is essential. As venography, the current gold standard test for deep vein thrombosis (DVT), is both invasive and costly, noninvasive diagnostic strategies for diagnosing DVT have been developed. Noninvasive tests often have to be combined to either raise the post-test probability of disease to a level justifying treatment or lower it to a level at which withholding treatment is warranted. Diagnostic algorithms involving clinical assessment, venous ultrasonography, and D-dimer testing have been validated in management trials of patients with DVT. The optimal strategy at individual institutions is dependent on local expertise and cost. Magnetic resonance venography has the potential to be used as a stand-alone test for DVT but requires further evaluation.     

Looking for deep vein thrombosis in suspected pulmonary embolism

Pulmonary embolism (PE) and deep vein thrombosis are two facets of the same disease, that is, venous thromboembolism (VTE). In patients with angiographically proven PE, the prevalence of proximal deep vein thrombosis by venography is around 70%. The sensitivity of compression ultrasonography (US) for the diagnosis of acute VTE in patients with a suspicion of PE is between 40 and 60%, with a high specificity (96 to 100%). Taking into account the 20 to 30% prevalence of PE in a population consulting for suspicion of this disease, the first line use of compression US will allow the diagnosis of acute VTE in half of patients with confirmed PE, that is, in 10 to 15% of patients addressed for suspicion of PE. In outpatients, the first line use of D-dimers which will exclude acute VTE in one-third of the initial population will slightly increase the reliability of compression US as a first imaging test. New tools of looking for deep vein thrombosis, such as computed tomographic venography coupled with computed tomographic pulmonary angiography, could become an interesting approach in the diagnostic strategy of PE, but require adequate evaluation in prospective studies.     

Practical diagnostic management of patients with clinically suspected deep vein thrombosis by clinical probability test,compression ultrasonography,and D-dimer test

PURPOSE: To evaluate a new noninvasive diagnostic strategy for ruling out deep vein thrombosis consisting of either a combination of low clinical probability and normal ultrasonography or a combination of moderate-to-high clinical probability, normal ultrasonography, and a normal D-dimer test. SUBJECTS AND METHODS: We studied 811 patients with clinically suspected deep vein thrombosis using a diagnostic management strategy that combined clinical probability, ultrasonography, and measurement of D-dimers. The primary endpoint was venous thromboembolism occurring during a 3-month follow-up. RESULTS: Of the 280 patients (35%) with a low clinical probability, 30 (11%) had an abnormal initial ultrasonography and were treated. Of the other 250 untreated patients with low clinical probability and a normal ultrasonography, 5 (2%; 95% confidence interval [CI]: 1% to 5%) developed a nonfatal venous thromboembolism during follow-up. Of the 531 patients (65%) with a moderate-to-high clinical probability, 300 (56%) had an abnormal ultrasonography. Of the remaining 231 patients with a normal ultrasonography, 148 had a normal D-dimer test; none of these patients developed deep vein thrombosis during follow-up (0%; 95% CI: 0% to 3%). Of the 83 patients with an abnormal D-dimer test, 77 underwent repeat ultrasonography about 1 week later; none of the 64 patients with a second normal ultrasound developed symptomatic deep vein thrombosis during follow-up (0%; 95% CI: 0% to 6%). CONCLUSIONS: This management strategy, which combines clinical probability, ultrasonography, and D-dimer measurements, is practical and safe in ruling out deep vein thrombosis in patients with clinically suspected thrombosis and reduces the need for repeat ultrasonography.     

Comparison of immunofiltration assay of plasma D-dimer with diagnostic imaging in deep vein thrombosis

This prospective study was designed to assess the diagnostic sensitivity, specificity and negative predictive value of the NycoCard D-dimer plasma immunofiltration assay in patients with suspected deep vein thrombosis (DVT) confirmed by ultrasonography/venography. 84 medical patients were recruited: 43 patients (51%) had proven venous thrombosis, 33 by venography and 10 by ultrasonography. The sensitivity of NycoCard D-dimer in patients with DVT was 95.3%, the specificity was 22.0% and the negative predictive value was 81.8%. An algorithm including the NycoCard D-dimer test for the acute management of DVT is proposed. This would enable low-risk patients to be discharged early from hospital, without imaging or anticoagulant therapy.     

Diagnosis of deep vein thrombosis by plasma-soluble fibrin or D-dimer

The present study was designed to determine the cutoff values of D-dimer and soluble fibrin (SF) for the diagnosis of deep venous thrombosis (DVT) and pulmonary embolism (PE) in Japanese patients. Plasma levels of these molecules were measured in 243 patients suspected of having DVT and 100 healthy volunteers (controls). Out of 243 patients, 20 patients were diagnosed with DVT. In the control group, plasma levels of D-dimer and SF did not show normal distribution, and the 95% confidence intervals (CI) of D-dimer and SF were 2.45 microg/mL and 6.92 microg/mL, respectively. Plasma levels of D-dimer and SF of patients with DVT were significantly higher than of those without DVT. In patients with DVT, the minimum values of D-dimer and SF were 1.71 and 1.44 microg/mL, respectively. When the cutoff value was set at the average+1 SD of those of the control (D-dimer, about 1.8 microg/mL; SF, about 1.4 microg/mL), 1 and 0 patient with DVT was overlooked, respectively. The sensitivity and specificity of D-dimer and SF for DVT were 95% and 100%, and 61.9% and 53.8%, respectively. When the cutoff value was set at 95% CI of the control (D-dimer, 2.5 microg/mL; SF, 6.9 microg/mL), 2 and 9 patients with DVT were overlooked, respectively. The sensitivity and specificity of D-dimer and SF were 90% and 50%, and 77.6% and 88.3%, respectively. When the cutoff values set at 2.5 microg/mL of D-dimer or 6.9 microg/mL of SF, 1 DVT patient was overlooked, with sensitivity and specificity of 95% and 69.5%. Our data suggest that both D-dimer and SF are useful markers for the diagnosis of DVT and that measurement of both D-dimer and SF increases the sensitivity and specificity for the diagnosis of DVT/PE.     

The diagnosis of clinically suspected venous thrombosis

The clinical diagnosis of venous thrombosis is highly non-specific. The reason for this is that none of the symptoms or signs of venous thrombosis is unique to this condition--that is, each can be caused by nonthrombotic disorders. Objective testing to confirm or exclude the diagnosis of venous thrombosis, then, is mandatory in patients with clinically suspected deep vein thrombosis.     

The diagnostic management of recurrent deep vein thrombosis and pulmonary embolism

The diagnostic management of recurrent venous thromboembolism (VTE) is a clinical dilemma. Clinical decision rules are well validated in patients with a first episode of clinically suspected VTE but are not validated in patients with a suspected recurrent event. D-dimer testing could safely exclude a recurrent VTE but is subject to several limitations. Imaging could objectively exclude or establish the diagnosis of recurrent VTE, but due to persistent residual abnormalities after the first or previous event, imaging interpretation can be difficult. To limit the presence of uncertain imaging test results, a standardized baseline examination after anticoagulation cessation should be considered. This review will elaborate on these issues and will discuss the recent advancements in this area.     

Reduced efficacy of clinical probability score and D-dimer assay in elderly subjects suspected of having deep vein thrombosis

The combined strategy of a pretest clinical probability (PCP) score and D-dimer has shown to be of value in the diagnosis of deep vein thrombosis (DVT). As D-dimer concentrations increase with age, the effect of age on the usefulness of this strategy was retrospectively investigated in outpatients suspected of having DVT. In all patients, participants of a prospective management trial, a PCP score and D-dimer (Tina-quant) were performed. In a total of 812 patients, 317 (39%) had thrombosis. Patients were divided into quartiles according to their age. Sensitivity and negative predictive value of a low/moderate PCP score and a normal D-dimer were 98-100% and did not differ between the different age quartiles. Specificity in the highest quartile was 17.4% compared with 49.2% in the youngest (P < 0.000001). The proportion of patients with a low/moderate PCP score and a normal D-dimer decreased with age: 12% in the highest quartile (>73.8 years) versus 25% in younger patients (P = 0.00005). We therefore conclude that the combined strategy of a low/moderate PCP score with a normal D-dimer test is safe for excluding DVT in all age groups, but is less useful in the elderly.     

The role of strain gauge plethysmography in the assessment of patients with suspected deep vein thrombosis

Suspicion of deep vein thrombosis (DVT) is a common reason for medical referral to hospital. Clinical signs and symptoms are notoriously unreliable, hence there is the need for objective testing. Strain gauge plethysmography (SGP) has been marketed as a technique for excluding lower limb DVT. We therefore set out to evaluate this screening tool. Over a 2 year period, 437 consecutive patients referred with suspected DVT were assessed using both plethysmography and Doppler ultrasound. When the two techniques were compared, plethysmography was found to have a negative predictive value of 90%. We conclude that strain gauge plethysmography has a role in the screening of patients with suspected DVT but should not be used as the sole method in patient assessment.     

The role of soluble cell adhesion molecules in patients with suspected deep vein thrombosis.

Activation of the endothelium, platelets and leukocytes has been shown to play an important role in the aetiology of deep venous thrombosis (DVT) in in-vitro experiments, resulting in the release of soluble cell adhesion molecules (sCAMs). We therefore assessed the value of soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin and soluble P-selectin for the diagnostic process in 69 consecutive patients with suspected DVT. Final diagnosis was based on the results of Duplex sonography or ascending venography. Thirty-seven patients (53.6%) finally suffered from DVT. Mean levels of sVCAM-1 were 589 +/- 530 ng/ml for controls and 587 +/- 328 ng/ml for patients. Corresponding levels concerning sICAM-1 were 316 +/- 161 and 342 +/- 186 ng/ml, those concerning soluble E-selectin were 54 +/- 38 and 42 +/- 18 ng/ml, and those concerning soluble P-selectin were 94 +/- 37 and 99 +/- 36 ng/ml (all P > 0.05). There was no significant correlation of the thrombus extension (all P > 0.05) or the duration of symptoms with sCAMs (all P > 0.05). In conclusion, we detected no significant differences concerning the concentration of four major sCAMs between patients with DVT and controls, so their assessment does not add any useful information for the diagnostic process of DVT.     

Comparison of six D-dimer methods in patients suspected of deep vein thrombosis.

We evaluated six D-dimer methods to determine their sensitivity, specificity, and negative predictive values (NPV) in symptomatic patients suspected of deep vein thrombosis (DVT). In patients suspected of DVT a whole blood D-dimer test (SimpliRED, Agen) was performed, and then tested using enzyme-linked immunosorbent assay (VIDAS D-Dimer, BioMerieux; Asserachrome D-Di, Stago International; Dimertest Gold, Agen) and automated immunoturbidometric methods (Advanced D-Dimer, Dade Behring; MiniQuant, Biopool). Each D-dimer method was independently compared with radiographic results to determine sensitivity and NPV. There were 151 patients enrolled in the study. Thirty-five (23.2%) patients had a positive Doppler ultrasound, with 26 proximal, eight distal, and one patient with both proximal and distal thrombus. Two patients (1.3%) had inconclusive studies and were excluded from the analyses. For all patients, the sensitivities for the rapid D-dimer methods were: SimpliRED, 82.3% [95% confidence interval (CI), 80.3-84.3%]; VIDAS D-Dimer, 91.4% (95% CI, 89.9-92.9%); MiniQuant D-Dimer, 96.3% (95% CI, 95.1-97.5%); and Advanced D-Dimer, 97.1% (95% CI, 96.3-97.9%). The sensitivity improved for SimpliRED (86.4%; 95% CI, 83.3-89.4%), VIDAS D-Dimer (95.5%; 95% CI, 85.0-100%), MiniQuant D-Dimer (100%; 95% CI, 96.9-100%) and Advanced D-Dimer (100%; 95% CI, 98.9-100%) in the inpatient population. The automated immunoturbidometric methods, the MiniQuant D-Dimer and Advanced D-Dimer, demonstrated comparable sensitivities and NPV with the VIDAS D-Dimer method in symptomatic patients suspected of DVT, which would suggest that these newer D-dimer methods could be used as part of the diagnostic algorithm for patients suspected of DVT.