A Cost-effectiveness Analysis of Diagnostic Algorithms of Deep Vein Thrombosis at the Emergency Department

Introduction

Suspected cases of deep vein thrombosis are common at emergency departments and they often require extensive and costly diagnostic testing. The objective of this study was to evaluate whether a diagnostic algorithm based upon pre-test probability and D-dimer in diagnosing deep vein thrombosis may be cost-effective from a societal perspective in a Swedish setting.

Material and Methods

The cost-effectiveness of two alternative diagnostic algorithms were calculated using decision analysis. An algorithm which out ruled deep vein thrombosis among low probability patients with negative D-dimer was compared to a traditional algorithm including compression ultrasonography and/or contrast venography for all patients. For sensitivity analysis, a third reversed algorithm, where D-dimer was followed by pre-test probability, was analyzed. Estimates of probabilities were obtained from a prospective management study, including 357 outpatients with clinical suspicion of deep vein thrombosis. Direct costs were estimated using prices from Scania, Sweden. Indirect costs were estimated using time spent at the local emergency department and gross average wages in Sweden.

Results

The total cost of the pre-test probability and D-dimer algorithm was estimated to €406 per patient and the traditional algorithm was estimated to €581 per patient. Reversing the order of the score and test resulted in an estimate of €421 per patient.

Conclusion

At no significant difference in diagnostic efficacy the algorithm based upon pre-test probability and D-dimer was cost-effective, while the reversed algorithm and diagnostic imaging for all patients were not.     

Prospective diagnostic accuracy assessment of the HemosIL HS D-dimer to exclude pulmonary embolism in emergency department patients

Introduction

Chest pain and shortness of breath are among the most common symptoms requiring immediate evaluation. Testing for pulmonary embolism (PE) has become easier and widespread due to D-dimer blood tests. Safe use of these tests is only possible if sensitivity is high and they are used in non-high probability patients. We evaluated diagnostic performance of the HemosIL HS D-dimer, which despite FDA approval in 2005, has been minimally reported in prospective standard clinical care.

Materials and methods

We used a prospective observational study design to follow patients in a single center with the HemosIL HS ordered for symptoms of possible PE with positive test result if > 243 ng/ml. The outcome was PE or deep venous thrombosis (DVT) at the time of presentation or subsequent 45 days determined by structured evaluation of imaging tests, phone, or medical record follow-up in all patients.

Results

529 patients received a D-dimer and 4.7% were ultimately diagnosed with PE or DVT. The sensitivity of the HemosIL HS was 96.0% (95% CI; 79.6 to 99.9%) specificity was 65.7% (95% CI; 61.4 to 69.8%) and likelihood ratio negative was 0.06 (95% CI; 0.01 to 0.42). The probability of PE in patients with a negative D-dimer was 1/332 or 0.3% (95% CI; 0.01% to 1.67%). The receiver operator curve had an area under the curve of 0.87 and supported the current cut-point as optimal.

Conclusions

The HemosIL HS D-dimer had high sensitivity, very low negative post-test probability and is useful in excluding PE in the acute care setting.     

Accuracy and usefulness of a clinical prediction rule and D-dimer testing in excluding deep vein thrombosis in cancer patients

Introduction

Deep vein thrombosis (DVT) can be safely and reliably excluded in patients with a low clinical probability and a negative D-dimer result but the accuracy and utility of such a strategy is less certain in cancer patients. We sough to compare the performance of the Wells pretest probability (PTP) model and D-dimer testing between patients with and without cancer and to examine the utility of the two PTP model classification schemes (low/moderate/high versus unlikely/likely) in excluding DVT in patients with cancer.

Materials and methods

Pooled analysis of databases from three prospective diagnostic studies evaluating consecutive outpatients with suspected DVT.

Results

A total of 2696 patients were evaluated. DVT was diagnosed in 403 (15%) patients overall and in 83 of 200 (41.5%) cancer patients. The PTP distribution and the prevalence of DVT in each PTP category were significantly different between patients with and without cancer, regardless of the classification used (p < 0.01). In patients with cancer, the negative predictive values of a low or unlikely PTP score in combination with a negative D-dimer result were 100% (95% CI 69.8%-100%) and 100% (95% CI 82.8%-96.6%), respectively. However, the specificities ranged from 46.2% (95%CI 27.1%-66.3%) to 57.1% (95%CI 41.1%-71.9%). Further testing was required in 94% of cancer patients using the low/moderate/high PTP classification and in 88% using the unlikely/likely stratification.

Conclusions

As in patients without cancer, the combination of a low or unlikely PTP with a negative D-dimer result can exclude DVT in patients with cancer. However, this strategy has limited utility because very few cancer patients present with this combination.     

Diagnosis and management of venous thromboembolism: Results of a survey on current clinical practice

Background

The implementation of evidence from clinical studies into daily clinical practice is not a straightforward process. We developed a standardized questionnaire to explore clinical practice patterns in the management of VTE, in particular about the use of pre-clinical probability and D-dimer testing and on the home treatment of pulmonary embolism (PE).

Methods

The standardized questionnaire was sent to all 394 physician members of the Italian Society of Thrombosis and Haemostasis (SISET) by e-mail. The questionnaire contained three groups of questions: about general information, about the diagnostic process for both deep venous thrombosis (DVT) and PE, and about home-therapy of PE.

Results

One hundred and twenty-eight (32.5%) physicians responded the questionnaire. For DVT diagnosis 69 (54.3%) physicians answered that they always use the D-dimer test; 4 (3.1%) do never use it; whereas only 11 (8.7%) take notice of the D-dimer result before visiting the patients; 38 (29.9%) use only clinical judgment to assess pre-clinical probability of disease. For the diagnosis of PE 80 (66.1%) physicians always use the D-dimer test, whereas 3 (2.5%) do never use it; whereas 14 (11.7%) take notice of the D-dimer result before visiting the patients; 50 (41.3%) use only clinical judgment to assess pre-clinical probability. Sixty-six (59.5%) clinicians declared to treat patients with PE at home, when feasible.

Conclusion

The diagnostic approach to VTE among expert physicians appears to be heterogeneous; in particular there is no widespread use of clinical prediction rules. The majority of expert physicians appear to consider the possibility of treating at home patients with PE.     

Risk of deep venous thrombosis (DVT) in bedridden or wheelchair-bound multiple sclerosis patients: A prospective study

Background

Multiple sclerosis (MS) often causes progressive loss of mobility, leading to limb paralysis. Venous and lymphatic stasis is a risk condition for venous thromboembolism (VTE). There is, however, no data on the frequency of VTE complicating the progression of MS. The aim of this study was to assess the frequency of deep vein thrombosis (DVT) in patients with late-stage MS attending a neurology center for rehabilitation.

Patients and Methods

A total of 132 patients with MS were enrolled, 87 women and 45 men, mean age 58 ± 11 years. The disease had started on average 18.7 years before; patients reported 9.6 hours bedridden per day or 14.3 hours wheelchair-bound. Only 25 patients reported a residual ability to walk alone or with help. Lower limb edema was present in 113 patients, bilateral in 41 cases. At admission all patients underwent extended compression ultrasonography. Their plasma D-dimer levels were measured. No antithrombotic prophylaxis was given.

Results

DVT was found in 58 patients (43.9%); 32 had a history of VTE. Forty of these patients (69%) had chronic lower limb edema, in 19 cases bilateral. D-dimer levels in the DVT patients were significantly higher than in patients without DVT (553 ± 678 vs. 261 ± 152 ng/mL, p = 0.0112, Mann-Whitney Test). Nearly half the DVT patients (26, 45%) had high D-dimer levels (701 ± 684 ng/mL). Of the 74 patients without DVT, 48 had normal D-dimer (193.37 ± 67.28 ng/mL) and 26 high (387.61 ± 187.42 ng/mL).

Conclusions

The frequency of DVT in late-stage MS may be over 40%. The long history of the disease means the onset of each episode cannot be established with certainty. A number of patients with positive CUS findings had negative D-dimer values, suggesting a VTE event in the past. However, the level of DVT risk in this series should lead physicians to consider the systematic application of long-term preventive measures.     

Use of the Delphi method to facilitate antithrombotics prescription during pregnancy

Introduction

Management of pregnant women at risk for venous thromboembolism (VTE) remains complex. Guidelines do not definitively fix optimal strategies due to limited trial data. Our objective was to build an easy-to-use tool allowing individualised, risk-adapted prophylaxis.

Materials and Methods

A Delphi exercise was conducted to collect 19 French experts’ opinions on pregnancy-related VTE.

Results

Experts with an active interest in clinical research and care of VTE and placental vascular complications were selected. The risk score was classified by an anonymous computer vote. A scoring system for VTE risk in pregnant women was developed, each score being associated with a specific treatment: graduated elastic compression stockings, aspirin, prophylactic Low Molecular Weight Heparin (LMWH: variable durations), or adjusted-dose of LMWH through pregnancy and postpartum.

Conclusions

Our simple consensual scoring system offers an individual estimation of thrombosis risk during pregnancy together with its related therapeutic strategy, in accordance with most of the new international recommendations. The accuracy of our individual risk score-based therapeutic guidance is currently being prospectively evaluated in a multicenter trial (Clinicaltrials.gov registry no: NCT00745212).     

Safety of excluding acute pulmonary embolism based on an unlikely clinical probability by the Wells rule and normal D-dimer concentration: A meta-analysis

Introduction

The Wells clinical decision rule (CDR) and D-dimer tests can be used to exclude pulmonary embolism (PE). We performed a meta-analysis to determine the negative predictive value (NPV) of an “unlikely” CDR (≤ 4 points) combined with a normal D-dimer test and the safety of withholding anti-coagulants based on these criteria.

Methods

Prospective studies that withheld anti-coagulant treatment from patients with clinically suspected PE and an “unlikely” CDR in combination with a normal D-dimer concentration without performing further tests were searched for in Medline, Cochrane and Embase. Primary endpoints were the recurrence rate of venous thromboembolism (VTE) and PE-related mortality during 3-months follow-up.

Results

Four studies including 1660 consecutive patients were identified. The pooled incidence of VTE after initial exclusion of acute PE based on an “unlikely” CDR and normal D-dimer was 0.34% (95%CI 0.036-0.96%), resulting in a NPV of 99.7% (95%CI: 99.0-99.9%, random effects-model). The risk for PE related mortality was very low: 1/1660 patients had fatal PE (0.06%, 95%CI 0.0017-0.46%).

Conclusion

Acute PE can be safely excluded in patients with clinically suspected acute PE who have an “unlikely” probability and a negative D-dimer test and anticoagulant treatment can be withheld. There is no need for additional radiological tests in these patients to rule out PE.     

Comparison of high specificity with standard versions of a quantitative latex D-dimer test in the assessment of community pulmonary embolism: HaemosIL D-dimer HS and Pulmonary Embolism

Background

D-dimer assays are sensitive but have poor specificity. False positive results lead to extra imaging and hospital admissions.

Objectives

To make a pilot comparison of the diagnostic accuracy of the standard quantitative latex HemosIL D-dimer assay with a newer HemosIL D-dimer HS version designed to have improved specificity.

Patients / Methods

Consecutive patients presenting from the community to an Emergency Department that were investigated for suspected pulmonary embolism using a D-dimer test were included in the study. Standard and D-dimer HS tests were performed. Pulmonary Embolism was diagnosed on the basis of imaging studies or post-mortem at any time from presentation to 90 days thereafter.

Results

The prevalence of Pulmonary Embolism was 4.5% (18/402). The sensitivity, specificity, negative predictive value, and positive predictive value for the standard quantitative D-dimer test was 100% (81.5 - 100.0), 49.2% (44.1 - 54.3),100% (98.1 - 100.0), and 8.5% (5.1 - 13.0), respectively, and 100% (81.5 - 100.0), 58.3% (53.2 - 63.3),100% (98.4 - 100.0), and 10.1% (6.1 - 15.5), for the D-dimer HS test. There were 35 (16%) fewer ‘false positives’ using the D-dimer HS assay compared with the standard assay.

Conclusions

D-dimer HS has superior specificity to the standard quantitative D-dimer test without any loss of sensitivity. The generation of fewer false positive results should lead to less unnecessary diagnostic imaging; the use of which is associated with increased hospital admissions and length of stay. The HS assay may therefore have significant health economic benefits.     

Circulating tissue factor positive microparticles in patients with acute recurrent deep venous thrombosis

Introduction

Circulating tissue factor positive microparticles (MPTF) were reported in a wide range of diseases with thrombotic tendency. Though D-dimer assay had a high negative predictive value for deep venous thrombosis (DVT) recurrence, there are currently no reliable positive predictors for recurrent DVT. We therefore quantified MPTF in patients with acute recurrent DVT to determine whether MPTF levels could be used to predict recurrent DVT.

Materials and Methods

Microparticles (MPs) were isolated from plasma of initial DVT patients (n = 25), recurrent DVT patients (n = 25) and sex- and age-matched healthy individuals (n = 25), stained with annexin V, cell-specific monoclonal antibodies (MoAbs) and a MoAb directed against tissue factor (TF), and analyzed by flow cytometry. We also determined the plasma procoagulant activity with a Human TF Chromogenic Activity Assay Kit.

Results

We found total MPTF to be elevated in recurrent DVT patients versus normal individuals (P = 0.001). The number of monocyte-derived MPTF in both initial and recurrent DVT was higher than in normal individuals (P < 0.01, respectively). The platelet and endothelial cell derived MPTF in recurrent DVT were significantly increased relative to other MPTF (P < 0.05), although there was no difference between initial DVT patients and normal individuals. We demonstrated elevated procoagulant activity of platelet-free plasma in DVT patients relative to normal individuals, and a positive correlation with MPTF.

Conclusions

The elevated MPTF could be a potentially predictor for DVT recurrence. Further studies are needed to validate its sensitivity and specificity.     

Clinical prediction of pulmonary embolism in respiratory emergencies

Introduction

The initial management of suspected pulmonary embolism (PE) is commonly done in respiratory departments, but is based on clinical prediction rules developed in other settings.

Objective

To determine the accuracy of established prediction rules for PE in patients with respiratory emergencies.

Design

A prospective study

Materials and Methods

Patients presenting to respiratory emergency department with acute symptoms and signs suggestive of PE (n = 183) and subsequently admitted to hospital were prospectively enrolled. Wells’ rule, original and revised Geneva scores, their components separately, and other common clinical parameters were recorded during admission. PE was diagnosed by perfusion lung scanning, computed tomographic pulmonary angiography, lower limb venous ultrasonography, magnetic resonance pulmonary angiography, and/or pulmonary angiography.

Results

PE was confirmed in 52 and ruled out in 131 patients. Tachycardia, atelectasis, elevated hemidiaphragm, clinical signs of deep-venous thrombosis, physician perception that PE is the likeliest diagnosis, previous thromboembolism, chest pain, and absence of chronic obstructive pulmonary disease or cough were associated with the presence of PE. These significant parameters could be combined for accurate pre-test PE prediction, with a newly devised combinatorial tool exhibiting the highest area under curve [0.92 (95% CI: 0.87-0.97)], followed by Wells’ rule [0.86 (95% CI 0.79-0.92)], the revised Geneva score [0.83 (95% CI 0.77-0.90)], and the original Geneva score [0.75 (95% CI 0.68-0.83)].

Conclusion

Wells’ rule and the revised Geneva score are more useful in diagnosing PE in respiratory emergencies. A newly devised prediction tool can be of even greater accuracy in this patient population.     

Performance of two relatively new quantitative D-dimer assays (Innovance D-dimer and AxSYM D-dimer) for the exclusion of deep vein thrombosis

Introduction

D-dimer assays are now widely used as the first-line test in the diagnostic algorithm of suspected deep vein thrombosis (DVT). The aim of this study was to evaluate the performance of two relatively new quantitative D-Dimer assays (Innovance™ and AxSYM®) by comparison with a clinical gold standard.

Patients and methods

311 samples from outpatients with clinical suspicion of DVT, included in a prospective management study, was analysed (prevalence of DVT 23%). The diagnostic workup included estimation of pre-test probability, D-dimer determination, objective imaging as well as 3 month clinical follow up of negative patients.

Results

No significant differences were seen in sensitivity and negative predictive values between Innovance, AxSYM and the reference assays. The area under the ROC curve was slightly lower for the AxSYM assay and the correlation to the reference assays was only moderate (r < 0.8) whereas the agreement with the Vidas assay was near excellent (κ = 0.8). The Innovance assay reached the highest AUC, showed a strong correlation with the reference assays (r ≥ 0.9) and a good agreement with the Vidas assay (κ = 0.76). In combination with a low pre-test probability score the Innovance assay reached a NPV of 100% (95% CI, 92-100) and the AxSYM assay 98% (95% CI, 87-100).

Conclusion

The Innovance and AxSYM assays show an overall good and comparable performance for the exclusion of DVT when compared to the established assays. Our results for the AxSYM assay indicate that the optimal cut-off value needs to be further evaluated.     

Comparison of the diagnostic performance of the original and modified Wells score in inpatients and outpatients with suspected deep vein thrombosis

Introduction

The original and modified Wells score are widely used prediction rules for pre-test probability assessment of deep vein thrombosis (DVT). The objective of this study was to compare the predictive performance of both Wells scores in unselected patients with clinical suspicion of DVT.

Methods

Consecutive inpatients and outpatients with a clinical suspicion of DVT were prospectively enrolled. Pre-test DVT probability (low/intermediate/high) was determined using both scores. Patients with a non-high probability based on the original Wells score underwent D-dimers measurement. Patients with D-dimers < 500 μg/L did not undergo further testing, and treatment was withheld. All others underwent complete lower limb compression ultrasound, and those diagnosed with DVT were anticoagulated. The primary study outcome was objectively confirmed symptomatic venous thromboembolism within 3 months of enrollment.

Results

298 patients with suspected DVT were included. Of these, 82 (27.5%) had DVT, and 46 of them were proximal. Compared to the modified score, the original Wells score classified a higher proportion of patients as low-risk (53 vs 48%; p < 0.01) and a lower proportion as high-risk (17 vs 15%; p = 0.02); the prevalence of proximal DVT in each category was similar with both scores (7-8% low, 16-19% intermediate, 36-37% high). The area under the receiver operating characteristic curve regarding proximal DVT detection was similar for both scores, but they both performed poorly in predicting isolated distal DVT and DVT in inpatients.

Conclusion

The study demonstrates that both Wells scores perform equally well in proximal DVT pre-test probability prediction. Neither score appears to be particularly useful in hospitalized patients and those with isolated distal DVT.     

Incidence and predictive factors of symptomatic thrombosis related to peripherally inserted central catheters in chemotherapy patients

Introduction

The incidence of symptomatic catheter-related deep vein thrombosis (DVT) in cancer patients remains unclear and there is a lack of reliable data on the risk factors of PICC-related DVT.

Materials and Methods

We performed a retrospective cohort study of consecutive cancer patients who received an ultrasound guided PICC line for the administration of chemotherapy. Univariable and multivariable logistic regression analyses were performed to identify risk factors for symptomatic PICC-related DVT.

Results

In total, 340 cancer patients obtained PICC lines for the administration of chemotherapy. Of these patients, 19 (5.6%; 95% CI: 3.6-8.6) developed symptomatic PICC-related DVT. Factors previously associated with catheter-related DVT, including side of catheter placement, lumen size, tip location, need for repositioning, and number of insertion attempts, were not significant determinants in our analysis. Patients with diabetes were three times more likely to develop PICC-related DVT (OR 3.0, p = 0.039), while the presence of COPD and metastatic cancer also increased the odds (OR 3.3, p = 0.078 and OR 2.3, p = 0.083 respectively). Diabetes remained a significant risk factor after adjustment for effect of metastases and COPD (OR 3.175, p = 0.039). Further, the presence of metastases was a significant predictor (OR 3.34, p = 0.024) in our multivariable model.

Conclusions

Symptomatic PICC-related DVT are frequent in cancer patients receiving chemotherapy. Previously described factors associated with catheter-related thrombosis were not predictive of PICC-related DVT in our study. Diabetes, advanced disease and COPD appear to increase the risk of developing PICC-related DVT in chemotherapy patients.     

Hypercoagulability after trauma: Hemostatic changes and relationship to venous thromboembolism

Background

Major trauma induces a hypercoagulable state, which is frequently complicated by pathological thrombosis. However the sequential changes in coagulation markers and their relationship to clinical thrombosis have been poorly characterized.

Methods

We measured several markers of in vivo coagulation and fibrinolysis and their regulation serially for 2 weeks after multi-system trauma in a prospective cohort of patients who received no anticoagulant prophylaxis. Asymptomatic deep vein thrombosis (DVT) was assessed by routine bilateral venography between day 12 and 14. Clinically suspected DVT and pulmonary embolism (PE) were investigated in a standardized manner.

Results

Among the 135 cohort patients the overall venous thromboembolism (VTE) rate was 59%. Markers of thrombin generation were markedly increased within 24 hours of injury, remained persistently elevated for about 5 days and then decreased by day 14. No early compensatory increase in Tissue Factor Pathway Inhibitor (TFPI) or the complex of Factor Xa and TFPI (FXa-TFPI) was seen; FXa-TFPI remained depressed throughout the study. There was no inverse relationship demonstrated between markers of thrombin generation and thrombin regulation. Acquired APC resistance and hypofibrinolysis did not appear to be important contributors to hypercoagulability after trauma. None of the coagulation markers were independently predictive of VTE. Increasing age was the only significant, independent predictor of VTE.

Conclusion

Major trauma leads to significantly increased and persistent thrombin generation with disruption of its regulation. Coagulation markers do not appear to add independent predictive value in detecting VTE. Increasing age is the most important clinical predictor of VTE after trauma.     

Hospital mortality due to pulmonary embolism and an evaluation of the usefulness of preventative interventions

Background

Mortality rates due to pulmonary embolism (PE) are difficult to estimate often due to the presence of comorbid disease.

Objectives

To determine the accuracy of hospital records in identifying PE cases, PE-related mortality, and the number of PE-related deaths which are potentially preventable.

Methods

Retrospective chart review of PE cases hospitalized at The Ottawa Hospital over an 8 year period. Cases were reviewed to determine accuracy of coding, as well as the certainty with which PE was the cause of death. In PE-related deaths, a determination was made as to whether any interventions may have been life-saving.

Results

498 cases of 612 (81%) cases coded as PE were correctly coded. 111 (22%) died during hospitalization, 63% of deaths were attributed to PE. The presence of a cardiorespiratory comorbidity or cancer was independently associated with an increased rate of death due to PE. 54% of PE-related deaths were determined to be potentially preventable, most commonly by appropriate DVT prophylaxis. A significantly higher number of cancer patients as compared to non-cancer patients may have potentially had their death due to PE prevented by an inferior vena cava filter (IVCF). Systemic thrombolysis was deemed to be potentially life-saving in 1/38 PE-related deaths.

Conclusion

Hospital mortality due to clinically recognized PE can be determined by chart review of PE cases identified using the ICD coding system. Death due to PE is often potentially preventable; in the subgroup with cancer and DVT/PE, an IVCF may be a potentially useful intervention to prevent death due to PE. Prospective studies are needed to confirm these results.     

Comparison of the clinical usefulness of two quantitative D-Dimer tests in patients with a low clinical probability of pulmonary embolism

Background

Quantitative D-Dimer tests are established methods in the non-invasive diagnostic management to rule out venous thromboembolism (VTE). The diagnostic performance and the clinical efficiency different D-Dimer assays in the exclusion of pulmonary embolism (PE) have not yet been compared in a clinical outcome study.

Objective

Evaluation of the efficiency and safety of excluding the diagnosis of PE with two different quantitative D-Dimer assays in consecutive patients with clinically suspected PE.

Patients and Methods

We studied the VTE-failure rate of 2206 consecutive patients with an unlikely clinical probability in whom VIDAS or Tinaquant D-Dimer tests were performed.

Results

The prevalence of PE in 1238 patients whose D-Dimer level was analyzed with Tinaquant assay was 11%. The VIDAS assay group consisted of 968 patients with a PE prevalence of 13%. The VIDAS assay had a sensitivity of 99.2% (95%CI; 96- > 99.9%), the Tinaquant assay of 97.3% (95%CI; 93 -99%). The negative predictive value (NPV) in the Tinaquant assay group was 99.4% (95%CI 98-99.8%) in comparison to 99.7% (95%CI 99-> 99.9%) in the VIDAS assay group. During 3 month of follow-up, there were no fatal cases of PE among patients with normal D-Dimer and unlikely clinical probability in both D-Dimer assay groups. In addition, the test efficiency of Tinaquant assay was significantly higher in comparison to VIDAS assay (52% vs 42%, p < 0.001).

Conclusion

Both Tinaquant and VIDAS D-Dimer tests perform equally well in combination with an unlikely clinical probability in excluding PE. The Tinaquant test was shown to be more efficient.     

The potential biomarkers for thromboembolism detected by SELDI-TOF-MS

Introduction

Few studies were concerned about searching for specific biomarkers for thromboembolic (arterial and venous) diseases by the use of Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS).

Materials and Methods

We screened for potential biomarkers in 69 plasma samples, including samples from 20 patients with idiopathetic deep vein thrombosis (DVT), 20 patients with acute myocardial infarction (AMI), and 29 healthy controls without a history of thromboembolism. Pretreated plasma samples were analyzed on the Protein Biology System IIc plus SELDI-TOF-MS (Ciphergen Biosystems, Fremont, CA). Proteomic spectra of mass to charge ratio (m/z) were generated by the application of plasma to immobilized metal affinity capture (IMAC-3) ProteinChip arrays activated with copper.

Results

A pattern of three biomarkers (m/z: 2 667, 5 914, and 6 890 Da, respectively) with a total accuracy of 100% was selected based on their collective contribution to the optimal separation between patients with AMI and healthy controls. Another spattern consisting of only one biomarker (m/z: 5 914 Da) could totally discriminate patients with DVT and control subjects. For further analysis between patients with AMI and those with DVT, a pattern of four biomarkers (m/z: 3 418, 5 271, 33 378, and 68 125 Da, respectively) was selected with a total accuracy of 82.5%.

Conclusions

Plasma proteomic profiling with SELDI-TOF-MS and ProteinChip technologies provides high sensitivity and specificity in discriminating patients with thrombosis and healthy subjects. The discovered biomarkers might show great potential for early diagnosis of thromboembolic diseases.     

Incidence and characteristics of asymptomatic distal deep vein thrombosis unexpectedly found at admission in an Internal Medicine setting

Introduction

Lower limb deep vein thrombosis (DVT) is the most frequent clinical manifestation of venous thromboembolism (VTE) and can involve proximal or distal veins. Distal DVT (dDVT) is often asymptomatic and data about its incidence and prognosis are scanty, especially in high risk medical inpatients. Therefore, no consensus exists on the value of detecting and treating dDVTs. Aim of study was to evaluate incidence and characteristics of asymptomatic isolated dDVT at admission in an Internal Medicine department.

Materials and methods

Consecutive patients hospitalized for acute medical illnesses, in whom VTE was not the admission diagnosis, underwent Doppler Ultrasonography. For all patients with dDVT standard treatment with therapeutic doses of low molecular weight heparin or fondaparinux was proposed. Follow-up visits were scheduled at 1, 6 and 12 weeks.

Results

One-hundred-fifty-four patients were enrolled. In 4.5% a proximal DVT and in 16.2% an asymptomatic dDVT were found. Female sex, elevated age and renal and electrolyte abnormalities were significantly associated to dDVT (p = 0.014, p = 0.009 and p = 0.046, respectively). Only low degree of mobility (LDM) was independently associated to dDVT [OR 7.97 (95%CI 2.42-26.27), p = 0.001)]. A high mortality rate, not for VTE-related causes, was found, especially in the first week, among dDVT patients.

Conclusions

We found a high incidence of clinically silent dDVTs. LDM evaluation could be useful to select patients at high risk in whom to perform a search for dDVT.     

Multicenter evaluation of a new quantitative highly sensitive D-dimer assay, the Hemosil® D-dimer HS 500, in patients with clinically suspected venous thromboembolism

Introduction

D-dimer testing is widely used in conjunction with clinical pretest probability (PTP) for venous thromboembolism (VTE) exclusion. We report on a multicenter evaluation of a new, automated, latex enhanced turbidimetric immunoassay [HemosIL® D-Dimer HS 500, Instrumentation Laboratory (IL)].

Materials and Methods

747 consecutive outpatients with suspected proximal deep vein thrombosis (DVT, n = 401) or pulmonary embolism (PE, n = 346) were evaluated at four university hospitals in a management study with a 3 month follow-up. Samples were tested at each center using the new D-dimer assay on an automated coagulation analyzer [ACL TOP (IL)], with clinical cut-off for VTE at 500 ng/mL (FEU).

Results

The sensitivity and negative predictive value (NPV) were 100% for all PTP subgroups (no false negative results); for both sensitivity and NPV the lower limit of the 95% CI in patients with moderate/low PTP was higher than 95%. The overall specificity was 45.1% (95%CI: 41.1-49.3%). Higher specificity value was recorded in the low PTP subgroup [49.2% (95%CI: 41.7-56.7)]. No significant differences were found between patients suspected of having DVT or PE; sensitivity and NPV were 100%. The reproducibility of the assay was good, being the total CVs% less than 10% for D-dimer concentration near the clinical cut-off.

Conclusions

The new, highly sensitive D-dimer assay proved to be accurate when used for VTE diagnostic work-up in outpatients. Based on 100% sensitivity and NPV and lower limit of the 95% CI higher than 95%, the assay can be used as a stand-alone test in patients with non high PTP.