H. Bounameaux

D-Dimer for venous thromboembolism diagnosis: 20 years later

Summary.u2002 Twenty years after its first use in the diagnostic workup of suspected venous thromboembolism (VTE), fibrin D‐dimer (DD) testing has gained wide acceptance for ruling out this disease. The test is particularly useful in the outpatient population referred to the emergency department because of suspected deep vein thrombosis (DVT) or pulmonary embolism (PE), in which the ruling out capacity concerns every third patient clinically suspected of having the disease. This usefulness is based on the high sensitivity of the test to the presence of VTE, at least for some assays. Due to its poor specificity precluding its use for ruling in VTE, DD testing must be integrated in comprehensive, sequential diagnostic strategies that include clinical probability assessment and imaging techniques such as lower limb venous compression ultrasonography for suspected DVT or multi‐slice helical computed tomography for suspected PE. The present narrative review updates the data available on the use of the various commercially available DD assays in the diagnostic approach of clinically suspected VTE in distinct patient populations or situations, including outpatients and inpatients, patients with cancer, older age, pregnancy, a suspected recurrent event, limited thrombus burden, and patients already on anticoagulant treatment.

Contribution of noninvasive evaluation to the diagnosis of pulmonary embolism in hospitalized patients

The effectiveness of new diagnostic tools for suspected pulmonary embolism (PE), such as clinical probability assessment, plasma D-dimer (DD) measurement and lower limb venous compression ultrasonography (US), has not been specifically studied in patients with a suspected PE occurring during hospital stay. This study applied a sequential, decision analysis-based strategy adding these instruments to a ventilation/perfusion lung scan in a cohort of 114 consecutive inpatients clinically suspected of PE in order to establish in how many patients a pulmonary angiogram could thereby be avoided. A definitive diagnosis could be established by the noninvasive protocol in 61% of these patients: normal/near-normal lung scan, 14%; high probability lung scan, 19%; clinical probability combined with lung scan result, 18%; and US, 8%. Specificity of DD was only 7% and contributed to the exclusion of PE in only two patients. Pulmonary angiography was required in 39% of patients. The 3-month thromboembolic risk in patients in whom PE was excluded by the diagnostic process was 0% (95% confidence interval 0-4.9%). In conclusion, a noninvasive work-up for suspected pulmonary embolism is effective in hospitalized patients, allowing to forego angiography in 61% of them, and it appears to be safe, although this should be further investigated. In contrast to outpatients, D-dimer measurement appears to be useless in hospitalized patients.

Clinical predictors of dual aspirin and clopidogrel poor responsiveness in stable cardiovascular patients from the ADRIE study

Summary.u2002 Background:u2002Poor response to both aspirin and clopidogrel (dual poor responsiveness [DPR]) is a major risk factor for recurrent ischemic events. Objectives:u2002The aim of this study was to identify factors associated with DPR, defined with specific tests, and derive a predictive clinical score. Methods:u2002We studied 771 consecutive stable cardiovascular patients treated with aspirin (nu2003=u2003223), clopidogrel (nu2003=u2003111), or both drugs (nu2003=u2003437). Aspirin responsiveness was evaluated by serum thromboxane (Tx)B2 assay, and clopidogrel responsiveness by calculating the platelet reactivity index (PRI) on the basis of the phosphorylation status of the vasodilator phosphoprotein. The analysis was focused on patients treated with both drugs, and on independent predictors of DPR. Results:u2002Among patients on dual therapy, there was no relevant correlation between TxB2 levels and PRI values (ru2003=u20030.11). Sixty‐seven patients (15.4%) had DPR. Diabetes [odds ratio (OR) 1.89, 95% confidence interval (CI) 1.06–3.39], high body weight (>u200386u2003kg vs. <u200377u2003kg, OR 4.74, 95% CI 2.49–9.73), low aspirin dose (75–81u2003mg vs. ≥u2003160u2003mg, OR 0.12, 95% CI 0.09–0.93) and high C‐reactive protein (CRP) level (>u20031.6u2003mgu2003L−1 vs. <u20030.6u2003mgu2003L−1, OR 3.66, 95% CI 1.74–8.72) were independently associated with DPR, via increased TxB2 levels, increased PRI, or both. These associations with TxB2 and PRI were reproduced across the whole population. With use of a factor‐weighed score (c‐indexu2003=u20030.74), the predicted prevalence of DPR was 57% in the highest strata of the score as compared with <u20034% for the lowest strata. Conclusions:u2002Diabetes, body weight, the aspirin dose and CRP levels are readily available independent predictors of DPR, and some are potential targets for reducing its prevalence.

Prevalence of factor V Leiden and prothrombin G20210A mutations in unselected patients with venous thromboembolism.

We determined the prevalence of factor V Leiden and of prothrombin G20210A mutations in a cohort of unselected outpatients (nu2003=u2003748) referred for suspected deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and a pooled analysis of similar studies was also performed. Based on the clinical presentation, the prevalence of factor V Leiden was 15·7% in the 83 patients with DVT and 14·1% in the 99 patients with PE compared with 5·3% in patients without DVT and/or PE (control group). The prevalence of the prothrombin G20210A mutation did not differ among the three groups (3·9% for controls, 4·8% for DVT and 3·9% for PE patients). We then divided the 99 patients with PE by separately analysing those with PE but without DVT (nu2003=u200357) and those with PE and DVT (nu2003=u200342). Compared with the control group, the prevalence of factor V Leiden was 10·5%, odds ratio (OR) 2·10 [95% confidence interval (95% CI) 0·68–5·45] in patients with primary PE and 19·1%, OR 4·20 (95% CI 1·54–10·30) in patients with DVT and PE. For the prothrombin G20210A mutation, no statistically significant differences were found between the control group and the three other groups. In conclusion, our data and the pooled analysis indicate that patients with primary PE are less often affected by the factor V Leiden mutation. No statistically significant differences were observed between patients and controls for the prothrombin G20210A mutation.

Differential value of risk factors and clinical signs for diagnosing pulmonary embolism according to age

Summary.u2002 Introduction:u2002The diagnostic value of clinical presentation of pulmonary embolism (PE) is uncertain in the elderly, who often have concomitant cardiopulmonary diseases that may mimic PE. The aim of our study was to assess the differential value of risk factors, symptoms and clinical signs of venous thromboembolism, results of electrocardiogram and chest X‐ray for the diagnosis of PE in suspected patients according to age. Methods:u2002We analyzed data from two outcome studies which enrolled 1721 consecutive patients presenting in the emergency department with clinically suspected PE defined as acute onset of new or worsening shortness of breath or chest pain without any other obvious etiology. All patients underwent a sequential diagnostic work‐up and a 3‐month follow‐up. Results:u2002The proportion of confirmed PE was 24.2% (416 of 1721). Strength of the association with PE did not differ according to age group for history of venous thromboembolism (VTE), recent surgery, tachypnea at admission or right ventricular strain on electrocardiogram. Active malignancy, hemoptysis, tachycardia, hemidiaphragmatic elevation and pleural effusion at chest X‐ray were no more associated with PE in the patients aged of 75u2003years or more. Finally, symptoms and signs of deep venous thrombosis, and an alternative diagnosis less probable than PE were associated with PE in all age groups, but the strength of this association decreased significantly with advancing age. Conclusion:u2002Some risk factors, symptoms and signs of VTE are less strongly or even not at all associated with PE in the elderly. Physicians should take this into account when attending elderly patients suspected of PE and when assessing their clinical probability of PE.

Identifying acutely ill medical patients requiring thromboprophylaxis

*Service Quality of Care, Geneva University Hospitals and Faculty of Medicine, Geneva; Sanofi-Synthelabo (Switzerland), Meyrin; and Divisionof Angiology and Hemostasis, Geneva University Hospitals and Faculty of Medicine, Geneva, SwitzerlandTo cite this article: Chopard P, Spirk D, Bounameaux H. Identifying acutely ill medical patients requiring thromboprophylaxis. J Thromb Haemost2006; 4: 915–6.

Optimal duration of oral anticoagulant therapy following deep vein thrombosis of lower limbs

Deep vein thrombosis of the lower limbs is usually treated with an initial course of heparin or low-molecular-weight heparin associated with oral anticoagulants which are started simultaneously, thereby allowing heparin to be stopped after 4-7 days. Although consensus conferences have proposed a uniform duration of oral anticoagulant therapy of 3 months, great uncertainties remain as to the optimal treatment duration in an individual patient. Two large-scale studies have recently demonstrated that short treatment durations (4 weeks or 6 weeks, respectively) are associated with about two-fold higher rates of thromboembolic recurrences over follow-up periods of 1-2 years compared with longer treatment durations (3 months or 6 months, respectively). However, because treatment duration is also a major determinant of the hemorrhagic risk on oral anticoagulants, it is essential to balance the protective effect of these agents against their bleeding risk. This paper reviews the literature on the antithrombotic effects and hemorrhagic risks of different durations of oral anticoagulant therapy following lower limb deep vein thrombosis and suggests tentative recommendations which range from a short anticoagulant course of 4 weeks in a patient with a low risk of thromboembolic recurrence and a high hemorrhagic risk (e.g. postoperative distal vein thrombosis) to 6 months or more in a patient with a low hemorrhagic risk and a high risk of thromboembolic recurrence (e.g. idiopathic proximal vein thrombosis in a patient with inherited thrombophilia or malignancy).

Effect of age on the assessment of clinical probability of pulmonary embolism by prediction rules

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Measurement of plasma D-dimer is not useful in the prediction or diagnosis of postoperative deep vein thrombosis in patients undergoing total knee arthroplasty

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

A new, semi-quantitative and individual ELISA for rapid measurement of plasma D-dimer in patients suspected of pulmonary embolism.

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