Combined use of pretest clinical probability score and latex agglutination D-dimer testing for excluding acute deep vein thrombosis Takashi Yamaki, MD, Motohiro Nozaki, MD, Hiroyuki Sakurai, MD, Yuji Kikuchi, MD, Kazutaka Soejima, MD, Taro Kono, MD, Atsumori Hamahata, MD, and Kaya Kim, MD, Tokyo, Japan Objective: Currently, the latex agglutination D-dimer assay is widely used for excluding deep vein thrombosis (DVT) but is considered less sensitive than the enzyme-linked immunosorbent assay-based D-dimer test. The purpose of the present study was to determine if a combination of different cutoff points, rather than a single cutoff point of 1.0 g/mL, on the latex agglutination D-dimer assay and the pretest clinical probability (PTP) score would be able to reduce the use of venous duplex ultrasound (DU) scanning in patients with suspected DVT. Methods: The PTP score and D-dimer testing were used to evaluate 989 consecutive patients with suspected DVT before venous DU scanning. After calculating the clinical probability scores, patients were divided into low-risk (<0 points), moderate-risk (1-2 points), and high-risk (>3 points) pretest clinical probability groups. Receiver operating characteristic (ROC) curve analysis was used to determine the appropriate D-dimer cutoff point for each PTP with a negative predictive value of >98% for a positive DU scan. Results: There were 886 patients enrolled. The study group included 609 inpatients (68.7%) and 277 outpatients (31.3%). The prevalence of DVT in this series was 28.9%. There were 508 patients (57.3%) classified as low-risk, 237 (26.8%) as moderate-risk, and 141 (14.9%) as high-risk PTP. DVT was identified in 29 patients (5.7%) with low-risk, 118 (49.8%) with moderate-risk, and 109 (77.3%) with high-risk PTP scores. ROC curve analysis was used to select D-dimer cutoff points of 2.6, 1.1, and 1.1 g/mL for the low-, moderate- and high-risk PTP groups, respectively. In the low-risk PTP group, specificity increased from 48.9% to 78.2% (P < .0001) with use of the different D-dimer cutoff value. In the moderate- and high-risk PTP groups, however, the different D-dimer levels did not achieve substantial improvement. Despite this, the overall use of venous DU scanning could have been reduced by 43.0% (381 of 886) if the different D-dimer cutoff points had been used. Conclusions: Combination of a specific D-dimer level with the clinical probability score is most effective in low-risk PTP patients for excluding DVT. In moderate- and high-risk PTP patients, however, the recommended cutoff points of 1.0 g/mL may be preferable. These results show that different D-dimer levels for patients differing in risk is feasible for excluding DVT using the latex agglutination D-dimer assay. ( J Vasc Surg 2009;50:1099-105.) The D-dimer is a specific fragment produced during the degradation of fibrin, and the D-dimer assay is a promising adjunctive tool for noninvasive diagnostic management of patients with suspected deep vein thrombosis (DVT).1 Several studies have shown that a new rapid enzyme-linked immunosorbent assay (ELISA) is a useful test for suspected DVT, showing high sensitivity, moderate specificity, and a high negative predictive value (NPV). However, the technique is time-consuming and not suitable for emergency use. In contrast, the early latex assay is considered to have insufficient sensitivity for use in clinical practice2 and is being replaced by newer latex assays with improved sensitivity and negative predictive value.3-7 The clinical pretest probability score (PTP) is a useful tool for selecting patients for further diagnostic examinaFrom the Department of Plastic and Reconstructive Surgery, Tokyo Women’s Medical University. Competition of interest: none. Reprint requests: Takashi Yamaki, MD, Department of Plastic and Reconstructive Surgery, Tokyo Women’s Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan (e-mail: [email protected]; [email protected] 0741-5214/$36.00 Copyright © 2009 by the Society for Vascular Surgery. doi:10.1016/j.jvs.2009.06.059 tion for DVT. The PTP score, developed by Well et al,8 is calculated from clinical and historical data to stratify patients into low, moderate, and high risk of DVT. Various combinations of pretest clinical probability scores and a normal D-dimer test value, or even a normal D-dimer value alone, have been suggested to be sufficiently accurate for exclusion of venous thromboembolism (VTE).9-12 The NPV and sensitivity of the D-dimer assay make it safe for exclusion of thrombosis in patients with a normal D-dimer value. A very sensitive D-dimer assay is required to exclude VTE when the clinical pretest probability is high, whereas a less sensitive D-dimer assay can only exclude VTE when the clinical pretest probability is low.13 Furthermore, the very low specificity of the D-dimer assay requires an increased cutoff value to reduce the incidence of false-positive results. Latex agglutination D-dimer assays are widely used in Japan, and NANOPIA D-dimer (Sekisui Medical Co, Ltd, Tokyo, Japan) is a new latex-based assay with a broad measurement range (0.5-60 g/mL). Without the combined use of PTP score, the NPV for the diagnosis of VTE reaches 100% using a cutoff value of 0.5 g/mL,14 which is similar to that of various D-dimer assays in excluding VTE in Europe and North America.15 With an increasing num1099 1100 Yamaki et al JOURNAL OF VASCULAR SURGERY November 2009 ber of low-PTP patients, reducing the number of falsepositive results decreases the number of additional investigations required to diagnose or exclude VTE. The purpose of the present study was to determine if a combination of different cutoff points rather than the manufacturer’s recommended cutoff point of 1.0 g/mL, according to the pretest clinical probability (PTP) score, would be able to reduce the use of venous duplex ultrasound (DU) scanning in a relatively large number of patients with suspected DVT using the latex agglutination D-dimer assay. MATERIALS AND METHODS Patients. Between February 2006 and February 2009, 989 consecutive referral patients with suspected DVT were prospectively evaluated at the Department of Plastic and Reconstructive Surgery, Tokyo Women’s Medical University Hospital. Inpatients and outpatients were included. Of 989 patients, 525 were referred from various surgical departments and 464 from medical departments. Exclusion criteria included (1) previously diagnosed DVT, (2) DU scan results suggesting features of chronic DVT, (3) diagnosed as having upper extremity DVT, (4) symptoms lasting ⬎1 month, (5) therapeutic dose anticoagulation instituted for ⬎48 hours before examination, or (6) clinically suspected or confirmed pulmonary embolism, with performance of DU scanning to exclude thrombosis in the lower limbs. Clinical probability score. The PTP for DVT was assessed by junior residents using a questionnaire developed by Wells et al.8 One point was added for each positive finding and 2 points were subtracted from the total if an alternative diagnosis as likely as, or more likely than, DVT was found. After the PTP scores were calculated, patients were divided into low-risk (ⱕ0 points), moderate-risk (1-2 points), and high-risk (ⱖ3 points) groups. D-dimer assay. After the PTP score was calculated for each patient, blood samples were collected at the clinical laboratory department, and D-dimer testing was performed by the examiners, who were not aware of the PTP scores. The plasma levels of D-dimer were measured using NANOPIA, a commercially available latex agglutination assay kit, and the results were expressed as micrograms per milliliter. It takes 10 minutes for the assay, and all D-dimer assays were performed by technicians who were unaware of the clinical characteristics of the patients. Briefly, the latex agglutination assay uses latex microparticles coated with a monoclonal antibody specific for D-dimer. Incubation with plasma results in the formation of macroscopic agglutinates. A positive test result is defined as a D-dimer level ⬎1.0 g/mL. Venous DU scans. All venous DU studies were performed by one experienced physician (T. Y.) who was blinded to the results of PTP and D-dimer testing. A color DU scanner (LOGIQ 7 PRO; GE Yokogawa Medical Systems, Tokyo, Japan) with a 5- to 10-MHz transducer was used. Initially, each patient was placed supine in the reverse Trendelenburg position at 15°. Venous DU scanning was started at the distal segment of the external iliac Fig 1. Flow chart summarizes the diagnostic process for deep vein thrombosis (DVT) used in the study. PTP, pretest clinical probability score. vein and the common femoral vein, and moved to the femoral vein at the adductor canal. The deep femoral vein and the anterior and posterior tibial veins were also recorded. Afterwards, the patient was placed prone with the knee flexed at 30°, and the residual popliteal, peroneal, gastrocnemius, and soleal veins were evaluated.16 The diagnosis of DVT was based on both noncompressibility of the vein on B-mode or no evidence of spontaneous flow on color Doppler imaging. If there was no intraluminal defect with full venous compressibility and a normal flow, the result was considered negative. Thrombosis was considered to be proximal if a thrombus was detected in the deep veins in the pelvis, the thigh, and popliteal region with or without calf vein thrombosis. Thrombosis was considered to be distal if a thrombus was detected only in the calf veins. Screening protocol. All the patients were stratified into low-, moderate- and high-risk groups according to the PTP method and underwent D-dimer testing. Patients who had low and moderate PTP and a D-dimer concentration within normal reference ranges required no further investigation. The remaining non-high-PTP patients with elevated D-dimer and high-PTP patients underwent a venous DU scan at presentation. Patients with a high PTP who showed an elevated D-dimer assay value and initial negative scan underwent repeat venous DU scanning after 1 week (Fig 1).17 Patients with proven DVT were monitored for at least 3 months while receiving oral anticoagulation medication. Statistical analysis. All data were analyzed using SPSS 16 software (SPSS Inc, Chicago, IL). The Wilcoxon nonparametric rank sum test was used to evaluate differences between means for continuous data, and the 2 test was used to evaluate differences between proportions. Analysis of variance (ANOVA), followed by the Fisher protected least significant difference post hoc test, was used for comparison of D-dimer JOURNAL OF VASCULAR SURGERY Volume 50, Number 5 Yamaki et al 1101 Table I. The pretest clinical probability score Pretest clinical probability category Active cancer: treatment ongoing, ⱕ6 months, or palliative Paralysis, paresis, or recent fixed immobilization of the lower extremity Recently bedridden ⬎3 days or major surgery ⱕ 4 weeks Localized tenderness along the distribution of the deep venous system Entire leg swollen Calf swelling by ⬎3 cm vs asymptomatic leg (measured below tibial tuberosity) Pitting edema Collateral superficial veins (nonvaricose) Alternative diagnosis as likely as or more likely than DVT Scorea Table II. Baseline patient characteristics No. (%) ⫹1 151 (17.0) ⫹1 150 (16.9) ⫹1 247 (27.9) ⫹1 ⫹1 141 (15.9) 29 (3.3) ⫹1 ⫹1 137 (15.5) 322 (36.3) ⫹1 11 (1.2) –2 440 (49.7) a Low risk (ⱕ0 points), moderate risk (1-2 points), high risk (ⱖ3 points). The examiner assesses each factor, and the score is calculated as the sum in each patient. One point is given for every positive finding, and 2 points are subtracted if an alternative diagnosis as likely as deep venous thrombosis is found.8 Characteristics No (%) or mean ⫾ SEM Patients, total Age, y Gender (% female) Inpatients Deep vein thrombosis Proximal Distal 886 64.4 ⫾ 16.0 587 (66.3) 609 (68.7) 256 (28.9) 104 (11.7) 152 (17.2) SEM, Standard error of the mean. Table III. Prevalence of deep vein thrombosis (DVT) by pretest clinical probability (PTP) risk classification Pretest clinical probability No. (%) DVT frequency, No. (%) High PTP Moderate PTP Low PTP Total 141 (15.9) 237 (26.8) 508 (57.3) 886 (100) 109 (77.3) 118 (49.8) 29 (5.7) 256 (28.9) assay means among the high-, moderate-, and low-risk PTP groups. The Fisher exact test was used for comparison of the sensitivity, specificity, positive predictive value (PPV), and NPV of the D-dimer assay between the different PTP categories. Receiver operating characteristic (ROC) curve analysis was used to determine the appropriate D-dimer cutoff point for each PTP group with a NPV of ⬎98%. Continuous data were expressed as mean ⫾ standard error of mean (SEM). Statistical significance was defined as P ⬍ .05. RESULTS Patient characteristics. Of the 989 consecutive patients evaluated, 103 were excluded on the basis of the criteria described in Methods. Thus, 886 patients were eligible for this study. The numbers and proportions of the patients in each risk category are reported in Table I.8 Of 247 postoperative inpatients, prophylaxis was pharmacologic in 129 and mechanical in 118. Surgical patients suspected of having DVT, including leg pain, edema, or a markedly elevated D-dimer level, were referred to our clinic ⱕ1 week after surgery. The mean age of these patients was 64 years (range, 16-102 years). There were 587 women (66.3%) and 299 men (33.7%). The study group included 609 inpatients (68.7%) and 277 outpatients (31.3%). Of the 886 patients evaluated, 256 (28.9%) were found to have DVT. DVT was proximal in 104 patients (11.7%) and distal in the remaining 152 (17.2%; Table II). Distribution of PTP and D-dimer assay values. Table III summarizes the distribution of the patients with low-, moderate-, and high-risk PTP according to the calculated clinical probability score. Of the 886 patients, 508 (57.3%) were classified as low-risk, 237 (26.8%) as moderate- Fig 2. Value of D-dimer assay by pretest clinical probability (PTP) risk classification. Analysis of variance for multiple comparison. *High vs low PTP, P ⬍ .0001. #High vs moderate PTP, P ⫽ .001. ¶Moderate vs low PTP, P ⬍ .0001. The error bars indicate the standard error of mean. risk, and 141 (15.9%) as high-risk PTP. The prevalence of DVT increased as the PTP score progressed. In this study, 61 patients had previous VTE; of these, 37 (60.7%) were classified as low-risk, 14 (23.0%) as moderate-risk, and 10 (16.3%) as high-risk PTP. The prevalences of DVTs were 5.41%, 57.1%, and 90%, respectively; therefore, the previous history of VTE did not affect the PTP score. Fig 2 shows the values of the D-dimer assay in terms of pretest clinical probability risk classification. The mean Ddimer value was significantly higher in the high-risk PTP than in the low-risk PTP patients (11.19 ⫾ 1.09 vs 3.12 ⫾ 0.28, JOURNAL OF VASCULAR SURGERY November 2009 1102 Yamaki et al Table IV. Discriminatory power of D-dimer testing using a single D-dimer point of 1.0 g/mL by pretest clinical probability (PTP) category Category Sensitivity no. (%) Specificity no. (%) PPV no. (%) NPV no. (%) All patients High PTP Moderate PTP Low PTP 254/255 (99.6) 109/109 (100) 117/117 (100) 28/29 (96.6) 262/628 (41.7) 3/32 (9.4) 16/120 (13.3) 243/476 (48.9) 254/620 (41.0) 109/138 (79.0) 117/221 (52.9) 28/261 (10.7) 262/263 (99.6) 3/3 (100) 16/16 (100) 243/244 (99.6) NPV, Negative predictive value; PPV, positive-predictive value. Table V. Sensitivity, specificity, and positive (PPV) and negative predictive value (NPV) for different D-dimer cutoff points Variable All patients PTP High Moderate Low Cutoff point g/mL Sensitivity no. (%) Specificity no. (%) PPV no. (%) NPV no. (%) 2.6/1.1/1.1 248/255 (97.3) 395/628 (62.9) 248/481 (51.6) 395/402 (98.3) 1.1 1.1 2.6 109/109 (100) 117/117 (100) 22/29 (75.9) 5/32 (15.6) 18/120 (15.0) 372/476 (78.2) 109/136 (80.1) 117/219 (53.4) 22/126 (17.5) 5/5 (100) 18/18 (100) 372/379 (98.2) NPV, Negative predictive value; PPV, positive-predictive value; PTP, pretest clinical probability. P ⬍ .0001). Similarly, the mean D-dimer value was significantly higher in the high-risk PTP than in the moderate-risk PTP patients (11.19 ⫾ 1.09 vs 8.25 ⫾ 0.59, P ⫽ .001). Patients with moderate PTP had a significantly higher D-dimer value than those with low PTP (8.25 ⫾ 0.59 vs 3.12 ⫾ 0.28, P ⬍ .0001). Discriminatory power of a single D-dimer cutoff point for each PTP category. The discriminatory power of a single D-dimer cutoff point of 1.0 g/mL for low-, moderate- and high-risk PTP patients, and for the entire study population, is summarized in Table IV. In the lowrisk PTP group, D-dimer testing provided 96.6% sensitivity and 99.6% NPV for diagnosis of DVT. In the moderateand high-risk PTP groups, D-dimer testing achieved 100% sensitivity and 100% NPV; however, as the PTP score increased from low to moderate, and to high, the specificity decreased from 48.9% to 13.3% to 9.4%, respectively. Discriminatory power using different D-dimer cutoff points for excluding DVT. To improve the discriminatory power of the D-dimer assay, ROC curve analysis was used to determine different cutoff points in the low-, moderate- and high-risk PTP groups. After creating ROC curves, cutoff points with the highest sensitivities and specificities were selected. Then NPVs of the cutoff points were tested if they were greater than 98%. Thus, D-dimer cutoff points of 2.6, 1.1, and 1.1 g/mL were selected for these groups, respectively. With these specific cutoff points, Ddimer testing was still able to provide ⬎98% NPV (Table V). When the specific cutoff point for the low-risk PTP patients were used, the specificity increased from 48.9% to 78.2% (P ⬍ .0001). In the moderate- and high-risk PTP patients, however, the specific cutoff points did not improve the specificity (P ⫽ .711 and P ⫽ .450, respectively). Finally, when a single cutoff point of 1.0 g/mL was used, 262 patients with a non-high PTP score and a normal D-dimer assay required no further investigation, and thus the use of venous DU scanning could have been reduced by 29.6% (262 of 886). With the use of specific D-dimer cutoff points, venous DU scanning could have reduced by 44.6% (395 of 886). Therefore, 133 additional patients could have been excluded compared with the recommended cutoff level of 1.0 g/mL accordingly. Study outcome. Repeated DU examinations were done in 27 patients with high-risk PTP who showed an abnormal D-dimer test result and an initial negative venous DU scan. After 1 week, two patients were found to have proximal DVT and anticoagulation was applied. The remaining 25 patients had no evidence of DVT, and no further examinations were performed. During 3 months of follow-up, patients with proven DVT did not have any further thromboembolic complications. DISCUSSION This study investigated the utility of a combination of different cutoff points for the latex agglutination D-dimer assay and PTP score to reduce the use of venous DU scanning in a relatively large number of patients with suspected DVT. Our main findings were that (1) NPV for the exclusion of DVT using a single D-dimer cutoff point of 1.0 g/mL exceeded 98% in each PTP category, (2) use of a specific cutoff point of 2.6 g/mL in low-risk PTP patients increased the specificity from 48.9% to 78.2% (P ⬍ .0001), and (3) the use of venous DU scanning would have been reduced by 44.0% if specific D-dimer cutsoff points had been selected. When D-dimer testing and PTP are used for exclusion of DVT, the outcome depends largely on the reliability of the D-dimer test. The combination of a low PTP and a normal D-dimer concentration can be considered a safe strategy for excluding thrombosis and for withholding anticoagulant therapy in patients with suspected VTE.9-13,17-19 Several methods are commercially available for measuring D-dimer concentra- JOURNAL OF VASCULAR SURGERY Volume 50, Number 5 tions: (1) latex agglutination, (2) microplate ELISA, (3) immunofiltration (membrane ELISA), and (4) whole-blood agglutination. Among various D-dimer tests, ELISA-based techniques have the highest sensitivity and NPV for DVT. The first-generation latex agglutination assays are based on the visible agglutination of antibody-coated latex particles. Positive samples may be serially diluted to provide a semiquantitative estimate of the D-dimer concentration. Although these assays are rapid and easy to perform, the results are qualitative, observer-dependent, and limited in their ability to detect minimally increased D-dimer concentrations. The second-generation latex immunoassays use the same basic technique as the first-generation assays but use a photometric analyzer to provide a quantitative measure of the D-dimer and are generally able to measure lower concentrations of D-dimer reproducibly.20 Among 556 consecutive outpatients with a suspected first episode of DVT, Bates et al21 demonstrated a NPV of 99.7% (95% confidence interval [CI], 98.2%-100%), a sensitivity of 98.2% (95% CI, 90.4%-100%), and a specificity of 60.4% (95% CI, 56.1%-64.7%) for exclusion of DVT using an automated, second-generation quantitative latex MDAD-Dimer assay (Organon Teknika Corp, now bioMérieux, Inc, Durham, NC). Although the prevalence of DVT was only 10%, they also showed that 50.9% of the patients with a low or moderate pretest probability and a negative D-dimer result could safely be excluded from further testing. Schutgens et al22 evaluated four new D-dimer assays and a classic ELISA in symptomatic outpatients with suspected DVT and concluded that the Tinaquant latex assay (Roche, Mannheim, Germany) had the highest NPV of 98%, and a high sensitivity of 99%, using a standard cutoff value. Another factor that could affect the discriminatory power of studies for DVT is the cutoff value of the D-dimer test. The sensitivity could be improved by lowering the cutoff value, but the subsequent decrease in specificity would lead to a large number of false-positive results. On the contrary, D-dimer cutoff values with very high specificity provide fewer false-positive results but are less sensitive for DVT and cannot be used to exclude the disease in all patients. Against this background, two studies concluded that an increased D-dimer cutoff value reduced the falsepositive rate but increased the false-negative rate. Another study, however, demonstrated that increasing the D-dimer cutoff value led to a rise in specificity without loss of sensitivity.23-25 Using data from a previously published study of 571 patients, Linkins et al13 reported that varying the Ddimer cutoff values according to the PTP score would have excluded VTE in more patients than if a single D-dimer cutoff point had been used. In that analysis, they found that in the high PTP score group, a D-dimer cutoff point of 0.2 g FEU mL–1 was required to achieve a NPV of 98% or higher. Similarly, in the low PTP score group, a D-dimer cutoff point of 2.1 g FEU mL–1 achieved a NPV of 98% or higher. By using this strategy, the number of patients with false-positive results also dropped from 89 to 9 in the low PTP group (n ⫽ 205). Yamaki et al 1103 Even in patients with established pulmonary embolism, our previous study demonstrated that combination of a specific D-dimer level with PTP score is effective for excluding DVT in low-risk PTP patients.26 In the present study, 45.9% of patients (233 of 508) with low PTP scores showed false-positive results when a single cutoff point of 1.0 g/mL was used. When a specific D-dimer cutoff point of 2.6 g/mL was selected for lowrisk PTP patients, the proportion with false-positive results dropped from 45.9% to 20.5% (104 of 508), a 25.4% change. Reducing the number of false-positive results could decrease the number of unnecessary venous DU scans, thus saving time and money. These results potentially provide a new strategy for diagnosis of DVT, as demonstrated in Fig 3. Patients who have a low PTP score and a D-dimer level of ⱕ2.6 require no further investigation, whereas patients with a low PTP score and a D-dimer level of ⬎2.6 undergo a single venous DU scan at presentation. Patients who have a moderate PTP score and a normal D-dimer level require no further investigation, and patients who have a moderate PTP score with an elevated D-dimer level should undergo a single venous DU scan at presentation. Finally, patients with a high PTP score who have an elevated D-dimer level and an initial negative scan undergo a repeat venous DU scan after 1 week because they have quite a high risk of DVT. Our study had a possible limitation. Although use of a specific D-dimer level substantially decreased the number of false-positive results in the low-risk PTP group, it did not improve the specificity among patients with moderate- or high-risk PTP, leading to a relatively high percentage of false-positive results among this group of patients. Thus, our study suggests that the D-dimer test may have a high NPV and a high sensitivity in patients with low PTP scores, whereas it has low utility in patients with moderate or high PTP scores. A larger prospective study may be required to confirm the validity of our strategy for excluding DVT among the general population. CONCLUSIONS Combination of a specific D-dimer level with the clinical probability score is an effective approach for excluding DVT in low-risk PTP patients. In patients with moderate or high PTP, however, the recommended cutoff point of 1.0 g/mL may be preferable. These results show that the use of different D-dimer levels for patients with different levels of risk is feasible when using the latex agglutination Ddimer assay for excluding DVT. AUTHOR CONTRIBUTIONS Conception and design: TY Analysis and interpretation: TY Data collection: MN, YK, KS, TK, AH, KK Writing the article: TY Critical revision of the article: TY, MN 1104 Yamaki et al JOURNAL OF VASCULAR SURGERY November 2009 Fig 3. Potential new diagnostic strategy for diagnosis of deep vein thrombosis (DVT) using different D-dimer levels. PTP, Pretest clinical probability score. Final approval of the article: TY, MN, HS, YK, KS, TK, AH, KK Statistical analysis: TY Obtained funding: Not applicable Overall responsibility: TY REFERENCES 1. 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;353:190-5. 2. Bounameaux H, de Moerloose P, Perrier A, Miron MJ. D-dimer testing in suspected venous thromboembolism: an update. QJM 1997;90:437-42. 3. Freyburger G, Trillaud H, Labrouche S, Gauthier P, Javorschi S, Bernard P, et al. 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