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Keywords:

  • calf thrombosis;
  • compression ultrasonography;
  • D-dimer;
  • deep vein thrombosis;
  • diagnosis;
  • sensitivity;
  • specificity;
  • Wells score

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

Summary.  Background:  Pretest clinical probability with the Wells rule and D-dimer have been widely investigated for the diagnosis of symptomatic proximal deep vein thrombosis (DVT) of the lower limbs, but they have not been formally tested for symptomatic isolated distal DVT diagnosis.

Objective:  To evaluate the diagnostic accuracy of the Wells rule and D-dimer for isolated distal DVT.

Design, Setting, and Patients:  This was a single-center, cross-sectional study including 873 consecutive outpatients with suspected DVT, in whom pretest clinical probability determination, D-dimer determination (STA Liatest; cut-off of < 500 ng mL−1) and complete compression ultrasonography of both lower limbs were performed.

Results:  The isolated distal DVT prevalence was 12.4% (90/725). The sensitivity of the Wells rule for isolated distal DVT was 47% (95% confidence interval [CI] 36–57%), the specificity was 74% (95% CI 70–77%), and the negative and positive predictive values were 91% (95% CI 88–93%) and 20% (95% CI 15–26%), respectively. Patients with isolated distal DVT had higher D-dimer levels than patients without DVT (1759 ± 1576 vs. 862 ± 1079 ng mL−1, P = 0.0001). D-dimer was negative in 13 patients with isolated distal DVT. D-dimer sensitivity and specificity for isolated distal DVT were 84% (95% CI 75–91%) and 50% (95% CI 46–54%), respectively, with a negative predictive value of 96% (95% CI 93–98%). In patients with low pretest clinical probability, the D-dimer negative predictive value was 99% (95% CI 95–100%).

Conclusion:  In clinically suspected DVT with negative proximal compression ultrasonography, pretest clinical probability with the Wells rule has a low diagnostic accuracy for isolated distal DVT. D-dimer has a better negative predictive value, but alone it does not exclude isolated distal DVT. In patients with low pretest clinical probability, D-dimer had a negative predictive value of > 95% for isolated distal DVT.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

Isolated distal deep vein thrombosis (IDDVT), i.e. thrombosis confined to the infrapopliteal veins of the lower limbs, is a frequent finding in symptomatic outpatients [1]. Compression ultrasonography in combination with a clinical decision rule and/or D-dimer testing has been widely investigated for the diagnosis of deep vein thrombosis (DVT) of the lower limbs [2]. However, validation studies have revealed that the sensitivity of ultrasonography for IDDVT diagnosis, even in symptomatic patients, is significantly lower than that for proximal DVT [1]. Wells et al. [3] developed a diagnostic rule to estimate the pretest clinical probability (PCP) of DVT, but its accuracy has not been validated in patients in whom IDDVT is suspected. The D-dimer test has been shown to have a high sensitivity and a high negative predictive value for DVT exclusion [4,5]. However, most studies employing D-dimer were performed without examination of the calf veins, or they were carried out in patient populations with a predominance of proximal DVT. As a result, these studies did not report the diagnostic accuracy for the subgroups of patients with IDDVT.

The purpose of this study was to evaluate the diagnostic accuracy of the Wells rule and D-dimer testing for IDDVT diagnosis in clinically suspected DVT with negative proximal compression ultrasonography.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

Study population

The study was performed from September 2009 to January 2011 in a tertiary-care teaching hospital (University Hospital S. Orsola-Malpighi, Bologna, Italy). Symptomatic outpatients referred by general practitioners or the emergency department to the vascular emergency room for suspected acute DVT of the lower limbs were eligible for the study. Patients were excluded if they were younger than 18 years, had been receiving vitamin K antagonists, low molecular weight heparin or fondaparinux for > 24 h, or were pregnant or in puerperium, with clinical suspicion of either pulmonary embolism or acute superficial vein thrombosis.

A personal and family history was obtained from each patient by the physician in charge, who also performed a physical examination and filled in the PCP questionnaire. Patients then underwent: (i) D-dimer testing; and (ii) whole-leg compression ultrasonography of both lower limbs. Patients with proximal DVT were excluded from the study.

The design of the study was cross-sectional. It was not possible to enroll all consecutive eligible patients, but the first three eligible patient of each day were included, to minimize selection bias. The enrollment was performed during business days.

The study was approved by the local Ethics Committee. Written informed consent was obtained from all patients.

PCP score

The PCP score for DVT was assessed with a questionnaire developed by Wells et al. [6]. One point was added for each of the following positive findings: (i) active cancer treatment ongoing or within the previous 6 months, or palliative treatment; (ii) paralysis, paresis or recent plaster immobilization of the lower legs; (iii) recent immobilization for > 3 days or major surgery within the last 4 weeks; (iv) localized tenderness/pain along the distribution of the deep venous system; (v) entire leg swollen; (vi) calf swelling by > 2 cm when compared with the asymptomatic leg; (vii) pitting edema greater in the symptomatic leg; and (viii) collateral superficial veins. Two points were subtracted from the total points if an alternative diagnosis as likely as or more likely than DVT was found. On the basis of such a checklist, PCP for DVT could be estimated to be low (score of ≤ 0), moderate (score of 1 or 2), or high (score of ≥ 3).

D-dimer

Blood samples for D-dimer testing were taken before ultrasonography investigation. Blood was drawn by clean venipuncture from an antecubital vein with a 19-gauge butterfly needle, and collected into 4-mL plastic tubes containing 0.4 mL of 0.106 m trisodium citrate. Whole blood was centrifuged at 2000 × g for 20 min at 20 °C. Technicians performing D-dimer testing were unaware of the symptoms of the patients.

The STA Liatest D-dimer (Diagnostica Stago, Asnières, France) is an automated and rapid microlatex D-dimer assay. Special mAb-coated latex particles agglutinate in the presence of D-dimer fibrin degradation products. The STA Liatest D-dimer assay was performed on the STA Compact coagulation analyzer, as previously described [7]. Agglutination causes greater light scattering which is recorded as an increase in OD. The results were expressed in ng mL−1 (expressed in fibrinogen equivalent units). As previously described, the cut-off value for DVT exclusion was 500 ng mL−1 [8].

Whole-leg ultrasonography investigation

Patients underwent a comprehensive real-time B-mode and color Doppler compression ultrasonography examination of both legs by a vascular medicine physician, as previously described [9]. Ultrasonography investigation was carried out with an EnVisor C HD instrument (Philips Medical System, Monza, Italy), with an L 12–5-MHz high-resolution broadband width linear array transducer, according to the method of Schellong [10]. The proximal deep veins were examined first, and then, in patients with normal proximal findings, the calf veins were evaluated. The following veins were scanned in the transverse plane over their entire length: posterior tibial veins, fibular veins, internal and external gastrocnemius veins, and soleal veins. The diagnosis of DVT was confirmed if there was lack of compression of the vein, combined with the absence of venous flow with distal compression. Patients with IDDVT were divided into three groups: those with thrombosis confined only to the muscle veins (internal and external gastrocnemius veins, and soleal veins), patients with axial calf vein thrombosis, and patients with both muscular and axial calf DVT. The vascular medicine physician was blind to D-dimer results.

In cases of suspected recurrent DVT, recurrence was diagnosed if a previously fully compressible segment (contralateral or ipsilateral) was no longer compressible, or if an increase of at least 4 mm in the diameter of the residual thrombus during compression was detected [11]. When thrombus diameter changed between 1.1 and 3.9 mm, or in cases of high/moderate clinical probability and normal proximal compression ultrasonography, the examination was repeated 5–7 days later.

Statistical analysis

Analysis was carried out with spss, version 15.0 (SPSS, Chicago, IL, USA). Relationships between variables were assessed with Pearson correlation for continuous variables, and the chi-square or Fisher exact test for categorical variables. Multivariate analysis of variance with Bonferroni’s correction for multiple comparisons was used to compare means among groups for normally distributed variables. Receiver operating characteristic (ROC) curves were prepared by plotting the sensitivity vs. 1 – specificity, and the area under the ROC curve (AUC) and the 95% confidence interval (CI) of the AUC for the D-dimer test were calculated. Categorical variables are expressed as frequency and percentage with 95% CI; continuous variables are expressed as mean ± standard deviation, and interquartile range is also reported. The significance level was set at ≤ 0.05.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

Figure 1 shows the study flow chart. Among 875 screened patients, two did not meet the inclusion criteria, and were excluded from the study. Proximal DVT was diagnosed at proximal compression ultrasonography in 148 patients, who were excluded from the study. The characteristics of enrolled patient (n = 725) are summarized in Table 1. The most frequent symptoms were leg pain and edema, and the most frequent risk factors for thrombosis were obesity, trauma, and history of vein thrombosis. The median time between the onset of symptoms and inclusion in the study was 6 days (range: 1–90 days). The time between the onset of symptoms and inclusion in the study was ≤ 7 days for 65% of the study population.

image

Figure 1.  Flow chart of the study. DVT, deep vein thrombosis; IDDVT, isolated distal deep vein thrombosis.

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Table 1.   Characteristic of the study population
  1. BMI, body mass index; HRT, hormone replacement therapy; IQR, interquartile range.

Age (years) ±SD (IQR)63.5 ± 17.2 (26.5)
Male/female, no. (%)291/435 (59.9)
BMI (kg m−2) ±SD (IQR)27.0 ± 4.8 (5.8)
Venous thromboembolism risk factors (%)
 Active cancer4.7
 Surgery9.7
 Mobility significantly reduced13.4
 Bed confinement5.0
 Trauma in symptomatic leg16.9
 History of vein thrombosis16.1
 Obesity22.5
 Use of HRT/estrogen-containing therapy3.9
Symptoms (%)
 Pain77.8
 Edema72.6
 Redness or rash20.5
 Leg warmth15.4

The prevalence of IDDVT was 12.4% (n = 90). Thrombosis confined only to the muscle veins was detected in 49 patients (54.4%), axial calf DVT in 26 patients (28.9%), and both muscular and axial calf DVT in 15 patients (16.7%).

As shown in Table 2, age and body mass index were similar in patients with and without IDDVT. Venous thromboembolism risk factors, such as reduced mobility, bed confinement, trauma of the symptomatic limb, and the use of hormone replacement therapy/estrogen-containing therapy, were more prevalent in patients with IDDVT than in those without. Patients with IDDVT more frequently had pain of the calf and less frequently had edema of the symptomatic limb than those without IDDVT.

Table 2.   Characteristic of the study population according to the presence/absence of isolated distal deep vein thrombosis (IDDVT)
 IDDVT-negativeIDDVT-positive P-value
  1. BMI, body mass index; HRT, hormone replacement therapy; SD, standard deviation.

Age (years) ±SD63.8 ± 16.061.0 ± 18.20.150
Male/female, no. (%)247/388 (61.1)44/46 (51.1)0.084
BMI (kg m−2) ± SD27.0 ± 4.726.9 ± 5.60.982
Venous thromboembolism risk factors (%)
 Active cancer4.65.60.599
 Surgery8.815.60.055
 Mobility significantly reduced10.434.40.001
 Bed confinement3.912.20.003
 Trauma in symptomatic leg15.427.80.006
 History of vein thrombosis16.115.70.921
 Obesity22.125.30.487
 HRT/estrogen-containing therapy3.18.90.016
Symptoms (%)
 Pain76.686.70.030
 Edema74.062.90.031
 Redness or rash21.414.80.190
 Leg warmth15.712.80.631

Table 3 shows the distribution of patients with low, moderate and high risk for thrombosis according to the calculated PCP. In the low-risk PCP category (PCP ≤ 0), IDDVT was identified in 20 patients (8.3%). In contrast, IDDVT was found in 58 (13.5%) moderate-risk patients (PCP = 1–2), and in 12 (22.2%) high-risk patients (PCP > 2).

Table 3.   Prevalence of isolated distal deep vein thrombosis (IDDVT) and D-dimer levels by pretest clinical probability risk classification
Pretest clinical probability n (%)Frequency of IDDVT, n (%)D-dimer (ng mL−1)
  1. Continuous variables are expressed as mean ± standard deviation (range).

> 38 (1.1)2 (25.0)2069 ± 2763 (240–8010)
346 (6.3)10 (21.7)1340 ± 1023 (190–4180)
2181 (25.0)32 (17.7)899 ± 957 (30–6880)
1249 (34.3)26 (10.4)858 ± 1279 (10–13780)
≤ 0241 (33.3)20 (8.3)933 ± 1183 (10–12610)
Total725 (100)90 (12.4) 

A moderate/high PCP (score ≥ 1) had a sensitivity of 78% (95% CI 68–85%), a specificity of 35% (95% CI 31–39%), and negative and positive predictive values of 85% (95% CI 79–89%), and 15% (95% CI 12–18%), respectively, for the diagnosis of IDDVT. A high PCP (score ≥ 3) had a sensitivity of 13% (95% CI 8–22%), a specificity of 93% (95% CI 91–95%), and negative and positive predictive values of 88% (95% CI 86–91%) and 22% (95% CI 13–35%), respectively, for the diagnosis of IDDVT.

D-dimer plasma levels were higher in patients with than in those without IDDVT (1759 ± 1576 vs. 862 ± 1079 ng mL−1, P = 0.0001). D-dimer plasma levels were higher in patients with both muscular and axial calf DVT than in those with thrombosis confined only to the muscle veins and in those with only axial calf vein thrombosis (2869 ± 1902 vs. 1641 ± 1538 vs. 1261 ± 1045 ng mL−1, respectively, P = 0.006). The ROC curve for the D-dimer test is shown in Fig. 2. The AUC was 0.73 (95% CI 0.67–0.79). Assuming a cut-off value of 500 ng mL−1 as suggested by Sidelmann et al. [8], 13 (14.4%) patients with IDDVT had negative results on a D-dimer test. All of the patients with negative D-dimer and IDDVT had a time of ≥ 4 days between the onset of symptoms and study inclusion. All of the patients with both muscular and axial calf DVT had a D-dimer level of > 500 ng mL−1. The sensitivity and specificity of D-dimer were 84% (95% CI 75–91%) and 50% (95% CI 46–54%), respectively, and the negative and positive predictive values were 96% (95% CI 93–98%) and 19% (95% CI 15–23%), respectively.

image

Figure 2.  Receiver operating characteristic curve analysis of accuracies of D-dimer testing for the presence of symptomatic isolated distal deep vein thrombosis. *Indicates cut-off value of 500 ng mL−1.

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D-dimer plasma levels according to PCP are reported in Table 3, and they did not correlate with PCP (ρ = 0.69, P = 0.71). The sensitivity, specificity and positive and negative predictive values of D-dimer according to PCP score are reported in Table 4. In patients with PCP < 1 (low risk for proximal DVT), D-dimer negative predictive value increased to 99% (95% CI 95–100%). Among the patients with IDDVT and negative D-dimer, seven patients had PCP = 2, five patients had PCP = 1, and only one had PCP < 1.

Table 4.   Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of D-dimer (cut-off value: 500 ng mL−1) for the diagnosis of isolated distal deep vein thrombosis according to pretest clinical probability score
Pretest clinical probabilitySensitivitySpecificityPPVNPV
  1. Data are expressed as % (95% confidence interval).

High100 (70–100)27 (16–42)27 (16–42)100 (70–100)
Moderate76 (63–86)52 (47–57)19 (14–25)94 (90–97)
Low95 (75–100)51 (45–58)16 (10–23)99 (95–100)

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

Our study shows that the Wells rule is less accurate in stratifying pretest probability for IDDVT than for proximal DVT. D-dimer alone has a better predictive negative value, but does not exclude IDDVT. In patients with negative proximal compression ultrasonography findings and at low risk for proximal DVT (PCP < 1), D-dimer has a negative predictive value of > 95% for IDDVT diagnosis.

The Wells score was developed in ambulatory patients referred to a tertiary-care center for a suspected first episode of proximal and distal lower limb DVT [3,12]. More recently, Wells et al. [6] published a modified score, adding an item for previously documented DVT. This modified Wells score has been validated in outpatients [6,13], emergency department patients[14], and inpatients from a university hospital [15]. The initial clinical model by Wells et al. was derived by the inclusion of IDDVT diagnosed by venography, but the subsequent validation studies using whole-leg ultrasonography gave contrasting results. Engelberger et al. [15] and Blättler et al. [16] showed a poor correlation between PCP and IDDVT diagnosis, but they enrolled only 36 patients and 19 patients with IDDVT, respectively. Other studies demonstrated a better negative predictive value of PCP for both proximal DVT and IDDVT [13,17]. However, most studies did not look for distal DVT [6,18,19], and the Wells score therefore seems to be able to stratify patients only for the risk of proximal DVT [20]. Our study, which included more IDDVT patients than previous studies, demonstrates that the Wells score poorly predicts IDDVT.

The role of D-dimer assays in the diagnosis of patients with suspected DVT has been extensively studied [5]. The D-dimer assay has proven to be a highly sensitive but non-specific test for the presence of venous thromboembolism [4], and to have a high negative predictive value for DVT in different patient populations [21–25]. D-dimer seems to have a lower sensitivity and a lower negative predictive value for IDDVT than for proximal DVT. Jennersjöet al. [26] reported that 35% of patients with IDDVT have normal D-dimer levels. Leroyer et al. [22,27] found that D-dimer had a predictive negative value for IDDVT diagnosis of < 90%, whereas other studies reported a negative predictive value for IDDVT diagnosis of ≥ 97% [23–25]. A meta-analysis showed that all D-dimer assays had higher sensitivity for proximal than for distal DVT: 98% vs. 86% for ELISA, 94% vs. 79% for latex agglutination, and 84% vs. 64% for whole-blood agglutination [5]. In our series, D-dimer with a cut-off value of 500 ng mL−1 had a similar sensitivity (84%) to that found in the previously mentioned meta-analysis, but a better predictive negative value (> 93%), for IDDVT diagnosis. It should be noted that 14% of total IDDVTs were missed with such a cut-off.

Our study was performed with the STA Compact analyzer. The studies evaluating the clinical value of the rapid STA Liatest D-dimer on the STA-R analyzer were carried out on patient populations with a predominance of proximal thrombosis [27,28], or did not report the sensitivity and diagnostic accuracy for the subgroups of proximal DVT and distal DVT separately [29]. Recently, it has been shown that the Liatest D-dimer has areas under the ROC curve of 0.91 for proximal DVT and 0.58 for IDDVT [8]. We found a better area under the ROC curve (0.73), suggesting a better sensitivity of D-dimer for IDDVT diagnosis than previously reported. Nevertheless, our series shows that D-dimer alone does not rule out the presence of IDDVT. It should be noted that D-dimer plasma levels varied with the type of IDDVT: patients with both muscle vein and deep calf vein thrombosis had higher D-dimer plasma levels than the others, and such patients had a D-dimer level of > 500 ng mL−1. This finding may reflect a higher thrombus burden or volume. Further studies are needed to address this issue.

We expected to find a low sensitivity and a low specificity of both PCP and D-dimer by selecting a population with negative proximal ultrasonography findings. We found that the Wells score still stratified subjects with IDVVT reasonably well among the low-PCP, moderate-PCP and high-PCP groups. Similarly to what was found for proximal DVT [5], D-dimer sensitivity and specificity varied according to PCP value, and, in patients at low risk (PCP < 1), D-dimer had a negative predictive value similar to that for proximal DVT diagnosis. In such patients, a low D-dimer level was able to exclude the presence not only of proximal DVT, but even of distal DVT. In patients with moderate risk (PCP = 1 or PCP = 2), we found several patients with IDDVT in whom D-dimer testing was negative. In patients with intermediate PCP, recent guidelines recommend the performance of one of the following initial tests: a highly sensitive D-dimer assay or proximal compression ultrasonography, or whole-leg ultrasonography [2]; in the case of negative D-dimer, no further testing is recommended [2]. With such an approach, several IDDVTs could be missed. However, the clinical benefit of diagnosing and treating IDDVT is still a matter of controversy [1], and we could speculate that IDDVT with PCP < 2 and negative D-dimer could be at low risk of proximal extension. In fact, we recently found that most untreated calf DVTs have a benign clinical course, and only some of them may have clinically relevant thrombotic outcomes [9].

Some limitations of the present study should be acknowledged. The patients investigated were not all consecutive patients referred to our vascular outpatient service, and a selection bias cannot be excluded. However, most of the included patients were subjects who were referred first in the morning, with the aim of reducing this bias. Moreover, no interobserver variability was assessed for IDDVT diagnosis. Finally, we did not follow up the patients with negative whole-leg ultrasonography findings, but a larger study has shown that anticoagulant therapy can be safely withheld after negative complete compression ultrasonography findings without further testing in the ambulatory office setting [30].

In conclusion, the Wells rule does not guarantee the same risk estimation of IDDVT as of proximal DVT. D-dimer has an acceptable negative predictive value in clinically suspected DVT with negative proximal compression ultrasonography findings. D-dimer alone does not exclude the presence of IDDVT in patients with a time of ≥ 4 days between the onset of symptoms and D-dimer assay. The combination of negative D-dimer and a low Wells rule score has a negative predictive value of > 95%. In patients with moderate risk, D-dimer had a lower negative predictive value, and further studies are needed to establish whether it is worthwhile diagnosing IDDVT in such patients.

Addendum

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

M. Sartori designed the study, analyzed the data and wrote the paper; B. Cosmi analyzed the data and revised the paper; C. Legnani was involved in the data analysis, in revising the paper, and in the laboratory diagnosis; E. Favaretto was involved in the patient management, collected the data, analyzed the data; L. Valdré, G. Guazzaloca and G. Rodorigo were involved in the patient management and collected the data; M. Cini was involved in the laboratory diagnosis and collected the data; G. Palareti designed the research and revised the paper. All the authors revised the manuscript and gave final approval of the version to be submitted.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

The authors state that they have no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
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