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. 2017 Apr 10;24(3):477–482. doi: 10.1177/1076029617700997

Residual Vein Thrombosis Echogenicity Is Associated to the Risk of DVT Recurrence: A Cohort Study

Bruna M Mazetto 1,✉, Fernanda L A Orsi 1,2, Sandra A F Silveira 1, Luis F Bittar 1, Mariane M C Flores-Nascimento 1, Kiara C S Zapponi 1, Marina P Colella 1, Erich V de Paula 1, Joyce M Annichino-Bizzacchi 1
PMCID: PMC6714655  PMID: 28393617

Abstract

Although deep vein thrombosis (DVT) recurrence is a common late complication of the disease, there are few predictive markers to risk-stratify patients long-term after the thrombotic event. The accuracy of residual vein thrombosis (RVT) in this context is controversial, possibly due to a lack of a standardized methodology. The objective of the study was to evaluate the accuracy of RVT echogenicity as a predictive marker of late DVT recurrence. To evaluate the accuracy of RVT echogenicity as a predictive marker of late DVT recurrence. This prospective study included patients with history of DVT in the past 33 months. Ultrasound examination was performed to detect the presence of RVT, and its echogenicity was determined by calculating the grayscale median (GSM) of the images. Blood samplings were taken for plasma D-dimer levels. Patients were followed-up for 28 months and the primary end point was DVT recurrence. Deep vein thrombosis recurrence was confirmed or excluded by ultrasound during the follow-up. Fifty-six patients were included, of which 10 presented DVT recurrence during the follow-up. D-dimer levels above 630 ng/mL conferred higher risk for recurrence with a negative predictive value of 94%. The absence of RVT was a protective marker for recurrence with a negative predictive value of 100%. Also, the presence of hypoechoic RVT, determined by GSM values below 24, positively predicted 75% of DVT recurrences. Our results suggest that the persistence of RVT and, particularly, the presence of hypoechoic thrombi (GSM < 24) are predictive markers of the risk of DVT recurrence. Residual vein thrombosis echogenicity, by GSM analysis, could represent a new strategy for the evaluation of recurrence risk in patients with DVT.

Keywords: recurrence, deep venous thrombosis, residual vein thrombosis, ultrasound

Introduction

Venous thromboembolism comprises deep vein thrombosis (DVT) and pulmonary embolism and can be recurrent in approximately 30% of the cases within 10 years.1

Unprovoked first DVT episode, male gender, and persistently elevated D-dimer2,3–7 are important risk factors for DVT recurrence. However, the prediction of recurrence in individual patients remains a challenge.

The role of residual venous thrombosis (RVT) as a risk factor for recurrence is controversial. The lack of a standardized methodology for RVT evaluation by conventional ultrasonography may explain, in part, why the results are divergent among different studies.7–10 Several clinical studies investigating arterial thrombosis have evaluated the echogenicity of atherosclerotic plaques by grayscale median (GSM) computer-assisted ultrasound (US) analysis.11–14 Grayscale median ≤ 25 predicted symptomatic embolization or stroke during carotid artery stenting.15 Despite having been well validated in cases of arterial thrombosis, there are few studies evaluating US-generated GSM in RVT.

The aim of this study was to evaluate the accuracy of RVT echogenicity determined by US-generated GSM, as a marker for the risk of long-term thrombosis recurrence.

Patients and Methods

Study Design, Patient Selection, and Follow-Up

This was a prospective study involving patients of both genders, aged ≥18 years, who had experienced a first symptomatic and idiopathic DVT episode, assisted at the Hematology and Hemotherapy Center of the University of Campinas. Inclusion criteria were history of idiophatic DVT or DVT associated with minor transient risk factors (hormone use or traveling), 5 months to 6 years from the acute episode, and at least 3 months of oral anticoagulation. Exclusion criteria have been described in a previous study with this population.16 During the period of the study, 385 patients with a history of DVT were attended at the clinic; however, 329 patients did not participate in the study due to the exclusion criteria or due to refusal to participate. Reasons for exclusion were venous thrombosis of other sites (n = 109), younger than 18 years or older than 80 years (n = 44), carriers of natural anticoagulant deficiency (n = 7), antiphospholipid syndrome or systemic autoimmune diseases (n = 25), cancer (n = 42), infection (n = 7), liver failure (n = 11), renal failure (n = 10), anticoagulant therapy (n = 64), and refusal to participate (n = 10).

Patients were evaluated on the day of inclusion in the study using a structured questionnaire regarding the presence of transient or permanent risk factors for thrombosis, concomitant diseases, medication use, alcohol abuse or smoking, and family history. All patients were submitted to blood sampling collection and US examination of both legs at the time of inclusion. Grayscale median was calculated using the US examination performed in the inclusion. The accuracy of this parameter in predicting DVT recurrence was determined during follow-up.

Patients included in the study were clinically reevaluated every 6 months for 2 years during outpatient visits, and the primary outcome was DVT recurrence. To evaluate the occurrence of both symptomatic and asymptomatic DVT, a new US was performed during the outpatients visits in the cases of clinical suspicion of DVT recurrence or at the end of the follow-up in the cases with no clinical suspicion of recurrence. Recurrent DVT was diagnosed in the case of a previously semicompressible segment (contralateral or ipsilateral) no longer compressible or in the case of the appearance of thrombus, which were not present in the previous study. The physician who confirmed the recurrence of DVT was not aware of the patient’s results regarding D-dimer levels or RVT.

The study was conducted in compliance with the Helsinki Declaration. This study was approved by the research ethics committee of the School of Medical Sciences of the University of Campinas (UNICAMP). A written informed consent was obtained from each patient, or their attending relatives, and from controls.

Duplex ultrasound examination and US-generated GSM

All vascular Doppler images were assessed by the same physician using a Siemens Sonoline G40 (Siemens Healthcare, Mountain View, California) with a convex transducer of 3 to 5 MHz and linear 5 to 10 MHz. As only 1 physician was responsible for the performance of the US, there was no interobserver variability. Incompressible venous segment without color flow was consistent with the presence of RVT. Grayscale median analyses were performed in the images of RVT detected by ultrasound.

Grayscale median is a standard method developed for atherosclerotic plaque characterization and, for that purpose the gray scale was defined according to blood and arterial wall brightness. The method used in the present study has been adapted from arterial evaluation, as previously described.15–17

In our study, a region assumed to be blood was selected, and the GSM defined as zero (minimum value). A region of the vein wall was selected, and its GSM defined as the value 200 (maximum value). After the 0 to 200 image calibration was performed, a region containing only the thrombus was depicted manually point by point to trace a line around the thrombus. Grayscale analysis was calculated using a program that was written-in-house in the MATLAB software version 7.12 (MathWorks, Inc, Natick, Massachusetts).

Laboratory Procedures

Sample collection

Blood samples were obtained from the participants at the time of enrollment. After overnight fasting, 2 citrate tubes were collected and samples were immediately centrifuged. Plasma obtained was separated and immediately stored at −80°C.

Evaluation of hypercoagulability by D-dimer

The quantification of plasma levels of D-dimer was performed by immunoturbidimetric analysis, as recommended by the manufacturer, in an automated coagulometer (BCS-XP, Siemens Healthcare, Marburg, Germany).

Statistical Analysis

Continuous data were described as medians and interquartile range (IQR), and categorical variables were described as total number and percentages. Categorical variables were compared using χ2 or the Fisher exact test, and continuous variables were compared using the Mann-Whitney test. Diagnostic accuracy was estimated using the receiver operating characteristic (ROC) procedure, which was also used to detect the best cutoff values associated with DVT recurrence. Accuracy of GSM as a marker of DVT recurrence was calculated according to GSM sensibility, specificity, predictive values, and likelihood ratio in predicting DVT recurrence. Cox regression was performed to estimate the risk of a new thrombotic event. Data were analyzed using SPSS version 20.0 (SPSS Inc, Chicago, Illinois) and GraphPad Prism version 6.0 (GraphPad Software Inc, La Jolla, California). Graphics were made using GraphPad Prism. P < .05 was considered statistically significant.

Results

Fifty-six patients were enrolled in the study, 35 (62.5%) patients were female, 34 (61%) DVT episodes were unprovoked, and 22 (39%) mainly by hormonal contraceptives (n = 17) and minor procedures (n = 5). Median age was 45 years (IQR: 31-53). For all patients, first DVT episode occurred at least 5 months before the day of the enrollment (median = 33 months, IQR: 19-41 months). Median follow-up was 28 months (range: 10-50 months). Patient’s characteristics are summarized in Table 1.

Table 1.

Patient’s Characteristics.

Recurrence (n = 10) Without Recurrence (n = 46) P
Gender (F/M) 5:5 30:16 .46
Median age (IQR) 41 (29-48) 46 (31-53) .30
Provoked/unprovoked 3:7 19:27 1
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Abbreviations: F, Female; IQR, interquartile range; M, Male.

During the follow-up, 10 patients (17.9%) presented the primary outcome, of which 5 events were asymptomatic. The cumulative risk for DVT recurrence was 11.2% after 4 years of DVT diagnosis and 37.5% after 6 years of diagnosis.

D-dimer levels were associated with the risk of the primary outcome, which was significantly higher in patients with DVT recurrence (D-dimer > 630 ng/mL; hazard ratio [HR] = 6.4, 95% CI = 1.3-30.5, P =.01; Figure 1A). The best cutoff value to discriminate those at risk for recurrent DVT was a D-dimer > 630 ng/mL (area under the ROC curve of 0.74, 95% CI: 0.58-0.96, sensitivity = 80%, specificity = 71.7%, positive predict value [PPV] = 36%, negative predictive value [NPV] = 94.1%, and likelihood ratio = 2.83).

Figure 1.

Figure 1.

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A, Risk of new thrombosis events during the follow-up according to D-dimer (DD) levels. B, Risk of new thrombosis events during the follow-up according to the presence of RVT.

All patients who presented recurrent DVT during the follow-up had RVT detected by US examination at the time of the enrollment, whereas only 50% of patients without recurrence had RVT. The risk for recurrence was higher among patients with RVT (HR = 9.129; 95% CI = 2.60-32.02, P < .001; Figure 1B).

The presence of RVT during US examination presented a sensitivity of 100%, specificity of 47.8%, PPV of 29.4%, NPV of 100%, and a likelihood ratio of 1.9 for DVT recurrence.

Regarding RVT echogenicity, the best cutoff value to discriminate patients at risk for thrombosis recurrence was GSM below 24, this value was achieved using the 85th percentile (area under the ROC curve of 0.56, 95% CI: 0.27-0.77, sensitivity of 30%, specificity of 98%, PPV of 75%, and NPV of 85% for thrombosis recurrence, with a likelihood ratio of 10). Table 2 summarizes the accuracy of the tests.

Table 2.

Overview of the D-Dimer Performance, Residual Venous Thrombosis, and GSM as Predictive Markers of Thrombosis Recurrence.a

D-Dimer ≤630 ng/mL D-Dimer >630 ng/mL RVT Negative RVT Positive GSM >24 GSM ≤24
No. of patients with recurrence (n = 10) 2 (20%) 8 (80%) 0 10 (100%) 7 (70%) 3 (30%)
No. of patients without recurrence (n = 46) 33 (72%) 13 (28%) 22 (48%) 24 (52%) 41 (98%) 1 (2%)
PPV 36% 29% 75%
NPV 94.1% 100% 85%
LR 2.83 1.9 10
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Abbreviations: LR, likelihood ratio; NPV, negative predictive value; PPV, positive predictive value; RVT, residual vein thrombosis.

aGrayscale median analysis was performed only in patients with RVT, and it was not performed in 4 patients with RVT.

The risk of recurrence associated with GSM <24 was 7.62 (95% CI = 2.60-21.5; P < .0001; Figure 2)

Figure 2.

Figure 2.

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Risk of new thrombosis events during the follow-up according to echogenicity of the thrombus.

Discussion

In recent years, major efforts have been made to identify clinical and laboratory parameters capable to stratify the risk of recurrence in patients with a first episode of VTE. Hereditary thrombophilias, coagulation factor levels, D-dimer, RVT, among several other factors have been evaluated isolated or as part of scores to guide clinical decision-making for these patients.4,18,19 Among these efforts, RVT can be regarded as a promising strategy, due to its noninvasive and relatively low-cost characteristics. However, challenges in standardizing this relatively subjective and operator-dependent strategy have so far precluded a more widespread adoption.20 In order to minimize the variability of US evaluation of RVT, we conducted a prospective study that evaluated the accuracy of evaluating the echogenicity of RVT as a predictive marker of DVT recurrence after a first acute DVT episode. In our study, the rates of DVT recurrence were similar to those described in the literature.3

Interestingly, we demonstrated that the presence of hypoechoic RVT (GSM <24) positively predicted 75% of DVT recurrences, and the absence of hypoechoic RVT predicted the nonrecurrence in 85% of cases.

The association of RVT and DVT recurrence has been controversial. The positive association between RVT and recurrence has been demonstrated by clinical studies7,8; another study, however, failed to show this association.10,21,22 A recent meta-analysis has proposed that RVT is a weak risk factor for DVT recurrence, particularly if detected long time after the acute thrombosis.23 Distinct results among previous clinical studies may be justified by the heterogeneity of the population studied, which included unprovoked/secondary DVT, and particularly by the heterogeneity of methods used to detect RVT. Regarding the previously published studies, four evaluated the qualitative absence or presence of RVT.24–27 In the remaining studies, different method were used such as the Siragusa,7,28,29 Prandoni,8–10,21,30Young,31 as well as combinations of these scores.32 Of note, a study that evaluated the interobserver agreement of RVT assessment showed considerable variations in the US measurements of vein diameter, thrombus echogenicity, and flow.33

Based on the wide variation of methods used to assess RVT, we postulated that a quantitative measurement of the echogenicity of residual thrombi would be helpful in standardizing the approach for RVT detection, thus facilitating the use of this parameter as a marker for DVT recurrence. Indeed, computer-assisted evaluation of RVT could minimize operator-dependent variability, and previous studies have suggested that thrombus echogenicity may be correlated with its histological characteristics.34,35 The clinical relevance of this strategy has been previously demonstrated in studies of arterial thrombosis.11,14,15

In fact, our results demonstrated that the echogenicity of RVT may be an auxiliary parameter to detect patients at risk for recurrence. Although the levels of D-dimer and the presence of RVT presented a good sensibility for recurrence, thrombus echogenicity had a higher specificity and PPV for recurrence (97% and 75%, respectively). Therefore, the echogenicity analysis by GSM could improve the probability to predict thrombosis recurrence when compared to D-dimer levels and the presence of RVT. As expected, D-dimer was significantly associated with DVT recurrence with values below the cutoff allowing the exclusion of DVT recurrence in 94% of patients. Although the association of RVT with DVT recurrence is controversial in the literature, in our cohort, the absence of RVT was capable of excluding DVT recurrence in 100% of patients. Our results are in agreement with previous studies and may validate D-dimer and RVT as risk markers for DVT recurrence. Furthermore, as the sensitivity of GSM was low, we believe that this marker may be evaluated in association with D-dimer levels.

Our study presents limitations that need to be considered. In the first place, the primary outcome includes both symptomatic and asymptomatic DVT. In the second place, although GSM is automatically calculated by imaging software, the method still presents some degree of operator dependence, in that the area of evaluation needs to be determined. Herein we used a protocol aimed to minimize potential inter- and intraoperator variabilities. On the other hand, our study represented a prospective evaluation of this new strategy, in a selected and relatively homogenous population of consecutive patients with DVT. Furthermore, all patients included in the study completed the entire follow-up period.

In conclusion, GSM analysis for assessment of RVT echogenicity appears to be a useful method for risk stratification of DVT recurrence. Larger and independent studies challenging the inherent difficulties of standardization of this strategy are warranted to evaluate whether GSM analysis could represent a new strategy for the evaluation of recurrence risk in patients with DVT.

Footnotes

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study received financial support from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, no 2012/14082-6).

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