Abstract
Background
Venous thromboembolism is a common disease seen in the emergency department and a cause of high morbidity and mortality, constituting a major health problem.
Objectives
To assess the potential benefit of follow-up ultrasound of patients who attended the emergency department with suspected superficial venous thrombosis or deep venous thrombosis and were found to have an initial negative whole-leg (or arm) ultrasound study.
Methods
This retrospective study included patients aged 18 years or older who were consecutively referred to a thrombosis clinic from the emergency department, with abnormal D-dimer test and moderate to high pre-test probability of deep venous thrombosis (Well's score ≥ 1), but a negative whole-leg (or arm) ultrasound. Demographic characteristics, symptom duration, laboratory and ultrasound data were recorded. At one-week follow-up, an experienced physician repeated ultrasound, and recorded the findings.
Results
From January 2017 to April 2018, 54 patients were evaluated. The mean age was 66.8 years (SD 15.0) and 63% were women. The average D-dimer was 2159.9 (SD 3772.0) ng/mL. Ultrasound abnormalities were found in 12 patients (22.2%; 95% confidence interval of 12.5 to 36.0%), with 4 patients having proximal deep venous thrombosis, distal deep venous thrombosis in 2 patients and superficial venous thrombosis in 6 patients. We did not find any significant differences in demographic characteristics, venous thromboembolism risk factors or laboratory parameters between patients with negative and positive follow-up ultrasound.
Conclusions
These preliminary findings suggest that a negative whole-leg (or arm) ultrasound in addition to an abnormal D-dimer in moderate to high deep venous thrombosis pretest probability patients, might be an insufficient diagnostic approach to exclude suspected deep venous thrombosis or superficial venous thrombosis. Confirmation of this higher than expected prevalence would support the need to repeat one-week ultrasound control in this population.
Keywords: Ultrasound, venous thromboembolism, deep vein thrombosis, superficial vein thrombosis, isolated deep vein thrombosis
Introduction
Venous thromboembolism (VTE) is a common disease seen in the emergency department (ED) and a major health problem. The incidence in the general population is 0.1–0.2% per year.1 Those with a previous history of deep vein thrombosis (DVT) are at risk of recurrence with evidence suggesting the risk of DVT is up to 50 times higher in patients with a previous DVT than those without.1,2
The most commonly used guidelines for VTE diagnosis and management are the American College of Chest Physicians (ACCP) antithrombotic guidelines3,4 and the National Institute for Health and Care Excellence (NICE) guidelines.5 Patients with suspected DVT or superficial vein thrombosis (SVT)6 of the lower extremities are generally investigated with color Doppler ultrasonography of the entire vein system (whole-leg US), from the ankle to the groin, which is an accurate method for the detection of thrombus in symptomatic patients. This approach offers a one-day answer, and after a single negative whole-leg US, no further testing is needed. Neither has to be repeated in one week (to rule out extension of thrombus to proximal veins), regardless of D-Dimer test or DVT pretest probability (Well's score).7 However, it requires skilled operators and may expose more patients to the risk of anticoagulation.
The present study was conducted to assess the follow-up of patients who attended the ED with suspected SVT or DVT after an initial negative whole-leg (or arm) US study.
Patients and methods
Patient selection
A total of 54 patients were enrolled in the present study from January 2017 to April 2018. Eligible patients were consecutively referred to a thrombosis clinic from the ED with a suspected symptomatic DVT or SVT of the lower or upper extremities, moderate or high DVT pretest probability (Well's score ≥1), abnormal D-dimer (Innovance®) result (>500 ng/mL) and negative color Doppler US of the entire vein system. They were scheduled for a repeat US within three to seven days. Subjects were followed up until discharge from the thrombosis clinic. Epidemiological characteristics, clinical manifestations, laboratory and ultrasound findings were retrospectively evaluated.
The study was conducted in accordance with the Declaration of Helsinki, and was approved by the Research Ethics Committee of La Paz University Hospital (PI-3306).
Initial patient assessment
Initial evaluation of the patient included taking medical history (demographic data, comorbidities, medications), physical exam and laboratory test result (including highly sensitive D-dimer assay Innovance®). VTE risk factors were assessed: recent immobilization, pregnancy, personal or family history of VTE, a known thrombophilia, autoimmune disease, varicose veins, obesity (Body Mass Index > 30 kg/m2), active cancer receiving antineoplastic treatment or oral contraceptives. According to our hospital protocol, any patient with clinically suspected DVT and low pretest probability (Well's score < 1) will have a D-dimer test to rule out DVT. Patients with moderate to high-risk pretest probability (Well's score ≥ 1) will have a whole-leg US and a D-dimer test to rule out DVT.
Ultrasound data collection
Radiologists in the department of radiology performed initial whole-leg US examination. This exam was performed by two radiology trainees who recorded the images supervised by a senior radiologist, with more than 10 years of experience. The follow-up US was performed by a physician from the thrombosis clinic with long-standing experience in vascular US (more than five years). In both cases, a whole-leg US protocol was performed, and the following veins were scanned transversally over their entire length: femoral veins, popliteal veins, anterior and posterior tibial veins, peroneal veins, medial and lateral gastrocnemius veins, soleal veins, the saphenofemoral/popliteal junctions, the trunk of the great saphenous vein (GSV) and small saphenous vein (SSV), and wherever thrombosis was clinically suspected. The initial study was performed using a Philips iU22 ultrasound machine, with a linear transducer (5–17 MHz) (Philips España, Madrid, Spain) and the follow-up study by a GE LOGIQ-e ultrasound system, with a linear transducer (5–10 MHz) (General Electric Healthcare, Madrid, Spain), which demonstrates both exams were performed by equally experienced physicians, followed same protocol and machines were of similar quality.
The diagnosis of DVT or SVT was confirmed by the presence of a non-compressible hypoechoic area in the course of an identified vein. If needed, augmentation maneuvers were performed to find a spontaneous or reverse-flow intraluminal color filling.
Outcome measures and definitions
We assessed the incidence of objectively proven symptomatic DVT or SVT during follow-up, after initial negative US, and compared both groups for statistical differences.
Statistical analysis
IBM SPSS software v20.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis of the data. Continuous variables were described as a mean with standard deviation (SD) and categorical variables were described as percentages. Comparisons of means were made using T-Student test and Chi-square test or Fisher's exact two-tailed test was used for categorical variables when it was appropriate. We considered a p-value < 0.05 to be statistically significant.
Results
A total of 54 patients were consecutively enrolled from January 2017 to April 2018. The general characteristic is listed in Table 1. The mean (SD) age was 66.8 (15.0) years. The majority of patients were women (63%, 34 patients). Three patients had upper extremity symptoms, whereas 51 patients had lower extremity symptoms. The most common DVT or SVT risk factors were varicose veins (44.4%, 24 patients), active cancer (24.1%, 13 patients) and personal (13%, 7 patients) or family (5.6%, 3 patients) history of VTE. Only one patient reported a congenital risk factor (hyperhomocysteinemia). None of them were obese; the mean weight was 61.3 kg (SD 4.6); 29.6% reported recent immobilization; 18.5% were treated with anti-platelet therapy at inclusion, one patient was anticoagulated with rivaroxaban 20 mg/od (atrial fibrillation) and one had prophylaxis with enoxaparin 40 mg/od (post-surgery). The average D-dimer was 2159.9 ng/mL (SD 3772.0). There were no other relevant laboratory abnormalities.
Table 1.
Demographic and clinical characteristics of the patients at presentation.
| Demographic characteristics | |
| Gender, woman (%) | 34 (63) |
| Age, years (SD) | 66.8 (15.03) |
| Weight, kg (SD) | 61.33 (4.6) |
| Clinical characteristics | |
| Interval between symptom onset and diagnosis, days (SD) | 13.0 (12.3) |
| Interval between diagnosis and resolution symptoms, days (SD) | 44.4 (22.1) |
| Risk factors for VTE | |
| Thrombophilia or congenital risk factors | 1 (1.8) |
| Varicose veins | 24 (44.4) |
| Active cancer | 13 (24.1) |
| Family history of VTE | 3 (5.6) |
| Personal history of VTE | 7 (13.0) |
| Pregnancy | 0 |
| Obesity | 0 |
| Recent immobilization | 16 (29.6) |
| Medication | |
| Antineoplastic treatment or oral contraception | 3 (5.6) |
| Anticoagulant treatment at inclusion | 2 (3.8) |
| Treated with anti-platelet therapy at inclusion | 10 (18.5) |
| Laboratory parameters | |
| Hb, g/dL (SD) | 13.6 (1.4) |
| WBC, ×109/L (SD) | 7.8 (2.5) |
| Platelets, ×109/L (SD) | 239.3 (84.7) |
| Creatinine, mg/dL (SD) | 0.9 (0.3) |
| INR (SD) | 1.0 (0.1) |
| aPTT, s. (SD) | 24.7 (3.6) |
| D-dimer, ng/mL (SD) | 2159.9 (3772.0) |
aPTT: activated partial thromboplastin time; DVT: deep vein thrombosis; INR: International normalized ratio; SD: standard deviation; SVT: superficial vein thrombosis; VTE: venous thromboembolism; WBC: white blood cells.
Of the 54 patients, who presented for repeat US at the scheduled three to seven days visit, most of them had unchanged symptoms (52 patients, 96%). Twelve patients (22.2%, 95% CI 12.5 to 36.0%) had abnormal US result (see Table 2). Demographic characteristics and risk factors for DVT were evenly distributed (see Table 3) between positive and negative US groups. We did not observe differences in laboratory parameters between these two groups.
Table 2.
Repeated ultrasound at one-week findings.
| N (%) | D-Dimer (ng/mL) | VTE risk factors | ||
|---|---|---|---|---|
| A | Proximal DVT | 4 (7.4) | ||
| 1 | Axillary vein | 1022 | None | |
| 2 | Popliteal and posterior tibial veins | 8217 | Recent immobilization | |
| 3 | Femoral vein | 1890 | Personal history of VTE (previous DVT, resolved and confirmed by repeated US) | |
| 4 | Popliteal, posterior tibial and small saphenous veins | 1799 | Recent immobilization, active cancer | |
| B | Distal DVT | 2 (3.7) | ||
| 5 | Gastrocnemius veins | 1397 | Hyperhomocysteinemia, recent immobilization | |
| 6 | Gastrocnemius veins | 9586 | Recent immobilization | |
| C | SVT | 6 (11.1) | ||
| 7 | Great saphenous vein | 1136 | Personal history of VTE | |
| 8 | Great and small saphenous veins | 2060 | Active cancer, varicose veins | |
| 9 | Small saphenous vein | 2130 | Varicose veins | |
| 10 | Small saphenous vein | 2271 | Varicose veins | |
| 11 | Small saphenous vein | 5975 | Active cancer | |
| 12 | Small saphenous vein | 6240 | Varicose veins | |
| D | Negative | 42 (77.8) | ||
DVT: deep vein thrombosis; SVT: superficial vein thrombosis; US: ultrasound; VTE: venous thromboembolism.
Table 3.
Risk factors for positive DVT or SVT at one-week follow-up.
| Negative US N = 42 | Positive US N = 12 | P | |
|---|---|---|---|
| Demographic characteristics | |||
| Male, N (%) | 28 (33.3) | 6 (50.0) | 0.292 |
| Female, N (%) | 14 (66.7) | 6 (50.0) | 0.292 |
| Age, years (SD) | 67.3 (13.0) | 65.0 (21.2) | 0.632 |
| Risk factors | |||
| Thrombophilia, N | 0 | 1 | – |
| Varicose veins, N (%) | 19 (46.3) | 5 (41.7) | 0.775 |
| Antineoplastic treatment/oral contraception, N (%) | 3 (7.3) | 0 | 1.000 |
| Personal history of VTE, N (%) | 5 (12.2) | 2 (16.7) | 0.687 |
| Anticoagulant treatment at inclusion, N (%) | 2 (4.8) | 0 | 0.743 |
| Treated with anti-platelet therapy at inclusion, N (%) | 7 (16.7) | 3 (25) | 0.512 |
| Recent immobilization, N (%) | 12 (28.6) | 4 (33.3) | 0.750 |
| Family history of VTE, N (%) | 2 (4.8) | 1 (8.3) | 0.634 |
| Active cancer, N (%) | 10 (24.4) | 3 (25) | 0.966 |
| Well's score (SD) | 1.5 (0.70) | 1.7 (0.78) | 0.864 |
| Laboratory parameters | |||
| D-dimer, ng/mL (SD) | 1566.2 (3923.6) | 3644.4 (3013.5) | 0.108 |
| Hb, g/dL (SD) | 13.7 (1.5) | 13.1 (1.2) | 0.202 |
| WBC, ×109/L (SD) | 7.8 (2.6) | 8.0 (2.2) | 0.778 |
| Platelets, ×109/L (SD) | 234 (74.1) | 256 (115.6) | 0.446 |
| INR (SD) | 1.01 (0.1) | 1.03 (0.12) | 0.516 |
| aPTT, s. (SD) | 24.8 (3.5) | 24.6 (4.2) | 0.872 |
| Creatinine, mg/dL (SD) | 0.89 (0.34) | 0.96 (0.27) | 0.511 |
| Heparin initiated at ED, N (%) | 19 (45.2%) | 9 (75%) | 0.069 |
aPTT: activated partial thromboplastin time; DVT: deep vein thrombosis; INR: international normalized ratio; SD: standard deviation; SVT: superficial vein thrombosis; VTE: venous thromboembolism; WBC: white blood cells.
Discussion
Our study shows that a follow-up US detected a vein thrombosis in a significant proportion of patients after a negative whole-leg (or arm) US, which could be higher than previously reported.3 According to a previous metaanalysis,3,8 with results from seven different management studies, estimated the incidence of VTE during the following three months after a negative whole-leg US to be 0.57% (standard deviation, SD 0.25–0.89%) with moderate quality evidence. This grade of evidence means that further research is likely to have an important impact on the confidence intervals and may change the estimate. Moreover, in this meta-analysis, few patients with intermediate or high pretest probability were included, concluding that additional investigations, including whole-leg US with D-dimer testing and formal pretest probability assessment were needed.8
We have identified a proximal DVT in a third of the positive US (4 patients, 7.4% of our cohort), which is more than 13 times higher than previously reported, prompting immediate anticoagulant therapy in these patients due to the increased risk of VTE.
One might consider that detecting SVT or isolated distal DVT may not be relevant, but patients with a previous episode of VTE have a higher chance of recurrence, and therefore increased morbidity and mortality.1 Regarding SVT, its diagnostic and therapeutic management are currently under debate and vary widely from one hospital to another.6 SVT has been reported to be simultaneous with DVT in 25% of the cases, and has a three month follow-up incidence of 8.3% for proximal DVT (OR 6.3).9,10 The progression for distal DVT into proximal has been estimated to be around 21.4%.3 On the other hand, anticoagulation might be associated with an increased risk of bleeding. Consequently, a personalized risk assessment is essential to improve management of recurrent VTE.
Although we are aware that in our study there are too few upper extremity cases to make meaningful conclusions about them, we would like to raise concern about the uncertainty in its management, often oriented on that of DVT of lower extremities, due to the limited and heterogeneous studies, compromising our clinical practice and the potential consequences. No large epidemiologic study specifically dedicated to upper limb DVT has been conducted, and the management is extrapolated from the lower limb experience, although it seems the incidence is increasing due to the growing use of central or peripheral venous catheters in the arm.11
To our knowledge, this is the first study evaluating the potential benefit of serial US follow-up performed in a thrombosis clinic of patients who attended the ED with suspected SVT or DVT with an initial negative whole-leg (or arm) US study. These results would support the need to repeat one-week US control in this population.
Among the strengths of our study are that all SVT or DVT were confirmed according to a rigorous protocol. The D-dimer test we used has a high reproducibility and negative predictive value in clinically symptomatic patients. Moreover, only experienced physicians performed the initial and follow-up US. Therefore, we believe that our recruitment of SVT or DVT is representative of that seen in routine practice.
There are several limitations to our study. We are aware of the potential referral bias; primary care physicians might have limited the patients they referred to the ED to those at higher risk of DVT or SVT. However, we believe that this risk, although real, resembles our clinical practice, limited by the easy access to the ED and US examination. Another limitation is that initial and follow-up US exams were performed by different physicians, on different machines and conditions. Although the impact of this limitation is reduced, since both groups were equally experienced, followed the same protocol and machines were of similar quality. There is an ongoing debate about the clinical significance of SVT6 and distal DVT,3 which accounted for more than half of the thrombosis seen, but was not an objective of this study. The small number of subjects and the unicentric study design would limit firm conclusions; therefore, we believe this study could be the initiative for further multi-centre studies, which could change our clinical practice.
Conclusion
A normal whole-leg (or arm) US might not be sufficient to exclude suspected DVT or SVT of the extremities in moderate to high-risk patients. Confirmation of this higher than expected prevalence would support the need to repeat one-week US control in moderate to high-risk patients, as well as, a protocol reappraisal of the approach to this exceedingly common problem.
Acknowledgments
We would like to thank the emergency department staff at our institution for their assistance and help.
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) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval
Research Ethics Committee of La Paz University Hospital.
Guarantor
YTC.
Contributors
Conception and design: YTC, ARN, AMV, TVV. Analysis and interpretation: YTC, ARN, AMV, CFC. Data collection: YTC, IPS, TVV. Writing the article: YTC, IPS. Critical revision of the article: YTC, ARN, AMV, TVV, CFC, ALH, TSB, MRD. Final approval of the article: YTC, ARN, AMV, IPS, CFC, ALH, TSB, MRD. Statistical analysis: YTC. Overall responsibility: YTC, ARN, AMV.
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