Scoring systems for the post-thrombotic syndrome

Transcription

1 Scoring systems for the post-thrombotic syndrome Arany Soosainathan, MB BChir, Hayley M. Moore, MRCS, MBBS, MA, Manjit S. Gohel, FRCS, MD, FEBVS, and Alun H. Davies, MA, DM, FRCS, London, United Kingdom Objective: To assess each of the scoring systems used to diagnose and classify post-thrombotic syndrome, a common chronic complication of deep vein thrombosis. The design of the study was a systematic review of the literature pertaining to post-thrombotic syndrome. Methods: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines by a search of PubMed (1948 to September 2011) using the search terms postthrombotic syndrome, postthrombotic syndrome, post-phlebitic syndrome, and postphlebitic syndrome. A manual reference list search was also carried out to identify further studies that would be appropriate for inclusion. The various scoring systems in use were identified and assessed against a list of criteria to determine their validity for use. For outcome measures, each scoring system was assessed for specific criteria, including interobserver reliability, association with ambulatory venous pressures, ability to assess severity of post-thrombotic syndrome, ability to assess change in condition over time, and association with patient-reported symptom severity. Results: The Villalta, Ginsberg, Brandjes, Widmer, CEAP, and Venous Clinical Severity Score systems all were assessed for the stated outcome measures. From their use in the literature, only the Villalta score was able to fulfill all the criteria described. The main criticism of the Villalta score in the literature appears to be its use of subjective measures. To that end, we propose that use of a venous disease-specific quality-of-life questionnaire in combination with the Villalta score may help standardize the subjective criteria. Conclusions: The Villalta score, combined with a venous disease-specific quality-of-life questionnaire, should be considered the gold standard for the diagnosis and classification of post-thrombotic syndrome. (J Vasc Surg 2013;57: ) Deep vein thrombosis (DVT) of the lower limbs is both a common and a serious disease, with an estimated incidence of 1 per 1000 people per year. 1 It can have a clear precipitant, such as surgery, malignancy, or inherited coagulation disorders, or occur spontaneously. A number of complications can follow DVT. The incidence and outcomes of acute complications such as pulmonary embolism are well reported, but post-thrombotic syndrome (PTS) is less well understood. This is a chronic condition, occurring in at least one third of patients who have a DVT. 2 It may be associated with leg pain and heaviness, edema, hyperpigmentation, lipodermatosclerosis, and venous ulceration, occurring to varying degrees in different patients. The pathophysiology underlying PTS is thought to be sustained venous hypertension, resulting from obstruction to venous flow, vein valvular incompetence, or a combination. As there is a considerable degree of overlap between the acute symptoms resulting from a DVT and those of PTS, there is a minimum time period (ranging from 6 months to 2 years in various studies 3-5 ) before From the Academic Section of Vascular Surgery, Department of Surgery & Cancer, Imperial College School of Medicine, Charing Cross Hospital. Author conflict of interest: none. Reprint requests: Professor Alun H. Davies, Academic Section of Vascular Surgery, Department of Surgery & Cancer, Imperial College School of Medicine, Charing Cross Hospital, Fulham Palace Road, London, W6 8RF, United Kingdom ( a.h.davies@imperial.ac.uk). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest /$36.00 Copyright Ó 2013 by the Society for Vascular Surgery. the condition is diagnosed. Patients with PTS have a significantly decreased quality of life 6 and the condition can result in a substantial psychological and economic burden. 7 However, although there is a large body of research concerning the natural history and treatment options of acute DVT, there is less evidence on the diagnosis and management of PTS. One of the reasons often cited for this is the lack of a clear gold standard definition of PTS. Instead, several scoring systems are used to both diagnose the condition and classify its severity. This review aims to describe the main scoring systems, illustrate how they have been used in studies investigating PTS, and outline whether one scoring system demonstrates advantages over the others. METHODS This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 8 The relevant studies and reviews were found through systematic searches of PubMed (1948 to September 2011). The search terms used were postthrombotic syndrome, postthrombotic syndrome, post-phlebitic syndrome, and postphlebitic syndrome. A manual reference list search was also carried out to identify further studies that would be appropriate for inclusion. The titles of the search results were screened with human and English language limits to identify the studies to be included. The abstracts and full text of these were then examined by two of the authors (A.S., H.M.) to identify those relevant to this review s scope, namely, those that referred to a PTS scoring system. Articles concerning the upper limb and children were excluded. All other articles including prospective and 254

2 Volume 57, Number 1 Soosainathan et al 255 Fig 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram. Summary of search strategy and results of literature review. retrospective studies, human participants, data related to adult (>18 years) patients, and lower limbs were included. Once the relevant articles were obtained, a list of the main PTS scoring systems in use was made. Each scoring system was then assessed for validity of use according to specific criteria, including interobserver reliability, association with ambulatory venous pressures (AVPs), ability to assess severity of PTS, ability to assess the change in condition over time, and association with patient-reported symptom severity. RESULTS The search strategy, carried out as described in Fig 1, resulted in 37 publications that fulfilled the inclusion criteria. Villalta. The Villalta score is a disease score specific for PTS. 9 It can be used to both diagnose and categorize the severity of the condition. It was developed in a crosssectional study of 100 patients who were assessed 6 to 36 months after DVT. Points are given for five symptoms (pain, cramps, heaviness, paresthesia, pruritus) and six clinical signs (pretibial edema, skin induration, hyperpigmentation, redness, venous ectasia, pain on calf compression). Points are given for each of these 11 descriptors according to severity (Table I), ranging from 0 for not present to 3 for severe. Furthermore, if a venous ulcer was present, the severity of the condition was classified as severe, regardless of the presence or absence of other signs or symptoms. The patient was diagnosed as having PTS if the Villalta score was $5 or if a venous ulcer was present. A score of 5-9 signifies mild disease, moderate disease, and $15 severe disease. The Villalta score was used in several studies to diagnose PTS. 2,10-15 Five studies used the Villalta score as originally described, with scores >5 confirming the diagnosis of PTS and a score >14 denoting severe PTS, 2,10,12-15 and one study used a modified Villalta score, giving a final score out of 9, with 4 being diagnostic and 7 the threshold for severe PTS. 11 When a diagnosis of PTS is made using the Villalta score, only one assessment giving a score >5 is

3 256 Soosainathan et al January 2013 Table I. Villalta s PTS score 9 Symptoms/clinical signs None Mild Moderate Severe Symptoms Pain 0 points 1 point 2 points 3 points Cramps 0 points 1 point 2 points 3 points Heaviness 0 points 1 point 2 points 3 points Paresthesia 0 points 1 point 2 points 3 points Pruritus 0 points 1 point 2 points 3 points Clinical signs Pretibial edema 0 points 1 point 2 points 3 points Skin induration 0 points 1 point 2 points 3 points Hyperpigmentation 0 points 1 point 2 points 3 points Redness 0 points 1 point 2 points 3 points Venous ectasia 0 points 1 point 2 points 3 points Pain on calf compression 0 points 1 point 2 points 3 points Venous ulcer Absent Present PTS, Post-thrombotic syndrome. required, in contrast to certain other scores, which require multiple assessments, with a set time interval in between. The Villata score has also been used as a continuous measurement for longer-term follow-up 3,16 to grade the severity of the condition 6,17 and to assess the effectiveness of treatments (Table II) The score has also been shown to yield reliable consistent results, whether used by physicians 9 or by other health professionals trained in using the scale. 20 As such, use of the Villalta score can be justified, whether in clinic settings to monitor the progress of patients or in studies assessing the impact of treatment. In addition, Villalta scores in patients with PTS appear to correlate with patient-perceived quality of life as well as with clinical measurements thought to be related to the pathophysiology underlying PTS, thus suggesting the Villalta score is a valid scale for clinical use. 6,21,22 Two studies assessed both the generic and the disease-specific healthrelated quality of life after DVT. 6,21 They showed that although quality-of-life scores tended to improve from baseline after DVT, patients who developed PTS had significantly worse disease-specific quality-of-life scores. 6,21 These lower scores were not present on the generic qualityof-life scores, thus attributing the difference to the condition. The results of the two studies, showing how the Villalta scores correlate with quality-of-life scores, are summarized in Fig 2. 6,21 In these two studies, the Villalta score was used to categorize PTS into mild, moderate, and severe (Table I). The Venous Insufficiency Epidemiological and Economic Study/Quality of Life (VEINES-QOL) and the Venous Insufficiency Epidemiological and Economic Study/Symptoms (VEINES-Sym) are patient-reported outcome scores that can be computed from a 25-item questionnaire. The items cover symptoms (heavy legs, aching legs, swelling, night cramps, heat or burning sensation, restless legs, throbbing, itching, tingling sensation, leg pain), limitations in daily activities, change over the past year, and psychological impact. The VEINES-QOL summary score aims to measure the overall impact of venous disease on a patient s life. The VEINES-Sym score Table II. Uses of the Villalta score in various studies Author (year) No. enrolled (completed follow-up) Application Prandoni et al 2 (1996) 355 (245) Diagnosis Van Dongen et al (244) Diagnosis Tick et al 11 (2008) 1916 (1668) Diagnosis Kahn et al Diagnosis Roumen-Klappe et al (110) Diagnosis (2009) Kahn et al Diagnosis Roumen-Klappe et al Diagnosis (2009) Kahn et al 6 (2002) 41 Classify severity Kahn et al 17 (2011) 43 (39) Classify severity Prandoni et al 3 (1997) 528 Long-term follow-up Kahn et al 16 (2008) 387 (260) Long-term follow-up Kahn et al 17 (2011) 43 (39) Evaluation of treatment O Donnell et al 18 (2008) 32 (26) Evaluation of treatment Prandoni et al Evaluation of treatment is a subscale that measures the specific impact of symptoms on daily life. In both measures, lower scores indicate lower quality of life. The data from Kahn et al 6 have remained unchanged. The data from Kahn et al 21 have had the results listed for mild PTS and moderate PTS amalgamated but otherwise unprocessed. In looking at the differences between existing classification systems, Kolbach et al 22 examined the association between AVP (measured via invasive methods) and the scores obtained from the various scoring systems. In this study, the Villalta score was one of the systems with a strong association with a high AVP value. However, there was a caveat to this conclusion; there was a considerable degree of overlap in AVPs in the different clinical severities of PTS, indicating that there is not a simplistic linear relationship between venous hypertension and PTS. In the absence of a gold standard with which to define the PTS, the wide spectrum of disease severity, and hence the difficulty in assessing validity of the various scoring systems, these surrogate measures (health-related quality of life and numerical measurements of pathophysiologic markers of the disease) suggest that the Villalta score correlates with the clinical and physiologic markers of the disease. Ginsberg. The Ginsberg score was designed in a crosssectional study looking at PTS developing after hip or knee arthroplasty. 5 It diagnosed patients as having PTS if the patient reported leg pain and swelling of a chronic nature (daily, for a period of at least 1 month), typical in character (aggravated by prolonged standing, improved by leg elevation), occurring at least 6 months after the initial DVT. Patients could be diagnosed with PTS only if they had both leg pain and swelling and if there was objective evidence of valvular incompetence. The presence of persistent occlusion was not included. The Ginsberg score was used in a study evaluating the efficacy of graduated

4 Volume 57, Number 1 Soosainathan et al None Mild/Moderate PTS Severe PTS Mean Scores Mean VEINES-QOL (2002) Mean VEINES-Sym (2002) Mean VEINES-QOL (2008) Mean VEINES-Sym (2008) Quality of Life Scores Fig 2. Graph demonstrating quality-of-life scores in patients with different degrees of post-thrombotic syndrome (PTS). 6,21 compression stockings in preventing and in treating PTS. 23 It also will be used to diagnose PTS in the SOX trial, which was designed to investigate the effectiveness of compression stockings in preventing PTS. 24 Kahn et al 25 compared the Ginsberg and Villalta scales with respect to the healthrelated quality of life of patients and with venous valvular reflux (as a physiologic indicator of chronic venous disease). In this study, they found that when the Villalta score was used, almost five times as many patients were diagnosed with PTS at 1 year than when the Ginsberg score was used. They also found that patients diagnosed with the condition when the Ginsberg score was used had higher mean numeric Villalta scores and lower quality-oflife scores, suggesting that the Ginsberg scale only identifies those patients with more severe disease. Furthermore, this score does not rate the severity of the condition and may not include patients with predominantly occlusive deep venous disease. Brandjes. The Brandjes score was developed as part of a trial looking at the effect of compression stockings on patients with symptomatic proximal DVT. 4 In a manner similar to the Villalta score, points are given for a number of subjective and objective criteria (Table III). These criteria were chosen from combined components of other scoring systems, 26,27 and patients were classified as having PTS based on their score over two consecutive visits, 3 months apart. A score of 3 or higher (including one objective criterion) diagnosed mild-moderate PTS, whereas a score of 4 or more from a list of more severe subjective and objective criteria defined severe PTS. Furthermore, a venous ulcer scored 4 points whereas all other criteria scored 1, so any patient who had a venous ulcer after DVT would be classified as having severe PTS. This leads to a problem that is also seen in the Widmer and the CEAP classifications, namely, that once a patient develops a venous ulcer, whether or not it heals, he or she will always be classified as having severe PTS. However, a study by Kolbach et al 22 investigating the relationship between AVP values and PTS score showed a strong association between severity as assessed by the Brandjes score and higher mean AVP values. Widmer. The Widmer classification was initially developed to grade chronic venous insufficiency, but it also has been utilized in studies of PTS. 28 The Widmer score is based purely on clinical signs (Table IV). It was used to diagnose PTS in the Cochrane Systematic Review evaluating compression therapy for treating PTS. 29 In the study by Kolbach et al 22 investigating the difference between scoring systems, the Widmer classification showed a moderate association with the Brandjes score and the CEAP score (k ¼ 0.52 and k ¼ 0.53, respectively). However, this review also noted that because clinical signs rarely change over time, except with deterioration, the Widmer score would not be ideal to use for measuring the outcome of treatment of PTS. CEAP. The CEAP score was designed to score all chronic venous disease, categorizing patients disease according to their clinical signs (C), etiology (E), anatomic

5 258 Soosainathan et al January 2013 Table III. Brandjes scoring system 4 Subjective criteria Objective criteria Symptoms Score Sign Score Spontaneous pain in calf 1 Calf circumference increased by 1 cm 1 Spontaneous pain in thigh 1 Ankle circumference increased by 1 cm 1 Pain in calf on standing/walking 1 Pigmentation 1 Pain in thigh on standing/walking 1 Venectasia 1 Edema of foot/calf 1 Newly formed varicosis 1 Heaviness of leg 1 Phlebitis 1 Spontaneous pain and pain on walking/standing 1 Venous ulcer 4 Impairment of daily activities 1 distribution (A), and pathophysiologic condition (P). 30 Each limb is categorized according to objective signs into one of seven classes (C 0 -C 6 ; Table V). A higher class may have any or all of the findings that define a less severe category. Each limb is also scored as to whether it is symptomatic (C 0-6,S ), or asymptomatic (C 0-6,A ). The diseased limb is then classified by whether the etiology of the venous disorder is congenital, primary, or secondary (E C, E P, E S ). The anatomic sites of venous disease are then denoted by A S for superficial sites, A D for deep sites, and A P for perforating sites. Any or all systems may be involved. For example, A S,D,P indicates disease at all sites. Finally, the pathophysiologic classification indicates whether the venous disease is caused by reflux (P R ), obstruction (P O ), or both (P R,O ). The CEAP classification was used in several studies to diagnose PTS 13,15,31-36 and was used to categorize severity of PTS in two of these studies. 31,35 Although use of this score has become widespread for chronic venous disease in general, there are difficulties in using this system to score patients with PTS. First, it involves alphabetic components that are not quantifiable, making the patient groups more difficult to compare. Second, certain criteria used to classify clinical class cannot change over time (eg, an active ulcer CEAP class 6 may heal, but the patient s disease score can never decrease below class 5). Furthermore, there is no standardization as to which CEAP classification signifies PTS. For example, in a study by Yamaki et al 36 into the factors predicting the development of PTS, the CEAP category C 0-3S, E S,A S,D,P,P R,O indicated no PTS, and the category C 4-6S, E S,A S,D,P,P R,O was used to diagnose PTS. However, other studies used a clinical signs score $3 to diagnose PTS. 13,15,32 Other studies used the clinical signs score not only to diagnose but also to classify the severity of PTS, 31,35 but not in a standardized way. Therefore, CEAP is not ideal as a PTS scoring system, which would aim to examine the effect of treatment as well as classify severity, and there is not yet an agreed CEAP class that is universally used to diagnose PTS. Venous Clinical Severity Score. As a result of the difficulties posed by the alphabetical elements of the CEAP score and the fact that it is limited in its ability to assess change over time, the Venous Clinical Severity Score (VCSS) was developed, 37 which is based on the CEAP classification and attributes scores to nine clinical Table IV. Widmer scoring system 28 Stage Symptoms 1 Ankle flare Subclinical edema 2 Edema Pigmentation Lipodermatosclerosis White (skin) atrophy 3 Leg ulcer Leg ulcer in the past Table V. CEAP classification 30 Class Signs 0 No visible or palpable signs of venous disease 1 Telangiectases, reticular veins, malleolar flare 2 Varicose veins 3 Edema without skin changes 4 Skin changes ascribed to venous disease (pigmentation, venous eczema, lipodermatosclerosis) 5 Skin changes as above with healed ulceration 6 Skin changes as above with active ulceration descriptors, marked from 0 to 3 according to severity. Another 0 to 3 points are allocated according to differences in background conservative therapy (ie, whether elastic stockings were used, and patient compliance with this treatment) to produce a score out of 30 (Table VI). The VCSS was used as an evaluation of endovascular treatment of PTS in a study by Wahlgren et al, 38 but there is no standard VCS score to diagnose or grade the severity of PTS. In the study by Kolbach et al 22 investigating the differences between the scoring systems, the VCSS showed a poor correlation with all other scoring systems (k ¼ ). In addition, a validity study by Meissner et al 39 examining the performance characteristics of the VCSS in assessing chronic venous disease showed that although the VCSS showed a good correlation with the CEAP score, there was statistically significant interobserver variability when assessing the component descriptors of pain,

6 Volume 57, Number 1 Soosainathan et al 259 Table VI. VCSS 37 Descriptor Score ¼ 0 Score ¼ 1 Score ¼ 2 Score ¼ 3 Pain None Occasional, not restricting activity, or requiring analgesia Varicose veins (>4-mm None Few, scattered: branch Daily, moderate limitation of activity, occasional analgesia Multiple: GS varicose veins diameter) varicosities confined to calf or thigh Venous edema None Evening ankle edema only Afternoon edema, above ankle Skin pigmentation None, or focal, low intensity (tan) Diffuse, but limited in area and old (brown) Inflammation None Mild cellulitis, limited to marginal area around ulcer Induration None Focal, circummalleolar (<5 cm) Diffuse over most of gaiter distribution (lower third) or recent pigmentation (purple) Moderate cellulitis, involves most of gaiter area (lower third) Medial or lateral, less than lower third of leg Daily, severe limitation of activities, or requiring regular analgesia Extensive: thigh and calf or GS and LS distribution Morning edema above ankle and requiring change of activities Wider distribution (above lower third) and recent pigmentation Severe cellulitis (lower third and above) or significant venous eczema Entire lower third of leg or more No. of active ulcers >2 Duration of active None < Not healed after 12 months ulceration, months Diameter of largest None <2 2-6 >6 ulcer, cm Compressive therapy Not used or noncompliant Intermittent use of stockings Wears elastic stocking most days Full compliance GS, Great saphenous; LS, lesser saphenous; VCSS, Venous Clinical Severity Score. Table VII. Comparison of the different PTS scoring systems Criteria Villalta Ginsberg Brandjes Widmer VCSS Interobserver reliability Yes No evidence No evidence No evidence No evidence a Association with AVP Yes Yes Yes Yes Yes Association with patient quality-of-life scores Yes Yes No evidence No evidence No evidence Validity Yes Yes Yes Yes Yes Ability to assess PTS severity Yes No Yes Yes Yes Ability to assess change over time/with treatment Yes No No No Yes AVP, Ambulatory venous pressure; PTS, post-thrombotic syndrome; VCSS, Venous Clinical Severity Score. a Interobserver reliability shown for chronic venous disease only, not for PTS. inflammation, and pigmentation. Therefore, although the VCSS does address some of the obstacles posed by the CEAP score, it has not yet been used in many studies concerning PTS, and it does not correlate well with existing scoring systems. DISCUSSION An ideal scoring system for PTS should be easy to use, valid, specific, have good interobserver reliability, be acceptable to patients, have a clear association with the pathophysiologic mechanism, and be able to categorize according to disease severity and identify improvement or deterioration in the condition. From the available evidence, only the Villalta score can lay claim to all of these features (Tables VII and VIII). It could be argued that the subjective criteria involved in calculating the score could reduce its reliability, and that perhaps further investigation into inter- and intraobserver reliability would be useful before the score was used in everyday practice. However, the Villalta score appears to be the most commonly used due to its ease and versatility of use in diagnosis, categorization of severity, and in follow-up. Indeed, in 2008 it was recommended at the International Society on Thrombosis and Haemostasis in Vienna that the Villalta scoring system be utilized in clinical trials as the scoring system of choice for the diagnosis and grading of PTS. 40 One caveat affecting all the different scoring systems concerns their validity. Without knowing the exact pathophysiologic process underlying the development of PTS, the scores are only able to measure markers of the disease, such as clinical features, AVPs, and patient symptoms. Thus, no score can be said to be truly valid because there is no clearly defined measurement that can correlate with PTS. Furthermore, only a few studies have examined whether the different scoring systems correlate with the markers of PTS mentioned earlier. 6,21,22,25 Although validity testing in this manner ensures that the scoring system is sensitive and specific for the condition for which it has been

7 260 Soosainathan et al January 2013 Table VIII. Literature illustrating the properties of the different PTS scoring systems Villalta Ginsberg Brandjes Widmer VCSS Interobserver reliability Rodger et al 20 (2008) No evidence No evidence No evidence No evidence Association with pathophysiology Kolbach et al 22 Kahn et al 25 (2006) Kahn et al 25 (2006) Kolbach et al 22 Kolbach et al 22 Kolbach et al 22 Validity Kahn et al 6 (2002) Kahn et al 21 (2008) Kahn et al 25 (2006) Kolbach et al 22 Kolbach et al 22 Kolbach et al 22 Kolbach et al 22 Kahn et al 25 (2006) Diagnosis Prandoni et al 2 (1996) Ginsberg et al 5 (2000) Brandjes et al 4 (1997) Widmer et al 28 No evidence van Dongen et al 10 Tick et al 11 (2008) Kahn et al 12 Roumen-Klappe et al 13 (2009) Kahn et al 14 Roumen-Klappe et al 15 (2009) Kahn et al 24 (2007) (1981) Kolbach et al 29 (2003) Categorization of Kahn et al 6 (2002) No Yes Yes No evidence severity Kahn et al 17 (2011) Identify change in Yes No No No Yes condition Evaluation of treatment for PTS Kahn et al 17 (2011) O Donnell et al 18 (2008) Prandoni 19 PTS, Post-thrombotic syndrome; VCSS, Venous Clinical Severity Score. Ginsberg et al 23 (2001) No evidence No evidence Wahlgren et al 38 (2010) designed, for conditions such as PTS, where measurable markers of the disease do not always correlate with clinical symptoms, this can give conflicting results. It also could be argued that an assessment of the impact of venous disease on a patient s quality of life should be part of a PTS score. As demonstrated in the study by Kahn et al, 6 patients with PTS have a significantly decreased quality of life, and this in itself is a symptom that contributes to the severity of the condition. Consequently, a quality-of-life questionnaire, such as the VEINES-QOL and VEINES-Sym, 41 in combination with the Villalta score, may aid in further clarifying the differences in the categories of severity of the condition and standardize some of the subjective criteria of the Villalta score. CONCLUSIONS PTS is a serious and debilitating condition. Although clinical research to identify the optimal management options has been conducted, the optimal method of defining and classifying PTS has been unclear. From looking at the studies conducted thus far, the frequency with which the Villalta score is used reflects its desirable properties, namely, its ease of use, its flexibility in being used for diagnosis, classification, and evaluation of treatment, and its validity. If the Villalta score were combined with a quality-of-life questionnaire, we believe this would further strengthen the validity of the score. As such, we recommend that the Villalta score combined with a venous disease specific quality-of-life questionnaire be considered as the gold standard for the diagnosis and classification of PTS. AUTHOR CONTRIBUTIONS Conception and design: AS, HM, MG, AD Analysis and interpretation: AS, HM, MG, AD Data collection: AS, HM Writing the article: AS, HM Critical revision of the article: AS, HM, MG, AD Final approval of the article: HM, MG, AD Statistical analysis: AS, HM, MG, AD Obtained funding: Not applicable Overall responsibility: AS, AD REFERENCES 1. Salzmann E, Hirsh J, Marder V. The epidemiology, pathogenesis, and natural history of venous thrombosis. In: Colman RW, editor. Hemostasis and thrombosis: basic principles and clinical practice. Philadelphia: Lippincott; p Prandoni P, Lensing AW, Cogo A, Cuppini S, Villalta S, Carta M, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125: Prandoni P, Villalta S, Bagatella P, Rossi L, Marchiori A, Piccioli A, et al. The clinical course of deep-vein thrombosis. Prospective longterm follow-up of 528 symptomatic patients. Haematologica 1997;82: Brandjes DP, Buller HR, Heijboer H, Huisman MV, de Rijk M, Jagt H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997;349:

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