REVIEW ARTICLE Relationship Between Deep Venous Thrombosis and the Postthrombotic Syndrome Susan R. Kahn, MD, MSc, FRCPC; Jeffrey S. Ginsberg, MD, FRCPC he postthrombotic syndrome (PTS) is a frequent complication of deep venous thrombo- sis (DVT). Clinically, PTS is characterized by chronic, persistent pain, swelling, and other signs in the affected limb. Rarely, ulcers may develop. Because of its prevalence, severity, and chronicity, PTS is burdensome and costly. Preventing DVT with the use of effective Tthromboprophylaxis in high-risk patients and settings and minimizing the risk of ipsilateral DVT re- currence are likely to reduce the risk of development of PTS. Daily use of compression stockings after DVT might reduce the incidence and severity of PTS, but consistent and convincing data about their effectiveness are not available. Future research should focus on standardizing diagnostic criteria for PTS, identifying patients at high risk for PTS, and rigorously evaluating the role of thrombolysis in preventing PTS and of compression stockings in preventing and treating PTS. In addition, novel thera- pies should be sought and evaluated. Arch Intern Med. 2004;164:17-26 The postthrombotic syndrome (PTS) is a CLINICAL PRESENTATION AND chronic condition that develops in 20% to PATHOPHYSIOLOGY OF PTS 50% of patients within 1 to 2 years of symptomatic deep venous thrombosis Patients with PTS complain of pain, (DVT). A severe form, which can include heaviness, swelling, cramps, itching, or venous ulcers, occurs in one quarter to one tingling in the affected limb. Typically, third of patients with PTS.1,2 Because of its symptoms are aggravated by standing or prevalence and chronicity, PTS is costly walking and improve with rest and to society and is a cause of substantial pa- recumbency. On physical examination, tient morbidity. edema, telangiectasias, hyperpigmenta- In this article, we critically review the tion, eczema, and varicose collateral evidence informing current understand- veins are often present. In severe cases, ing of the pathophysiology, epidemiol- lipodermatosclerosis and ulceration may ogy, diagnosis, and management of PTS. result3-6 (Table 1). The burden of PTS from both a patient and The pathophysiology of PTS is in- a societal perspective is discussed. Using completely understood, but it is thought standard criteria to grade the quality of the that the acute thrombus itself, associated available evidence, we provide recommen- mediators of inflammation, and the pro- dations for the prevention and treatment cess of vein recanalization in the weeks af- of PTS. This article also acknowledges con- ter DVT induce damage to venous valves, troversies in the field and key areas of on- leading to valvular incompetence (reflux). going and future research. Valvular incompetence, persistent ve- nous obstruction, or both cause venous hy- 6-8 From the Department of Medicine, McGill University, Center for Clinical Epidemiology pertension, which leads to edema, tis- & Community Studies, Sir Mortimer B. Davis Jewish General Hospital, Montreal, sue hypoxia, and, in some cases, skin 6,7 Quebec (Dr Kahn); and Department of Medicine, McMaster University, McMaster ulceration. A number of clinical stud- University Medical Center, Hamilton, Ontario (Dr Ginsberg). The authors have no ies have suggested that valvular reflux in relevant financial interest in this article. the proximal veins, particularly the pop- (REPRINTED) ARCH INTERN MED/ VOL 164, JAN 12, 2004 WWW.ARCHINTERNMED.COM 17 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Asymptomatic DVT not be made in the absence of clini- Table 1. Clinical Features cal symptoms; while most patients of Postthrombotic Syndrome Whether asymptomatic DVT (ie, de- with symptomatic PTS have valvu- tected by routine screening) leads to lar incompetence, many with val- Leg Symptoms* Signs PTS is controversial. One study found vular incompetence do not have that the frequency of PTS 2 to 7 years PTS.43 Heaviness Edema afterhiporkneearthroplastywassimi- Three clinical scales for the di- Pain Telangiectasia 32,44,45 Swelling Venous ectasia larly low (approximately 5%) in pa- agnosis of PTS are available and Itching Varicose veins tients whose routine predischarge have been used in a number of clini- Cramps Venous dilation venogram showed proximal DVT, calf cal studies. They are presented in de- Paresthesia Hyperpigmentation DVT, or no DVT.32 All patients with tail in Table 2.32,44-46 Bursting pain Stasis dermatitis (eczema) DVT received 6 to 12 weeks of anti- Redness coagulanttherapy.Otherinvestigators IMPACT OF PTS Dependent cyanosis Lipodermatosclerosis have also found low rates of PTS af- 33,34 Healed ulcer ter asymptomatic DVT. Con- Population-Based Studies: Open ulcer versely, some groups have shown that Incidence and Prevalence asmanyas25%to33%ofpatientswith *Symptom pattern: worsened by activity, asymptomatic DVT develop PTS.35,36 The prevalence of PTS is influ- standing; improved by rest, recumbency. Differences in patient selection, study enced by the incidence of DVT. De- design, and definition of PTS may ex- spite advances in its prevention and plain these discrepant results, but if treatment, the annual incidence of liteal vein, is associated with clini- 9-13 confirmed, this would support the venous thromboembolism (VTE) cal manifestations of PTS. There- clinical relevance of asymptomatic (ie, DVT and pulmonary embo- fore, preventing valve damage and DVT in studies of thromboprophy- lism) has not decreased and is 1.0 reducing venous hypertension are laxis37 and would provide a rationale to 1.6 per 1000 persons per year, likely to be important in prevent- for reducing the risk of such with a per-person lifetime inci- ing PTS. thrombi.38,39 dence of 2% to 5%.47-51 Approxi- mately 250000 new cases of VTE oc- FACTORS THAT PREDICT Patient Characteristics cur in the United States each year.48 THE DEVELOPMENT OF PTS The population burden of PTS is dif- AFTER DVT In prospective studies, clinical fea- ficult to estimate because of vary- tures such as delay in initiating treat- ing definitions of PTS and a ten- Recurrent DVT ment for DVT; risk factors for throm- dency to undercode chronic bosis; family history of thrombosis; conditions. In a recent study, cu- The only clearly identified risk fac- protein C, protein S, or antithrom- mulative rates of venous stasis were tor for PTS is recurrent, ipsilateral bin deficiency; or the presence of the 7.3% at 1 year, 14.3% at 5 years, DVT, which increases the risk of PTS lupus anticoagulant have not been 19.7% at 10 years, and 26.8% at 20 1,14-17 found to increase the risk of devel- years after DVT; the cumulative risk as much as 6-fold. Recurrent 1,14 19 DVT probably causes additional oping PTS. In retrospective stud- of ulcer was 3.7% by 20 years. It damage to already compromised ve- ies, factors predictive of PTS were in- is estimated that more than one nous valves and further venous out- creasing age, female sex, hormone quarter of the at least 170000 new flow obstruction. therapy, varicose veins, abdominal cases of venous stasis syndrome per surgery, and increased body mass in- year represent PTS.52 40,41 Characteristics of dex. the Initial DVT Clinical Studies: DIAGNOSIS OF PTS Frequency of PTS After DVT There is little correlation between the There is no gold standard test for the The frequency of PTS after objec- venographic severity of the initial diagnosis of PTS. In patients with ob- tively diagnosed DVT is difficult to thrombus and subsequent develop- jectively confirmed DVT and a typi- estimate. Many studies have used ment of PTS.1,18 In some studies, the cal clinical presentation, PTS is usu- surrogate end points such as reflux risk of PTS was higher in patients ally the correct diagnosis. As it or abnormal results of venography with proximal rather than distal usually takes 3 to 6 months after without consideration of clinical (calf) DVT,19-22 while in others the acute DVT for the initial pain and symptoms and signs, and few have site of the initial thrombus did not swelling to resolve, a diagnosis of used validated PTS scores. influence the subsequent develop- PTS should be deferred until after Nonetheless, a few prospec- ment of PTS.1,18,23-25 In prospective this time. Objective evidence of ve- tive studies have provided key in- studies, reported rates of PTS after nous valvular incompetence by Dop- formation on the frequency of PTS distal DVT have ranged from 20% to pler ultrasound or by plethysmog- after symptomatic DVT. In a longi- 80%.25-31 Hence, calf DVT is associ- raphy helps to confirm the diagnosis tudinal cohort study of patients with ated with a significant risk of sub- in symptomatic patients.10,11,20,25,42 a first episode of acute symptom- sequent PTS. However, a diagnosis of PTS should atic DVT, Prandoni et al1 found that (REPRINTED) ARCH INTERN MED/ VOL 164, JAN 12, 2004 WWW.ARCHINTERNMED.COM 18 ©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 2. Clinical Scales for the Diagnosis of Postthrombotic Syndrome Developed Rates Test Specifically Severity PTS Scale Criteria Used to Diagnose PTS Characteristics for PTS of PTS Ginsberg et al32 Pain and swelling of limb of Ն1-mo duration, typical character (worse at end Not assessed Yes No of day or with prolonged sitting/standing, better after night’s rest and leg elevation) that occurs Ն6 mo after acute DVT and Objective evidence of valvular