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Keywords:

  • deep venous thrombosis;
  • post-thrombotic syndrome;
  • epidemiology;
  • risk factors;
  • prevention;
  • treatment

Summary

  1. Top of page
  2. Summary
  3. How does PTS present clinically?
  4. What is the underlying pathophysiology of PTS?
  5. How is PTS diagnosed?
  6. Which DVT patients are at risk of developing PTS?
  7. How often does PTS occur after DVT?
  8. What is the impact of PTS on patients and society?
  9. How does should PTS be managed? ()
  10. Future areas for research
  11. Conclusion
  12. Acknowledgments
  13. References

The post-thrombotic syndrome (PTS) develops in up to one half of patients after symptomatic deep venous thrombosis (DVT) and is the most common complication of DVT. Typical features of PTS include chronic pain, swelling, heaviness, oedema and skin changes in the affected limb. In severe cases, venous ulcers may develop. The frequency of PTS is likely to be reduced by preventing DVT with the use of effective thromboprophylaxis in high-risk patients and settings and by minimising the risk of ipsilateral DVT recurrence. Use of compression stockings for 2 years after DVT appears to reduce the incidence and severity of PTS but issues remain regarding their use and effectiveness. Future research should focus on elucidating the pathophysiology and risk factors for PTS, assessing the safety and effectiveness of catheter-directed thrombolysis to prevent PTS and evaluating the optimal use of compression stockings to prevent and treat PTS. In addition, new therapies to treat PTS should be sought and evaluated.

Post-thrombotic syndrome (PTS) is a chronic condition that develops in 20–50% of patients after deep venous thrombosis (DVT) (Prandoni et al, 1996; Kahn & Ginsberg, 2004; Stain et al, 2005; Schulman et al, 2006). As such, it is the most common complication of venous thromboembolism (VTE). PTS reduces quality of life (Kahn et al, 2002) and incurs significant direct and indirect societal costs (Bergqvist et al, 1997). To date, however, PTS has received little attention within the field of VTE research. For example, in the numerous clinical trials of therapies for VTE that have directly influenced our current-day clinical practices, PTS has almost never been included as a measure of outcome. Possible reasons for the lack of attention to this common condition on the part of physicians and researchers include lack of knowledge of the high incidence of PTS, uncertainty as to how to diagnose PTS as no ‘gold standard’ test exists, or the perception that PTS is untreatable, inevitable, or takes years to develop after DVT.

This article reviews the current understanding of the clinical presentation, pathophysiology, diagnosis, risk factors, epidemiology and management of PTS. The burden of PTS from the patient's and society's perspective is discussed. Finally, PTS research priorities are highlighted.

How does PTS present clinically?

  1. Top of page
  2. Summary
  3. How does PTS present clinically?
  4. What is the underlying pathophysiology of PTS?
  5. How is PTS diagnosed?
  6. Which DVT patients are at risk of developing PTS?
  7. How often does PTS occur after DVT?
  8. What is the impact of PTS on patients and society?
  9. How does should PTS be managed? ()
  10. Future areas for research
  11. Conclusion
  12. Acknowledgments
  13. References

Post-thrombotic syndrome is termed a ‘syndrome’ because it is associated with groupings of symptoms and clinical signs, which may vary from patient to patient. Patients with PTS experience pain, heaviness, swelling, cramps, itching or tingling in the affected limb. Symptoms may be present in various combinations and may be persistent or intermittent. Typically, symptoms are aggravated by standing or walking and improve with resting, leg elevation and lying down. Signs that may be noted on physical examination of the limb include oedema, telangiectasias, hyperpigmentation, eczema, varicose collateral veins and, in severe cases, lipodermatosclerosis and ulceration (Kurz et al, 1999) (Table ITable III).

Table I.   Typical clinical features of the post-thrombotic syndrome.
Leg symptomsSigns
HeavinessOedema
PainPeri-malleolar telangiectasiae
SwellingVenous ectasia
ItchingHyperpigmentation
CrampsRedness
ParesthesiaDependent cyanosis
Bursting painLipodermatosclerosis
Healed ulcer
Symptom patternOpen ulcer
Worse with activity, standing, walking 
Better with rest, recumbency 
Table III.   Strategies for the prevention and management of PTS.
Prevention
 Prevent index DVT with the use of thromboprophylaxis in high-risk patients and settings as recommended in evidence-based consensus guidelines.
 Prevent recurrent ipsilateral DVT by providing anticoagulation of appropriate intensity and duration for the initial DVT and by targeted use of appropriate thromboprophylaxis if long-term anticoagulation is discontinued.
 Use of knee-length, 30–40 mm Hg ECS elastic compression stockings for up to 2 years after DVT; optimal duration uncertain
 The role of thrombolysis for the prevention of PTS is not yet established. Catheter-directed thrombolysis requires further evaluation in properly designed trials before it is endorsed as being effective in reducing the risk of PTS.
Management
 Elastic compression stockings reduce odema and may improve PTS symptoms.
 Intermittent pneumatic compression units are effective for severe symptomatic PTS.
 Venoactive agents, such as aescin (e.g. as found in horse chestnut) or rutosides, may offer short term improvement of PTS symptoms; large controlled trials addressing long-term effectiveness and safety are needed.
 Compression therapy, skin care and topical dressings are used to treat venous ulcers.

What is the underlying pathophysiology of PTS?

  1. Top of page
  2. Summary
  3. How does PTS present clinically?
  4. What is the underlying pathophysiology of PTS?
  5. How is PTS diagnosed?
  6. Which DVT patients are at risk of developing PTS?
  7. How often does PTS occur after DVT?
  8. What is the impact of PTS on patients and society?
  9. How does should PTS be managed? ()
  10. Future areas for research
  11. Conclusion
  12. Acknowledgments
  13. References

When DVT is diagnosed, standard anticoagulant treatment prevents thrombus extension and embolisation to the pulmonary arteries, but does not directly lyse the acute thrombus. Follow-up studies of patients with DVT who were treated with anticoagulants have shown that in most cases, only partial clearance of thrombus occurs and return of normal physiological function of the vein is rare (Piovella et al, 2002; Prandoni et al, 2002). Even in patients who do achieve clot lysis, permanent damage to venous valves occurs frequently, conceivably via thrombus-induced activation of inflammation (Roumen-Klappe et al, 2002) or scarring associated with acute and resolving thrombosis, leading to valve incompetence (reflux). Indeed, the use of thrombolysis to treat DVT, while achieving high rates of clot lysis, has not been definitively shown to improve venous haemodynamics or reduce the risk of PTS, compared with standard anticoagulation (Wells & Forster, 2001).

Based on the above and on results of venous haemodynamic studies in patients with PTS, it is likely that the pathophysiology of this syndrome involves the interplay of two processes: (i) damage to delicate venous valves by the thrombus itself or by associated inflammatory mediators, which causes valvular reflux; and (ii) residual venous obstruction because of incomplete thrombus clearance, which leads to impaired venous return. Both processes lead to increased venous pressure (venous hypertension), which results in reduced calf muscle perfusion, increased tissue permeability and the associated clinical manifestations of PTS (e.g. pain, effort intolerance, swelling).

How is PTS diagnosed?

  1. Top of page
  2. Summary
  3. How does PTS present clinically?
  4. What is the underlying pathophysiology of PTS?
  5. How is PTS diagnosed?
  6. Which DVT patients are at risk of developing PTS?
  7. How often does PTS occur after DVT?
  8. What is the impact of PTS on patients and society?
  9. How does should PTS be managed? ()
  10. Future areas for research
  11. Conclusion
  12. Acknowledgments
  13. References

By definition, PTS is a syndrome and there is no gold standard laboratory, imaging or functional test that establishes the diagnosis. In patients with objectively confirmed prior DVT who have typical PTS symptoms and signs, PTS is usually the correct diagnosis. In some patients, it may take up to 3–6 months for the initial pain and swelling associated with acute DVT to resolve, hence a diagnosis of PTS should be deferred until after the acute phase has passed. While objective evidence of venous valvular incompetence by Doppler ultrasound or by plethysmography may help to confirm the diagnosis of PTS in symptomatic patients, PTS should not be diagnosed if clinical symptoms are absent. This is because, while many patients with symptomatic PTS have valvular incompetence, many DVT patients develop valvular incompetence but do not have symptomatic PTS (Milne et al, 1994; Kahn et al, 2006a).

Three clinical scales for the diagnosis of PTS have been developed (Villalta et al, 1994; Porter et al, 1995; Ginsberg et al, 2000) and are summarised in Table II. These have been used to assess the presence and grade the severity of PTS in a number of clinical studies, including trials of therapies to prevent or treat PTS. However, none has undergone full evaluation of reliability, validity or responsiveness to change and their use for the routine clinical monitoring of DVT patients has not been assessed. Moreover, differences in the test characteristics of these measures could help to explain the differing rates of PTS that have been reported in long-term follow-up studies of patients with DVT. For example, in a recent study of a population of patients evaluated 1 year after symptomatic DVT, the proportion of patients classified as having PTS was almost fivefold higher with the Villalta measure than with the Ginsberg measure, and the agreement between the two measures was poor (Kahn et al, 2006a). Another recent study detected substantial differences in the ability of various PTS measures to discriminate between legs affected by DVT and those of controls (Kolbach et al, 2005). Research aimed at validating and standardising diagnostic criteria for PTS to improve the uniformity of its’ diagnosis in clinical studies and to enhance the ability to compare results of different studies would be of value.

Table II.   Clinical scales for the diagnosis of post-thrombotic syndrome (PTS).
PTS scaleCriteria used to diagnose PTSDeveloped specifically for PTSRates severity of PTS
  1. *CEAP: Clinical-Etiology-Anatomic-Pathophysiologic. Modifications of CEAP (Clinical Severity Score, Venous Segmental Disease Score) have been proposed (Rutherford et al, 2000).

  2. †Developed for chronic venous disease in general.

  3. ‡Increasing CEAP class is intended to reflect increased severity of signs of chronic venous disease; symptoms and their severity are not considered.

  4. PTS = postthrombotic syndrome.

Villalta scale (Villalta et al, 1994)Five symptoms (pain, cramps, heaviness, pruritus, paresthesia)YesYes
Six signs (oedema, skin induration, hyperpigmentation, venous ectasia, redness, pain during calf compression)
Each rated as 0 (absent), 1 (mild), 2 (moderate) or 3 (severe)
Points are summed to yield total score:
0–4: No PTS
5–14: Mild/moderate PTS
15 or more, or presence of ulcer: Severe PTS
Ginsberg measure (Ginsberg et al, 2000; Ginsberg et al, 2001)Pain and swelling of limb of ≥1 month duration, typical character (worse end of day or with prolonged sitting/standing, better after night's rest and leg elevation) that occurs ≥6 months after acute DVTYesNo
CEAP classification* (Porter et al, 1995)Patients with chronic venous disease classified into one of seven clinical classes (Class 0–6) according to presence of clinical signs. Each class may include signs present in lower-order class.No†No‡
Class:
0. Symptoms only; no visible or palpable signs of venous disease
1. Telangiectasias, reticular veins, malleolar flare
2. Varicose veins
3. Oedema, no skin changes
4. Skin changes (e.g., pigmentation, eczema, lipodermatosclerosis)
5. Skin changes with healed ulcer
6. Skin changes with active ulcer
Each clinical class is then subclassified as to:
Aetiology (congenital, primary, secondary)
Anatomy (superficial, deep, perforator veins)
Pathophysiology (reflux, obstruction, both)

Which DVT patients are at risk of developing PTS?

  1. Top of page
  2. Summary
  3. How does PTS present clinically?
  4. What is the underlying pathophysiology of PTS?
  5. How is PTS diagnosed?
  6. Which DVT patients are at risk of developing PTS?
  7. How often does PTS occur after DVT?
  8. What is the impact of PTS on patients and society?
  9. How does should PTS be managed? ()
  10. Future areas for research
  11. Conclusion
  12. Acknowledgments
  13. References

Risk factors that are apparent at the time of DVT diagnosis

Age and sex.  Two studies found that increasing age was associated with a higher risk of developing PTS (Prandoni et al, 2004; Van Dongen et al, 2005), but other studies did not (Kahn et al, 2002; Kahn et al, 2005a; Stain et al, 2005). In one study, male sex was a weak risk factor for PTS (Stain et al, 2005). Overall, there do not appear to be consistent relationships between age or sex and the development of PTS.

Body mass index (BMI).  Results of prospective studies suggest that higher BMI is associated with a greater risk of PTS. In a small cohort study of patients with symptomatic proximal DVT who were followed for 12 months, patients who developed PTS had significantly higher mean BMI than those who did not develop PTS and BMI >28 was associated with an odds ratio for PTS of 3·5 (Ageno et al, 2003). In a substudy to a trial that compared two intensities of long-term warfarin anticoagulation for unprovoked (idiopathic) proximal DVT, adjusted analyses indicated that higher BMI was associated with increased severity of PTS (Kahn et al, 2005a). Similarly, Van Dongen et al (2005) found that BMI >25 was a significant independent predictor of PTS after proximal DVT. As obesity is a potentially modifiable risk factor, the role of weight reduction in the prevention or management of PTS merits evaluation.

Thrombophilia.  Inherited and acquired thrombophilic disorders increase the risk of developing a first episode of VTE (Bauer, 2005) and in some studies, increased the risk of recurrent VTE (Palareti & Cosmi, 2004). Whether these disorders also increase the risk of developing PTS is of interest and relevance. In a longitudinal cohort study of predictors of PTS, there were no associations between the risk of developing PTS and deficiencies of antithrombin, Protein C or Protein S or the presence of lupus-like anticoagulants (Prandoni et al, 1996). As this was an older study, testing for the common genetic thrombophilias was not yet available. In a recent cohort study, the presence of factor V Leiden, Prothrombin gene mutation or elevated factor VIII levels were not predictive of the development of PTS (Van Dongen et al, 2005). A study by our group found that in patients with idiopathic (unprovoked) DVT, the presence of factor V Leiden or Prothrombin mutation was an independent predictor of both a lower risk and reduced severity of PTS (Kahn et al, 2005a), a finding which was unexpected and is currently undergoing further evaluation in prospective studies. Hence, from the limited data available, it does not appear that thrombophilia increases the risk of developing PTS.

Characteristics of the initial VTE.  In recent prospective studies, the likelihood of developing PTS was not influenced according to whether DVT was idiopathic (unprovoked) or secondary (because of surgery, trauma or cancer) (Prandoni et al, 2004; Stain et al, 2005; Van Dongen et al, 2005). With regard to the relationship between the severity or location of the initial thrombus and the subsequent development of PTS, results have been inconsistent, which may be due at least in part to a combination of differing study methodologies, patients and definitions of PTS. In some studies, the risk of PTS was higher in patients with proximal rather than distal (calf) DVT (Lindner et al, 1986; Monreal et al, 1993) while in other studies neither the site nor the extent of the initial thrombus predicted the development of PTS (Browse et al, 1980; Philbrick & Becker, 1988; Prandoni et al, 1996). Indeed, some prospective studies reported rates of PTS after distal DVT that were as high as 20–80% (Schulman et al, 1986; McLafferty et al, 1998). Hence, distal (calf vein) DVT appears to be associated with a substantial risk of subsequent PTS.

Asymptomatic DVT.  Deep venous thrombosis is sometimes diagnosed in asymptomatic patients by performing screening imaging tests in high-risk situations, for example postoperatively. Such imaging tests have included 125I-fibrinogen uptake testing, contrast venography or venous duplex ultrasound. A recent meta-analysis (Wille-Jorgensen et al, 2005) pooled seven studies of patients with asymptomatic, objectively confirmed postoperative DVT and reported that the overall relative risk of developing PTS was 1·6 [95% confidence interval (CI) 1·24–2·02] as compared with patients without asymptomatic DVT on imaging tests. Moreover in 2005, Schindler and Dalziel reported among total knee and total hip arthroplasty patients that 18 months after ultrasound-diagnosed and treated asymptomatic postoperative DVT, about 24% of patients had developed persistent oedema in the affected leg, compared with 1% of patients without postoperative DVT (Schindler & Dalziel, 2005). These findings indicate that asymptomatic DVT can lead to PTS, which could help to explain the lack of a clinical history of DVT in some patients who have postthrombotic changes in their limbs.

Risk factors that manifest during long-term follow-up after DVT

Intensity, quality and duration and of oral anticoagulation  A few recent studies have provided interesting data regarding the relationship between the duration, intensity and quality of oral anticoagulation and the subsequent development of PTS. Intensity of long-term anticoagulation does not appear to influence the risk of developing PTS, as shown in a recent study by our group (Kahn et al, 2005a) of patients with unprovoked proximal DVT treated with anticoagulants for an average of 2·2 years. After an initial 3 month period of treatment with warfarin targeted to an International Normalised Ratio (INR) of 2·0–3·0, there was no difference in the risk of developing PTS among patients who were randomised to a target warfarin intensity of 1·5–1·9 vs. 2·0–3·0 (Kahn et al, 2005a). However, the quality of anticoagulation in the first months after DVT may influence the risk of developing PTS. In a study of 244 DVT patients treated with vitamin K antagonists (target INR 2·0–3·0) for 3 months, those who spent >50% of the time with a subtherapeutic INR (INR <2·0) had an almost threefold higher risk of developing PTS (Van Dongen et al, 2005). This suggests that poor quality of anticoagulant therapy early after DVT may promote PTS, perhaps because of suboptimal clot resolution. Finally, with regard to the duration of anticoagulant therapy, in a cohort study of 406 patients followed for a median of 60 months after diagnosis of a first DVT, there was no difference in the risk of PTS among patients who received anticoagulation for <6 months, 6–12 months or >12 months (Stain et al, 2005).

Taken together, these results suggest that factors that trigger PTS may occur in the first weeks to months after acute DVT, appear to be promoted by inadequate initial anticoagulation, but are little influenced by intensity or duration of long-term anticoagulation.

Recurrent DVT.  The most important risk factor for PTS is recurrent ipsilateral DVT, which in a number of studies was found to increase the risk of PTS as much as 10-fold (Prandoni et al, 1996; Prandoni et al, 2004; Van Dongen et al, 2005), probably by causing further damage of compromised venous valves or by aggravating venous outflow obstruction. By extension, it is therefore important to prevent recurrent DVT by providing an adequate intensity and duration of anticoagulation for the initial DVT and by using thromboprophylaxis to prevent DVT in high-risk patients and settings as recommended in regularly updated evidence-based consensus guidelines (Geerts et al, 2004).

Residual thrombosis on ultrasound.  The presence of residual thrombosis on ultrasound appears to be a risk factor for recurrent DVT after anticoagulant treatment of acute DVT (Piovella et al, 2002; Prandoni et al, 2002) and could plausibly promote the development of PTS because of persistent venous obstruction or valve damage. However, in recent studies that have examined this issue, modest [odds ratio (OR) 1·69; 95% CI 1·23–2·32] (Prandoni et al, 2005) or no associations (Kahn et al, 2005a) between the presence of residual vein thrombosis and the development of PTS were found.

Persistent elevation of D-dimer.  Elevated D-dimer is a risk factor for first and recurrent DVT (Cushman et al, 2003; Cosmi et al, 2005). Elevated levels of D-dimer (defined as cut-off of >500 ng/ml on an enzyme-linked immunosorbent assay), measured 3 weeks after withdrawal of oral anticoagulant therapy, were found to be a modest risk factor (OR 1·9, 95% CI 1·0–3·9) for PTS in a recent study (Stain et al, 2005). These results require confirmation in large prospective studies.

How often does PTS occur after DVT?

  1. Top of page
  2. Summary
  3. How does PTS present clinically?
  4. What is the underlying pathophysiology of PTS?
  5. How is PTS diagnosed?
  6. Which DVT patients are at risk of developing PTS?
  7. How often does PTS occur after DVT?
  8. What is the impact of PTS on patients and society?
  9. How does should PTS be managed? ()
  10. Future areas for research
  11. Conclusion
  12. Acknowledgments
  13. References

Over the last two decades, the annual incidence of VTE has remained stable and is estimated to be 1·0–1·6 per 1000 persons per year, with a per-person lifetime incidence of c.5% (Silverstein et al, 1998). Approximately 250 000 new cases of VTE occur in the United States each year. Hence, the prevalence of PTS is on the rise in the population. A recent population-based study showed that cumulative rates of venous stasis after DVT were 7% at 1 year, 14% at 5 years, 20% at 10 years and 27% at 20 years and the cumulative risk of ulcer was 4% by 20 years (Mohr et al, 2000). More than a quarter of the c.170 000 new cases of venous stasis per year are considered to represent cases of PTS.

Prospective studies have provided important information on the frequency of PTS after symptomatic DVT. In a longitudinal cohort study of patients with a first episode of symptomatic DVT, the cumulative incidence of PTS was 17% after 1 year (severe in 3%), 23% after 2 years, 28% after 5 years (severe in 9%) and 29% after 8 years (Prandoni et al, 1996). In the control arm of a recent trial to evaluate the use of compression stockings to prevent PTS in patients with symptomatic proximal DVT, the cumulative rate of PTS at 2 years was 49%, and severe PTS occurred in 12% of patients by the end of 5 years follow-up (Prandoni et al, 2004). In both studies, the majority of cases of PTS occurred within 2 years of the initial DVT. Our recent systematic review, of European and North American studies of the occurrence of PTS in prospectively followed DVT patients, showed that the pooled incidence of any PTS was 46%, of severe PTS (including venous ulcers) was 15%, and that in most cases, the condition developed within 1–2 years of the acute DVT (Kahn & Ginsberg, 2004). Indeed, PTS is a very frequent complication of DVT.

What is the impact of PTS on patients and society?

  1. Top of page
  2. Summary
  3. How does PTS present clinically?
  4. What is the underlying pathophysiology of PTS?
  5. How is PTS diagnosed?
  6. Which DVT patients are at risk of developing PTS?
  7. How often does PTS occur after DVT?
  8. What is the impact of PTS on patients and society?
  9. How does should PTS be managed? ()
  10. Future areas for research
  11. Conclusion
  12. Acknowledgments
  13. References

Post-thrombotic syndrome is not merely a cosmetic or ‘nuisance’ problem. Rather, PTS is costly and burdensome to patients and society, both in terms of money spent and effect on quality of life and productivity. A US study estimated that the annual direct cost of PTS is at least $200 million dollars (Heit et al, 2001). A Swedish study estimated that over a 15 year follow-up, the average cost of treating PTS was c.US$4700, or 75% of the cost of treating the primary DVT (Bergqvist et al, 1997). In a Brazilian study, the mean annual cost of treating PTS was the equivalent of US$426 for mild-to-moderate PTS and US$1188 for severe PTS (Ramacciotti et al, 2006). In a recent Canadian study, the annual cost of venous ulcer care in Ottawa alone was >$1 000 000 and a large number of these cases are secondary to previous DVT (Harrison et al, 2001). The indirect costs of PTS are also significant as DVT and PTS affect persons of working age. For example, it is estimated that 2 million workdays are lost annually in the United States because of leg ulcers (Phillips et al, 1994). Research performed by our group has shown that patients with PTS have significantly poorer quality of life than DVT patients without PTS (Kahn et al, 2002; Kahn et al, 2005a), that quality of life is lower than in patients with other forms of chronic venous disease (Kahn et al, 2004) and that impairment in quality of life is, on average, worse than in patients with osteoarthritis or chronic lung disease (Kahn et al, 2002; Kahn et al, 2005b).

How does should PTS be managed? (Table III)

  1. Top of page
  2. Summary
  3. How does PTS present clinically?
  4. What is the underlying pathophysiology of PTS?
  5. How is PTS diagnosed?
  6. Which DVT patients are at risk of developing PTS?
  7. How often does PTS occur after DVT?
  8. What is the impact of PTS on patients and society?
  9. How does should PTS be managed? ()
  10. Future areas for research
  11. Conclusion
  12. Acknowledgments
  13. References

Prevention of PTS

Thromboprophylaxis.  As PTS is a consequence of DVT and thromboprophylaxis is an effective means of preventing DVT, it is highly likely, by extrapolation, that use of thromboprophylaxis in high risk patients and settings as recommended in evidence-based consensus guidelines (Geerts et al, 2004) will prevent cases of PTS. However, practice audits continue to demonstrate that thromboprophylaxis is underutilised (Kahn et al, 2006b). Further, while thromboprophylaxis is effective, its use does not eliminate the risk of VTE. Moreover, nearly 50% of VTE events occur unpredictably and are therefore not preventable with thromboprophylaxis. Strategies that focus on preventing the development of PTS after DVT are therefore more likely to be effective in reducing the frequency of PTS than are attempts to prevent the index DVT. As ipsilateral DVT recurrence is an important risk factor for PTS, preventing recurrent DVT by providing anticoagulation of appropriate intensity and duration for the initial DVT is an important goal (Kearon, 2004).

Thrombolysis.  Thrombolytic therapy used in conjunction with heparin for the treatment of acute DVT leads to higher rates of vein patency and better preservation of valve function than does the use of heparin alone (Goldhaber et al, 1984; Ng & Rivera, 1998). However, the effectiveness and safety of thrombolysis for the prevention of PTS is as yet uncertain (Wells & Forster, 2001). A few trials of systemic thrombolysis for the treatment of DVT have assessed PTS as a study endpoint. Among 51 patients with acute proximal DVT, symptoms and signs of PTS were less frequent at the 19-month follow-up in those who received streptokinase compared with those who received heparin alone (35% vs. 92%) (Elliot et al, 1979). Similarly, in a trial of 42 patients with acute proximal DVT, signs of PTS at 6-year follow-up were less frequent in streptokinase than in heparin recipients (24% vs. 67%) (Arnesen et al, 1982). In a blinded trial of 83 proximal DVT patients, those treated with a 4-hour systemic infusion of tissue plasminogen activator had higher rates of achieving >50% clot lysis than heparin-treated patients (58% vs. 0%, P = 0·002) and among trial patients who achieved >50% clot lysis, PTS occurred less frequently (25% vs. 56%, P = 0·07) (Turpie et al, 1990). While suggestive, these results are not considered to be definitive due to small numbers of patients studied, differing definitions of PTS, and for some trials, retrospective assessment for PTS.

Catheter-directed thrombolysis, which involves direct delivery of a fibrinolytic drug into the clot via a catheter introduced within the thrombosed vein, may be safer and more effective than systemic thrombolytic therapy and could hold promise as a means of preventing PTS. Results of a non-randomised study of 68 iliofemoral DVT patients enrolled in a registry who underwent successful catheter-directed thrombolysis suggested that such patients had fewer PTS symptoms, better physical functioning and less health distress at the 16-month follow-up than 30 similar patients who received anticoagulation alone (Comerota et al, 2000). In a prospective, single centre, non-randomised study of 51 patients with acute iliofemoral DVT, those who chose to receive multimodality therapy that included catheter-directed thrombolysis with balloon angioplasty or stenting followed by anticoagulation, had significantly better resolution of venous symptoms at 5 years than those who chose anticoagulation alone (78% vs. 30%, P = 0·0015) (AbuRahma et al, 2001). Finally, a small single-centre randomised trial of 35 patients with acute iliofemoral DVT reported better venous physiological outcomes (venous function, valve patency) at the 6-month follow-up among catheter-directed thrombolysis recipients compared with those who received anticoagulation alone, but signs and symptoms of PTS were not reported (Elsharawy & Elzayat, 2002).

While the above results are of interest, as yet, there is no clear, high quality evidence to support the use of thrombolysis as a means to prevent PTS, and because of the lack of such evidence, consensus bodies recommend against the routine use of systemic or catheter directed thrombolysis for the initial treatment of DVT (Buller et al, 2004). In order to definitively address this important issue, large, rigorously conducted multicentre controlled trials of standard anticoagulation versus catheter-directed thrombolysis to prevent PTS are required.

Elastic compression stockings.  Graduated elastic compression stockings (ECS) decrease oedema and improve tissue microcirculation (Pierson et al, 1983). Knee-length and thigh-length ECS appear to have equal physiological effects, but the former are easier to apply and more comfortable (Benko et al, 2001).

To date, three trials have evaluated the effectiveness of long-term use of ECS for the prevention of PTS after DVT. In the first, 194 patients with symptomatic proximal DVT were randomly allocated to daily use of a custom, made-to-measure 30–40 mm Hg knee-length ECS for at least 2 years or no stocking (Brandjes et al, 1997). PTS was diagnosed using a scoring system that incorporated symptoms and signs. Use of ECS resulted in a decrease from 47% to 20% of mild/moderate PTS and a decrease from 23% to 11% of severe PTS. A subsequent randomised trial conducted by Ginsberg et al (2001)compared the effect of active stockings to sham stockings (no haemodynamic effect; one or two sizes too large) to prevent PTS in proximal DVT patients who had venous valvular incompetence but no symptoms or signs of PTS 1 year after the initial event. PTS was diagnosed using the Ginsberg PTS measure (Table II). No benefit of daily ECS was shown; 0 (0%) of the 24 patients in the active stocking group developed PTS, compared with one (4·3%) of 23 participants treated with sham stockings (P = 0·49) (Ginsberg et al, 2001). Finally, a recent trial by Prandoni et al (2004) evaluated the effectiveness of ‘off the rack’ 30–40 mm Hg ECS versus no stockings in 180 patients with a first episode of symptomatic proximal DVT. The 2-year cumulative incidence of PTS, diagnosed using Villalta's scale (Table II), was 25% in the stocking group compared with 49% in the control group (hazard ratio 0·49; P = 0·011).

A recent meta-analysis that pooled these three studies (n = 421) reported an overall 54% relative risk reduction in PTS with use of ECS (Kolbach et al, 2003a). However, a number of important questions remain. Firstly, the lack of blinding in the two positive studies reduces confidence in the results because scales used to diagnose PTS and to assess its severity have subjective elements that are susceptible to reporting bias. Moreover, it is not yet known how long stockings need to be worn, which compression strength is optimal and whether they are of benefit to patients with distal DVT. Although ECS are unlikely to cause harm, they are difficult to apply, uncomfortable, expensive and require replacement every few months. Pending results of ongoing multicentre, placebo-controlled studies, providing stockings to patients who have residual leg pain or swelling after DVT and continuing them for as long as the patient derives symptomatic benefit is a reasonable approach.

Treatment of PTS

There are few treatment options for PTS. To date, there is no evidence that long-term use of diuretics is effective for the treatment of PTS-related oedema. Clinicians often prescribe physical compression methods to counteract increased venous pressure. ECS on an as-needed basis may reduce swelling in some patients with PTS (Prandoni, 2005) and should be tried. However, their treatment benefit has not been definitively shown in the setting of PTS and is primarily extrapolated from studies of patients with chronic venous disease (Kurz et al, 1999). Indeed, a recent Cochrane review (Kolbach et al, 2003b) concluded that there is no evidence to support the use of ECS to treat PTS, and while intermittent pneumatic compression units may be of benefit for the management of severe, intractable PTS symptoms or severe oedema, they are cumbersome, expensive and there are no data on their long-term effects. Regarding medications to treat PTS, there is limited evidence that ‘venoactive’ agents, such as aescin or rutosides, may reduce symptoms of chronic venous insufficiency (Diehm, 1996) and in one study, improved PTS symptoms in the short-term (Prandoni, 2005). However, the long-term benefit and safety of these medications have not been evaluated in large controlled trials. Post-thrombotic venous ulcers are generally treated with compression therapy, leg elevation and topical dressings but are often refractory to therapy and tend to recur (Kurz et al, 1999). Finally, surgical treatments for PTS, such as venous valve repair or venous bypass have been evaluated primarily in small patient series at single, specialised centres and appear to be of limited value (Eklof et al, 1998).

Future areas for research

  1. Top of page
  2. Summary
  3. How does PTS present clinically?
  4. What is the underlying pathophysiology of PTS?
  5. How is PTS diagnosed?
  6. Which DVT patients are at risk of developing PTS?
  7. How often does PTS occur after DVT?
  8. What is the impact of PTS on patients and society?
  9. How does should PTS be managed? ()
  10. Future areas for research
  11. Conclusion
  12. Acknowledgments
  13. References

Post-thrombotic syndrome research has significantly lagged behind research in acute VTE. Studies are needed to better elucidate the pathophysiology and risk factors for PTS. Large-scale, ideally placebo-controlled, trials are needed to evaluate the effectiveness, optimal timing, strength and duration of use of ECS in preventing and treating PTS. Multicentre trials of catheter-directed thrombolysis to prevent PTS in patients with proximal DVT are also required. The potential value of venoactive agents, diuretics, anti-inflammatory medications and emerging novel therapies should be evaluated in well-designed trials that use a standardised approach to PTS diagnosis.

Conclusion

  1. Top of page
  2. Summary
  3. How does PTS present clinically?
  4. What is the underlying pathophysiology of PTS?
  5. How is PTS diagnosed?
  6. Which DVT patients are at risk of developing PTS?
  7. How often does PTS occur after DVT?
  8. What is the impact of PTS on patients and society?
  9. How does should PTS be managed? ()
  10. Future areas for research
  11. Conclusion
  12. Acknowledgments
  13. References

Post-thrombotic syndrome is burdensome and costly to patients and society. At present, effective, evidence-based treatments for PTS are lacking, which is a source of difficulty and frustration for patients with PTS. Until effective treatments are found, prevention of PTS is the key to reducing its overall impact on patients and society. Preventing DVT recurrence is likely to reduce the risk of PTS. Daily use of graduated ECS after DVT may reduce the risk of PTS. As of yet, there is no established role for thrombolysis in preventing PTS.

References

  1. Top of page
  2. Summary
  3. How does PTS present clinically?
  4. What is the underlying pathophysiology of PTS?
  5. How is PTS diagnosed?
  6. Which DVT patients are at risk of developing PTS?
  7. How often does PTS occur after DVT?
  8. What is the impact of PTS on patients and society?
  9. How does should PTS be managed? ()
  10. Future areas for research
  11. Conclusion
  12. Acknowledgments
  13. References
  • AbuRahma, A.F., Perkins, S.E., Wulu, J.T. & Ng, H.K. (2001) Iliofemoral deep vein thrombosis: conventional therapy versus lysis and percutaneous transluminal angioplasty and stenting. Annals of Surgery, 233, 752760.
  • Ageno, W., Piantanida, E., Dentali, F., Steidl, L., Mera, V., Squizzato, A., Marchesi, C. & Venco, A. (2003) Body mass index is associated with the development of the post-thrombotic syndrome. Thrombosis and Haemostasis, 89, 305309.
  • Arnesen, H., Hoiseth, A. & Ly, B. (1982) Streptokinase of heparin in the treatment of deep vein thrombosis. Follow-up results of a prospective study. Acta Medica Scandinavica, 211, 6568.
  • Bauer, K. (2005) Hypercoagulable States. Hematology, 10 Suppl 1, 39.
  • Benko, T., Cooke, E.A., McNally, M.A. & Mollan, R.A. (2001) Graduated compression stockings: knee length or thigh length. Clinical Orthopaedics and Related Research, 383, 197203.
  • Bergqvist, D., Jendteg, S., Johansen, L., Persson, U. & Odegaard, K. (1997) Cost of long-term complications of deep venous thrombosis of the lower extremities: an analysis of a defined patient population in Sweden. Annals of Internal Medicine, 126, 454457.
  • Brandjes, D.P.M., Buller, H.R., Heijboer, H., Hulsman, M.V., De Rijk, M. & Jagt, H. (1997) Randomized trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet, 349, 759762.
  • Browse, N.L., Clemenson, G. & Thomas, M.L. (1980) Is the Postphlebitic leg always postphlebitic? Relation between postphlebitic phlebographic appearances of deep-vein thrombosis and late sequelae. BMJ, 281, 11671170.
  • Buller, H.R., Agnelli, G., Hull, R.D., Hyers, T.M., Prins, M.H. & Raskob, G.E. (2004) Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest, 126, 401S428S.
  • Comerota, A.J., Throm, R.C., Mathias, S.D., Haughton, S. & Mewissen, M. (2000) Catheter-directed thrombolysis for iliofemoral deep venous thrombosis improves health-related quality of life. Journal of Vascular Surgery, 32, 130137.
  • Cosmi, B., Legnani, C., Cini, M., Guazzaloca, G. & Palareti, G. (2005) D-dimer levels in combination with residual venous obstruction and the risk of recurrence after anticoagulation withdrawal for a first idiopathic deep vein thrombosis. Thrombosis and Haemostasis, 94, 969974.
  • Cushman, M., Folsom, A.R., Wang, L., Aleksic, N., Rosamond, W.D., Tracy, R.P. & Heckbert, S.R. (2003) Fibrin fragment D-dimer and the risk of future venous thrombosis. Blood, 101, 12431248.
  • Diehm, C. (1996) Comparison of leg compression stocking and oral horse-chestnut seed extract therapy in patients with chronic venous insufficiency. Lancet, 347, 292294.
  • Eklof, B.G., Kistner, R.L. & Masuda, E.M. (1998) Venous bypass and valve reconstruction: long term efficacy. Vasc Med, 3, 157164.
  • Elliot, M.S., Immelman, E.J., Jeffery, P., Benatar, S.R., Funston, M.R., Smith, J.A., Shepstone, B.J., Ferguson, A.D., Jacobs, P., Walker, W. & Louw, J.H. (1979) A comparative randomized trial of heparin versus streptokinase in the treatment of acute proximal venous thrombosis: an interim report of a prospective trial. British Journal of Surgery, 66, 838843.
  • Elsharawy, M. & Elzayat, E. (2002) Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial. European Journal of Vascular and Endovascular Surgery, 24, 209214.
  • Geerts, W.H., Pineo, G.F., Heit, J.A., Bergqvist, D., Lassen, M.R., Colwell, C.W. & Ray, J.G. (2004) Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest, 126, 338S400S.
  • Ginsberg, J.S., Gent, M., Turkstra, F., Buller, H.R., MacKinnon, B., Magier, D. & Hirsh, J. (2000) Postthrombotic syndrome after hip or knee arthroplasty. Archives of Internal Medicine, 160, 669672.
  • Ginsberg, J., Hirsh, J., Julian, J., Vander, L.M., Magier, D., MacKinnon, B. & Gent, M. (2001) Prevention and treatment of postphlebitic syndrome: results of a 3-part study. Archives of Internal Medicine, 161, 21052109.
  • Goldhaber, S., Buring, J., Lipnick, R. & Hennekens, C. (1984) Pooled analyses of randomized trials of streptokinase and heparin in phlebographically documented acute deep venous thrombosis. American Journal of Medicine, 76, 393397.
  • Harrison, M., Graham, I., Friedberg, E., Lorimer, K. & Vandevelde-Coke, S. (2001) Assessing the population with leg and foot ulcers. Canadian Nurse, 97, 1823.
  • Heit, J.A., Rooke, T.W., Silverstein, M.D., Mohr, D.N., Lohse, C.M., Petterson, T.M., O'Fallon, M. & Melton III, L.J. (2001) Trends in the incidence of venous stasis syndrome and venous ulcer: a 25-year population-based study. Journal of Vascular Surgery, 33, 10221027.
  • Kahn, S.R. & Ginsberg, J.S. (2004) Relationship between deep venous thrombosis and the postthrombotic syndrome. Archives of Internal Msedicine, 164, 1726.
  • Kahn, S.R., Hirsch, A. & Shrier, I. (2002) Effect of post-thrombotic syndrome on health-related quality of life after deep venous thrombosis. Archives of Internal Medicine, 162, 11441148.
  • Kahn, S.R., M'Lan, C.E., Lamping, D.L., Kurz, X., Bérard, A., Abenhaim, L., & for the VEINES Study Group (2004) The influence of venous thromboembolism on quality of life and severity of chronic venous disease. Journal of Thrombosis and Haemostasis, 2, 21462151.
  • Kahn, S.R., Kearon, C., Julian, J.A., MacKinnon, B., Kovacs, M.J., Wells, P., Crowther, M.A., Anderson, D.R., Van Nguyen, P., Demers, C., Solymoss, S., Kassis, J., Geerts, W., Rodger, M., Hambleton, J. & Ginsberg, J.S. (2005a) Predictors of the post-thrombotic syndrome during long-term treatment of proximal deep vein thrombosis. Journal of Thrombosis and Haemostasis, 3, 718723.
  • Kahn, S.R., Ducruet, T., Lamping, D.L., Arsenault, L., Miron, M.J., Roussin, A., Desmarais, S., Joyal, F., Kassis, J., Solymoss, S., Desjardins, L., Johri, M. & Shrier, I. (2005b) Prospective evaluation of health-related quality of life in patients with deep venous thrombosis. Archives of Internal Medicine, 165, 11731178.
  • Kahn, S.R., Desmarais, S., Ducruet, T., Arsenault, L., Ginsberg, J.S., & VETO Study Investigators (2006a) Comparison of performance of two clinical scales to diagnose the post-thrombotic syndrome: Correlation with patient-reported disease burden and valvular reflux. Journal of Thrombosis and Haemostasis, 4, 907908.
  • Kahn, S.R., Panju, A., Geerts, W., Pineo, G.F., Desjardins, L., Turpie, A.G.G., Glezer, S., Thabane, L. & Sebaldt, R.J. (2006b) Multicenter evaluation of the use of venous thromboembolism prophylaxis in acutely ill medical patients in Canada. Thrombosis Research, In Press, Corrected Proof.
  • Kearon, C. (2004) Long-term management of patients after venous thromboembolism. Circulation, 110, I10I18.
  • Kolbach, D.N., Sandbrink, M.W.C., Hamulyak, K., Neumann, H.A.M. & Prins, M.H. (2003a) Non-pharmaceutical measures for prevention of post-thrombotic syndrome. The Cochrane Database of Systematic Reviews (Protocol) 2003, Issue 4. Art. No.: CD004174. DOI: 10.1002/14651858.CD004174.
  • Kolbach, D., Sandbrink, M., Neumann, H. & Prins, M. (2003b) Compression therapy for treating stage I and II (Widmer) post-thrombotic syndrome. The Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD004177. DOI: 10.1002/14651858.CD004177.
  • Kolbach, D.N., Neumann, H.A. & Prins, M.H. (2005) Definition of the post-thrombotic syndrome, differences between existing classifications. European Journal of Vascular and Endovascular Surgery, 30, 404414.
  • Kurz, X., Kahn, S.R., Abenhaim, L., Clement, D., Norgren, L., Bacaglini, U., Berard, A., Cooke, J.P., Cornu-Thenard, A., Depairon, M., Dormandy, J.A., Durand-Zaleski, I., Fowkes, G.R., Lamping, D.L., Partsch, H., Scurr, J.H., Zuccarelli, F. (1999) Chronic venous disorders of the leg: epidemiology, outcomes, diagnosis and management - Summary of an evidence-based report of the VEINES task force. International Angiology, 18, 83102.
  • Lindner, D.J., Edwards, J.M., Phinney, E.S., Taylor, L.M. & Porter, J.M. (1986) Long-term hemodynamic and clinical sequelae of lower extremity deep vein thrombosis. Journal of Vascular Surgery, 4, 436442.
  • McLafferty, R.B., Moneta, G.L., Passman, M.A., Brant, B.M., Taylor, L.M., Jr. & Porter, J.M. (1998) Late clinical and hemodynamic sequelae of isolated calf vein thrombosis. Journal of Vascular Surgery, 27, 5056.
  • Milne, A.A., Stonebridge, P.A., Bradbury, A.W. & Ruckley, C.V. (1994) Venous function and clinical outcome following deep vein thrombosis. British Journal of Surgery, 81, 847849.
  • Mohr, D.N., Silverstein, M.D., Heit, J.A., Petterson, T.M., O'Fallon, W.M. & Melton III, L.J. (2000) The venous stasis syndrome after deep venous thrombosis or pulmonary embolism: a population based study. Mayo Clinic Proceedings, 75, 12491256.
  • Monreal, M., Martorell, A., Callejas, J., Valls, R., Llamazares, J., Lafoz, E. & Arias, A. (1993) Venographic assessment of deep vein thrombosis and risk of developing post-thrombotic syndrome: a prospective study. Journal of Internal Medicine, 233, 233238.
  • Ng, C.M. & Rivera, J.O. (1998) Meta-analysis of streptokinase and heparin in deep vein thrombosis. American Journal of Health-System Pharmacy, 55, 19952001.
  • Palareti, G. & Cosmi, B. (2004) Predicting the risk of recurrence of venous thromboembolism. Current Opinion in Hematology, 11, 192197.
  • Philbrick, J.T. & Becker, D.M. (1988) Calf deep venous thrombosis. A wolf in sheep's clothing? Archives of Internal Medicine, 148, 21312138.
  • Phillips, T., Stanton, B., Provan, A. & Lew, R. (1994) A study of the impact of leg ulcers on quality of life: financial, social, and psychologic implications. Journal of the American Academy of Dermatology, 31, 4953.
  • Pierson, S., Pierson, D., Swallow, R. & Johnson, G.J. (1983) Efficacy of graded elastic compression in the lower leg. JAMA, 249, 242243.
  • Piovella, F., Crippa, L., Barone, M., Vigano, D.S., Serafini, S., Galli, L., Beltrametti, C. & D'Angelo, A. (2002) Normalization rates of compression ultrasonography in patients with a first episode of deep vein thrombosis of the lower limbs: association with recurrence and new thrombosis. Haematologica, 87, 515522.
  • Porter, J.M., Moneta, G.L., & An International Consensus Committee on Chronic Venous Disease (1995) Reporting standards in venous disease: An update. Journal of Vascular Surgery, 21, 635645.
  • Prandoni, P. (2005) Elastic stockings, hydroxyethylrutosides or both for the treatment of post-thrombotic syndrome. Thrombosis and Haemostasis, 93, 183185.
  • Prandoni, P., Lensing, A., Cogo, A., Cuppini, S., Villalta, S., Carta, M., Cattelan, A., Polistena, P., Bernardi, E. & Prins, M. (1996) The long-term clinical course of acute deep venous thrombosis. Annals of Internal Medicine, 125, 17.
  • Prandoni, P., Lensing, A.W.A., Prins, M.H., Bernardi, E., Marchiori, A., Bagatella, P., Frulla, M., Mosena, L., Tormene, D., Piccioli, A., Simioni, P. & Girolami, A. (2002) Residual Venous Thrombosis as a Predictive Factor of Recurrent Venous Thromboembolism. Annals of Internal Medicine, 137, 955960.
  • Prandoni, P., Lensing, A.W.A., Prins, M.H., Frulla, M., Marchiori, A., Bernardi, E., Tormene, D., Mosena, L., Pagnan, A. & Girolami, A. (2004) Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Annals of Internal Medicine, 141, 249256.
  • Prandoni, P., Frulla, M., Sartor, D., Concolato, A. & Girolami, A. (2005) Vein abnormalities and the post-thrombotic syndrome. Journal of Thrombosis and Haemostasis, 3, 401402.
  • Ramacciotti, E., Gomes, M., De Aguiar, E.T., Caiafa, J.S., De Moura, L.K., Araujo, G.R., Truzzi, A. & Dietrich-Neto, F. (2006) A cost analysis of the treatment of patients with post-thrombotic syndrome in Brazil. Thrombosis Research, In Press, Corrected Proof.
  • Roumen-Klappe, E., Der Heijer, M., Van Uum, S., Van Der Ven-Jongekrijg, J., Van Der Graaf, F. & Wollersheim, H. (2002) Inflammatory response in the acute phase of deep vein thrombosis. Journal of Vascular Surgery, 35, 701706.
  • Rutherford, R.B., Padberg, F.T., Comerota, A.J., Kistner, R.L., Meissner, M.H. & Moneta, G.L. (2000) Venous severity scoring: An adjunct to venous outcome assessment. Journal of Vascular Surgery, 31, 13071312.
  • Schindler, O.S. & Dalziel, R. (2005) Post-thrombotic syndrome after total hip or knee arthroplasty: incidence in patients with asymptomatic deep venous thrombosis. Journal of Orthopaedic Surgery (Hong Kong), 13, 113119.
  • Schulman, S., Granqvist, S., Juhlin-Dannfelt, A. & Lockner, D. (1986) Long-term sequelae of calf vein thrombosis treated with heparin or low-dose streptokinase. Acta Medica Scandinavica, 219, 349357.
  • Schulman, S., Lindmarker, P., Holmstrom, M., Larfars, G., Carlsson, A., Nicol, P., Svensson, E., Ljungberg, B., Viering, S., Nordlander, S., Leijd, B., Jahed, K., Hjorth, M., Linder, O. & Beckman, M. (2006) Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. Journal of Thrombosis and Haemostasis, 4, 734742.
  • Silverstein, M.D., Heit, J.A., Mohr, D.N., Petterson, T.M., O'Fallon, W.M. & Melton, L.J., III (1998) Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Archives of Internal Medicine, 158, 585593.
  • Stain, M., Schonauer, V., Minar, E., Bialonczyk, C., Hirschl, M., Weltermann, A., Kyrle, P.A. & Eichinger, S. (2005) The post-thrombotic syndrome: risk factors and impact on the course of thrombotic disease. Journal of Thrombosis and Haemostasis, 3, 26712676.
  • Turpie, A.G., Levine, M.N., Hirsh, J., Ginsberg, J.S., Cruickshank, M.K., Jay, R.M. & Gent, M. (1990) Tissue Plasminogen Activator (rt-PA) vs Heparin in Deep Vein Thrombosis. Chest, 97, 172S175S.
  • Van Dongen, C.J., Prandoni, P., Frulla, M., Marchiori, A., Prins, M.H. & Hutten, B.A. (2005) Relation between quality of anticoagulant treatment and the development of the postthrombotic syndrome. Journal of Thrombosis and Haemostasis, 3, 939942.
  • Villalta, S., Bagatella, P., Piccioli, A., Lensing, A., Prins, M. & Prandoni, P. (1994) Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome (abstract). Haemostasis, 24, 158a.
  • Wells, P. & Forster, A.J. (2001) Thrombolysis in deep vein thrombosis: Is there still an indication? Thrombosis and Haemostasis, 86, 499508.
  • Wille-Jorgensen, P., Jorgensen, L.N. & Crawford, M. (2005) Asymptomatic postoperative deep vein thrombosis and the development of postthrombotic syndrome. A systematic review and meta-analysis. Thrombosis and Haemostasis, 93, 236241.