The post thrombotic syndrome
The post thrombotic syndrome (PTS) (sometimes called 'post-phlebitic syndrome') is a chronic condition that develops in 20–40% of patients within 1–2 years after symptomatic deep venous thrombosis (DVT). A severe form, which can include venous ulcers, affects 1/4 to 1/3 of patients with PTS . In contrast to research gains in the areas of diagnosis, prevention and treatment of acute venous thromboembolism (VTE), PTS has been understudied and as a result, treatment options are limited.
Patients with PTS experience pain, heaviness, swelling, or other symptoms in the affected limb, which are typically aggravated by standing or walking and improve with rest and recumbency. Edema, venous ectasia, hyperpigmentation, eczema, and varicose collateral veins may be apparent. In severe cases, ulceration can occur .
Since PTS is a direct consequence of DVT, its prevalence is influenced by the incidence of DVT. Despite advances in VTE prevention and treatment, the annual incidence of VTE has not decreased over time, and remains at 1.0–1.6 per 1000 persons per year, with a per-person lifetime incidence of 2–5% [3, 4]. Because of its prevalence and chronicity, PTS is expensive, both in terms of direct medical costs and indirect costs such as loss of productivity and thus it is burdensome to patients and society .
Risk factors for the development of PTS
While hereditary and acquired risk factors that predispose to the development of VTE are widely known , factors that influence the development of PTS after DVT have not been well elucidated. The only clearly identified clinical risk factor for PTS is recurrent, ipsilateral DVT [7, 8]. The site (proximal vs. distal), size and occlusiveness of the initial DVT and the intensity (i.e. target INR) of long term anticoagulation for DVT do not appear to reliably predict PTS [1, 7–10]. It is not clear why some patients develop PTS while others recover from their DVT. As a result, physicians are unable to provide their DVT patients with reliable, individualized prognostic information.
Potential role of inflammation, d-Dimer and thrombophilia in the post-thrombotic syndrome
While the pathophysiology of PTS is incompletely understood, it is likely that the acute thrombus itself, associated mediators of inflammation, and the process of vein recanalization in the weeks following DVT induce damage to venous valves, leading to valvular incompetence (reflux). Valvular incompetence and/or persistent venous obstruction by thrombus cause venous hypertension, which promotes capillary leakage of plasma proteins, erythrocytes and leukocytes and the development of venous ectasia and varicosities. The result is edema, tissue hypoxia, and ultimately, in some cases, skin ulceration [11–14].
Inflammation and thrombosis are closely interrelated [15–17]. It has been appreciated over the last few years that arterial atherothrombosis is, at least in part, an inflammatory disease, and that elevations in markers of inflammation, such as C-reactive protein (CRP), increase the risk of future clinical cardiovascular events . Clinically, patients with DVT exhibit cardinal signs of inflammation such as redness, warmth, swelling, pain and fever. Several clinical studies have examined the association between levels of inflammatory markers and venous thrombosis, and found that a two- to six-fold increase in the risk of DVT associated with elevations in plasma levels of CRP, interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1 or tumor necrosis factor (TNF)-alpha . A recent paper showed that CRP is elevated in patients with acute DVT (median 37.5 mg/L) compared with controls (5.0 pg/L), and that levels decline during the first 5 days of DVT treatment. Similar trends were noted for IL-6 , leading the authors to conclude that the thrombotic process produces a systemic inflammatory response and to speculate whether the observed decrease in levels was partly caused by treatment with heparin, which is known to have anti-inflammatory properties distinct from its anticoagulant properties . Whether levels of markers of inflammation are predictive of PTS has not previously been examined.
D-dimer is a degradation product of cross-linked fibrin that reflects fibrinolysis and is an indirect marker of coagulation activation. Recent work performed by our group and by others suggests that D-dimer levels appear to be a significant predictor of first VTE  and of recurrent VTE [23–28], whether measured during or after anticoagulation. Independent of VTE recurrence, persistent coagulation activation, as reflected by elevated D-dimer levels, may also predict a higher risk of developing PTS after DVT .
Thrombophilia refers to an inherited or acquired predisposition to VTE. Over 10% of the general population is affected by one or more identifiable inherited thrombophilias which have been shown to underlie at least 1/3 of cases of VTE . The most common inherited thrombophilias are the single nucleotide polymorphisms Factor V Leiden, which renders coagulation factor V resistant to the anticoagulant effects of activated protein C , and Prothrombin G20210A, which leads to elevated plasma prothrombin levels [32, 33]. Recent studies have also established that elevation of Factor VIII level is an inherited risk factor both for first and for recurrent VTE [34–36], independent of age, sex, Factor V Leiden, Prothrombin G20210A or markers of acute phase activation such as CRP [35, 37, 38].
While results of a few studies to date suggest that thrombophilia does not increase the risk of developing PTS [7, 8, 10], not all thrombophilias have been examined and interactions among disorders have not been studied. Further investigation of the potential link between thrombophilia and PTS is warranted.
Management of PTS
PTS could be averted by primary prevention of the initial DVT with the judicious use of thromboprophylaxis , and by preventing recurrent ipsilateral DVT by prescribing adequate anticoagulation for the initial DVT . However, at least 1/2 of all cases of DVT occur unpredictably, hence are not preventable [41, 42]. There is no definitive evidence that using thrombolysis to treat DVT reduces the incidence of PTS . The treatment of established PTS is limited and frustrating for patients. Severe PTS can be managed with long-term use of an intermittent compression extremity pump [44, 45]. Management of venous ulcers is labor intensive and protracted, and involves compression therapy, leg elevation, topical dressings, and sometimes surgery [2, 46]. Ulcers are often recalcitrant to treatment, and tend to recur .
A significant reduction in the overall burden of PTS is unlikely to be achieved by attempts to prevent the initial DVT or by treatment of established PTS. Rather, strategies that focus on preventing the development of PTS in patients with DVT are more likely to be effective and cost-effective in reducing the patient and societal impact of PTS.
Elastic compression stockings for the prevention of PTS
Graduated elastic compression stockings (ECS) work by providing graded compression to the leg that is highest at the ankle, which assists the calf muscle pump, reduces venous hypertension and valvular reflux, and consequently reduces edema, improves tissue microcirculation, and prevents skin breakdown [48, 49]. Both knee-length and thigh-length stockings appear to have equal physiological effects, but knee-length ECS are easier to apply and are more comfortable . The effectiveness of daily use of ECS to prevent PTS is supported by two studies [8, 51] but challenged by another . All three studies have limitations that could affect their validity and generalizability. The first trial, Brandjes' study of 194 patients with symptomatic proximal DVT, provides evidence supporting the effectiveness of ECS. Patients were randomized to daily use of custom-made, knee-length ECS applied within 2–3 weeks of diagnosis for at least 2 years (class II compression, i.e. 30–40 mm Hg pressure at the ankle), or no stocking. Use of ECS resulted in a 50% reduction in the incidence of PTS, diagnosed using a modification of Villalta's clinical PTS scale , or an absolute decrease from 47% to 20% of mild/moderate PTS and from 23% to 11% of severe PTS . In contrast, a randomized trial conducted by Ginsberg suggested that ECS were not of benefit in preventing PTS . A strength of Ginsberg's study was the use of a control comparison group that wore sham stockings (i.e. stockings that were 1–2 sizes too big to be effective). However, because of the small number of patients with PTS, benefit or harm of up to 30% could not be definitively excluded. Recently, Prandoni published the results of a trial performed at a single center in Italy to evaluate the effectiveness of ECS to prevent PTS . Among 180 patients with proximal DVT, those randomized to wear daily ECS had a 50% reduction in the rate of PTS after a 2 year period, compared with controls. This study, like Brandjes', lacked a placebo control, an important limitation due to the subjective nature of many of the components of the standardized scale that was used to diagnose PTS . As the Prandoni study was the first, single positive study of "off-the-rack" elastic compression stockings, it requires replication. Also, as the study was conducted entirely at a single center in Italy, further evaluation of the generalizability of this data to North American clinical practice in a multi-center study is needed.
In light of the above, we believe that a large scale, randomized placebo-controlled trial of ECS to prevent PTS is needed to provide definitive evidence of effectiveness, or lack of effectiveness, of ECS. This will allow physicians to make informed, evidence-based decisions regarding their use in DVT patients. Furthermore, such a trial will permit prospective evaluation of the predictive role of markers of inflammation, d-Dimer and thrombophilia in PTS.