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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Ann Pharmacother. Author manuscript; available in PMC 2011 December 26.
Published in final edited form as:
Ann Pharmacother. 2009 November; 43(11): 1824–1835.
Published online 2009 September 8. doi:  10.1345/aph.1M185
PMCID: PMC3245967
NIHMSID: NIHMS281829

Contemporary Issues in the Prevention and Management of Postthrombotic Syndrome

Sara R Vazquez, BCPS, PharmD, Clinical Pharmacist, Andrew Freeman, MD, Visiting Clinical Instructor, Ryan C VanWoerkom, BS, Medical Student, and Matthew T Rondina, MD, Assistant Professor

Abstract

OBJECTIVE

To provide an evidence-based review and clinical summary of postthrombotic syndrome (PTS).

DATA SOURCES

A literature review was performed via MEDLINE (1950–July 1, 2009) and International Pharmaceutical Abstracts (1970–June 2009) searches using the terms post-thrombotic syndrome, post-phlebitic syndrome, deep vein thrombosis, and compression stockings.

DATA SYNTHESIS

PTS is best characterized as a chronic syndrome of clinical signs and symptoms including pain, swelling, parasthesias, and ulceration in the affected limb following deep vein thrombosis (DVT). It occurs in up to half of patients with symptomatic DVT, usually within the first 2 years. Although the pathophysiology of PTS is not well understood, a thrombus may cause venous hypertension and valvular incompetence resulting in edema, tissue hypoxia, and in severe cases, ulceration. Risk factors for PTS include recurrent ipsilateral DVT, obesity, and poor quality of anticoagulant therapy. PTS diagnosis is based on the presence of typical signs and symptoms and may be made using one of several clinical scoring systems. Prevention of PTS should focus on DVT prevention and the use of elastic compression stockings following DVT, while fibrinolysis remains under investigation as an effective method for PTS prevention. The treatment of PTS may include either pharmacologic or mechanical modalities, although none of these regimens has been rigorously tested. Pharmacists have the opportunity to provide more comprehensive antithrombotic management by educating patients and providers on PTS, recommending appropriate preventive therapy, assisting patients in obtaining and adhering to this therapy, and assisting providers with the management of PTS.

CONCLUSIONS

Providers should be proactive in preventing PTS, with pharmacists taking an active role in optimal DVT prevention, identifying patients at risk for PTS, and counseling and directing preventive therapies.

Keywords: compression stockings, deep vein thrombosis, edema, postphlebitic syndrome, postthrombotic syndrome, venous thromboembolism

Postthrombotic syndrome (PTS) is a chronic and often debilitating complication of deep vein thrombosis (DVT). The classic symptoms of PTS are pain, swelling, edema, and venous ectasia in the affected limb following a DVT. Severe PTS can lead to chronic lower extremity ulceration, resulting in limited mobility and the need for frequent medical care. Even in less severe cases of PTS, the quality of life (QoL) of patients may be significantly limited.1,2

In the US, an estimated 600,000 cases of venous thromboembolism (VTE) occur annually, with over 375,000 cases of DVT. Similar estimates report an additional 296,000 fatal VTE events.3 Other studies have reported the overall annual incidence of VTE to be approximately 120 per 100,000.4 While pulmonary embolism and recurrent DVT are well-recognized complications of DVT, it is becoming clearer that PTS is a potentially severe, costly, and debilitating condition that is underrecognized by many health-care practitioners. The aim of this article is to increase awareness of PTS by providing a review of its incidence, burden, and pathophysiology, as well as current prevention and treatment modalities. Additionally, we highlight areas where pharmacists can play a significant role in the prevention and management of PTS.

Data Sources

A literature review was performed via MEDLINE (1950–July 1, 2009) and International Pharmaceutical Abstracts (1970–June 2009) searches using the terms post-thrombotic syndrome, post-phlebitic syndrome, deep vein thrombosis, and compression stockings. We reviewed English-language publications, including randomized controlled trials, meta-analyses, case reports, and literature reviews, and selected publications deemed most clinically relevant to the topic of PTS.

Epidemiology

HOW COMMON IS PTS?

PTS is the most common complication of DVT, with symptoms occurring in up to half of patients following a first episode of symptomatic DVT, typically within the first 2 years. Most studies have reported an overall incidence of 20–50% for PTS,510 but differences in the definition of PTS, diagnostic modalities, and PTS scales have limited a more precise estimation of the true incidence.

The reported incidence of PTS following asymptomatic DVT is less clear. While some studies have shown that as many as 25–33% of patients with asymptomatic DVT develop PTS, other investigations have found either low rates of PTS or no significant difference in the rates of PTS with asymptomatic proximal DVT or calf DVT, compared with no DVT.5,11,12 Most of these studies examined postoperative orthopedic surgery patients, were limited by smaller sample sizes, and differed in the definition of PTS and the methods employed for the diagnosis of DVT.

WHAT IS THE EFFECT OF PTS ON QUALITY OF LIFE?

Because PTS symptoms are typically more severe with standing or physical activity, PTS has been associated with a reduced QoL. For example, Kahn et al.13 studied both validated generic and venous disease–specific QoL measures. They found that of 387 patients with acute DVT, those who developed PTS had lower scores and significantly less improvement in QoL when assessed 2 years following the index event. QoL scores were negatively correlated with the severity of PTS symptoms. PTS was the only independent predictor of venous disease–specific QoL, suggesting that the development of PTS may have the largest effect on QoL after DVT. Additionally, multiple studies have demonstrated that patients with PTS have a significantly poorer QoL than DVT patients without PTS or patients with other forms of chronic venous disease.2,14,15

WHAT IS THE COST OF PTS?

The estimated healthcare costs of treating PTS add significantly to the cost of treating DVT. The annual cost of PTS in the US has been estimated at approximately $200 million, with costs over $3800 per patient in the first year alone.16 Annual per-patient cost increases with disease severity.1,8,17 Venous ulceration is the most expensive complication, costing nearly an additional $8000 per patient.18 The indirect costs of PTS are significant as well. It is estimated that over one quarter of the 170,000 cases of venous stasis syndrome are a result of PTS and that up to 2 million work days are lost per year due to complications related to leg ulcers.1,2,8

HOW DOES PTS DEVELOP?

Despite ongoing investigations into the pathophysiology of PTS, the mechanisms and processes leading to its development are not entirely clear. Inflammatory mediators and the acute thrombus itself may damage the venous wall and cause valvular incompetence which, in turn, leads to venous hypertension and reduced calf muscle perfusion with subsequent altered muscle metabolism.19,20 Increased tissue permeability present in PTS likely results from a combination of increased venous pressure augmented by angiostatic chemokines. Thus, as vessel diameter increases due to valvular incompetence and inflammatory-mediated chemokine changes, fluid accumulates and permeability markedly increases.21 Taken together, these processes lead to edema, tissue hypoxia, and in severe cases, lipodermatosclerosis and ulceration (Figure 1).5,8

Figure 1
The pathophysiology of postthrombotic syndrome. Thrombus damages venous valves, leading to valvular insufficiency and venous hypertension. This process may ultimately lead to the erythema, pain, and swelling characteristics of postthrombotic syndrome. ...

WHAT ARE RISK FACTORS FOR PTS?

The location and size of the initial DVT may predict the risk of PTS.6 For example, proximal DVT has been associated with a 30% higher risk of developing PTS compared with distal DVT.10 In addition, ipsilateral DVT increases the risk of PTS 6- to 10-fold.6,8,22 This higher risk may reflect the additional damage of recurrent thrombosis on the venous valves and endothelium. The presence of residual thrombus on ultrasound has not been definitively shown to increase the risk of PTS.14,23

Although neither age nor sex has been shown to definitively increase the risk of PTS,10,14,22,2426 obesity (body mass index ≥30 kg/m2), which is a major risk factor for DVT, is associated with an increased risk and severity of PTS. This higher risk may be due to increased venous pressure promoting venous reflux in already compromised veins in the setting of chronic debilitation and poor muscle function.8,10,14,24 The presence of an identified thrombophilia is associated with an increased risk of venous leg ulcers but does not increase the risk of PTS.10,22,27

DO THE DURATION, INTENSITY, AND QUALITY OF ANTICOAGULATION THERAPY AFFECT THE RISK OF PTS?

Neither the duration (6 wk vs 6 mo) nor the intensity (international normalized ratio [INR] target 2.5 vs 1.7) of anticoagulation affects the risk of PTS.14 The quality of anticoagulation management, however, does correlate with the risk of PTS. van Dongen et al.26 reported that patients with DVT with subtherapeutic anticoagulation (INR <2.0) more than 50% of the time during their first 3 months of warfarin treatment had an increased risk of developing PTS during the 5-year follow-up period (OR 2.71). Importantly, tight INR control may mitigate the risk of PTS. When comparing patients who had a subtherapeutic INR over 30% of the time with those whose INR was therapeutic over 30% of the time, the OR for developing PTS was 1.89. When patients’ INRs were outside the therapeutic range 90% of the time, the OR for developing PTS increased to 3.69.

Since pharmacists often provide anticoagulation management and monitoring, they are uniquely positioned to identify patients at risk for PTS and can help to ensure that patients are educated on the importance of maintaining therapeutic anticoagulation to prevent complications of DVT, such as PTS.

Diagnosis

Typically, PTS is characterized by lower extremity swelling and pain. These symptoms are often worse with activity and improved with rest or elevation of the affected limb. Other symptoms include cramping, tingling, and itching. On examination, patients with PTS may have edema, erythema, varicose veins, and eczema; severe cases may be associated with chronic ulcers.28 When a patient presents with these unilateral symptoms, has a history of DVT, and new or recurrent DVT is excluded, a diagnosis of PTS may be made clinically.5,28 Ideally, the diagnosis of PTS should be deferred until 3–6 months after the index DVT, as symptoms due to acute DVT may take this long to completely resolve.

There are now 4 clinical scoring systems that may be helpful for the diagnosis of PTS. These include Widmer staging,29 Villalta scale,30 Ginsberg measure,11,31 and Clinical-Etiologic-Anatomic-Pathophysiologic (CEAP) classification32 (Table 1). There is no clear advantage of using one of these scales over the others. Both the CEAP and Widmer scales are more general classifications and may be used in evaluating both PTS and chronic venous disease, while the Villalta scale and Ginsberg measure are specific for PTS. Although the Villalta scale appears to be gaining in use and popularity, none of these scales has undergone rigorous validation. Differences in the interrater reliability of these scales may be one of the reasons why reported rates of PTS vary in published studies.33

Table 1
Clinical Scales for the Diagnosis of Postthrombotic Syndrome

Documenting valvular incompetence by Doppler ultra-sonography or by plethysmography is not necessary if typical PTS signs and symptoms are present in a patient with a history of DVT. If valvular incompetence is identified by imaging without the presence of typical signs and/or symptoms of PTS, a diagnosis of PTS should not be made,28,34 as many patients with a history of DVT will have evidence of valvular incompetency on imaging studies. A recent article calls for an established uniform definition of PTS to provide greater validity between researchers and practical use for clinicians.35

Prevention

DVT PREVENTION

Arguably, the most effective way to prevent PTS is to prevent DVT from occurring. We now have a number of well-designed, randomized studies demonstrating that pharmacologic prophylaxis effectively reduces the risk of DVT and pulmonary embolism in patients at risk.36 Unfortunately, despite these high-quality data, many hospitalized patients are either not correctly identified as being at risk (and thus do not receive appropriate thromboprophylaxis) or receive a prophylaxis regimen that is not supported with current recommendations (eg, aspirin alone or mechanical devices alone when a pharmacologic agent is more appropriate and there is no appreciable bleeding risk).36,37 All providers, including nurses, pharmacists, and physicians, should be engaged in recognizing at-risk patients and ensuring that appropriate prophylaxis is ordered and administered in a timely fashion.

ELASTIC COMPRESSION STOCKINGS

What Are They and How do They Work?

One method of preventing the development of PTS is the use of elastic compression stockings (ECS). ECS provide graduated levels of compression (highest pressure at the ankle, lowest pressure at the knee or thigh) to assist the calf muscle and improve tissue circulation, although the exact mechanism is not well understood.38,39 In general, the lower strength stockings are used for prevention or treatment of minor venous conditions, and the higher strength are used for more severe venous conditions (Table 2).

Table 2
Types and Uses of Elastic Compression Stockingsa

What is the Evidence?

The benefit of using ECS for the prevention of PTS was first seen in a small number of observational trials.34,40,41 Four randomized, controlled trials have been published with conflicting results regarding the efficacy of ECS in the prevention of PTS (Table 3).22,31,42,43 Both the Brandjes et al.43 and Prandoni et al.22 trials demonstrated benefit of ECS for PTS prevention, while the Ginsberg et al.31 and Aschwanden et al.42 trials did not. Each of these trials has limitations. The 2 positive studies were nonblinded, contrasted with the Gins-berg trial, which utilized a placebo stocking (stocking 1–2 sizes too large, thus producing no hemodynamic effect) for comparison. Some state that the use of a placebo stocking may have actually been a confounder, since it is possible the placebo stocking could have provided some unknown degree of compression.44 Finally, the Aschwanden trial was actually underpowered for its primary outcome of detecting post-thrombotic skin changes.

Table 3
Randomized Controlled Trials Assessing the Efficacy of Elastic Compression Stockings for the Prevention of Postthrombotic Syndrome

A meta-analysis of the Brandjes, Ginsberg, and Prandoni trials by Kolbach et al.44 reported that the use of ECS significantly reduced the incidence of all PTS (OR 0.31; 95% CI 0.20 to 0.48) and of severe PTS (OR 0.39; 95% CI 0.20 to 0.76). A meta-analysis by Giannoukas et al.45 also found that the use of ECS reduced the risk of PTS (RR 0.52; 95% CI 0.40 to 0.67). The Giannoukas meta-analysis included the above 3 trials plus an additional 37-patient trial that randomized patients to either bed rest and no compression or early ambulation (plus either Unna boot bandages or 30- to 40-mm Hg strength compression stockings) for 9 days.46

Limitations of both meta-analyses were the lack of a uniform definition of PTS, varying compression regimens (specifically with regard to strength, timing, and duration), varying assessments of adherence, and varying duration of anticoagulation. Further, the trial46 included in the second meta-analysis assessed early ambulation combined with compression therapy as a preventive strategy, so we are unable to assess the source of treatment benefit.

A large, randomized, multicenter controlled trial in progress may clarify these issues.47 The SOX trial investigators are randomizing patients to a 30- to 40-mm Hg strength stocking or a 5-mm Hg placebo stocking, which is similar to a store-bought trouser sock (Table 3). Results from the SOX trial are not expected for several more years.

What Strength ECS to Prescribe?

The compression strength of stockings used in these randomized trials ranged from 20 to 40 mm Hg.22,31,42,43 The clinical trials using 30- to 40-mm Hg strength stockings demonstrated the most efficacy in reducing the risk of PTS and is reflected in current recommendations for PTS prevention48 (Appendix I). However, currently, there are no data directly comparing the efficacy of different strengths of ECS for PTS prevention and further studies are needed to determine the minimum effective strength.

Appendix I
Summary of Recommendations: Elastic Compression Stockings for the Prevention of the Postthrombotic Syndrome

What is the Timing and Duration of ECS Therapy?

The optimal time of initiation and duration of ECS therapy after a diagnosis of DVT remain controversial. No published studies to date have specifically evaluated the timing of stocking application on the incidence of PTS. The randomized controlled trials cited above employed ECS at various time points (immediately upon DVT diagnosis up to 1 y after diagnosis).22,31,42,43 One randomized trial assessed the effects of early versus later application of ECS on vein recanalization following DVT.49 Patients were prescribed 25.5–32.5 mm Hg ECS within the first 14 days after the initiation of DVT treatment. Fifty-two patients completed 90 days of follow-up. In the early compression therapy group, 82% of occluded venous segments were completely recanalized at 90 days, as compared with 60% complete recanalization in the control group (OR 0.27; 95% CI 0.07 to 0.89). No patients in either group demonstrated PTS symptoms at 90 days (method of PTS diagnosis not defined). However, PTS was a secondary endpoint, with the number of patients too small and study duration too short to make a definitive assessment.

The early application of ECS may have opposing effects on adherence. Patients usually experience the most leg pain and swelling in the first few weeks following DVT diagnosis and may associate improvement in their symptoms with the use of ECS. The randomized trials that applied ECS early (within the first month following DVT diagnosis) had excellent adherence rates (76–93%).22,42,43 The one trial that employed a late application of ECS (at 1 y following DVT diagnosis) did not report adherence data.31 However, if patients have significant lower extremity swelling immediately following DVT diagnosis, they may require a different size stocking early in therapy as opposed to later in therapy, requiring additional purchases of stockings. Also, the early leg pain and swelling may actually prohibit many patients from using the stockings.

Regarding the duration of ECS, trial data demonstrate that the incidence of PTS is highest in the first 2 years following a diagnosis of proximal DVT and does not change appreciably after 2 years.22,42,43 These reports imply that compression therapy will likely be beneficial at least for this duration of time, although indefinite use may be reasonable in patients with ongoing signs or symptoms of PTS.

Consistent with current recommendations from the American College of Physicians, the American Academy of Family Physicians, and the American College of Chest Physicians (ACCP), providers should discuss PTS with and prescribe ECS for all patients within the first month following acute proximal DVT diagnosis, preferably within the first 2 weeks after diagnosis, and continuing for a minimum of 2 years48,50 (Appendix I).

What Are the Barriers to Patient Adherence to ECS?

Patient adherence is perceived to be a barrier to the routine use of ECS due to discomfort, difficulty with putting them on, and cost.51 Clinical trials, which used varying definitions for “regular” use of ECS, reported adherence rates between 54% and 93%.22,4043 Although one might expect to see a lower rate of adherence outside the setting of a clinical trial, of 78 patients surveyed in routine clinical settings, 87% reported daily use of ECS.51 Adherence rates are significantly lower in patients with distal DVT, as these patients generally have fewer or less severe symptoms.40,51

To improve patient adherence to ECS, providers may prescribe knee-length ECS, similar to what was used in most clinical trials. Compared with thigh-length ECS, the knee-length products are just as effective but may be much more comfortable for patients.52 Based on the mechanism and design of the stockings, it is thought that as long as the highest pressure is applied at the ankle, the stocking will provide the desired effect of reducing pain and edema, regardless of the location of the clot.38 As was the practice in most clinical trials, patients should be instructed to wear the stocking only on the affected leg during waking hours.22,31,38,39,43 Difficulty putting on the stockings is often a barrier to patient adherence.51 There are several things that patients can do to make this process easier (Appendix I).

Cost was also cited as a perceived barrier to adherence.51 ECS 30– 40 mm Hg can be purchased at most medical supply stores with a prescription; the average cost is approximately $40–50 per pair (results of an informal survey of local medical supply stores, May 18, 2009), which may not be reimbursed by some third-party insurers.

There are other important items to remember when prescribing ECS (Appendix I). Patients’ ankle and calf circumferences should be measured to obtain the appropriate size stocking. For optimal accuracy, these measurements should be taken in the earliest part of the day when leg swelling is minimal. The stockings should be replaced every 6 months so that proper elasticity and, hence, efficacy is maintained.22,31,43 Despite the demonstrated benefit of ECS for the prevention of PTS, patients with peripheral arterial insufficiency should not receive compression therapy.22,38,42,47

Does Exercise Prevent PTS?

Some have proposed that exercise and/or early ambulation (with or without compression therapy) following a diagnosis of DVT may help to reduce the risk of PTS. In one study, patients who received compression therapy plus early mobilization had significantly lower Villalta scores 2 years post-DVT compared with patients who were prescribed bed rest and no compression therapy.46 Another study demonstrated that patients may continue to wear ECS during exercise, but that stockings will not necessarily help to improve symptoms during or caused by exercise, nor will they increase exercise capacity.53

How Can PTS Prevention with ECS Be Improved?

As providers, we should ensure that ECS are prescribed for all patients with proximal DVT to optimize PTS prevention efforts. Despite recommendations from evidence-based guidelines, a survey conducted by Kahn et al.51 revealed that only one third of 34 Canadian physicians routinely prescribe ECS following DVT diagnosis, and only half prescribe the recommended strength stocking (30– 40 mm Hg). Recent data suggest that rates of ECS prescription may not be higher in specialty anticoagulation providers.54 Pharmacists can improve the rate of ECS prescribing by initiating protocols and policies for prescribing ECS, so that this becomes standard practice across institutions. The pharmacist who interacts regularly with patients who have DVT is in the position to identify patients at risk for PTS and to recommend appropriate preventive therapy. The pharmacist can also assist patients in obtaining ECS and educating them in their proper use. By taking this active role, pharmacists can improve patient adherence to use of ECS, prevent PTS, and make a major impact on decreasing this long-term complication of DVT.

DOES USING FIBRINOLYTICS FOR ILIOFEMORAL DVT PREVENT PTS?

Patients with acute iliofemoral DVT appear to be at higher risk of developing severe PTS.55 Although conventional treatment for iliofemoral DVT is a parenteral anticoagulant followed by warfarin, this therapy does not reliably lead to recanalization of affected vein segments.56 Studies investigating the use of systemic fibrinolytics in conjunction with un-fractionated heparin (UFH) reported that vein patency and valve function appeared to be better compared with the use of heparin alone.57,58 In addition, meta-analysis data from 5 studies encompassing 110 patients demonstrated that the incidence of PTS was lower in patients with DVT who were treated with streptokinase and UFH compared with those treated with UFH alone (42.5% vs 69.6%, OR 0.46, 95% CI 0.21 to 0.99).59 These data, of course, are limited by the small sample sizes, significant heterogeneity in the different study designs, the lack of a uniform definition of PTS, and incomplete study follow-up.60

In comparison, catheter-directed thrombolysis (CDT) is a method by which a fibrinolytic agent is delivered via catheter into a clot within a thrombosed vein. Several recent trials have studied the benefit of CDT in iliofemoral DVT. Although different in study design and outcome measures, these trials reported that in carefully selected patients, the use of CDT as an adjunct to standard treatment (ie, a heparinoid and warfarin) improved venous patency and was associated with fewer long-term symptoms of PTS.6164 For example, a retrospective survey in patients with iliofemoral DVT reported that patients treated with CDT in addition to standard anticoagulation (n = 68) had significantly fewer PTS symptoms (p = 0.006) than did those treated with anticoagulation alone (n = 30).62 Subsequently, the ACCP now recommends that CDT (or systemic thrombolysis if CDT is unavailable) be used in select patient populations (iliofemoral DVT, symptoms for <14 days, good functional status, life expectancy ≥1 y, low bleeding risk) for the purpose of reducing acute symptoms and postthrombotic morbidity.48

Treatment

MECHANICAL

Studies have employed various mechanical methods to treat PTS, including compression, elevation, and dressings (Table 4). Most authors have focused primarily on edema as a measurable outcome in response to PTS treatment.65 Physical compression methods include any type of circular pressure on the leg. Utilized techniques include adherent tape, Unna’s paste boot, ECS, and newer venous return assist devices, such as the Venowave. Although these treatments are frequently prescribed, their benefit has not been clearly established. A review of patients with Widmer stage I and II PTS found no benefit of ECS (30–40 mm Hg at the ankle) compared with placebo.66 In patients with severe PTS, intermittent pneumatic compression (IPC) did reduce symptom severity and increase blood oxygenation.6769 Clinical guidelines reflect this research, and the ACCP suggests compression therapy for mild leg edema and IPC for severe leg edema.48

Table 4
Treatment of Postthrombotic Syndrome

PHARMACOLOGIC

There are several pharmacologic treatments available for PTS-related edema and venous ulcers (Table 4). Although none of these has proven safety and efficacy in large clinical trials, they may provide symptomatic relief. Patients using pentoxifylline demonstrated significantly improved venous ulcer healing at 6 months.70 A meta-analysis of 11 randomized trials evaluated and supported pentoxifylline’s effectiveness (RR 1.56; 95% CI 1.14 to 2.13),71 although not all trials reached statistical significance.72 A pentoxifylline regimen of 400 mg 3 times daily was largely uniform across the studies included in the meta-analysis.71 One study compared pentoxifylline 400 mg 3 times daily with 800 mg 3 times daily and found no significant difference in ulcer healing rates. Duration of therapy was not specifically studied and varied from as little as 6 weeks (or healing of the ulcer) to 6 months. According to the meta-analysis, pentoxifylline is well tolerated, with gastrointestinal upset as the most common adverse effect. Aescin (or escin), the main active component of horse chestnut, has antiinflammatory, vasoconstrictive, and vaso-protective properties73; it is primarily effective in the treatment of venous ulcers. In a 12-week study of patients with chronic venous insufficiency, treatment with aescin 50 mg twice daily reduced PTS symptoms similarly compared with ECS.74 Rutosides (rutin), naturally occurring, yellow crystalline flavonol glycosides, affect capillary permeability and have been studied more in chronic venous insufficiency than in PTS specifically.75 When applied either topically or systemically, rutosides do appear to improve leg edema and blood flow in these patients.48,7678 For pharmacologic treatment of PTS, the ACCP recommends pentoxifylline 400 mg 3 times daily in conjunction with localized care and compression or IPC devices for venous leg ulcers. For persistent venous ulcers, the ACCP recommends treatment with rutosides.48 There are currently no formal recommendations for using aescin as a treatment for PTS-related complications.

Pharmacists can help in the treatment of PTS by making recommendations for appropriate pharmacotherapy and monitoring for drug interactions with any new therapy, as many of these patients may still be taking warfarin for treatment of their DVT.

Upper Extremity PTS

The development of PTS after upper extremity DVT is less well studied than after lower extremity DVT, but the incidence appears to be approximately 15% overall, with a range reported in studies between 7% and 46%.79 No published trials have evaluated the efficacy of compression devices and/or venoactive drugs in upper extremity PTS. We echo the recommendations of the 2008 ACCP guidelines against the use of preventive therapy for PTS in patients with upper extremity DVT. In patients with upper extremity PTS symptoms that do not resolve, elastic bandages or compression sleeves may provide some symptom relief.48 Additionally, referring these patients to a lymphedema clinic may be helpful.

Areas of Future Study

There are several areas where additional investigations and studies will help us to better understand how to prevent and treat PTS. First, the clinical scoring systems for diagnosis of PTS have not been validated (Table 1). A validated diagnostic tool will improve the quality and uniformity of clinical trials and allow us to better define and assess the impact of PTS on patients with DVT. Second, there are still unanswered questions regarding the optimal prevention of PTS. Although several trials have demonstrated the efficacy of ECS for PTS prevention, the minimum compression strength necessary and the optimal timing and duration of compression therapy remain unknown. We need data on whether ECS are effective or even necessary for prevention of PTS following either asymptomatic or distal DVT. In addition, the role of fibrinolytic therapy in reducing PTS is still unclear. Finally, additional treatment options for PTS with demonstrated safety and efficacy are needed, particularly in the area of pharmacotherapy.

Summary

PTS is a common and costly complication of DVT and significantly affects a patient’s QoL. Acute DVT and the accompanying inflammation cause valvular incompetence and venous hypertension, which result in the pain, swelling, and venous ulceration that are associated with PTS. Preventive efforts should be multifaceted, and we must not forget the importance of evidence-based DVT prophylaxis in patients identified as being at risk. Once DVT has occurred, we should ensure optimal anticoagulation control, monitor for signs and symptoms of PTS, and provide appropriate preventive therapy. ECS, when applied within the first few weeks following DVT and continued regularly for at least 2 years, are effective in preventing PTS. Fibrinolytic therapy for acute iliofemoral DVT may be appropriate for carefully selected patients. Finally, if patients develop PTS, the diagnosis should be made based on clinical signs and symptoms; imaging is usually unnecessary. Treatment of PTS includes pharmacologic agents, such as aescin or horse chestnut, rutosides, and pentoxifylline, and compression therapy and wound care for venous ulcers. Pharmacists have the opportunity to provide more comprehensive antithrombotic management by providing education to all patients with DVT regarding PTS, recommending and/or prescribing appropriate preventive therapy, assisting patients in obtaining and adhering to this therapy, and assisting providers with the diagnosis and management of PTS.

Footnotes

Financial disclosure: None reported

Contributor Information

Sara R Vazquez, University of Utah Thrombosis Service, Department of Pharmacy Services, University of Utah, Salt Lake City, UT.

Andrew Freeman, Internal Medicine, Department of Internal Medicine, School of Medicine, University of Utah.

Ryan C VanWoerkom, School of Medicine, University of Utah.

Matthew T Rondina, Internal Medicine, Co-Director, Anticoagulation Services, University Thrombosis Service, Department of Internal Medicine, School of Medicine, University of Utah.

References

1. Ashrani AA, Heit JA. Incidence and cost burden of post-thrombotic syndrome. J Thromb Thrombolysis. 2009 doi: 10.1007/s11239-009-0309-3. Epub 18 Feb 2009. [PubMed] [Cross Ref]
2. Kahn SR, Hirsch A, Shrier I. Effect of postthrombotic syndrome on health-related quality of life after deep venous thrombosis. Arch Intern Med. 2002;162:1144–8. [PubMed]
3. Heit JA, Cohen AT, Anderson FA., Jr on behalf of the VTEIAG. Estimated annual number of incident and recurrent, non-fatal and fatal venous thromboembolism (VTE) events in the US (abstract) ASH Annual Meeting Abstracts. 2005;106:910.
4. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ., 3rd Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158:585–93. [PubMed]
5. Kahn SR, Ginsberg JS. Relationship between deep venous thrombosis and the postthrombotic syndrome. Arch Intern Med. 2004;164:17–26. doi: 10.1001/archinte.164.1.17. [PubMed] [Cross Ref]
6. Prandoni P, Lensing AWA, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125:1–7. [PubMed]
7. Schulman S, Lindmarker P, Holmstrom M, et al. Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. J Thromb Haemost. 2006;4:734–42. doi: 10.1111/j.1538-7836.2006.01795.x. [PubMed] [Cross Ref]
8. Shbaklo H, Kahn SR. Long-term prognosis after deep venous thrombosis. Curr Opin Hematol. 2008;15:494–8. doi: 10.1097/MOH.0b013e32830abde2. [PubMed] [Cross Ref]
9. Kahn SR, Shrier I, Julian JA, et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med. 2008;149:698–707. [PubMed]
10. Tick LW, Kramer MH, Rosendaal FR, Faber WR, Doggen CJ. Risk factors for post-thrombotic syndrome in patients with a first deep venous thrombosis. J Thromb Haemost. 2008;6:2075–81. doi: 10.1111/j.1538-7836.2008.03180.x. [PubMed] [Cross Ref]
11. Ginsberg JS, Turkstra F, Buller HR, MacKinnon B, Magier D, Hirsh J. Postthrombotic syndrome after hip or knee arthroplasty: a cross-sectional study. Arch Intern Med. 2000;160:669–72. [PubMed]
12. Persson LM, Lapidus LJ, Lärfars G, Rosfors S. Asymptomatic deep venous thrombosis is associated with a low risk of post-thrombotic syndrome. Eur J Vasc Endovasc Surg. doi: 10.1016/j.ejvs.2008.03.021. Epub 29 May 2009. [PubMed] [Cross Ref]
13. Kahn SR, Shbaklo H, Lamping DL, et al. Determinants of health-related quality of life during the 2 years following deep vein thrombosis. J Thromb Haemost. 2008;6:1105–12. doi: 10.1111/j.1538-7836.2008.03002.x. [PubMed] [Cross Ref]
14. Kahn SR, Kearon C, Julian JA, et al. Predictors of the post-thrombotic syndrome during long-term treatment of proximal deep vein thrombosis. J Thromb Haemost. 2005;3:718–23. doi: 10.1111/j.1538-7836.2005.01216.x. [PubMed] [Cross Ref]
15. Kahn SR, M’Lan CE, Lamping DL, Kurz X, Berard A, Abenhaim L. The influence of venous thromboembolism on quality of life and severity of chronic venous disease. J Thromb Haemost. 2004;2:2146–51. doi: 10.1111/j.1538-7836.2004.00957.x. [PubMed] [Cross Ref]
16. Caprini JA, Botteman MF, Stephens JM, et al. Economic burden of long-term complications of deep vein thrombosis after total hip replacement surgery in the United States. Value Health. 2003;6:59–74. [PubMed]
17. Heit JA, Rooke TW, Silverstein MD, et al. Trends in the incidence of venous stasis syndrome and venous ulcer: a 25-year population-based study. J Vasc Surg. 2001;33:1022–7. doi: 10.1067/mva.2001.113308. [PubMed] [Cross Ref]
18. Bergqvist D, Jendteg S, Johansen L, Persson U, Odegaard K. Cost of long-term complications of deep venous thrombosis of the lower extremities: an analysis of a defined patient population in Sweden. Ann Intern Med. 1997;126:454–7. [PubMed]
19. Roumen-Klappe EM, Janssen MC, Van Rossum J, et al. Inflammation in deep vein thrombosis and the development of post-thrombotic syndrome: a prospective study. J Thromb Haemost. 2009;7:582–7. doi: 10.1111/j.1538-7836.2009.03286.x. [PubMed] [Cross Ref]
20. Qvarfordt P, Eklof B, Ohlin P, Plate G, Saltin B. Intramuscular pressure, blood flow, and skeletal muscle metabolism in patients with venous claudication. Surgery. 1984;95:191–5. [PubMed]
21. Bauer D, Grebe R, Ehrlacher A. A new method to model change in cutaneous blood flow due to mechanical skin irritation part I: comparison between experimental and numerical data. J Theor Biol. 2006;238:575–87. doi: 10.1016/j.jtbi.2005.06.023. [PubMed] [Cross Ref]
22. Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med. 2004;141:249–56. [PubMed]
23. Prandoni P, Frulla M, Sartor D, Concolato A, Girolami A. Vein abnormalities and the post-thrombotic syndrome. J Thromb Haemost. 2005;3:401–2. doi: 10.1111/j.1538-7836.2004.01106.x. [PubMed] [Cross Ref]
24. Ageno W, Piantanida E, Dentali F, et al. Body mass index is associated with the development of the post-thrombotic syndrome. Thromb Haemost. 2003;89:305–9. doi: 10.1267/THRO03020305. [PubMed] [Cross Ref]
25. Kahn SR. Frequency and determinants of the postthrombotic syndrome after venous thromboembolism. Curr Opin Pulm Med. 2006;12:299–303. doi: 10.1097/01.mcp.0000239543.40078.17. [PubMed] [Cross Ref]
26. van Dongen CJ, Prandoni P, Frulla M, Marchiori A, Prins MH, Hutten BA. Relation between quality of anticoagulant treatment and the development of the postthrombotic syndrome. J Thromb Haemost. 2005;3:939–42. doi: 10.1111/j.1538-7836.2005.01333.x. [PubMed] [Cross Ref]
27. Stain M, Schonauer V, Minar E, et al. The post-thrombotic syndrome: risk factors and impact on the course of thrombotic disease. J Thromb Haemost. 2005;3:2671–6. doi: 10.1111/j.1538-7836.2005.01648.x. [PubMed] [Cross Ref]
28. Kahn SR. The post-thrombotic syndrome: progress and pitfalls. Br J Haematol. 2006;134:357–65. doi: 10.1111/j.1365-2141.2006.06200.x. [PubMed] [Cross Ref]
29. Widmer LK, Zemp E, Widmer TM, et al. Late results in deep vein thrombosis of the lower extremity. Vasa. 1985;14:264–8. [PubMed]
30. Villalta S, Bagetella P, Piccioli A, Lensing A, Prins M, Pradoni P. Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome (abstract) Haemostasis. 1994;24:158a.
31. Ginsberg JS, Hirsh J, Julian J, et al. Prevention and treatment of post-phlebitic syndrome: results of a 3-part study. Arch Intern Med. 2001;161:2105–9. [PubMed]
32. Porter JM, Moneta GL. Reporting standards in venous disease: an update. International Consensus Committee on Chronic Venous Disease. J Vasc Surg. 1995;21:635–45. [PubMed]
33. Kahn SR, Desmarais S, Ducruet T, Arsenault L, Ginsberg JS. Comparison of the Villalta and Ginsberg clinical scales to diagnose the post-thrombotic syndrome: correlation with patient-reported disease burden and venous valvular reflux. J Thromb Haemost. 2006;4:907–8. doi: 10.1111/j.1538-7836.2006.01824.x. [PubMed] [Cross Ref]
34. Milne AA, Ruckley CV. The clinical course of patients following extensive deep venous thrombosis. Eur J Vasc Surg. 1994;8:56–9. [PubMed]
35. Kahn SR, Partsch H, Vedantham S, Prandoni P, Kearon C. Definition of post-thrombotic syndrome of the leg for use in clinical investigations: a recommendation for standardization. J Thromb Haemost. 2009;7:879–83. doi: 10.1111/j.1538-7836.2009.03294.x. [PubMed] [Cross Ref]
36. Geerts WH, Bergqvist D, Pineo GF, et al. Chest. 8. Vol. 133. 2008. Prevention of venous throm-boembolism: American College of Chest Physicians evidence-based clinical practice guidelines; pp. 381S–453S. [PubMed] [Cross Ref]
37. Yu H, Dylan ML, Lin J, Dubois RW. Hospitals’ compliance with prophylaxis guidelines for venous thromboembolism. Am J Health Syst Pharm. 2007;64:69–76. doi: 10.2146/ajhp060115. [PubMed] [Cross Ref]
38. Jones NA, Webb PJ, Rees RI, Kakkar VV. A physiological study of elastic compression stockings in venous disorders of the leg. Br J Surg. 1980;67:569–72. [PubMed]
39. Pierson S, Pierson D, Swallow R, Johnson G., Jr Efficacy of graded elastic compression in the lower leg. JAMA. 1983;249:242–3. [PubMed]
40. Franzeck UK, Schalch I, Jager KA, Schneider E, Grimm J, Bollinger A. Prospective 12-year follow-up study of clinical and hemodynamic sequelae after deep vein thrombosis in low-risk patients (Zurich study) Circulation. 1996;93:74–9. [PubMed]
41. Ziegler S, Schillinger M, Maca TH, Minar E. Post-thrombotic syndrome after primary event of deep venous thrombosis 10 to 20 years ago. Thromb Res. 2001;101:23–33. [PubMed]
42. Aschwanden M, Jeanneret C, Koller MT, Thalhammer C, Bucher HC, Jaeger KA. Effect of prolonged treatment with compression stockings to prevent post-thrombotic sequelae: a randomized controlled trial. J Vasc Surg. 2008;47:1015–21. doi: 10.1016/j.jvs.2008.01.008. [PubMed] [Cross Ref]
43. Brandjes DP, Buller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet. 1997;349:759–62. doi: 10.1016/S0140-6736(96)12215-7. [PubMed] [Cross Ref]
44. Kolbach DN, Sandbrink MW, Hamulyak K, Neumann HA, Prins MH. Non-pharmaceutical measures for prevention of post-thrombotic syndrome. Cochrane Database Syst Rev. 2004:CD004174. doi: 10.1002/14651858.CD004174.pub2. [PubMed] [Cross Ref]
45. Giannoukas AD, Labropoulos N, Michaels JA. Compression with or without early ambulation in the prevention of post-thrombotic syndrome: a systematic review. Eur J Vasc Endovasc Surg. 2006;32:217–21. doi: 10.1016/j.ejvs.2005.11.036. [PubMed] [Cross Ref]
46. Partsch H, Kaulich M, Mayer W. Immediate mobilisation in acute vein thrombosis reduces post-thrombotic syndrome. Int Angiol. 2004;23:206–12. [PubMed]
47. Kahn SR, Shbaklo H, Shapiro S, et al. Effectiveness of compression stockings to prevent the post-thrombotic syndrome (the SOX Trial and Bio-SOX biomarker substudy): a randomized controlled trial. BMC Cardiovasc Disord. 2007;7:21. doi: 10.1186/1471-2261-7-21. [PMC free article] [PubMed] [Cross Ref]
48. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Chest. 8. Vol. 133. 2008. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines; pp. 454S–545S. [PubMed] [Cross Ref]
49. Arpaia G, Cimminiello C, Mastrogiacomo O, de Gaudenzi E. Efficacy of elastic compression stockings used early or after resolution of the edema on recanalization after deep venous thrombosis: the COM.PRE Trial. Blood Coagul Fibrinolysis. 2007;18:131–7. doi: 10.1097/MBC.0b013e328011f2dd. [PubMed] [Cross Ref]
50. Snow V, Qaseem A, Barry P, et al. Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2007;146:204–10. [PubMed]
51. Kahn SR, Elman E, Rodger MA, Wells PS. Use of elastic compression stockings after deep venous thrombosis: a comparison of practices and perceptions of thrombosis physicians and patients. J Thromb Haemost. 2003;1:500–6. [PubMed]
52. Benko T, Cooke EA, McNally MA, Mollan RA. Graduated compression stockings: knee length or thigh length. Clin Orthop Relat Res. 2001;383:197–203. [PubMed]
53. Kahn SR, Azoulay L, Hirsch A, Haber M, Strulovitch C, Shrier I. Effect of graduated elastic compression stockings on leg symptoms and signs during exercise in patients with deep venous thrombosis: a randomized cross-over trial. J Thromb Haemost. 2003;1:494–9. [PubMed]
54. Wittkowsky AK, Nutescu EA, Devine EB. Compression stockings to prevent post-thrombotic syndrome: a role for anticoagulation clinics? J Thromb Thrombolysis. 2008;26:248–50. doi: 10.1007/s11239-007-0176-8. [PubMed] [Cross Ref]
55. Strandness DE, Jr, Langlois Y, Cramer M, Randlett A, Thiele BL. Long-term sequelae of acute venous thrombosis. JAMA. 1983;250:1289–92. [PubMed]
56. Markel A, Manzo RA, Bergelin RO, Strandness DE., Jr Valvular reflux after deep vein thrombosis: incidence and time of occurrence. J Vasc Surg. 1992;15:377–82. [PubMed]
57. Eklof B, Kistner RL. Is there a role for thrombectomy in iliofemoral venous thrombosis? Semin Vasc Surg. 1996;9:34–45. [PubMed]
58. Elliot MS, Immelman EJ, Jeffery P, et al. A comparative randomized trial of heparin versus streptokinase in the treatment of acute proximal venous thrombosis: an interim report of a prospective trial. Br J Surg. 1979;66:838–43. [PubMed]
59. Ng CM, Rivera JO. Meta-analysis of streptokinase and heparin in deep vein thrombosis. Am J Health Syst Pharm. 1998;55:1995–2001. [PubMed]
60. Wells PS, Forster AJ. Thrombolysis in deep vein thrombosis: is there still an indication? Thromb Haemost. 2001;86:499–508. [PubMed]
61. AbuRahma AF, Perkins SE, Wulu JT, Ng HK. Iliofemoral deep vein thrombosis: conventional therapy versus lysis and percutaneous transluminal angioplasty and stenting. Ann Surg. 2001;233:752–60. [PubMed]
62. Comerota AJ, Throm RC, Mathias SD, Haughton S, Mewissen M. Catheter-directed thrombolysis for iliofemoral deep venous thrombosis improves health-related quality of life. J Vasc Surg. 2000;32:130–7. doi: 10.1067/mva.2000.105664. [PubMed] [Cross Ref]
63. Elsharawy M, Elzayat E. Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial. Eur J Vasc Endovasc Surg. 2002;24:209–14. [PubMed]
64. Gogalniceanu P, Johnston CJC, Khalid U, et al. Indications for thrombolysis in deep venous thrombosis. Eur J Vasc Endovasc Surg. 2009;38:192–8. doi: 10.1016/j.ejvs.2009.03.023. [PubMed] [Cross Ref]
65. Kurz X, Kahn SR, Abenhaim L, et al. Chronic venous disorders of the leg: epidemiology, outcomes, diagnosis and management. Summary of an evidence-based report of the VEINES task force. Venous Insufficiency Epidemiologic and Economic Studies. Int Angiol. 1999;18:83–102. [PubMed]
66. Kolbach DN, Sandbrink MW, Neumann HA, Prins MH. Compression therapy for treating stage I and II (Widmer) post-thrombotic syndrome. Cochrane Database Syst Rev. 2003:CD004177. doi: 10.1002/14651858.CD004177. [PubMed] [Cross Ref]
67. Ginsberg JS, Magier D, Mackinnon B, Gent M, Hirsh J. Intermittent compression units for severe post-phlebitic syndrome: a randomized crossover study. CMAJ. 1999;160:1303–6. [PMC free article] [PubMed]
68. Kolari PJ, Pekanmaki K, Pohjola RT. Transcutaneous oxygen tension in patients with post-thrombotic leg ulcers: treatment with intermittent pneumatic compression. Cardiovasc Res. 1988;22:138–41. [PubMed]
69. Pekanmaki K, Kolari PJ, Kiistala U. Laser Doppler vasomotion among patients with post-thrombotic venous insufficiency: effect of intermittent pneumatic compression. Vasa. 1991;20:394–7. [PubMed]
70. Colgan MP, Dormandy JA, Jones PW, Schraibman IG, Shanik DG, Young RA. Oxpentifylline treatment of venous ulcers of the leg. BMJ. 1990;300:972–5. [PMC free article] [PubMed]
71. Jull A, Arroll B, Parag V, Waters J. Pentoxifylline for treating venous leg ulcers. Cochrane Database Syst Rev. 2007:CD001733. doi: 10.1002/14651858.CD001733.pub2. [PubMed] [Cross Ref]
72. Dale JJ, Ruckley CV, Harper DR, Gibson B, Nelson EA, Prescott RJ. Randomised, double blind placebo controlled trial of pentoxifylline in the treatment of venous leg ulcers. BMJ. 1999;319:875–8. [PMC free article] [PubMed]
73. Pittler MH, Ernst E. Horse-chestnut seed extract for chronic venous insufficiency. A criteria-based systematic review. Arch Dermatol. 1998;134:1356–60. [PubMed]
74. Diehm C, Trampisch HJ, Lange S, Schmidt C. Comparison of leg compression stocking and oral horse-chestnut seed extract therapy in patients with chronic venous insufficiency. Lancet. 1996;347:292–4. [PubMed]
75. de Jongste AB, Jonker JJ, Huisman MV, ten Cate JW, Azar AJ. A double blind three center clinical trial on the short-term efficacy of 0-(beta-hydroxyethyl)-rutosides in patients with post-thrombotic syndrome. Thromb Haemost. 1989;62:826–9. [PubMed]
76. Belcaro G, Rosaria Cesarone M, Ledda A, et al. O-(beta-hydroxyethyl)-rutosides systemic and local treatment in chronic venous disease and microangiopathy: an independent prospective comparative study. Angiology. 2008;59:7S–13S. doi: 10.1177/0003319707312021. [PubMed] [Cross Ref]
77. Cesarone MR, Belcaro G, Grossi MG. O-(beta-hydroxyethyl)-rutosides (Paroven; Venoruton): new studies, improved safety, and novel cardiovascular applications. Angiology. 2008;59:5S–6S. doi: 10.1177/0003319707313094. [PubMed] [Cross Ref]
78. Frick RW. Three treatments for chronic venous insufficiency: escin, hydroxyethylrutoside, and Daflon. Angiology. 2000;51:197–205. [PubMed]
79. Elman EE, Kahn SR. The post-thrombotic syndrome after upper extremity deep venous thrombosis in adults: a systematic review. Thromb Res. 2006;117:609–14. [PubMed]