The post-thrombotic syndrome: progress and pitfalls

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.     

Relationship between deep venous thrombosis and the postthrombotic syndrome

The postthrombotic syndrome (PTS) is a frequent complication of deep venous thrombosis (DVT). Clinically, PTS is characterized by chronic, persistent pain, swelling, and other signs in the affected limb. Rarely, ulcers may develop. Because of its prevalence, severity, and chronicity, PTS is burdensome and costly. Preventing DVT with the use of effective thromboprophylaxis in high-risk patients and settings and minimizing the risk of ipsilateral DVT recurrence are likely to reduce the risk of development of PTS. Daily use of compression stockings after DVT might reduce the incidence and severity of PTS, but consistent and convincing data about their effectiveness are not available. Future research should focus on standardizing diagnostic criteria for PTS, identifying patients at high risk for PTS, and rigorously evaluating the role of thrombolysis in preventing PTS and of compression stockings in preventing and treating PTS. In addition, novel therapies should be sought and evaluated.     

The Post-thrombotic Syndrome: The Forgotten Morbidity of Deep Venous Thrombosis

The postthrombotic syndrome (PTS) is the most common complication of deep venous thrombosis (DVT) yet has received little attention from clinicians and researchers. Clinically, PTS is characterized by chronic pain, swelling, heaviness and other signs in the affected limb. In severe cases, venous ulcers may develop. PTS is burdensome and costly to patients and society because of its high prevalence, severity and chronicity. Preventing DVT with the use of effective thromboprophylaxis in high-risk patients and settings and minimizing the risk of ipsilateral DVT recurrence are likely to reduce the frequency of PTS. Compression stockings worn daily after DVT appear to reduce the incidence and severity of PTS but questions regarding their use and effectiveness remain. Future research should focus on identifying patients at high risk for PTS, assessing the role of thrombolysis in preventing PTS and evaluating the optimal use of compression stockings in preventing and treating PTS. In addition, new therapies to treat PTS should be sought and evaluated.     

Frequency and determinants of the postthrombotic syndrome after venous thromboembolism

PURPOSE OF REVIEW: Postthrombotic syndrome (PTS) is the most common complication of deep venous thrombosis (DVT). Identifying which patients are at high risk of developing PTS would help improve the management of patients with DVT and allow physicians to provide patients with individualized information on their expected prognosis. This review discusses the knowledge gained from key studies over the last decade on the incidence and determinants of PTS, with special emphasis on published studies from the last 2 years. RECENT FINDINGS: About a third to half of DVT patients will develop PTS, in most cases within 1-2 years of acute DVT. Important risk factors for PTS appear to be ipsilateral recurrence of DVT, poor quality of initial anticoagulation for the treatment of DVT and increased body mass index. SUMMARY: Preventing DVT recurrence by providing adequate intensity and duration of anticoagulation for the initial DVT and using effective thromboprophylaxis in high-risk settings is likely to reduce the frequency of PTS. Despite some advances in identifying risk factors for PTS, however, it is still not possible to reliably predict an individual patient's risk of developing PTS after an episode of DVT. Further studies of clinical determinants and biological markers of increased risk of PTS are needed to ultimately improve long-term prognosis after DVT.     

Guidance for the prevention and treatment of the post-thrombotic syndrome

The post-thrombotic syndrome (PTS) is a frequent, potentially disabling complication of deep vein thrombosis (DVT) that reduces quality of life and is costly. Clinical manifestations include symptoms and signs such as leg pain and heaviness, edema, redness, telangiectasia, new varicose veins, hyperpigmentation, skin thickening and in severe cases, leg ulcers. The best way to prevent PTS is to prevent DVT with pharmacologic or mechanical thromboprophylaxis used in high risk patients and settings. In patients whose DVT is treated with a vitamin K antagonist, subtherapeutic INRs should be avoided. We do not suggest routine use of elastic compression stockings (ECS) after DVT to prevent PTS, but in patients with acute DVT-related leg swelling that is bothersome, a trial of ECS is reasonable. We suggest that selecting patients for catheter-directed thrombolytic techniques be done on a case-by-case basis, with a focus on patients with extensive thrombosis, recent symptoms onset, and low bleeding risk, who are seen at experienced hospital centers. For patients with established PTS, we suggest prescribing 20–30 mm Hg knee-length ECS to be worn daily. If ineffective, a stronger pressure stocking can be tried. We suggest that intermittent compression devices or pneumatic compression sleeve units be tried in patients with moderate-to-severe PTS whose symptoms are inadequately controlled with ECS alone. We suggest that a supervised exercise training program for 6 months or more is reasonable for PTS patients who can tolerate it. We suggest that management of post-thrombotic ulcers should involve a multidisciplinary approach. We briefly discuss upper extremity PTS and PTS in children.     

Postthrombotic syndrome: incidence, prevention, and management

Mild to severe postthrombotic sequelae, including chronic pain, edema, and ulceration, arise in one third of patients short after deep vein thrombosis (DVT). Recurrent DVT is closely associated with the development of postthrombotic syndrome (PTS), whereas if the extent and location of DVT might be relevant remains unclear. Chronic venous hypertension and abnormal microvessel or lymphatic function also correlates with PTS. The diagnosis of PTS is based on clinical grounds only if patients report a history of documented DVT; otherwise, objective testing is required. To abate the prevalence of PTS, the best policy is represented by prevention of recurrent thrombosis and use of stockings. Despite a plenty of surgical options, conservative treatment is preferable because half of the patients improve or remain stable during follow-up, provided they wear elastic stockings. Clinical presentation has a prognostic value, as patients with initially severe symptoms enjoy a more favorable outcome than those who progressively deteriorate over time.     

The role of thrombolysis in the clinical management of deep vein thrombosis

Acute Deep Venous Thrombosis (DVT) therapies have been judged primarily on their ability to prevent symptomatic pulmonary embolism, early thrombus progression, and recurrent VTE. The cornerstones of current management of DVT, supported by the 2008 American College of Chest Physicians (ACCP) guidelines, are the routine use of anticoagulant therapy, graduated elastic compression stockings, and early ambulation. For selected appropriate patients with extensive acute proximal DVT, while the French recommendations (Afssaps 2009) still consider thrombolysis not indicated, ACCP guidelines now suggest in-situ thrombolysis in addition to anticoagulation to reduce the risk of subsequent postthrombotic syndrome (PTS) and recurrent DVT (Grade 2 B recommendation). Contemporary invasive endovascular treatments, called pharmacomechanical treatment, mitigate the drawbacks (major bleeding) historically associated with systemic thrombolytic approaches, by means of intra-thrombus delivery of drugs, followed by mechanical dispersion to accelerate lysis and then aspiration of remaining drug and clot debris. The proof of concept for the "open vein" hypothesis - that a strategy of early thrombus removal can reduce the incidence of PTS long term - comes incrementally and randomized trials (ATTRACT trial with a 2016 target completion date) are currently under way and might lead to a shift of the paradigms of the management of acute DVT focused on active thrombus removal.     

Post‐thrombotic syndrome: prevalence,prognostication and need for progress

Despite considerable progress in the diagnosis and treatment of deep‐vein thrombosis (DVT) of the lower extremities, one of every 2–3 patients will develop within 2 years post‐thrombotic sequelae, which are severe in approximately 10% of cases and produce considerable socio‐economic consequences. Among factors potentially related to the development of the post‐thrombotic syndrome (PTS) are older age, obesity, a history of previous ipsilateral DVT, iliac‐femoral location of the current thrombosis, failure to promptly recover from the acute symptoms and insufficient quality of oral anticoagulant therapy. Based on recent findings, the lack of vein recanalization within the first 6 months after DVT appears to be an important predictor of PTS, while the role of venous reflux is controversial. According to the results of recent clinical studies, the prompt administration of adequate compression elastic stockings in patients with symptomatic DVT has the potential to halve the frequency of PTS, and when carefully supervised and instructed to wear proper elastic stockings, more than 50% of patients have the potential to either remain stable or improve during long‐term follow‐up. Nevertheless, due to limitations in current therapies, the management of PTS is demanding and often frustrating. Further research is required to optimize the prevention and management of this common and burdensome complication of DVT.     

Incidence, risk factors and skin manifestations of post-thrombotic syndrome: a four-year follow-up of patients included in the EDITH study

Purpose

Despite appropriate therapy 10 to 100% of patients with deep vein thrombosis (DVT) of the lower limbs will develop post-thrombotic syndrome (PTS). The aim of this study was to evaluate the incidence of PTS in the EDITH cohort and to estimate the association between initial patients’ characteristics and the risk of development of PTS.

Methods

One hundred and eighty patients included in the EDITH study for a first event of DVT of the lower limbs without clinical signs of venous insufficiency were recalled 4 years after their initial thrombotic event. PTS was diagnosed according to the Villalta score.

Results

Ninety-five patients (45 men, mean age 50.7 ± 16.9 years) were evaluated for PTS. Among them, 28.4% (95% CI 19.3–37.5) developed PTS but none had severe PTS. The most frequent clinical signs of PTS were varicose veins (59%), corona phlebectatica (48%), swelling leg (30%) and pigmented dermatitis (26%). No single risk factor was associated with PTS development (age, sex, BMI thrombophilia, etiology, localization, recurrence, symptomatic DVT and familial history of DVT).

Conclusion

PTS is a frequent disease. However, lack of uniformity of diagnosis criteria in the different studies does not make possible the estimation of PTS risk factors.     

Postthrombotic syndrome

Despite considerable progress in the diagnosis and treatment of deep vein thrombosis (DVT) of the lower extremities, one of every three patients will develop postthrombotic sequelae within 2 years; these sequelae are severe in approximately 20% of cases and produce considerable socioeconomic consequences. Among factors potentially related to the development of the postthrombotic syndrome (PTS) are older age, obesity, insufficient oral anticoagulant therapy, and recurrent ipsilateral thrombosis. Whether the extent and location of the initial thrombosis are associated with the development of PTS is controversial. Based on recent findings, the lack of vein recanalization within the first 6 months appears to be an important predictor of PTS, whereas the development of transpopliteal venous reflux is not. The diagnosis of PTS can be made on clinical grounds for patients with a history of DVT. The combination of a standardized clinical evaluation with the results of compression ultrasonography and Doppler ultrasound helps diagnose or exclude a previous proximal vein thrombosis. According to the results of recent clinical studies, the prompt administration of adequate compression elastic stockings in patients with symptomatic DVT has the potential to reduce the frequency of late PTS development by half. The management of this condition is demanding and often frustrating. However, when carefully supervised and instructed to wear proper elastic stockings, more than 50% of patients will either remain stable or improve during long-term follow-up. Clinical presentation helps predict the prognosis; the outcome of patients who refer with initially severe manifestations is more favorable than that of patients whose symptoms deteriorate progressively over time.     

The postthrombotic syndrome

Following deep vein thrombosis (DVT), one of every two patients will develop postthrombotic syndrome (PTS), which causes remarkable consequences on the socioeconomic level. Residual thrombosis is an important predictor of PTS, and severe early symptoms, old age, obesity, improper anticoagulation, recurrent thrombosis and varicose veins are major risk factors. Diagnosis of PTS is mainly based on the clinical findings for patients with a history of DVT, while in those without it, instrumental diagnosis might help in detecting a previous DVT. Prompt administration of adequate compression elastic stockings (ECS) in patients with symptomatic DVT reduces the frequency of PTS by half. Usually, the management of an established PTS is demanding, and often discouraging. However, when carefully supervised and instructed to wear proper ECS, more than 50% of patients either remain quiescent or improve during long-term follow-up.     

Compression stockings to prevent post-thrombotic syndrome: a role for anticoagulation clinics?

Anticoagulation clinics are increasingly used to manage oral anticoagulant therapy in patients with venous thromboembolic disease (VTE). Such clinics may be in a position to assume greater responsibility for other aspects of the long-term management of VTE, including prevention of post-thrombotic syndrome (PTS). Current guidelines suggest use of graduated elastic compression stockings with a pressure of 30–40 mm Hg at the ankle for 2 years following the diagnosis of deep vein thrombosis (DVT) to prevent PTS. A survey of anticoagulation clinic providers was conducted to determine to what extent patients with DVT are prescribed compression stockings and by whom, and the degree of compression and duration of therapy prescribed. Survey results show a very low rate of use of compression stockings in patients with DVT, and limited adherence to current recommendations for strength and duration of use. We believe that healthcare providers practicing in anticoagulation clinics should be encouraged to expand their scope of practice into a more comprehensive model of antithrombosis care, including prevention of PTS. By doing so, the extent of use of compression stockings might be increased, and adherence to current guidelines for strength and duration of compression might be improved.     

Travel and thrombosis

The available evidence suggests an association between long distance travel and the development of venous thromboembolism. The main problem for travellers and physicians is the interpretation of the evidence and its translation into appropriate advice on the risk and the prevention of thrombosis. Most available data relate to air travel. Thrombosis risk is greater following journeys of more than 8 h and those at greatest risk are travellers with a history of venous thromboembolism or risk factors. Based on the best evidence available the risk of symptomatic venous thromboembolism after flights of more than 12 h is 0.5%. It is likely that stasis plays a major role in the aetiology of travel related thrombosis. The evidence for hypobaric hypoxia induced coagulation activation requires confirmation. There is evidence that compression stockings and low molecular weight heparin prevent asymptomatic deep vein thrombosis (DVT) but clinical DVT has been observed in long distance flyers in spite of prophylaxis with aspirin and stockings.     

The rationale and evidence for the treatment of lower-extremity deep venous thrombosis with thrombolytic agents

This article presents the rationale and evidence for the treatment of lower-extremity deep venous thrombosis (DVT) with thrombolytic agents. DVT is a common condition that has both acute and chronic complications. Standard treatment including anticoagulation therapy and compression stockings may not be entirely adequate, because a significant proportion of patients eventually develop severe post-thrombotic syndrome (PTS). Thrombolytic agents offer a potential advantage because they may reduce residual vein stenosis and valve damage. The authors performed a systematic review of published randomized trials evaluating thrombolytic agents for DVT. The authors determined that thrombolysis therapy results in greater lysis and complication rates than does anticoagulation alone. The authors also found that PTS incidence is lower in patients treated with thrombolytics. However, several methodological flaws limit the conclusions with respect to reduction in PTS. Therefore, the authors conclude that although the lysis rate is greater for thrombolytic agents, they cannot be recommended routinely for DVT treatment.     

Incidence and cost burden of post-thrombotic syndrome

Post-thrombotic syndrome (PTS) is a long-term complication of deep-vein thrombosis (DVT), manifesting as swelling, pain, edema, venous ectasia, and skin induration of the affected limb. PTS has been estimated to affect 23–60% of individuals with DVT, frequently occurring within 2 years of the DVT episode. Symptomatic DVT, post-operative asymptomatic DVT, and recurrent DVT are all risk factors for the development of PTS. Treatment of PTS is often ineffective and treatment-related costs represent a healthcare burden. Therefore, prevention of DVT is essential to reduce PTS, and thus improve outcomes and reduce overall healthcare costs. Although recommended by guidelines, appropriate DVT prophylaxis remains considerably underused. This review evaluates the incidence, risk factors, and economic impact of PTS. Increasing the awareness of PTS, and the methods to prevent this complication may help reduce its incidence, improve long-term outcomes in patients, and decrease resulting costs associated with treatment.     

A thrombolytic regimen for high-risk deep venous thrombosis may substantially reduce the risk of postthrombotic syndrome in children

Important predictors of adverse outcomes of thrombosis in children, including postthrombotic syndrome (PTS), have recently been identified. Given this knowledge and the encouraging preliminary pediatric experience with systemic thrombolysis, we sought to retrospectively analyze our institutional experience with a thrombolytic regimen versus standard anticoagulation for acute, occlusive deep venous thrombosis (DVT) of the proximal lower extremities in children in whom plasma factor VIII activity and/or D-dimer concentration were elevated at diagnosis, from within a longitudinal pediatric cohort. Nine children who underwent the thrombolytic regimen and 13 who received standard anticoagulation alone were followed from time of diagnosis with serial clinical evaluation and standardized PTS outcome assessments conducted in uniform fashion. The thrombolytic regimen was associated with a markedly decreased odds of PTS at 18 to 24 months compared with standard anticoagulation alone, which persisted after adjustment for significant covariates of age and lag time to therapy (odds ratio [OR] = 0.018, 95% confidence interval [CI] = < 0.001-0.483; P = .02). Major bleeding developed in 1 child, clinically judged as not directly related to thrombolysis for DVT. These findings suggest that the use of a thrombolysis regimen may safely and substantially reduce the risk of PTS in children with occlusive lower-extremity acute DVT, providing the basis for a future clinical trial.     

No effectiveness of anticoagulants for thromboprophylaxis after non-major knee arthroscopy: a systemic review and meta-analysis of randomized controlled trials

Arthroscopic knee surgery is the most commonly performed orthopedic procedure worldwide and whether thromboprophylaxis should be undertaken after knee arthroscopy is still controversial. To evaluate the efficacy of thromboprophylaxis for deep venous thrombosis (DVT) and venous thromboembolism (VTE) after knee arthroscopic surgery. A meta-analysis was conducted using data from eight randomized trials (4148 patients) to compare thromboprophylaxis with placebo or no prophylactic treatment in patients undergoing knee arthroscopy. The benefits and harms of thromboprophylaxis were evaluated, including the incidence of asymptomatic DVT, symptomatic VTE, pulmonary embolism and anti-coagulation related adverse events. Thromboprophylaxis significantly decreased the incidence of DVT (95% CI 0.07–0.64, P?=?0.006) and symptomatic VTE in patients undergoing knee arthroscopy (95% CI 0.23–0.76, P?=?0.004), but not significantly decreased the incidence of pulmonary embolism (n.s.). Regarding to non-major knee arthroscopy surgery (simple surgical procedures without ligament reconstruction), no significant difference of the incidence of DVT or symptomatic VTE was noted between thromboprophylactic group and control group (n.s.). Thromboprophylactic treatment showed higher incidence rate of anti-coagulation related adverse events compared with the control group (95% CI 1.12–1.90, P?=?0.005). There was no significant difference of the incidence of clinically relevant major bleeding between the two groups (n.s.). This meta-analysis indicates no effectiveness of thromboprophylaxis for preventing DVT or symptomatic VTE in patients undergoing non-major knee arthroscopy. Regarding to patient undergoing knee ligament construction, the thromboprophylactic strategy should mainly take into account the patient’s risk factors.     

Extended venous thromboembolism prophylaxis after colorectal cancer surgery: the current state of the evidence

There is level one evidence to support combined mechanical and chemical thromboprophylaxis for 7–10 days after colorectal cancer surgery, but there remains a paucity of data to support extended prophylaxis after discharge. The aim of this clinical review is to summarise the currently available evidence for extended venous thromboprophylaxis after elective colorectal cancer surgery. Clinical review of the major clinical guidelines and published clinical data evaluating extended venous thromboprophylaxis after elective colorectal cancer surgery. Five major guideline recommendations are outlined, and the results of the five published randomised controlled trials are summarised and reviewed with a specific focus on the efficacy and cost-effectiveness of extended heparin prophylaxis to prevent clinically relevant post-operative venous thromboembolism (VTE) after colorectal cancer surgery. Extended VTE prophylaxis after colorectal cancer surgery reduces the incidence of asymptomatic screen detected deep venous thrombosis (DVT) only, with no demonstrable reduction in symptomatic DVT, symptomatic PE, or VTE related death. Evidence for cost-effectiveness is limited. As the incidence of clinical VTE is very low in this patient subgroup overall, future research should be focused on higher risk patient subgroups in whom a reduction in VTE may be both more demonstrable and clinically relevant.     

Interventional approaches to deep vein thrombosis

The last decade has seen increased use of aggressive, catheter-based methods of treating deep vein thrombosis (DVT). In this article, we outline the risks, benefits, and uncertainties surrounding endovascular DVT therapies, describe clinical situations in which endovascular treatment options should reasonably be considered, and update the reader on new outcome data that pertains to catheter-based DVT interventions. Endovascular thrombolytic therapy is reasonable to perform for selected patients with DVT causing acute limb-threatening circulatory compromise, acute inferior vena cava occlusion, or acute iliofemoral DVT for the purposes of limb salvage and relief of presenting DVT symptoms, and appears likely to prevent post-thrombotic syndrome (PTS) in patients with proximal DVT. A multicenter randomized trial, the ATTRACT Study, is currently underway in the United States to determine whether pharmacomechanical catheter-directed thrombolysis (PCDT) is sufficiently safe and effective to be recommended for routine use in proximal DVT patients. Selected patients with established moderate-to-severe PTS in association with an occluded iliac vein or a refluxing saphenous vein may also be amenable to endovascular intervention to reduce venous hypertension, alleviate symptoms, and improve limb function and quality of life. Pending the results of further studies, an individualized approach to patient selection for interventional DVT therapies is recommended.     

Local and systemic thrombolytic therapy for acute deep venous thrombosis

This article presents a review of the treatment of lower-extremity deep venous thrombosis (DVT) with systemic and catheter-directed thrombolysis (CDT) and percutaneous mechanical thrombectomy (PMT). Standard treatment including anticoagulation therapy and compression stockings may not be entirely adequate, because a significant proportion of patients eventually develop post-thrombotic syndrome (PTS). Thrombolytic agents might offer a potential advantage because they cause faster and more complete clot resolution, which may reduce or prevent residual vein stenosis and valve damage. Thrombolytic therapy results in greater lysis, but also in higher complication rates than does anticoagulation alone. Major bleeding occurs in 11% of patients treated with thrombolytic therapy. The incidence of PTS tends to be lower in patients treated with thrombolytics. However, several methodological flaws limit the conclusions with respect to reduction in PTS. No adequate randomised controlled trials have been performed comparing CDT or PMT with conventional therapy. Given the current data, thrombolytic treatment, CDT or PMT should not be applied except in extraordinary cases. First, the long-term effectiveness in terms of reducing PTS, although possible, remains uncertain. Second, the risks of thrombolytic therapy and PMT are higher. Third, current conventional therapy is relatively inexpensive, convenient and safe.