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.     

Demonstration of the cause of acute renal failure in a case of IgD multiple myeloma

In adults diagnosed with deep vein thrombosis (DVT), challenges remain in the management of the acute event whilst remaining alert to long‐term morbidity. The addition of non‐vitamin K antagonist oral anticoagulants (NOACs) to the pharmacopoeia represents the first of a number of recent advancements in the management of DVT. Worldwide, uptake of these agents has been avid, although drug selection, reversal and chronic treatment effects continue to be controversial areas. Multi‐centre studies to evaluate the impact of NOACs on long‐term outcomes, including thrombosis recurrence and post‐thrombotic syndrome (PTS), are ongoing. Validation of tools capable of predicting PTS would enable patient selection for early aggressive intervention, such as local thrombolysis. Such interventional strategies are gaining momentum as initial approaches and would benefit from large randomized controlled trials.     

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.     

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.     

The post-thrombotic syndrome: current knowledge,controversies, and directions for future research

The post-thrombotic syndrome (PTS) is a long-term complication of deep venous thrombosis (DVT) that is characterized by chronic, persistent pain, swelling and other signs in the affected limb. PTS is common, burdensome and costly. It is likely to increase in prevalence, since despite widespread use of and improvements in the efficacy of thromboprophylaxis, the incidence of DVT has not decreased over time. About 20-50% of patients develop PTS within 1-2 years of symptomatic DVT, and severe PTS, which can include venous ulcers, occurs in 5-10% of cases. Although there is no gold standard for the diagnosis of PTS, the presence of typical clinical features in a patient with previous DVT provides strong supporting evidence. Objective evidence of venous valvular incompetence helps to confirm the diagnosis in symptomatic patients. Preventing ipsilateral recurrence of DVT, by ensuring an adequate duration and intensity of anticoagulation for the initial DVT and by prescribing situational thromboprophylaxis after discontinuation of oral anticoagulants, is likely to reduce the risk of developing PTS. There is no proven role for thrombolysis of the initial DVT to prevent PTS. Daily use of graduated compression stockings after DVT may reduce the risk of PTS, and may prevent worsening of established PTS. Pending the results of ongoing studies, stockings are recommended in patients with persistent symptoms or swelling after DVT. Future research should focus on standardizing criteria for PTS diagnosis, identification of DVT patients at high risk for PTS, and rigorously evaluating the effectiveness of stockings, thrombolysis, and venoactive drugs in preventing or treating PTS.     

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

The cornerstones of current management of deep vein thrombosis (DVT) are the routine use of anticoagulant therapy, graduated elastic compression stockings, and early ambulation. Thrombolytic therapy was previously reserved only for patients with life-, limb-, or organ-threatening complications. However, the postthrombotic syndrome has been increasingly recognized as a frequent and serious long-term complication of DVT. In parallel, endovascular thrombolytic methods have evolved considerably in recent years, prompting discussion and controversy as to whether they should be more liberally used. In some centers, pharmacomechanical catheter-directed thrombolysis is now routinely used in the treatment of acute iliofemoral DVT. Randomized trials are currently under way to determine when the use of pharmacomechanical catheter-directed thrombolysis is appropriate in patients presenting with acute proximal DVT.     

Deep venous thrombosis screening in patients with inherited bleeding disorders and central venous catheters

Summary. Children with inherited bleeding disorders often require central venous catheters (CVCs). Although CVCs are known to be complicated by deep venous thrombosis (DVT), little is known about the timeline of DVT development or risk of post‐thrombotic syndrome (PTS). The aim of this study was to determine the timeline and confirm the incidence of thrombosis in patients with bleeding disorders who have CVCs. In 2002, we instituted a screening programme to monitor for CVC‐related complications in children with haemophilia and von Willebrand disease. This is a retrospective review of this cohort. All children with CVC followed up between 1 January 2000 and 1 June 2009 were evaluated for DVT every 24 months with contrast venography and Doppler sonography. An institutional PTS severity scale was utilized at each visit. Thirty‐six patients had 37 CVCs placed. Thirty patients had imaging studies, with DVT observed in 14 (47%). Most cases of DVT were diagnosed at the first venogram (median CVC duration 26 months). There were no abnormal ultrasound results. Sixteen patients (44%) had clinical findings consistent with PTS, including 10 (71%) with an abnormal venogram. Dilated chest wall veins appeared to be more strongly associated with underlying DVT (positive predictive value of 0.8) than arm circumference discrepancy. Successful transition to use of peripheral veins occurred at a median of 11 months after abnormal venograms. CVC‐related DVT is common in children with inherited bleeding disorders and likely occurs earlier than previously thought. Clinical signs of PTS are also common, but long‐term sequelae and severity of PTS are not known.     

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.     

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.     

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.     

The post-thrombotic syndrome

One of every three patients with deep-vein thrombosis of the lower extremities will develop, within 5 years, post-thrombotic sequelae that vary from minor signs to severe manifestations such as chronic pain, intractable edema, and leg ulceration. The post-thrombotic syndrome (PTS) develops as a result of the combination of venous hypertension due to persistent outflow obstruction or valvular incompetence and abnormal microvasculature or lymphatic function. Among factors potentially related to the development of PTS, recurrent ipsilateral thrombosis plays a major role. Whether the extent and the location of the initial thrombosis are associated with the development of PTS is still controversial. The diagnosis of PTS can be accepted on clinical grounds for patients with a history of venous thrombosis. The combination of a standardized clinical evaluation with the results of compression ultrasonography and Doppler ultrasonography helps diagnose or exclude a previous proximal-vein thrombosis. Prevention of recurrent thrombosis and use of compression elastic stockings are the cornerstones of PTS prevention. The management of this condition is demanding and often frustrating. Although several surgical procedures have been tested, conservative treatment is largely preferable, as more than 50% of patients either remain stable or improve during long-term follow-up, if carefully supervised and instructed to wear proper elastic stockings. Clinical presentation helps predict the prognosis, being the outcome of patients who refer with initially severe manifestations more favorable than that of patients whose symptoms progressively deteriorate over time.     

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.     

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.     

Endovenous therapy for deep venous thrombosis: The TORPEDO trial

Objectives. We compared the efficacy and safety of percutaneous endovenous intervention (PEVI) plus anticoagulation with anticoagulation alone in the reduction of venous thromboembolism (VTE) and post‐thrombotic syndrome (PTS) in acute proximal deep venous thrombosis (DVT). Background. Recurrent VTE and PTS are common complications of DVT. There are no randomized trials investigating the efficacy of PEVI in the reduction of the above complications. Methods. Patients with symptomatic proximal DVT were randomized to receive PEVI plus anticoagulation or anticoagulation alone. Anticoagulation consisted of intravenous unfractionated heparin or subcutaneous low‐molecular weight heparin plus warfarin. PEVI consisted of one or more of a combination of thrombectomy, balloon venoplasty, stenting, or local low‐dose thrombolytic therapy. Results. At 6 months follow‐up, recurrent VTE developed in 2 of 88 patients of the PEVI plus anticoagulation group versus 12 of 81of the anticoagulation‐alone group (2.3% vs. 14.8%, P = 0.003). PTS developed in 3 of 88 patients of the PEVI plus anticoagulation Group and 22 of 81 of the anticoagulation‐alone group (3.4% vs. 27.2%, P < 0.001). Conclusions. In patients with symptomatic proximal DVT, PEVI plus anticoagulation may be superior to anticoagulation—alone in the reduction of VTE and PTS at 6 months. © 2010 Wiley‐Liss, Inc.     

Thrombolytic therapy for deep vein thrombosis

Opinion statement  The incorporation of endovascular interventions into mainstream clinical practice for patients with deep vein thrombosis (DVT) has been changing rapidly as a result of four major trends. First, there now is a much greater appreciation among practicing physicians of the major impact of the postthrombotic syndrome (PTS) on DVT patients’ late quality of life. Second, there have been rapid advances in the methods by which thrombus can be rapidly removed using endovascular techniques, resulting in greater efficiency and treatment safety. Third, these changes together have spurred a major change in recommended DVT treatment paradigms: there is now published expert consensus that adjunctive endovascular DVT thrombolysis should be strongly considered as a first-line treatment strategy for selected patients with extensive acute proximal DVT. Finally, DVT researchers from multiple subspecialties have finally come together in a major multidisciplinary clinical trial project to subject endovascular DVT thrombolysis to the rigorous scientific testing that is needed for clinicians to be confident in its efficacy, safety, and cost-effectiveness as a first-line DVT treatment strategy. Pending the results of this and other studies, medical physicians should routinely inform DVT patients about the long-term consequences of DVT; ensure that they understand the importance of anticoagulant therapy and elastic compression stockings in preventing PTS; provide a balanced discussion of the risks, benefits, and uncertainties associated with endovascular DVT thrombolysis to patients with extensive proximal DVT; and develop collaborative clinical and research relationships with physicians experienced with endovascular DVT therapy.     

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.     

Statins,inflammation and deep vein thrombosis: a systematic review

Venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism. The 2009 JUPITER trial showed a significant decrease in DVT in non-hyperlipidemic patients, with elevated C-reactive protein (CRP) levels, treated with rosuvastatin. The effects of statins on thrombosis are unclear, prompting this literature review. A literature search was performed (1950 to February 2011) with MEDLINE, EMBASE, and PUBMED databases including the following keywords: “statins”, “hydroxymethylglutaryl-CoA reductase inhibitors”, “VTE”, “PE”, “DVT”, and either “anti-coagulation” or “inflammation”. Editorials, reviews, case reports, meta-analysis and duplicates were excluded. Inflammatory biomarkers of DVT, include interleukin (IL)-6, CRP, IL-8, and monocyte chemotactic protein 1 (MCP-1). Statin therapy reduces IL-6 expression of CRP and MCP-1, usually elevated in VTE. Reduction of IL-6 induced MCP-1 has been linked to vein wall fibrosis, promoting post thrombotic syndrome (PTS) and recurrent DVT in patients. Also, our review suggests that the anti-thrombotic effects are likely exhibited through the anti-inflammatory properties of statins. This work supports that statin therapy has the ability to decrease the incidence and recurrence of VTE and the potential to decrease PTS. This is mainly due to the anti-inflammatory effects of statins and may explain why normolipidemic patients, with elevated CRP, appear to have the greatest reduction in VTE. Given their low risk of bleeding, statins have the potential to serve as a safe adjunctive pharmacological therapy to current treatments in select patients with VTE, however further investigations into this concept are needed and essential.     

Presenting D‐dimer and early symptom severity are independent predictors for post‐thrombotic syndrome following a first deep vein thrombosis

Post‐thrombotic syndrome (PTS) is the most common complication of deep vein thrombosis (DVT). Current preventative strategies are limited to the daily wear of graduated compression stockings (GCS). The aim of this study was to evaluate early predictors of PTS. One hundred and twenty‐two consecutive patients with a first DVT were prospectively recruited from diagnosis and followed for up to 6 months post‐end of anticoagulation. D‐dimer was measured in 107 participants at presentation and Villalta scale was evaluated in 70 participants at a median of 2 weeks following diagnosis. PTS developed in 51·6% of participants. GCS were obtained by 78·1% of participants, with 33·7% reporting daily wear at the end of follow‐up. Mean early Villalta scale was significantly higher in those with PTS (8·1 ± 3·7) compared to those without (2·6 ± 2·7, P < 0·001). Median D‐dimer was significantly higher in those with PTS [3260 ng/ml, interquartile range (IQR) 820–8000 ng/ml] compared to those without (1540 ng/ml, IQR 810–2520 ng/ml, P < 0·001). The adjusted odds ratio for every one point increase in early Villalta scale was 1·78 [95% confidence interval (CI), 1·19–2·64; P = 0·005] and for D‐dimer >1910 ng/ml it was 2·71 (95% CI, 1·05–7·03; P = 0·04). These markers could enable targeted counselling regarding GCS for those at high risk of PTS.