Post-thrombotic (postphlebitic) syndrome

INTRODUCTION — Post-thrombotic syndrome refers to symptoms and signs of chronic venous insufficiency that develop following deep vein thrombosis (DVT) and is a common, burdensome, and costly complication [1,2]. The term "post-thrombotic" replaces the prior terminology "postphlebitic" syndrome [3]. A combination of reflux due to valvular incompetence and venous hypertension due to thrombotic obstruction is thought to underlie the pathophysiology of post-thrombotic syndrome [4,5]. Symptoms and signs of post-thrombotic syndrome may include leg pain, leg heaviness, vein dilation, edema, skin pigmentation, and venous ulcers. Our approach to the diagnosis, treatment, and prevention of post-thrombotic syndrome is in broad agreement with published guidelines from the American Heart Association [6]. Prevention of DVT through thromboprophylaxis, timely recognition and treatment of DVT, and prevention of recurrent DVT will continue to have the greatest impact on reducing the overall burden of post-thrombotic syndrome [7]. The treatment of lower extremity DVT is discussed separately. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)".)

PATHOPHYSIOLOGY — Post-thrombotic syndrome develops as a consequence of long-standing venous hypertension [7]. A combination of reflux due to valvular incompetence and venous hypertension due to thrombotic obstruction is thought to contribute to post-thrombotic syndrome [4,5]. One study identified a high peak reflux velocity in the deep proximal veins as an independent predictor of post-thrombotic syndrome [8]. Increased venous pressures are transmitted to the capillary beds, promoting transudation of fluid and large molecules, resulting in tissue edema, subcutaneous fibrosis, and, finally, tissue hypoxia and ulceration [9-11]. (See "Pathophysiology of chronic venous disease".)

Acute deep vein thrombosis (DVT) causes obstruction of venous outflow, which can be partial or complete. Vein wall remodeling as a consequence of venous thrombosis, as identified in ultrasound studies, appears to be directly related to the thrombus [12]. Increased levels of inflammatory cytokines or adhesion molecules, such as interleukin-6 and intercellular adhesion molecule-1, have also been linked with the development of post-thrombotic syndrome, suggesting that inflammation may play a role in the pathophysiology of post-thrombotic syndrome [13-15]. The inflammatory response to acute thrombosis and the process of recanalization directly damages venous valves.

Reflux occurs early, progressively increasing from 17 percent of patients at one week to 69 percent of patients at one year following the diagnosis of DVT [16]. The degree of initial vein occlusion correlates with the likelihood of developing reflux [16]. Reflux in the more proximal lower extremity veins may be particularly important to the development of post-thrombotic syndrome. However, popliteal valve incompetence has also been found to increase the risk of post-thrombotic syndrome, particularly when combined with residual vein thrombosis [17,18]. (See 'Risk factors' below.)

Recanalization is a complex process involving intrinsic events within the thrombus and is related to an increase in endogenous fibrinolysis [19,20]. An inverse relationship between levels of fibrinolytic inhibitors and the degree of recanalization has been described [19]. Over time, the amount of thrombus decreases, and in some cases, the lumen reestablishes itself (ie, recanalization). More rapid resolution of thrombus may preserve valvular function [21-23]. Recanalization can be seen as early as six weeks from diagnosis [24,25], but approximately one half of legs have residual thrombus causing partial obstruction [26]. The rate of recanalization appears to be related to the initial thrombus load [26] and thrombus site with distal thrombi undergoing more rapid and complete resolution [27].

EPIDEMIOLOGY — The reported incidence of post-thrombotic syndrome varies widely, in part due to inhomogeneous patient populations and diagnostic criteria. Older studies reported rates up to 100 percent; contemporary studies cite incidences ranging from 20 to 80 percent [7,28,29]. Among studies that use validated diagnostic criteria, the incidence is approximately 50 percent in the first year in spite of anticoagulation [18]. Severe post-thrombotic syndrome occurs in 5 to 10 percent of patients [29,30].

Most patients who develop post-thrombotic syndrome become symptomatic within two years from the acute episode [7,31]. However, the incidence of severe post-thrombotic syndrome progressively accumulates. In a study of 93 patients who were followed for six years, the incidence of the post-thrombotic syndrome was 49 percent after one year and 55 percent after two years, without further increase up to six years [18]. In a larger prospective study, the cumulative incidence of post-thrombotic syndrome at one, two, and five years was 17, 23, and 28 percent, respectively; these percentages did not increase thereafter [32]. The incidence of severe skin changes indicative of chronic venous insufficiency, including venous ulcer, increased from 2.6 percent at one year to 9.3 percent at five years.

Risk factors — Observational studies identify various factors that influence the risk of developing the post-thrombotic syndrome [33-38]. In general, factors that are thought to be important to the development of post-thrombotic syndrome can be broadly characterized as patient specific, related to the inciting deep vein thrombosis (DVT), or related to the treatment of DVT, and are discussed below [39]. Ongoing research seeks to identify biological markers that may predict the risk of post-thrombotic syndrome in individual patients.

A model to identify patients at highest risk of developing post-thrombotic syndrome has been developed and validated [40,41]. High-risk predictors were index DVT in the iliac vein, body mass index of ≥35 kg/m², and moderate-severe Villalta severity category at DVT diagnosis. Compared with patients with a score of 0, those with a score of ≥4 had an odds ratio of 5.9 for developing post-thrombotic syndrome.

Patient-specific — Patient-specific factors that may increase the risk for post-thrombotic syndrome include preexisting primary venous insufficiency, older age [42,43], obesity [33,34,44], and varicose veins [33,45]. There does not appear to be a consistent relationship between sex and the development of post-thrombotic syndrome [33-35,39,42,43,46].

Thrombophilia does not appear to increase the risk for developing post-thrombotic syndrome [30,32-34,42,47]. In one retrospective review of 677 patients, no significant differences in the incidence of post-thrombotic syndrome were seen between those patients with thrombophilia (antithrombin, protein C and S deficiencies, lupus anticoagulant, factor V Leiden) compared with those without thrombophilia [47]. However, this is controversial as there are data in favor of an association as well [30].

Related to DVT characteristics

●Primary versus recurrent DVT – The development of recurrent ipsilateral DVT is strongly associated with the risk for post-thrombotic syndrome [32,34,48,49]. The risk for post-thrombotic syndrome is increased up to sixfold, likely due to worsened venous outflow obstruction and damage to already compromised valves. Other poor prognostic factors include the combination of reflux and obstruction and multisegmental venous involvement [50]. This suggests that prevention of recurrent thrombosis is the most important intervention to prevent post-thrombotic syndrome in patients presenting with DVT.

●Symptomatic versus asymptomatic DVT – The incidence of post-thrombotic syndrome is probably lower after asymptomatic DVT, such as that detected on postoperative screening [51]. A systematic review concluded that asymptomatic postoperative DVT still substantially increases the risk of post-thrombotic syndrome; however, there was evidence of significant publication bias in the review [52].

●Proximal versus distal DVT – Several studies have found a greater absolute risk of trophic skin changes following venous thrombosis for proximal compared with distal thrombosis, and with deep or combined deep and superficial thrombosis compared with only superficial thrombosis [34,35,53-58]. However, other studies have not demonstrated a greater risk for proximal over distal thrombosis [32,59]. It is important to note that "proximal" DVT has included both iliofemoral and femoropopliteal thrombosis. In a study of 387 patients followed over three years, patients with more extensive proximal (femoral or iliac vein) DVT had significantly worse post-thrombotic syndrome scores at all visits (adjusted average increase of >2 points on the Villalta scale) than those with distal or popliteal DVT [34]. Similarly, proximal DVT increased the risk for post-thrombotic syndrome twofold compared with distal DVT [35]. Symptoms of post-thrombotic syndrome after distal DVT appear to be milder [60].

●Residual thrombus – Residual thrombus within the first six months after the thrombotic episode appears to be an important risk factor for post-thrombotic syndrome. In a study of 180 patients who were followed for at least three years after an episode of acute proximal DVT, post-thrombotic syndrome developed in 24 percent without vein abnormalities, but in 47 percent with at least one abnormality [17]. The incidence of post-thrombotic syndrome was 48 percent in patients with residual vein thrombosis, 27 percent in patients with popliteal vein valve incompetence, and 54 percent in patients with both. In a substudy of the IDEAL DVT trial, post-thrombotic syndrome was significantly less prevalent in patients without residual vein obstruction (46 versus 54 percent) [61].

Related to DVT treatment — Minimizing the development of post-thrombotic syndrome is related to timely and adequate pharmacologic treatment of DVT. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)".)

●Antithrombotic treatment – The risk of post-thrombotic syndrome is greater in patients who do not maintain adequate anticoagulation during initial treatment for their DVT [36,42,62]. The risk may also vary depending upon the type of anticoagulant used [63-66]. Antithrombotic therapy for the treatment of DVT is discussed elsewhere. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)".)

•In one study comparing patients whose international normalized ratio (INR) was subtherapeutic (<2.0) with those whose INR was ≥2.0 for more than 50 percent of readings in the first three months of treatment, the risk of the post-thrombotic syndrome was significantly increased over five-year follow-up (odds ratio 2.71, 95% CI 1.44-5.10) [42]. In a later study, the overall frequency of post-thrombotic syndrome in patients with subtherapeutic anticoagulation was 33.5 percent, compared with 21.6 percent in those with an INR below 2.0 for ≤20 percent of the time [62].

•Due to their rapid onset, ease of administration, and more predictable pharmacokinetics, direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban, and edoxaban, could be associated with more effective anticoagulation and a reduced incidence of post-thrombotic syndrome [63,66]. Support for this hypothesis comes from experimental evidence and suggests that direct thrombin inhibitors and factor Xa inhibitors hasten clot lysis compared with warfarin. A post-hoc analysis of a clinical trial and another observational study suggest that post-thrombotic syndrome may be less frequent in patients with DVT treated with DOACs [64,66]. Prospective confirmation from large clinical trials is lacking [65]. However, in a review of 349 patients included in the RE-COVER study, the prevalence of post-thrombotic syndrome was similar for 166 patients treated with dabigatran compared with 183 treated with warfarin [67]. A meta-analysis reported a lower incidence of PTS after DVT treated with rivaroxaban compared with warfarin [68].

•The risk of developing venous ulceration may be lower in patients treated with low-molecular-weight heparin compared with oral anticoagulation, which could be due to more consistent anticoagulation. A pooled analysis of two trials found a lower risk of self-reported skin ulcers in patients treated with low-molecular-weight heparin (risk ratio 0.13, 95% CI 0.02-0.71) [69]. Vein recanalization rates following DVT were also higher in patients receiving low-molecular-weight heparin [70].

●Thrombolysis – Post-thrombotic complications develop predominantly in those patients in whom the initial DVT-related venous symptoms tend to persist [34]. The use of thrombolytic therapy to treat acute proximal DVT may decrease the risk of post-thrombotic syndrome by reducing clot burden or possibly preventing proximal vein valve dysfunction [21,71,72]. In a trial that randomly assigned 692 patients with acute proximal DVT to anticoagulation alone or anticoagulation plus pharmacomechanical thrombolysis, the overall incidence of post-thrombotic syndrome was similar as were quality of life measures. However, moderate-to-severe post-thrombotic syndrome occurred in fewer patients in the thrombolysis group compared with the control group (18 versus 24 percent; risk ratio 0.73; 95% CI 0.54-0.98). There were more major bleeding events within 10 days in the thrombolysis group (1.7 versus 0.3 percent). A smaller trial that evaluated ultrasound-accelerated catheter-directed thrombolysis had similar results [72]. (See "Overview of iliocaval venous obstruction" and "May-Thurner syndrome" and "Endovenous intervention for iliocaval venous obstruction".)

●Graduated compression stockings – Graduated compression stockings can be used following the development of lower extremity DVT to improve lower extremity symptoms such as edema. However, there are conflicting data on the long-term effectiveness of graduated compression stockings for preventing post-thrombotic syndrome. While two older small open-label trials reported that elastic compression stockings were effective for preventing post-thrombotic syndrome [43,73], a later large, multicenter trial showed no evidence of benefit of active compression stocking used for two years [74]. Thus, routine use of compression stockings for two years to prevent post-thrombotic syndrome in patients with DVT is no longer recommended. In the IDEAL-DVT trial, an individualized duration of therapy based on post-thrombotic symptoms/signs was noninferior to the standard 24 month duration of therapy [75]. In a subanalysis of the IDEAL-DVT trial, patients who received compression therapy immediately after DVT had a significantly lower percentage of residual vein obstruction (46.3 versus 66.7 percent) [61]. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Supportive therapies'.)

CLINICAL FEATURES

Symptoms and signs — Symptoms of post-thrombotic syndrome may be intermittent or persistent, may appear several weeks or months following a deep venous thrombosis, or may continue without interruption following an acute event [10]. The clinical manifestations of post-thrombotic syndrome are nonspecific but are essentially those of chronic venous disease and are discussed in detail separately. Summarized briefly, symptoms and signs can include extremity pain, heaviness, venous dilation, edema, pigmentation, trophic skin changes, and venous ulcers [76]. Edema occurs in approximately two thirds of patients with post-thrombotic syndrome, skin pigmentation in approximately one third, and venous ulceration in less than 5 percent. Trophic changes tend to occur between two and four years after deep vein thrombosis (DVT), with no further changes between 5 and 12 years [4,32]. (See "Clinical manifestations of lower extremity chronic venous disease".)

Scoring systems — The Clinical-Etiology-Anatomy-Pathophysiology (CEAP) classification is useful for characterizing chronic venous disease. Classification systems used in the diagnosis and management of lower extremity chronic venous disease are reviewed elsewhere. (See "Classification of lower extremity chronic venous disorders", section on 'CEAP classification'.)

The clinical severity of post-thrombotic syndrome has been scored using the Villalta score, which has been recommended as an international standard to diagnose and classify the severity of post-thrombotic syndrome [1,76]. A higher score indicates a greater severity of post-thrombotic syndrome, with a score of >15 suggesting severe post-thrombotic syndrome. (See "Classification of lower extremity chronic venous disorders", section on 'Villalta scale'.)

D-dimer — D-dimers are detectable at levels greater than 500 ng/mL (ie, 500 mcg/L) of fibrinogen equivalent units in nearly all patients with venous thromboembolism but are nonspecific for post-thrombotic syndrome. Elevated D-dimer measured in the absence of oral anticoagulants may also be predictive of recurrent venous thromboembolism [77,78].

An elevated D-dimer level may signal persistent activation of clotting or inflammatory pathways and is thought by some to be a predictor of post-thrombotic syndrome [35,79]. In one study, 45 percent of 305 patients with acute, symptomatic DVT developed post-thrombotic syndrome as determined by the Villalta scale. Mean D-dimer at four-month follow-up was significantly higher in patients who developed post-thrombotic syndrome compared with those who did not (712 versus 444 mcg/L) [79]. D-dimer levels were affected by warfarin administration, with lower levels seen in patients taking warfarin (with or without post-thrombotic syndrome). (See "Classification of lower extremity chronic venous disorders", section on 'Villalta scale'.)

DIAGNOSIS — The diagnosis of post-thrombotic syndrome is predominantly clinical [1,7]. In patients with a known history of deep vein thrombosis (DVT) and obvious symptoms/signs of chronic venous insufficiency, a clinical diagnosis of post-thrombotic syndrome can be made; additional diagnostic testing is generally not necessary [7]. Because the symptoms of post-thrombotic syndrome can be variable over time and can be similar to those of an acute DVT, expert consensus is to wait up to six months following an acute DVT before making a diagnosis [6]. Venous imaging, typically duplex ultrasound, may be useful for patients in whom the clinical signs of chronic venous insufficiency are not obvious, those with a clinical history that suggests DVT but for whom diagnostic testing was not performed, and in those with severe symptoms.

For those without an objectively proven prior DVT, duplex ultrasound can often diagnose or exclude a prior DVT [7,80]. Incompressibility indicates a high likelihood of a proximal vein thrombosis. For patients with normal venous compression, findings of popliteal reflux and/or a Villalta score >8 (see 'Scoring systems' above) is highly specific for a prior DVT [80]. In the absence of symptoms, venous abnormalities alone, such as venous reflux, persistent venous obstruction, or both as shown by invasive or noninvasive diagnostic studies, do not allow a patient with a history of DVT to be defined as having post-thrombotic syndrome [81]. If there is no evidence of venous reflux or obstruction on imaging or physiologic studies, patients with lower extremity symptoms associated with swelling may have another etiology. (See 'Differential diagnosis' below.)

In patients with severe symptoms, it may be worth investigating whether the patient has a venous abnormality that may benefit from intervention, such as a residual iliac vein stenosis or occlusion, or proximal venous reflux. Venous duplex and intravascular ultrasound along with venography are the main imaging modalities for assessing obstruction or venous reflux in patients with post-thrombotic syndrome. (See 'Treatment' below.)

DIFFERENTIAL DIAGNOSIS — Clinical conditions that may result in symptoms and signs of lower extremity pain, fatigue, or swelling include primary venous insufficiency, increased body mass index leading to lipedema (lipoedema), lymphedema, tumor or arterial aneurysm causing venous obstruction, Baker's cyst, and extremity injury, among others.

Given that the clinical symptoms and signs and venous duplex findings are nonspecific, a history of deep vein thrombosis (DVT) alone distinguishes post-thrombotic syndrome as a secondary cause of venous insufficiency from primary venous insufficiency, for which there is not an obvious inciting factor, and the other entities listed above. (See "Clinical manifestations of lower extremity chronic venous disease", section on 'Approach to the patient'.)

Masses leading to venous obstruction, such as those caused by arterial aneurysm, Baker's cyst, or tumor, may be obvious during physical examination of the groin and popliteal fossa but difficult to identify in patients who are obese or have significant extremity swelling. These, as well as obstructing pelvic masses, can be identified using ultrasound, or cross-sectional imaging if needed. (See "Popliteal artery aneurysm" and "Popliteal (Baker's) cyst".)

Conditions that can cause lower extremity edema and lymphedema are reviewed separately. (See "Clinical manifestations and evaluation of edema in adults", section on 'Peripheral edema' and "Clinical features and diagnosis of peripheral lymphedema".)

TREATMENT — Conservative management of venous insufficiency as a result of post-thrombotic syndrome is similar to that of other patients with chronic venous disease and is discussed in detail elsewhere. Conservative management includes exercise, limb elevation, compression therapy, and possibly pharmacologic therapy [81,82].

Exercise — Exercise training may improve symptoms of post-thrombotic syndrome [83]. Patients should be encouraged to exercise (ankle flexion, walking) to increase calf muscle strength, leg flexibility and overall cardiovascular fitness, and to elevate the extremity when at rest.

Compression therapy — Once a diagnosis of post-thrombotic syndrome is established, compression therapy is the cornerstone of managing symptoms and the sequelae of chronic venous disease, including post-thrombotic syndrome [81,82,84]. Commonly used forms of compression include compression stockings, short stretch bandages, zinc paste bandages (eg, Unna boot), and multilayer compression. The choice depends upon the severity of symptoms and presence of edema, skin changes, or ulceration. In one trial, 93 percent of the patients, each of whom was motivated to prevent the long-term sequelae of deep vein thrombosis, were compliant with their prescribed compression regimen [85]. Compliance is particularly important for patients with ulceration to achieve ulcer healing and prevent ulcer recurrence. Compression therapy for the treatment of chronic venous insufficiency is discussed in detail separately. (See "Compression therapy for the treatment of chronic venous insufficiency", section on 'Static compression therapy'.)

Intermittent pneumatic compression or lymphedema therapy may offer symptomatic relief for patients with moderate-to-severe post-thrombotic syndrome [86]. In a small clinical trial conducted in patients with severe post-thrombotic syndrome, intermittent pneumatic compression reduced intractable edema [87]. In a later trial, a novel lower limb venous-return assist device improved the clinical manifestations of severe post-thrombotic syndrome alone and in combination with compression stockings [88]. (See "Compression therapy for the treatment of chronic venous insufficiency", section on 'Dynamic compression therapy'.)

Pharmacologic therapy — A number of pharmacologic agents have been used in the treatment of chronic venous disease to aid with lower extremity symptoms, as well as for the local treatment of skin changes and venous ulceration. For patients who are unable to tolerate, are not compliant with, or in whom compression therapy is contraindicated (eg, occlusive arterial disease), we suggest escin (ie, horse chestnut seed extract).

Skin and ulcer care — Dry skin, itching, and eczematous changes are treated with moisturizers and, if needed, a midpotency topical corticosteroid. We suggest avoiding topical products with common sensitizers (eg, lanolin, neomycin, nickel). When venous insufficiency is associated with severe edema, weeping, eczema, or ulceration, compression stockings or elastic or nonelastic compression bandages are used. When compression bandages are chosen, we suggest multilayered compression bandages rather than single-layer bandages. (See "Compression therapy for the treatment of chronic venous insufficiency" and "Evaluation and management of chronic venous insufficiency including venous leg ulcer", section on 'Ulcer care'.)

Venous intervention — Endovascular or surgical interventions in appropriately selected patients with venous obstruction or reflux may decrease the incidence of recurrent ulceration and skin changes and improve quality of life in patients with chronic venous disease. In the past, venous interventions were reported to have inferior results in patients with post-thrombotic syndrome compared with treatment of primary venous insufficiency [89,90]. However, these older studies involved primarily open venous procedures, and the newer procedures have not been well studied in trials that specifically evaluate outcomes in patients with post-thrombotic syndrome.

If venous outflow obstruction is present, it should be addressed first. Occluded or stenotic iliac vein segments can be treated using percutaneous angioplasty with or without stenting, venous bypass, or endophlebectomy [76,91-96]. In a study of 44 patients (of whom eight had post-thrombotic syndrome), the technical success rate for iliac venous stenting was 95 percent [91]. Venous clinical severity scores in treated patients were improved from a median score of 8.5 to 2, and the median venous disability score improved from 2 to 0. Primary, assisted primary, and secondary patency rates of the treated venous segments at three years were 73, 88, and 90 percent, respectively. The results were not stratified by the etiology of the venous disease. In another study of 82 limbs in 78 patients, successful recanalization of chronic venous obstruction improved venous quality measures [97]. (See "Endovenous intervention for iliocaval venous obstruction".)

Surgical vein bypass is an option for selected patients with severe proximal venous reflux, but only if percutaneous intervention has failed to restore flow; however, it is limited to certain high-volume referral centers [96,98-100]. Venous valve reconstruction (including valve transplant, valvuloplasty, and endograft valves) has been largely unsuccessful in the treatment of these patients and has been abandoned by many of the original advocates. (See "Techniques used for open iliocaval venous reconstruction".)

Focal symptoms and patients with venous ulceration may benefit from treatment of incompetent superficial veins. Ablation procedures are discussed in detail separately. (See "Injection sclerotherapy techniques for the treatment of telangiectasias, reticular veins, and small varicose veins" and "Techniques for radiofrequency ablation for the treatment of lower extremity chronic venous disease" and "Techniques for endovenous laser ablation for the treatment of lower extremity chronic venous disease" and "Approach to treating symptomatic superficial venous insufficiency", section on 'Intervention for axial vein reflux'.)

PROGNOSIS — When patients are prescribed elastic compression stockings and are supervised appropriately, more than 50 percent of patients remain stable or improve during long-term follow-up, regardless of the initial severity of the post-thrombotic syndrome [7].

Quality of life — Post-thrombotic syndrome causes significant disability and economic burden for patients and the health care system [101,102]. Chronic venous insufficiency, including that due to post-thrombotic syndrome, can have a significant negative effect on quality of life [46,101,103,104]. In a study of patients two years after treatment for deep venous thrombosis, quality-of-life measures of patients with post-thrombotic syndrome were comparable to published norms for those with angina, cancer, or heart failure [103].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Superficial vein thrombosis, deep vein thrombosis, and pulmonary embolism" and "Society guideline links: Chronic venous disorders".)

SUMMARY AND RECOMMENDATIONS

●Post-thrombotic syndrome consists of symptoms and signs of chronic venous insufficiency that develop following deep vein thrombosis (DVT) and is a consequence of long-standing venous hypertension thought to be due to a combination of thrombotic vein occlusion and venous valvular incompetence. Post-thrombotic syndrome occurs in up to 50 percent of patients within the first year following acute thrombosis, in spite of anticoagulation. Severe post-thrombotic syndrome develops in 5 to 10 percent of patients. (See 'Introduction' above and 'Pathophysiology' above and 'Epidemiology' above.)

●Patient characteristics that may be important for the development of post-thrombotic syndrome include primary venous insufficiency, older age, obesity, and preexisting varicose veins. The most important factors related to the inciting DVT include proximal DVT, moderate-severe Villalta severity category at DVT diagnosis, inadequate anticoagulation during initial treatment of DVT, residual thrombus in the vein, and recurrent DVT. (See 'Risk factors' above.)

●The clinical manifestations of post-thrombotic syndrome are those of chronic venous insufficiency and may include extremity pain, limb heaviness, vein dilation, extremity edema, skin pigmentation, trophic skin changes, and venous ulcers. Edema is the most common manifestation, occurring in approximately two thirds of patients. (See 'Clinical features' above and "Clinical manifestations of lower extremity chronic venous disease".)

●A diagnosis of post-thrombotic syndrome is predominantly clinical. For patients with a known history of DVT and obvious symptoms/signs of chronic venous insufficiency, a clinical diagnosis of post-thrombotic syndrome can be made; additional diagnostic testing is generally not necessary. However, venous imaging, typically duplex ultrasound, may be useful for patients in whom the clinical signs of chronic venous insufficiency are not obvious, those with a clinical history that suggests DVT but in whom studies were not performed, or to identify proximal vein stenosis or occlusion in those with severe symptoms. (See 'Diagnosis' above.)

●The management of patients with venous insufficiency as a result of post-thrombotic syndrome is similar to that for other patients with chronic venous disease and includes limb elevation, exercise, compression therapy, and possibly pharmacologic therapy. The choice of compression therapy depends upon the severity of symptoms and presence of edema, skin changes, or ulceration. Recommendations for treating chronic venous insufficiency are listed below and discussed in detail elsewhere. (See 'Treatment' above.)

•For all patients with chronic venous symptoms, we suggest leg elevation (when possible), leg exercises (ankle flexion, walking) to increase calf muscle strength, and graduated compression stockings (Grade 2C). (See "Compression therapy for the treatment of chronic venous insufficiency", section on 'Static compression therapy'.)

•For patients who are unable to tolerate compression therapy, are not compliant with compression therapy, or in whom compression therapy is contraindicated (eg, occlusive arterial disease), we suggest horse chestnut seed extract (Grade 2B). A typical dose is 300 mg (standardized to 50 mg of escin) twice daily.

•Dry skin, itching, and eczematous changes are treated with moisturizers and, if needed, a midpotency topical corticosteroid. We suggest avoiding topical products with common sensitizers (eg, lanolin, neomycin, nickel) (Grade 2C).

•When venous insufficiency is associated with severe edema, weeping, eczema, or ulceration, compression stockings or elastic or nonelastic compression bandages are used. When compression bandages are chosen, we suggest multilayered compression bandages rather than single-layer bandages (Grade 2B). (See "Compression therapy for the treatment of chronic venous insufficiency" and "Compression therapy for the treatment of chronic venous insufficiency", section on 'Compression bandages'.)

●For patients with severe symptoms and evidence of proximal vein stenosis or occlusion on vein imaging studies, venous intervention may decrease the incidence of skin changes and ulceration and improve quality of life. (See 'Venous intervention' above and "Endovenous intervention for iliocaval venous obstruction".)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Patrick C Alguire, MD, FACP, who contributed to an earlier version of this topic review.