How I Treat in Brief: Managing Post-Thrombotic Syndrome

Anat Rabinovich, MD, of Soroka University Medical Center at the Ben-Gurion University of the Negev in Israel and Susan R. Kahn, MD, MSc, of the Center for Clinical Epidemiology and the department of medicine at McGill University in Montreal, discussed how to manage post-thrombotic syndrome, a chronic complication of deep vein thrombosis. Below, we summarize their approach.

This material was repurposed from “How I treat post-thrombotic syndrome,” published in the May 17, 2018 issue of Blood.

  • Post-thrombotic syndrome (PTS) is a form of chronic venous insufficiency that develops in approximately 20 to 50 percent of people who have experienced a deep vein thrombosis (DVT).
  • The principal risk factors for PTS are anatomically extensive DVT, recurrent ipsilateral DVT, obesity, and older age.
  • Symptoms of PTS vary, and include heaviness, tiredness, swelling, itching, cramps, paresthesia, and venous claudication. Symptoms worsen with activity and improve with rest, but increase in intensity over the course of a day.
  • Diagnosis of PTS should be deferred until 3 to 6 months after DVT, once the initial pain and swelling has resolved.
  • For patients with established PTS, treatment options include elastic compression stockings (ECS), exercise, and lifestyle modifications; however, the effectiveness of ECS is controversial. Patients with refractory or severe forms of PTS may undergo surgical or endovascular interventions.

Post-thrombotic syndrome (PTS) is a form of chronic venous insufficiency (CVI) with varying clinical manifestations ranging from minimal discomfort to chronic pain. PTS is increasingly being recognized as a frequent consequence of deep vein thrombosis (DVT), affecting between 20 to 50 percent of patients.

PTS presents a substantial economic and morbidity burden. Total PTS-associated treatment costs (including imaging studies, laboratory and pathology testing, pharmacy claims, and hospital admissions – which are the main cost driver) are much higher among patients with DVT who develop PTS, compared with those who do not. Surveys also have shown that patients’ self-reported, health-related quality of life was on par with people living with severe chronic diabetes or congestive heart failure.

Given this burden, early diagnosis and treatment of PTS is essential to preserving patients’ health-related quality of life.

What Causes PTS?

PTS is thought to develop after DVT because of the onset of ambulatory venous hypertension, which leads to reduced calf muscle perfusion and increased tissue permeability, causing chronic edema, tissue hypoxia, progressive calf pump dysfunction, subcutaneous fibrosis, and, ultimately, skin ulceration.

DVT leads to chronic venous hypertension via two principal mechanisms: valvular reflux and residual venous obstruction. DVT also triggers inflammation-induced valvular damage in involved segments.

Signs and Symptoms of PTS

The signs, symptoms, and severity of PTS vary from patient to patient, ranging from minimal discomfort to severe chronic pain, intractable edema, and leg ulceration (TABLE 1). They tend to worsen with activity and improve with rest. The intensity of symptoms generally increases over the course of the day and can wax and wane over time.

Symptoms of PTS include leg heaviness, tiredness, swelling, itching, cramps, paresthesia, and venous claudication (limping and/or pain due to inadequate venous drainage from the legs). Signs of PTS include dermatologic manifestations, like redness, hyperpigmentation, and skin thickening.

Each symptom is self-rated by the patient, and each clinical sign is rated by the clinician as 0 (absent), 1 (mild), 2 (moderate), or 3 (severe), except ulcer, which is marked as present or absent. A total score of 0 to 4 indicates the absence of PTS, and a score of >4 indicates PTS: mild = 5-9; moderate = 10-14; severe >14 or the presence of an ulcer.

Diagnosing PTS

There is no objective diagnostic test for PTS, which is primarily diagnosed on clinical grounds in a patient with manifestations of CVI and a previous episode of DVT in the preceding three months. However, the

International Society on Thrombosis and Haemostasis recommends performing two consecutive assessments using the Villalta scale, a clinical scale developed specifically for PTS: The first is sufficient to make a diagnosis, and the second assessment three months later measures grade and severity (TABLE 2).

There also is no specific recommended time limit following DVT to diagnose PTS. Because it can take a few months for the initial pain and swelling associated with acute DVT to resolve, a diagnosis of PTS should be deferred at least until after the acute phase (about 3 to 6 months) following the DVT.

Each symptom is self-rated by the patient, and each clinical sign is rated by the clinician as 0 (absent), 1 (mild), 2 (moderate), or 3 (severe), except ulcer, which is marked as present or absent. A total score of 0 to 4 indicates the absence of PTS, and a score of >4 indicates PTS: mild = 5-9; moderate = 10-14; severe >14 or the presence of an ulcer.

Predicting PTS

The risk factors for PTS are not completely understood, making it difficult to predict which patients will develop PTS. However, recent studies have improved our understanding of the epidemiology, risk factors, and prevention of PTS, and we have identified several clinical and biologic factors that influence the risk.

Risk factors apparent at the time of DVT diagnosis

The risk of PTS is two- to threefold higher in patients who develop proximal DVT (especially with involvement of the iliac or common femoral vein), compared with those who develop distal DVT. Pre-existing primary venous insufficiency also increases the risk of PTS up to twofold. Other risk factors include a body mass index (BMI) of more than 30 kg/m2 and older age.

In our clinic, we use a clinical prediction rule for PTS in patients with a first proximal DVT that includes the following high-risk factors at the time of DVT diagnosis: index DVT in iliac vein, BMI ≥35 kg/m2, and severe acute DVT symptoms and signs.

Risk factors related to the treatment of DVT

Insufficient or subtherapeutic anticoagulation with vitamin K agonists (VKAs) in the first three months after DVT has been associated with an increased risk of PTS. Low-molecular-weight heparins may be more effective than VKAs for PTS prevention, and it is still unclear whether DVT treatment with newer, direct oral anticoagulants is more effective than VKAs for PTS prevention.

At this point, there are insufficient data available about the protective ability of the various anticoagulants, so possible better protection against PTS is not in itself a valid reason to choose one available parenteral or oral anticoagulant over another.

The following factors have little or no impact on the risk of developing PTS: sex, whether DVT was provoked or unprovoked, and inherited thrombophilia.

Risk factors apparent during follow-up after acute DVT

Ipsilateral DVT recurrence increases the risk of PTS by four- to sixfold. Persistent venous symptoms and signs one month after acute DVT also increase risk of subsequent PTS.

Inflammation markers associated with a higher PTS risk include: C-reactive protein; interleukin (IL)-6, IL-8, and IL-10; intercellular adhesion molecule (ICAM)-1; and higher levels of matrix metalloproteinase (MMP)-1 and MMP-8, measured at varying time points after DVT diagnosis. The predictive value of D-dimer levels has not been established.

Preventing PTS

Patients with several risk factors at any point during DVT diagnosis and follow-up should be closely monitored for signs of PTS. For patients on VKA treatment, rigorous international normalized ratio monitoring is recommended, particularly during the first three months post-DVT.

Because recurrent ipsilateral DVT is an important risk factor for PTS, preventing recurrent DVT by providing optimal, appropriate-duration anticoagulation for the initial DVT is an important goal of management.

Elastic compression stockings (ECS) could plausibly play a role in preventing PTS, but the data are conflicting. In light of the available evidence and international consensus guidelines, we do not routinely prescribe ECS to all DVT patients, instead we prescribe a trial of 20 to 30 mm Hg or 30 to 40 mm Hg below-knee ECS to patients who have residual leg swelling or discomfort after proximal or distal DVT. We monitor symptoms and continue ECS for as long as the patient derives symptomatic benefit or is able to tolerate them. To maximize benefit, patients should be educated on how to apply and use ECS and on the importance of compliance.

Because inflammation may contribute to PTS development, drugs with anti-inflammatory properties could have a preventive effect on PTS, but this requires investigation in randomized controlled trials.

In addition to optimal anticoagulation, early clot removal, such as catheter-directed thrombolysis (CDT) or pharmacomechanical CDT, can be considered for certain patients, including those with severe DVT in which the arterial circulation is compromised, because CDT is likely to be associated with a lower risk of major bleeding than systemic thrombolysis. CDT could also be considered on a case-by-case basis in patients younger than 65 years old with extensive acute proximal DVT who have a good functional status and a low risk of bleeding.

Treating PTS

Few treatment strategies for established PTS have been studied in well-designed clinical trials, so there is a lack of evidence-based management options.

Prolonged anticoagulation

It is common clinical practice to prolong anticoagulation in patients with PTS, but there is no consensus on the value of extending anticoagulation beyond the duration recommended for the treatment of DVT in patients with established PTS. It also is uncertain if having PTS increases the risk of ipsilateral recurrent venous thromboembolism after anticoagulation is stopped.

Exercise and lifestyle

Evidence from small studies suggest that exercise training (focused on increasing leg strength, leg flexibility, and overall cardiovascular fitness) lessened PTS severity and improved quality of life.

Other lifestyle modifications include:

  • promoting venous return by avoiding a sedentary lifestyle
  • elevating the legs when seated or in bed when lying down
  • avoiding prolonged exposure to heat
  • maintaining a nonobese body weight
  • using a moisturizing cream to avoid skin dryness and subsequent skin breakdown

Compression therapy

As noted earlier, ECS are a cornerstone of PTS management, although their use is based primarily on extrapolation from experiences of patients with primary CVI. An initial therapeutic trial of 20 to 30 mm Hg knee-length ECS can be followed by stronger pressure (30-40 or 40-50 mm Hg) stockings if lower-pressure stockings are ineffective. For patients with severe symptoms unresponsive to ECS, a trial of a venous-return assist device (such as Venowave) is recommended. Intermittent pneumatic compression is also an option for patients with moderate to severe symptoms.

Medications

Venoactive drugs that have been considered for the treatment of PTS include rutosides, defibrotide, and hidrosmin. However, a meta-analysis evaluating the effectiveness of these drugs for PTS found low-quality evidence to support their use. Further, there is no evidence that use of diuretics is effective for the treatment of PTS-related edema.

Venous ulcer management

Patients who develop severe PTS and venous leg ulcers should be managed by a multidisciplinary team including an internist, dermatologist, vascular surgeon, and wound-care nurse. PTS-related ulcers typically are treated with compression therapy; leg elevation; topical dressings; and pentoxifylline, a pharmacologic agent considered to improve tissue blood flow and oxygen delivery. For recurrent ulcers or those that are refractory to therapy, surgery or endovascular procedures should be considered.

Endovascular and surgical options

If conservative management fails to improve symptoms, endovascular or surgical treatments (such as stent placement for chronic iliac vein obstruction or venous bypass surgery) can be considered for symptom relief in select patients with severe PTS. However, the lack of good-quality evidence prevents robust recommendations regarding these procedures.

Research Needs

PTS is known to be a frequent complication of DVT, yet there are several gaps in our understanding of the prevention and management of PTS. An improved understanding of the pathophysiology of PTS, for example, would help researchers identify future therapeutic targets. Validated clinical prediction rules to predict PTS risk would allow us to more accurately select patients for preventive treatment.

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